Title:
PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
Kind Code:
A1


Abstract:
This document discloses molecules having the following formula (“Formula One”):

embedded image

and processes associated therewith.




Inventors:
Lo, William C. (Fishers, IN, US)
Hunter, James E. (Indianapolis, IN, US)
Watson, Gerald B. (Zionsville, IN, US)
Patny, Akshay (Waltham, MA, US)
Iyer, Pravin S. (Secunderabad, IN)
Boruwa, Joshodeep (Noida, IN)
Application Number:
15/435332
Publication Date:
06/08/2017
Filing Date:
02/17/2017
Assignee:
Dow AgroSciences LLC (Indianapolis, IN, US)
Primary Class:
International Classes:
C07D405/04; A01N37/10; A01N37/18; A01N37/34; A01N37/36; A01N43/08; A01N43/16; A01N43/20; A01N43/36; A01N43/40; A01N43/50; A01N43/54; A01N43/60; A01N43/80; A01N43/82; A01N43/84; A01N47/32; C07C63/74; C07C211/29; C07C211/42; C07C233/14; C07C233/59; C07C233/65; C07C233/66; C07C235/80; C07C237/06; C07C243/34; C07C243/36; C07C243/38; C07C255/57; C07C259/06; C07C271/14; C07C275/24; C07C317/32; C07C323/59; C07C327/42; C07C327/48; C07C335/14; C07D207/27; C07D209/08; C07D209/48; C07D211/58; C07D213/40; C07D213/56; C07D213/61; C07D213/64; C07D213/74; C07D213/75; C07D233/64; C07D237/32; C07D239/26; C07D241/12; C07D249/08; C07D249/10; C07D249/14; C07D271/10; C07D277/32; C07D277/64; C07D295/073; C07D295/096; C07D295/155; C07D295/192; C07D307/14; C07D307/52; C07D309/14; C07D331/04
View Patent Images:



Primary Examiner:
HIRT, ERIN E
Attorney, Agent or Firm:
CORTEVA AGRISCIENCE LLC (INDIANAPOLIS, IN, US)
Claims:
We claim:

1. A composition comprising a molecule according to Formula One: embedded image wherein: (a) R1 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15), (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2; (b) R2 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15), (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2; (c) R3 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15), (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2; (d) R4 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15), (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2; (e) R5 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15), (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2; (f) R6 is a (C1-C8)haloalkyl; (g) R7 is selected from H, F, Cl, Br, I, OH, (C1-C8)alkoxy, and halo(C1-C8)alkoxy; (h) R8 is selected from H, (C1-C8)alkyl, halo(C1-C8)alkyl, OR14, and N(R14)(R15); (i) R9 is selected from H, F, Cl, Br, I, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, OR14, and N(R14)(R15); (j) R10 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, cyclo(C3-C6)alkyl, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), NR14R15, C(═O)H, C(═O)N(R14)(R15), CN(R14)(R15)(═NOH), (C═O)O(C1-C8)alkyl, (C═O)OH, heterocyclyl, (C2-C5)alkenyl, halo(C2-C5)alkenyl, (C2-C5)alkynyl, (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from OH, (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, NR14R15, and (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, and N(R14)(R15); (k) R11 is selected from C(═X5)N(R14)((C1-C8)alkylC(═X5)N(R14)(R15)) wherein each X5 is independently selected from O, or S; (l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, and cyclo(C3-C6)alkyl; (m) R13 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, and halo(C1-C8)alkoxy; (n) each R14 is independently selected from H, (C1-C8)alkyl, (C2-C5)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2); (o) each R15 is independently selected from H, (C1-C8)alkyl, (C2-C5)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), 0-(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2); (p) each R16 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo; (q) each R17 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo; (r) X1 is selected from N and CR12; (s) X2 is selected from N, CR9, and CR13; (t) X3 is selected from N and CR9; and (v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(═O)R14), N(R14)(C(═S)R14), N(R14)(C(═O)N(R14)(R14)), N(R14)(C(═S)N(R14)(R14)), N(R14)(C(═O)N(R14)((C2-C8)alkenyl)), N(R14)(C(═S)N(R14)((C2-C8)alkenyl)), wherein each R14 is independently selected.

2. A composition according to claim 1 further comprising: (a) one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties; or (b) one or more compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists; or (c) both (a) and (b).

3. A composition according to claim 1 wherein further comprising one or more compounds selected from: (3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdepallethrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl, picloram-olamine, picloram-potassium, picloram-triethylammonium, picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium α-naphthaleneacetate, pp′-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuron-methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, α-ecdysone, α-multistriatin, and α-naphthaleneacetic acid.

4. A composition according to claim 1 further comprising an agriculturally acceptable carrier.

5. A process comprising applying a composition according to claim 1, to an area to control a pest, in an amount sufficient to control such pest.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, and claims the benefit of, U.S. patent application Ser. No. 14/880,790, which was filed on Oct. 12, 2015, which is a continuation of, and claims the benefit of, U.S. patent application Ser. No. 14/133,094, which was filed on Dec. 18, 2013, which claims the benefit of, and priority from, U.S. provisional patent application Ser. No. 61/739,025, which was filed on Dec. 19, 2012, the entire disclosures of these applications are expressly incorporated herein by reference.

FIELD OF THE DISCLOSURE

The invention disclosed in this document is related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molecules, and processes of using such molecules to control pests.

BACKGROUND OF THE DISCLOSURE

Pests cause millions of human deaths around the world each year. Furthermore, there are more than ten thousand species of pests that cause losses in agriculture. The world-wide agricultural losses amount to billions of U.S. dollars each year.

Termites cause damage to all kinds of private and public structures. The world-wide termite damage losses amount to billions of U.S. dollars each year.

Stored food pests eat and adulterate stored food. The world-wide stored food losses amount to billions of U.S. dollars each year, but more importantly, deprive people of needed food.

There is an acute need for new pesticides. Certain pests are developing resistance to pesticides in current use. Hundreds of pest species are resistant to one or more pesticides. The development of resistance to some of the older pesticides, such as DDT, the carbamates, and the organophosphates, is well known. But resistance has even developed to some of the newer pesticides, for example, imidacloprid.

Therefore, for many reasons, including the above reasons, a need exists for new pesticides.

DEFINITIONS

The examples given in the definitions are generally non-exhaustive and must not be construed as limiting the invention disclosed in this document. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached.

“Alkenyl” means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.

“Alkenyloxy” means an alkenyl further consisting of a carbon-oxygen single bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy.

“Alkoxy” means an alkyl further consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.

“Alkyl” means an acyclic, saturated, branched or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, (C3)alkyl which represents n-propyl and isopropyl), (C4)alkyl which represents n-butyl, sec-butyl, isobutyl, and tert-butyl.

“Alkynyl” means an acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl.

“Alkynyloxy” means an alkynyl further consisting of a carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy.

“Aryl” means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.

“(Cx-Cy)” where the subscripts “x” and “y” are integers such as 1, 2, or 3, means the range of carbon atoms for a substituent—for example, (C1-C4)alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each individually.

“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.

“Cycloalkenyloxy” means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.

“Cycloalkyl” means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.

“Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo[2.2.2]octyloxy.

“Halo” means fluoro, chloro, bromo, and iodo.

“Haloalkoxy” means an alkoxy further consisting of, from one to the maximum possible number of identical or different, halos, for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.

“Haloalkyl” means an alkyl further consisting of, from one to the maximum possible number of, identical or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.

“Heterocyclyl” means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone. Examples of aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.

Additional examples include the following

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DETAILED DESCRIPTION OF THE DISCLOSURE

This document discloses molecules having the following formula (“Formula One”):

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wherein:

(a) R1 is selected from

    • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
    • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
    • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
    • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
    • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;

(b) R2 is selected from

    • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
    • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
    • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
    • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
    • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;

(c) R3 is selected from

    • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
    • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
    • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
    • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
    • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;

(d) R4 is selected from

    • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
    • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
    • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
    • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
    • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;

(e) R5 is selected from

    • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), N(R14)(R15),
    • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from CN and NO2,
    • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from CN and NO2,
    • (4) substituted (C1-C8)alkoxy, wherein said substituted (C1-C8)alkoxy has one or more substituents selected from CN and NO2, and
    • (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C1-C8)alkoxy has one or more substituents selected from CN and NO2;

(f) R6 is a (C1-C8)haloalkyl;

(g) R7 is selected from H, F, Cl, Br, I, OH, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;

(h) R8 is selected from H, (C1-C8)alkyl, halo(C1-C8)alkyl, OR14, and N(R14)(R15);

(i) R9 is selected from H, F, Cl, Br, I, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, OR14, and N(R14)(R15);

(j) R10 is selected from

    • (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, cyclo(C3-C6)alkyl, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), S(O)(C1-C8)alkyl, S(O)(halo(C1-C8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(C1-C8)alkyl), NR14R15, C(═O)H, C(═O)N(R14)(R15), CN(R14)(R15)(═NOH), (C═O)O(C1-C8)alkyl, (C═O)OH, heterocyclyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl,
    • (2) substituted (C1-C8)alkyl, wherein said substituted (C1-C8)alkyl has one or more substituents selected from OH, (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, NR14R15, and
    • (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(C1-C8)alkyl, has one or more substituents selected from (C1-C8)alkoxy, S(C1-C8)alkyl, S(O)(C1-C8)alkyl, S(O)2(C1-C8)alkyl, and N(R14)(R15);

(k) R11 is selected from C(═X5)N(R14)((C1-C8)alkylC(═X5)N(R14)(R15)) wherein each X5 is independently selected from O, or S;

(l) R12 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, and cyclo(C3-C6)alkyl;

(m) R13 is selected from (v), H, F, Cl, Br, I, CN, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, and halo(C1-C8)alkoxy;

(n) each R14 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H

    • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
    • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
    • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
    • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);

(o) each R15 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, substituted (C1-C8)alkyl, halo(C1-C8)alkyl, substituted halo(C1-C8)alkyl), (C1-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (C1-C8)alkyl-C(═O)N(R16)(R17), C(═O)(C1-C8)alkyl, C(═O)(halo(C1-C8)alkyl), C(═O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(═O)O(C1-C8)alkyl, C(═O)H

    • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
    • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
    • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
    • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, (C3-C6)cycloalkyl S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), heterocyclyl, C(═O)(C1-C8)alkyl, C(═O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);

(p) each R16 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl

    • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
    • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
    • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
    • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
    • (q) each R17 is independently selected from H, (C1-C8)alkyl, substituted-(C1-C8)alkyl, halo(C1-C8)alkyl, substituted-halo(C1-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C1-C8)alkyl-aryl, (C1-C8)alkyl-(substituted-aryl), O—(C1-C8)alkyl-aryl, O—(C1-C8)alkyl-(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C1-C8)alkyl-heterocyclyl, (C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl-heterocyclyl, O—(C1-C8)alkyl-(substituted-heterocyclyl), O—(C1-C8)alkyl
    • wherein each said substituted (C1-C8)alkyl has one or more substituents selected from CN, and NO2,
    • wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2,
    • wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo, and
    • wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(C1-C8)alkyl, (C1-C8)alkoxy, halo(C1-C8)alkoxy, S(C1-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C1-C8)alkyl is independently selected), and oxo;
    • (r) X1 is selected from N and CR12;
    • (s) X2 is selected from N, CR9, and CR13;
    • (t) X3 is selected from N and CR9; and
    • (v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(═O)R14), N(R14)(C(═S)R14), N(R14)(C(═O)N(R14)(R14)), N(R14)(C(═S)N(R14)(R14)), N(R14)(C(═O)N(R14)((C2-C8)alkenyl)), N(R14)(C(═S)N(R14)((C2-C8)alkenyl)), wherein each R14 is independently selected.

In another embodiment of this invention R1 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R2 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R3 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R4 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R5 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R2 and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, R3, and R5 are H.

In another embodiment of this invention R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, and R5 are H.

In another embodiment of this invention R2, R3, and R4 are independently selected from F and Cl and R1 and R5 are H.

In another embodiment of this invention R1 is selected from Cl and H.

In another embodiment of this invention R2 is selected from CF3, CH3, Cl, F, and H.

In another embodiment of this invention R3 is selected from OCH3, CH3, F, Cl, or H.

In another embodiment of this invention R4 is selected from CF3, CH3, Cl, F, and H.

In another embodiment of this invention R5 is selected from F, Cl, and H.

In another embodiment of this invention R6 may be selected from any combination of one or more of the following—halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.

In another embodiment of this invention R6 is trifluoromethyl.

In another embodiment of this invention R7 may be selected from any combination of one or more of the following—H, F, Cl, Br, and I.

In another embodiment of this invention R7 is selected from H, OCH3, and OH.

In another embodiment of this invention R8 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.

In another embodiment of this invention R8 is selected from CH3 and H.

In another embodiment of this invention R9 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R10 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, CN, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, halo(C8)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In another embodiment of this invention R10 may be selected from any combination of one or more of the following—H, Cl, Br, CH3, and CF3.

In another embodiment of this invention R10 is selected from Br, C(═NOH)NH2, C(═O)H, C(═O)NH2, C(═O)OCH2CH3, C(═O)OH, CF3, CH2CH3, CH2OH, CH3, Cl, CN, F, H, NH2, NHC(═O)H, NHCH3, NO2, OCH3, OCHF2, and pyridyl.

In another embodiment of this invention R11 may be selected from any combination of one or more of the following—C(═O)N(H)(C((CH3)2)C(═O)N(H)(CH2CF3)), C(═O)N(H)(CH(CH3)C(═O)N(H)(CH2CF3)), C(═O)N(H)(CH(CH2CH3)C(═O)N(H)(CH2CF3)), C(═O)N(H)(CH(CH3)C(═S)N(H)(CH2CF3)), C(═O)N(H)(C((CH3)2)C(═S)N(H)(CH2CF3)), and C(═S)N(H)(C((CH3)2)C(═S)N(H)(CH2CF3)).

In another embodiment of this invention R11 is C(═(O or S))N(H)(((C1-C8)alkyl)C(═(O or S))N(H)(halo(C1-C8)alkyl)), which may be used in combination with any embodiment of R1 through R10 and X1 through X3.

In another embodiment of this invention R12 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R12 is selected from CH3, and H.

In another embodiment of this invention R13 may be selected from any combination of one or more of the following—H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.

In another embodiment of this invention R13 is selected from CH3, Cl and H.

In another embodiment of this invention R12-R13 are a hydrocarbyl linkage containing CH═CHCH═CH.

In another embodiment of this invention R14 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), O—(C8)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17), ethyl-C(═O)N(R16)(R17), (C3)alkyl-C(═O)N(R16)(R17), (C4)alkyl-C(═O)N(R16)(R17), (C5)alkyl-C(═O)N(R16)(R17), (C6)alkyl-C(═O)N(R16)(R17), (C7)alkyl-C(═O)N(R16)(R17), and (C8)alkyl-C(═O)N(R16)(R17).

In another embodiment of this invention R14 may be selected from any combination of one or more of the following—H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O—CH2-halopyridyl, and CH2C(═O)N(H)(CH2CF3).

In another embodiment of this invention R15 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), O—(C8)alkyl-(substituted-heterocyclyl), methyl-C(═O)N(R16)(R17), ethyl-C(═O)N(R16)(R17), (C3)alkyl-C(═O)N(R16)(R17), (C4)alkyl-C(═O)N(R16)(R17), (C5)alkyl-C(═O)N(R16)(R17), (C6)alkyl-C(═O)N(R16)(R17), (C7)alkyl-C(═O)N(R16)(R17), and (C8)alkyl-C(═O)N(R16)(R17).

In another embodiment of this invention R15 may be selected from any combination of one or more of the following—H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl, O—CH2-halopyridyl, and CH2C(═O)N(H)(CH2CF3).

In another embodiment of this invention R16 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), and O—(C8)alkyl-(substituted-heterocyclyl).

In another embodiment of this invention R16 may be selected from any combination of one or more of the following—H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.

In another embodiment of this invention R17 may be selected from any combination of one or more of the following—H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O—(C3)alkyl-aryl, O—(C4)alkyl-aryl, O—(C5)alkyl-aryl, O—(C6)alkyl-aryl, O—(C7)alkyl-aryl, O—(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O—(C3)alkyl-(substituted-aryl), O—(C4)alkyl-(substituted-aryl), O—(C5)alkyl-(substituted-aryl), O—(C6)alkyl-(substituted-aryl), O—(C7)alkyl-(substituted-aryl), O—(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O—(C3)alkyl-heterocyclyl, O—(C4)alkyl-heterocyclyl, O—(C5)alkyl-heterocyclyl, O—(C6)alkyl-heterocyclyl, O—(C7)alkyl-heterocyclyl, O—(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl-(substituted-heterocyclyl), O—(C3)alkyl-(substituted-heterocyclyl), O—(C4)alkyl-(substituted-heterocyclyl), O—(C5)alkyl-(substituted-heterocyclyl), O—(C6)alkyl-(substituted-heterocyclyl), O—(C7)alkyl-(substituted-heterocyclyl), and O—(C7)alkyl-(substituted-heterocyclyl).

In another embodiment of this invention R17 may be selected from any combination of one or more of the following—H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.

In another embodiment of this invention X1 is CR12, X2 is CR13, and X3 is CR9.

In another embodiment of this invention a heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms.

The molecules of Formula One will generally have a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.

The benzyl alcohol of Formula IV, wherein R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, can be synthesized in two ways. One way, disclosed in step a of Scheme I, is by treatment of the ketone of Formula II, wherein R1, R2, R3, R4, R5, and R6 are as previously disclosed, with a reducing agent, such as sodium borohydride (NaBH4), under basic conditions, such as aqueous sodium hydroxide (NaOH), in a polar protic solvent, such as methyl alcohol (MeOH) at 0° C. Alternatively, an aldehyde of Formula III, wherein R1, R2, R3, R4, R5, and R7 are as previously disclosed, is allowed to react with trifluorotrimethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride (TBAF) in a polar aprotic solvent, such as tetrahydrofuran (THF), as in step b of Scheme I. The compound of Formula IV can be transformed into the compound of Formula V, wherein Y is selected from Br, Cl or I, and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, by reaction with a halogenating reagent, such as N-bromosuccinimide (NBS) and triethyl phosphite in a non-reactive solvent, such as dichloromethane (CH2Cl2) at reflux temperature to provide Y═Br, or such as thionyl chloride and pyridine in a hydrocarbon solvent, such as toluene at reflux temperature to provide Y═Cl, as in step c of Scheme I.

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Formation of the styrene coupling partners can be accomplished as in Schemes II, III IV and V.

In Scheme II, a vinylbenzoic acid of Formula VI, wherein R11 is (C═O)OH and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be converted in two steps to the vinylbenzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, and X are as previously disclosed. As in step d of Scheme II, the benzoic acid of Formula VI is treated with oxalyl chloride in the presence of a catalytic amount of N,N-dimethylformamide (DMF) in a non-reactive solvent such as CH2Cl2 to form the acid chloride, which is subsequently allowed to react with an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, in the presence of a base, such as triethylamine (TEA), in a polar aprotic solvent, such as THF, to provide the vinyl benzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, as in step e of Scheme II.

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In Schemes III and IV, a halobenzoic acid of Formula VIII, wherein R18 is Br or I, R11 is (C═O)OH and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed can be converted to a vinylbenzoic acid ester of Formula VIIb1 or Formula VIIb2, wherein R18 is Br or I, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. In step f of Scheme III, the halobenzoic acid of Formula VIII, wherein R18 is Br, is treated with a base, such as n-butyllithium (n-BuLi), and DMF in a polar, aprotic solvent, such as THF, at a temperature of about −78° C. The resulting formyl benzoic acid is allowed to react with an acid, such as sulfuric acid (H2SO4), in the presence of an alcohol, such as ethyl alcohol (EtOH), as in step g, to provide the formyl benzoic acid ethyl ester of Formula IX, wherein R11 is (C═O)O(C1-C6 alkyl), and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The vinyl benzoic acid ester of Formula VIIb1 is accessed via reaction of the compounds of Formula IX, with a base, such as potassium carbonate (K2CO3), and methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, at ambient temperature, as in step h of Scheme III.

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In step i of Scheme IV, the halobenzoic acid of Formula VIII, wherein R18 is Br, R11 is (C═O)OH, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, is treated with di-tert-butyl dicarbonate in the presence of a base, such as TEA and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent, such as THF, at ambient temperature. The resulting benzoic acid tert-butyl ester is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such a tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4), and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, as in step j, to provide the vinyl benzoic acid ester of Formula VIIb2, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.

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In step k of Scheme V, the vinyl benzoic acid ester of Formula VIIb2, wherein R10 is Br, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously defined, can be further transformed into the corresponding vinyl benzoic acid ester of Formula VIIb3, wherein R10 is CN, R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with copper(I) cyanide (CuCN) in a polar aprotic solvent, such as DMF, at 140° C.

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Coupling of the compounds of Formula V with the compounds of Formula VIIa, VIIb1, VIIb2 and VIIb3 can be accomplished as in Schemes VI, VII, and VIII. In step l of Scheme VI, a compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzamide of Formula VIIa, wherein R11 is (C═O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of copper(I) chloride (CuCl) and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.

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In step l of Scheme VII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb1, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xa, wherein R11 is (C═O)O(C1-C6 alkyl), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xa are then converted to the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, by either a two-step process as disclosed in steps m and n or in one step as disclosed in step o. In step m of Scheme VII, the ester of Formula Xa is saponified to the corresponding acid under acidic conditions, such as about 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent, such as 1,4-dioxane, at about 100° C. The acid can subsequently be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed using peptide coupling reagents, such as 1-hydroxybenzotriazole (HOBt), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 1-hydroxy-7-azabenzotriazole (HOAt), or O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a base, such as N,N-diisopropylethylamine (DIPEA) or DMAP to give the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. Alternatively, the ester of Formula Xa is allowed to react with an amine (HN(R14)(R15)) in the presence of a solution of trimethylaluminum in toluene in a non-reactive solvent, such as CH2Cl2, at ambient temperature, as in step o of Scheme VII, to access the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.

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In step l of Scheme VIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula VIIb2 or VIIb3, wherein R11 is (C═O)O(C1-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the compounds of Formula Xb, wherein R11 is (C═O)OH, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xb are then converted to the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, in one step as disclosed in step n. In step n of Scheme VIII, the acid of Formula Xb can be coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, using peptide coupling reagents, such as HOBt, EDC.HCl, PyBOP, CIP, HOAt, or HBTU in the presence of a base, such as DIPEA or DMAP to give the molecules of Formula One, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.

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In step t of Scheme XIII, the vinyl benzyl chloride of Formula XIa, wherein R11 is —CH2C1 and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding phthalimide-protected benzyl amine of Formula XIIa, wherein R11 is CH2N(Phthalimide), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70° C.

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In step u of Scheme XIV, the 4-methylbenzonitrile of Formula XIIIa, wherein R11 is CH3 and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding benzyl bromide of Formula XIVa, wherein R11 is CH2Br and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with NBS and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride (CCl4) at 77° C. The nitrile group (CN) of Formula XIVa can be reduced to the corresponding aldehyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M HCl as in step v of Scheme XIV. The compound of Formula XVa can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIa, wherein R11 is CH2N(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XIV. In step w of Scheme XIV, the aldehyde of Formula XVIa can be converted to the olefin of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient temperature.

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The aldehyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be reacted with a nucleophile, such as 2-aminopyridine, in a polar aprotic solvent, such as N,N-dimethylacetamide (DMA), in the presence of a base, such as K2CO3, at ambient temperature to provide the compound of Formula XVII, wherein R11 is CH2NH(2-pyridine) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, as in step x of Scheme XV. In step w of Scheme XV, the compound of Formula XVII can be converted to the olefin of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.

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In a two-step, one-pot reaction as in steps y and z of Scheme XVI, the compound of Formula XIX can be reacted with the compounds of Formula XX, wherein R10 and R11 are Cl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, in the presence of a base, such as sodium hydride (NaH), and a polar aprotic solvent, such as DMF, at ambient temperature to provide the compounds of Formula XXI, wherein R10 is Cl, R11 is (CH)NH2CO2CH2CH3, X1 is N, and R9, R13, X2, and X3 are as previously defined.

Hydrolysis and decarboxylation of the compounds of Formula XXI can be accomplished by reaction under acidic conditions, such as with 3 N HCl, at reflux temperature, to afford the compounds of Formula XXII, wherein R10 is Cl, R11 is CH2NH2.HCl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI. The compounds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIIIa, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R9, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in the presence of a base, such as TEA, and an aprotic solvent, such as toluene, at reflux temperature as in step ab of Scheme XVI. The bromide of Formula XXIIIa can be converted to the olefin of Formula XIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R13, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux temperature, as in step ac of Scheme XVI.

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In step u of Scheme XVII, the 4-methylnaphthonitrile of Formula XIIIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH3, and R12, R13, X1 and X2 are as previously defined, can be transformed into the corresponding naphthyl bromide of Formula XIVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2Br, and R12, R13, X1 and X2 are as previously disclosed, by reaction with NBS and AIBN in a non-reactive solvent, such as CCl4 at 77° C. The nitrile group (CN) of Formula XIVb can be reduced to the corresponding aldehyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2Br, and R12, R13, X1 and X2 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0° C., followed by quenching with 1.0 M HCl as in step v of Scheme XVII. The compound of Formula XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R12, R13, X1 and X2 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60° C. as in step t of Scheme XVII. In step w of Scheme XVII, the aldehyde of Formula XVIb can be converted to the olefin of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R8, R12, R13, X1 and X2 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient temperature.

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The compound of Formula XXIV, wherein R11 is NHNH2.HCl and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be transformed into the corresponding phthalimide-protected hydrazine of Formula XXV, wherein R11 is NHN(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in glacial acetic acid (AcOH) at reflux temperature as in step ad of Scheme XVIII. The bromide of Formula XXV can be converted to the olefin of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R10, R13, X1, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a polar aprotic solvent such as 1,2-dimethoxyethane at 150° C. under microwave conditions, as in step ae of Scheme XVIII.

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In step af of Scheme XIX, the compound of Formula XXVI, wherein R11 is B(OH)2, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react with 2-hydroxyisoindoline-1,3-dione in the presence of CuCl and pyridine in a solvent, such as 1,2-dichlorobenzene, at ambient temperature to provide the compound of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.

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In step l of Scheme XX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIa, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIa, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIa is removed as in step ag of Scheme XX by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIa, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIa can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by acylation with an anhydride, such as acetic anhydride, and a base, such as TEA, in a non-reactive solvent such as CH2Cl2 at 0° C. as in step ah1 of Scheme XX.

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In step l of Scheme XXI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIb, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIb is removed as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIb, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah2a of Scheme XXI.

In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═S)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a thioacid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as DMF, as in step ah2 of Scheme XXI.

In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, in two steps. The first step (step ah3a of Scheme XXI) involves reaction with an aldehyde in a polar protic solvent such as MeOH, followed by reaction with NaBH4. The second step (step ah3b of Scheme XXI) involves acylation with an acid chloride, such as cyclopropylcarbonyl chloride, and a base, such as TEA, in a non-reactive solvent such as CH2Cl2 at ambient temperature of Scheme XXI.

In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isocyanate (step ai1 of Scheme XXI) or a carbamoyl chloride (step ai2 of Scheme XXI) in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C.

In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═S)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C., as in steps aj of Scheme XXI.

In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a dicarbonate, such as di-tert-butyl dicarbonate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at ambient temperature, as in steps ak of Scheme XXI.

In yet another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C═O)(C═O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a chlorooxalic acid ester, such as 2-chloro-2-oxoacetate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C., as in steps al of Scheme XXI.

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In step l of Scheme XXII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIc, wherein R10 is C1, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R12, R13, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIc is removed as in step ag of Scheme XXII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIc, wherein R10 is C1, R11 is CH2NH2, X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIc can be transformed into the compounds of Formula One, wherein R10 is Cl, R11 is CH2N(C═O)(R14), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXII.

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In step l of Scheme XXIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2N(Phthalimide) and R8, R9, R12, R13, X1 and X2 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIId is removed as in step ag of Scheme XXIII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXIII.

In another embodiment, the compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C═O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1 and X2 are as previously disclosed, by reaction with an isocyanate in the presence of a base such as TEA and in a non-reactive solvent such as CH2Cl2 at 0° C. as in step ai1 of Scheme XXIII.

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In step l of Scheme XXIV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIe, wherein R11 is NHN(Phthalimide) and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIe, wherein R11 is NHN(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIe is removed as in step ag of Scheme XXIV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIe, wherein R11 is NHNH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIe can be transformed into the compounds of Formula One, wherein R11 is NHN(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXIV.

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In step l of Scheme XXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula XXVIIf, wherein R11 is ON(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIf is removed as in step ag of Scheme XXV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90° C. to provide the compounds of Formula XXVIIIf, wherein R11 is ONH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIf can be transformed into the compounds of Formula One, wherein R11 is ON(C═O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt.H2O, EDC.HCl and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step ah2b of Scheme XXV.

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In step l of Scheme XXVI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compounds of Formula One, wherein R11 is CH2NH(2-pyridine), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.

The compounds of Formula One can be further elaborated by standard methods. For example, when R11 contains a thioether, the thioether can be oxidized to the sulfone by treatment with oxone in the presence of an acetone:water mixture at ambient temperature. When R11 contains an oxalate ester, the compound of Formula One can be transformed into the corresponding oxalamide by reaction with an amine hydrochloride and a solution of trimethylaluminum in toluene in a non-reactive solvent such as CH2Cl2.

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In Scheme XXVII, a fluorobenzaldehyde of Formula XXIX, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by reaction with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as K2CO3, in a solvent such as DMF as in step aj. In step ak, the (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX is converted to a (1,2,4-triazol-1-yl)vinyl benzene of Formula XXXIa wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the presence of a base, such as K2CO3, in an aprotic solvent, such as 1,4-dioxane.

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In Scheme XXVIII, a bromofluorobenzene of Formula XXXII, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)vinylbenzene of Formula XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed in two steps. In step al, the bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as K2CO3, in a solvent such as DMF to generate the (1,2,4-triazol-1-yl)bromobenzene. In step cl, the (1,2,4-triazol-1-yl)bromobenzene is reacted with vinyl boronic anhydride pyridine complex in the presence of a catalyst, such as Pd(PPh3)4, and a base, such as K2CO3 in a solvent such as toluene.

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Coupling of the compounds of Formula V with compounds of Formula XXXIa and XXXIb can be accomplished as in Schemes XXIX. In step l, a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R9, R10, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the molecules of Formula One, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed.

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In Scheme XXX, compounds of Formula XXXIII wherein R11 is a 3-nitro-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed can be converted to compounds of Formula One, wherein R11 is a 3-amido-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed by a two-step process. In step am, the 3-nitro-1,2,4-triazol-1-yl group is reduced to a 3-amino-1,2,4-triazol-1-yl group in the presence of zinc dust and ammonium chloride (NH4Cl) in a protic solvent, such as MeOH. In step an, the 3-amino-1,2,4-triazol-1-yl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl chloride, in the presence of a base, such as TEA, in a solvent such as CH2Cl2.

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In step ao of Scheme XXXI, a bromophenyl methyl ketone of Formula XXXIV wherein R10, X1, X2, and X3 are as previously disclosed is converted to an phenyl methyl ketone of the Formula XXXV wherein R11 is a 1,2,4-triazol-1-yl group, and R10, X1, X2, and X3 are as previously disclosed by treatment with 1,2,4-triazole in the presence of a base, such as cesium carbonate (Cs2CO3), and a catalyst, such as copper iodide (CuI), in a solvent, such as DMF. In step ap, the 1,2,4-triazolylacetophenone of Formula XXXV is converted to the trimethylsilyl enol ether of Formula XXXVI by treatment with trimethylsilyl trifluoromethanesulfonate in the presence of a base, such as TEA, in an aprotic solvent, such as CH2Cl2. In step aq, the silyl enol ether is reacted with a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene at a temperature of about 180° C. to generate a ketone of the Formula XXXVII, wherein R11 is a 1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed. In step ar, the ketone of the Formula XXXVII is treated with methylmagnesium bromide in an aprotic solvent, such as THF to generate the tertiary alcohol. The tertiary alcohol then undergoes an elimination reaction when treated with a catalytic amount of p-toluenesulfonic acid in a solvent, such as toluene, when heated to a temperature to allow azeotropic removal of water to produce compounds of Formula One wherein R11 is a 1,2,4-triazol-1-yl group, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed, as in step as.

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In Scheme XXXII, a compound of Formula XXXVIII, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula One, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an alkylamine substituent with the ring carbon atoms form a 5- or 6-membered cyclic ring and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with an alkylamine, such as 3,3,3-trifluoropropylamine, in the presence of a reducing agent, such as sodium cyanoborohydride (NaBH3CN), in a solvent, such as 1,2-dichloroethane (DCE).

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In Scheme XXXIII, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XL, wherein X1, X2, and X3 are as previously disclosed, by treatment with a reducing agent, such as NaBH3CN, in a solvent, such as AcOH, as in step au. In step av, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile (MeCN). The bromide of Formula XL can be converted to the olefin of Formula XLI, wherein R8, X1, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a polar aprotic solvent such as dimethylsulfoxide (DMSO) at 100° C., as in step aw.

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In Scheme XXXIV, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLII, wherein X1, X2, and X3 are as previously disclosed in two steps. In step ax, the olefin is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2, and a ligand, such as triphenylphosphine, and a base, such as Cs2CO3, in a solvent mixture such as THF/water. In step ay, the nitrogen atom is protected with a BOC group by reaction with di-tert-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as MeCN.

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In step l of Scheme XXXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XLI or XLII, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 150° C. to provide the corresponding compounds of Formula XLIIIa or XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed.

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In Scheme XXXVI, a compound of Formula XLIIIa, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to a molecule of Formula XLIV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid (TFA), in a solvent such as CH2Cl2, as in step az. Compounds of the Formula XLIV can then be transformed into compounds of the Formula XLV wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step ba, the indoline is treated with sodium nitrite (NaNO2), in an acid, such as concentrated HCl, at a temperature around 5° C., to form the nitrosoindole. In step bb, the nitrosoindole is reacted with NH4Cl in the presence of zinc powder in a protic solvent, such as MeOH. In step be, compounds of the Formula XLV are transformed into compounds of the Formula XLVI, wherein X4 is N(R14)(C(═O)R14) and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with and acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.

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In Scheme XXXVII, a compound of Formula XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed is converted to an indole of Formula XLVII, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with TFA, in a solvent such as CH2Cl2, as in step bd. Compounds of the Formula XLVII can be transformed into compounds of the Formula XLVIII wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by reaction with 4-nitrophenyl-2-((tert-butoxycarbonyl)amino)acetate in the presence of potassium fluoride (KF) and a crown ether, such as 18-crown-6-ether, in a solvent, such as MeCN, as in step be. Compounds of the Formula XLVIII can be transformed into compounds of the Formula XLIX, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps. In step bf, the Boc group is removed by treatment with TFA, in a solvent such as CH2Cl2. In step bg, the amine is treated with 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.

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In Scheme XXXVIII, a compound of Formula L, wherein X1, X2, and X3 are as previously disclosed is converted to a compound of the Formula LI, wherein X1, X2, and X3 are as previously disclosed by treatment with copper (II) sulfate pentahydrate and Zn powder in a base, such as NaOH as in step bh. Compounds of the Formula LI can be transformed into compounds of the Formula LII wherein X1, X2, and X3 are as previously disclosed, by reaction with hydrazine, in a solvent such as water, at a temperature around 95° C., as in step bi. In step bj, the olefin of the Formula LIII wherein X1, X2, and X3 are as previously disclosed is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCl2(dppf), and a base, such as K2CO3, in a solvent mixture such as DMSO. Compounds of the Formula LIV, wherein X1, X2, and X3 are as previously disclosed, can be formed from compounds of the Formula LIII by reaction with ethyl bromoacetate, in the presence of a base, such as Cs2CO3, in a solvent, such as DMF.

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In step l of Scheme XXXIX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of Formula LIV, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a temperature of about 180° C. to provide the corresponding compound of Formula LV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed. The compound of Formula LV can be further transformed into a compound of the Formula LVI, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step bl, the ester is hydrolyzed to the acid in the presence of HCl and AcOH, at a temperature of about 100° C. In step bm, the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2.

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In step bn of Scheme XL, carboxylic acids of the Formula LVII, wherein R11 is C(═O)OH and R8, R10, X1, X2, and X3 are as previously disclosed and compounds of the Formula V, wherein Y is Br and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed are allowed to react in the presence of CuCl and 2,2-bipyridyl in a solvent, such as N-methyl pyrrolidine, at a temperature of about 150° C. to afford compounds of Formula LVIII, wherein R11 is (C═O)OH and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed. Compounds of the Formula LVIII can be further transformed to the corresponding benzamides of Formula LIX, wherein R11 is (C═O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed, by treatment with an amine, such as 2-amino-N-(2,2,2-trifluoroethyl)acetamide, PyBOP, and a base, such as DIPEA, in a polar aprotic solvent, such as CH2Cl2, as in step bo.

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EXAMPLES

The examples are for illustration purposes and are not to be construed as limiting the invention disclosed in this document to only the embodiments disclosed in these examples.

Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased as Sure/Seal™ from Aldrich and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Molecules are given their known names, named according to naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molecule, the molecule is named using conventional naming rules. 1H NMR spectral data are in ppm (δ) and were recorded at 300, 400, or 600 MHz, and 13C NMR spectral data are in ppm (δ) and were recorded at 75, 100, or 150 MHz, unless otherwise stated.

Example 1: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)

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Step 1 Method A. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)

To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (procured from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol)) in MeOH (100 milliliters (mL)) at 0° C. were added NaBH4 (3.33 g, 92.5 mL) and 1 N aqueous NaOH solution (10 mL). The reaction mixture was warmed to 25° C. and stirred for 2 hours (h). After the reaction was deemed complete by thin layer chromatography (TLC), saturated aqueous NH4Cl solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether (Et2O) and washed with water (3×50 mL). The organic layer was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to afford the title compound as a liquid (4.0 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, 1H); ESIMS m/z 242.97 ([M−H]).

Step 1 Method B. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2)

To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in THF (250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of TBAF. The reaction mixture was stirred at 25° C. for 8 h. After the reaction was deemed complete by TLC, the reaction mixture was diluted with 3 N HCl and then was stirred for 16 h. The reaction mixture was diluted with water and was extracted with ethyl acetate (EtOAc; 3 x). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (8.41 g, 60%).

The following compounds were made in accordance with the procedures disclosed in Step 1 Method A of Example 1 above.

2,6-Difluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile

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The product was isolated as a brown solid: mp 83-87° C.; 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J=9.0 Hz, 2H), 5.12 (d, J=6.0 Hz, 1H), 3.06 (s, 1H); ESIMS m/z 237.1 ([M+H]+).

1-(3,5-Difluoro-4-methoxyphenyl)-2,2,2-trifluoroethanol

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The product was isolated as a pale yellow liquid: 1H NMR (300 MHz, CDCl3) δ 7.06 (d, J=8.4 Hz, 2H), 4.97-4.94 (m, 1H), 4.03 (s, 3H), 2.64 (s, 1H); EIMS m/z 242.1 ([M]+); IR (thinfilm) 3459, 1135 cm−1.

1-(3,4-Dichlorophenyl)-2,2-difluoropropan-1-ol

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The product was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.65-7.62 (m, 2H), 7.41 (d, J=8.4 Hz, 1H), 6.49 (d, J=5.1 Hz, 1H), 4.87-4.78 (m, 1H), 1.53 (t, J=18.9 Hz, 3H); EIMS m/z 240.0 ([M]+); IR (thinfilm) 3434, 1131, 801, 512 cm−1.

The following compounds were made in accordance with the procedures disclosed in Step 1 Method B of Example 1 above.

2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanol (AI3)

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The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 278 ([M+H]+); IR (thin film) 3420, 1133, 718 cm−1.

1-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanol (AI4)

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The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 262 ([M+H]+); IR (thin film) 3420, 1133, 718 cm−1.

1-(3,4-Dichlorophenyl)-2,2,2-trifluoroethanol (AI5)

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The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H), 2.60 (s, 1H); EIMS m/z 244 ([M]+).

1-(3,5-Dibromophenyl)-2,2,2-trifluoroethanol

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (s, 2H), 5.08-5.02 (m, 1H), 4.42 (bs, 1H); EIMS m/z 333.7 ([M]+); IR (thin film) 3417, 2966, 1128, 531 cm−1.

2,2,2-Trifluoro-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethanol

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The title molecule was isolated as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.45-7.37 (m, 2H), 5.11 (q, J=6.4 Hz, 1H), 3.22 (bs, 1H); 13C NMR (101 MHz, CDCl3) δ 162.42 (d, J=249.5 Hz), 137.46 (d, J=7.8 Hz), 132.89 (qd, J=33.5, 7.9 Hz), 123.67 (q, J=283.8 Hz), 122.92 (q, J=270.68 Hz), 120.10 (t, J=4.1 Hz), 118.13 (d, J=23.0 Hz), 113.94 (dq, J=24.2, 3.9 Hz), 71.57 (q, J=32.4 Hz); EIMS m/z 262 ([M]+).

1-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol

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The product was isolated as a white solid (4.98 g, 77%): mp 42-46° C.; 1H NMR (400 MHz, CDCl3) δ 7.83-7.50 (m, 3H), 5.10 (p, J=6.2 Hz, 1H), 2.88 (d, J=4.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 137.12, 135.84, 131.4, 133.03 (q, J=33.3 Hz), 127.15 (q, J=3.8 Hz), 124.50 (q, J=308.0 Hz), 123.45 (q, J=301.8 Hz), 123.04, 72.06 (q, J=32.5 Hz); 19F NMR (376 MHz, CDCl3) δ −62.93, −78.43; EIMS m/z 278 ([M]+).

2,2,2-Trifluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanol

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The product was isolated as a brown liquid: 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=6.8 Hz, 1H), 7.69-7.67 (m, 1H), 7.28-7.23 (m, 1H), 5.05-5.02 (m, 1H); ESIMS m/z 261.1 ([M−H]); IR (thin film) 3418, 1131 cm−1.

2,2,2-Trifluoro-1-(3,4,5-trifluorophenyl)ethanol

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The product was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.19-7.10 (m, 2H), 5.03-4.96 (m, 1H), 2.85 (bs, 1H); EIMS m/z 230.1 ([M]+).

2,2,2-Trifluoro-1-(2,3,4-trifluorophenyl)ethanol

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The product was isolated as a clear colorless liquid (4.61 g 66%): 1H NMR (400 MHz, CDCl3) δ 7.23 (qd, J=7.4, 6.1, 4.2 Hz, 1H), 6.93 (tdd, J=9.2, 6.9, 2.2 Hz, 1H), 5.25 (q, J=6.3 Hz, 1H), 3.02-2.74 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 151.79 (ddd, J=254.5, 9.8, 3.4 Hz), 149.52 (ddd, J=253.5, 11.0, 3.5 Hz), 139.67 (dt, J=252.5, 15.3 Hz), 123.68 (q, J=282.2 Hz), 122.48 (dt, J=8.2, 4.1 Hz), 118.95 (dd, J=10.6, 3.6 Hz), 112.73 (dd, J=17.7, 3.9 Hz), 66.58-64.42 (m); 19F NMR (376 MHz, CDCl3) δ −78.95 (d, J=6.2 Hz), −132.02 (dd, J=20.0, 8.2 Hz), −137.89 (m), 159.84 (t, J=20.3 Hz); EIMS m/z 230 ([M]+).

2,2,2-Trifluoro-1-(2,4,5-trichlorophenyl)ethanol

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The product was isolated as a white solid (3.37 g, 73%): mp 70-73° C.; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=2.5 Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 5.72-5.57 (m, 1H), 2.85 (d, J=4.8 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −77.84.

1-(4-Chloro-3-nitrophenyl)-2,2,2-trifluoroethanol

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The product was isolated as a yellow oil (6.52 g, 73%): 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=2.0 Hz, 1H), 7.75-7.51 (m, 2H), 5.16 (m, 1H), 3.41 (d, J=4.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 147.65, 134.44, 132.23, 132.17, 128.11, 124.66, 123.60 (q, J=283.8), 70.99 (q, J=32.6 Hz); 19F NMR (376 MHz, CDCl3) δ −78.47; EIMS m/z 230 ([M]+).

2,2,2-Trifluoro-1-(4-fluoro-3,5-dimethylphenyl)ethanol

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The product was isolated as a white solid (6.49 g, 84%): mp 45-49° C.; 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=6.8 Hz, 2H), 4.89 (m, 1H), 2.63 (d, J=4.3 Hz, 1H), 2.27 (d, J=2.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 160.45 (d, J=246.0 Hz), 128.73, 127.97, 124.92 (d, J=18.6 Hz), 124.19 (q, J=279.1 Hz), 72.36 (q, J=32.0 Hz), 14.61 (d, J=4.1 Hz); 19F NMR (376 MHz, CDCl3) δ −78.48, −120.14; EIMS m/z 222 ([M]+).

2,2,2-Trifluoro-1-(4-fluoro-3-methylphenyl)ethanol

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The product was isolated as a white solid (2.12 g, 33%): mp 40-46° C.; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=7.4 Hz, 1H), 7.25-7.14 (m, 1H), 7.01 (t, J=8.9 Hz, 1H), 5.05-4.63 (m, 1H), 3.03 (d, J=4.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 161.91 (d, J=247.0 Hz), 130.62 (d, J=5.6 Hz), 129.41 (d, J=3.5 Hz), 126.55 (d, J=8.5 Hz), 115.19 (d, J=22.9 Hz), 72.23 (q, J=32.1 Hz), 14.44 (d, J=3.6 Hz); 19F NMR (376 MHz, CDCl3) δ −78.57, −116.15; EIMS m/z 208 ([M]+).

1-(3-Chloro-4-methylphenyl)-2,2,2-trifluoroethanol

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The product was isolated as a clear colorless oil (4.99 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.10 (m, 2H), 4.79 (q, J=6.1 Hz, 1H), 2.89 (bs, 1H), 2.25 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 137.64, 134.67, 132.99, 131.09, 128.01, 125.58, 124.02 (q, J=284.8 Hz), 72.08 (q, J=32.3 Hz); 19F NMR (376 MHz, CDCl3) δ −78.39; EIMS m/z 224.5 ([M]+).

1-(3,4-Dibromophenyl)-2,2,2-trifluoroethanol

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The product was isolated as a clear colorless oil (5.92 g, 88%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.29 (dd, J=8.3, 2.0 Hz, 1H), 4.99 (qd, J=6.4, 4.2 Hz, 1H), 2.75 (d, J=4.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 134.52, 133.81, 132.60, 127.45, 126.19, 125.16, 123.71 (q, J=283.8 Hz), 71.57 (q, J=32.5 Hz); 19F NMR (376 MHz, CDCl3) δ −78.44; EIMS m/z 334 ([M]+).

2,2,2-Trifluoro-1-(3-(trifluoromethoxy)phenyl)ethanol

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The product was isolated as a clear colorless oil (20.9 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.55-7.36 (m, 3H), 7.33-7.14 (m, 1H), 5.06 (m, 1H), 2.80 (br m, 1H); 13C NMR (101 MHz, CDCl3) δ 149.36 (q, J=2.0 Hz), 136.04, 129.99, 125.78, 123.91 (q, J=282.8 Hz), 121.90, 120.31 (q, J=258.6 Hz),120.12, 72.04 (q, J=32.3 Hz); 19F NMR (376 MHz, CDCl3) δ −57.92, −78.49; EIMS m/z 260 ([M]+).

2-Fluoro-5-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile

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The product was isolated as a clear colorless oil (5.47 g, 58%): 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.9, 2.2 Hz, 1H), 7.76 (ddd, J=7.8, 5.0, 2.3 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), δ 5.09 (qd, J=6.3, 4.2 Hz, 1H), 3.12 (bm, 1H); 13C NMR (101 MHz, CDCl3) δ 163.49 (d, J=261.7 Hz), 134.23 (d, J=8.6 Hz), 132.67, 131.17, 123.66 (q, J=282.4 Hz), 116.79 (d, J=20.1 Hz), 113.39, 100.96 (d, J=194.9), 71.07 (q, J=32.5 Hz); 19F NMR (376 MHz, CDCl3) δ −78.70, −105.22; EIMS m/z 219 ([M]+).

1-(3-Bromo-5-chlorophenyl)-2,2,2-trifluoroethanol

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The product was isolated as a yellow liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.67 (s, 1H), 7.57 (s, 1H), 7.15 (d, J=5.7 Hz, 1H); EIMS m/z 288 ([M]+); IR (thin film) 3435, 1175, 750 cm−1.

1-(3-Bromo-5-fluorophenyl)-2,2,2-trifluoroethanol

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The product was isolated as a pale yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.29-7.26 (m, 1H), 7.18 (d, J=8.8 Hz, 1H), 5.03-4.98 (m, 1H), 3.60 (bs, 1H); EIMS m/z 272.0 ([M]+); IR (thin film) 3400, 1176, 520 cm−1.

1-(3,5-Dichlorophenyl)-2,2,3,3,3-pentafluoropropan-1-ol

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Using pentafluoroethyltrimethylsilane, the product was isolated as a white solid (6.22 g, 88%): mp 71-73° C.; 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J=1.9 Hz, 1H), 7.37 (d, J=1.8 Hz, 2H), 5.11 (dt, J=16.2, 5.7 Hz, 1H), 2.62 (d, J=4.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 136.90, 135.31, 129.84, 126.38, 70.94 (dd, J=28.2, 23.1 Hz); 19F NMR (376 MHz, CDCl3) δ −81.06, −120.94 (d, J=277.5 Hz), −129.18 (d, J=277.5 Hz); EIMS m/z 295 ([M]+).

2,2,3,3,3-Pentafluoro-1-(3,4,5-trichlorophenyl)propan-1-ol

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Using pentafluoroethyltrimethylsilane, the product was isolated as an off white semi solid: 1H NMR (300 MHz, DMSO-d6) δ 7.78 (s, 2H), 7.29 (d, J=5.4 Hz,), 5.50-5.40 (m, 1H); EIMS m/z 328.0 ([M]+); IR (thin film) 3459, 1188, 797 cm−1.

2,2,2-Trifluoro-1-(3-(trifluoromethyl)phenyl)ethanol

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The product was isolated as a light yellow (13.8 g, 89%): 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.70-7.67 (m, 2H), 7.55 (t, J=7.8 Hz, 1H), 5.12 (q, J=6.6 Hz, 1H), 2.76 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −62.8, −78.5; EIMS m/z 244 ([M]+).

1-(3,4-Dichloro-5-methylphenyl)-2,2,2-trifluoroethanol

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The product was isolated as an off pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.26 (s, 1H), 4.98-4.95 (m, 1H), 2.61 (d, J=4.4 Hz, 1H), 2.44 (s, 3H); EIMS m/z 258.1 ([M]+); IR (thin film) 3421, 2926, 1129, 748 cm−1.

1-(3-Chloro-5-ethylphenyl)-2,2,2-trifluoroethanol

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The product was isolated as an off brown liquid (0.43 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.31-7.30 (m, 2H), 6.99 (d, J=5.7 Hz, 1H), 5.23-5.16 (m, 1H), 2.67 (m, 2H), 1.19 (t, J=7.8 Hz, 3H); EIMS m/z 238.0 ([M]+); IR (thin film) 3361, 1172, 749 cm−1.

1-(4-Bromo-3,5-dichlorophenyl)-2,2,2-trifluoroethanol

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The product was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.75 (s, 2H), 7.24 (d, J=6.0 Hz, 1H), 5.34-5.29 (m, 1H); EIMS m/z 321.88 ([M]+); IR (thin film) 3420, 1706, 1267, 804, 679 cm−1.

1-(3,5-Dibromo-4-chlorophenyl)-2,2,2-trifluoroethanol

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The product was isolated as a pale yellow gum: 1H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 2H), 7.20 (d, J=6.0 Hz, 1H) 5.34-5.30 (m, 1H); EIMS m/z 366.0 ([M]+).

Step 2. 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1)

To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL), were added NBS (2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 ([M]+).

The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 1.

5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (AI6)

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The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 2H), 5.00 (m, 1H); EIMS m/z 340.00 ([M]+).

5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (AI7)

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The product was isolated as a colorless oil (320 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 2H), 5.00 (m, 2H); EIMS m/z 324.00 ([M]+).

4-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichlorobenzene (AI8)

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The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H); EIMS m/z 306.00 ([M]+).

1,3-Dibromo-5-(1-bromo-2,2,2-trifluoroethyl)benzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (s, 2H), 5.04-4.97 (m, 1H); EIMS m/z 394.6 ([M]+); IR (thin film) 1114, 535 cm−1.

1-(1-Bromo-2,2,2-trifluoroethyl)-3-fluoro-5-(trifluoromethyl)benzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=8.4 Hz, 1H), 7.79-7.77 (m, 2H), 6.40-6.34 (m, 1H); EIMS m/z 324.00 ([M]+); IR (thin film) 1175, 525 cm−1.

1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluoromethyl)benzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.67 (s, 1H), 7.64 (s, 1H), 5.15-5.09 (m, 1H); EIMS m/z 340.00 ([M]+); IR (thin film) 1178, 750, 540 cm−1.

4-(1-Bromo-2,2,2-trifluoroethyl)-1-fluoro-2-(trifluoromethyl)benzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.75-7.72 (m, 2H), 7.28-7.24 (m, 1H), 5.19-5.16 (m, 1H); EIMS m/z 326.0 ([M]+); IR (thin film) 1114, 571 cm−1.

5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trifluorobenzene

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, CDCl3) δ 7.23-7.12 (m, 2H), 5.05-4.98 (m, 1H); EIMS m/z 292.0 ([M]+); IR (thin film) 1116, 505 cm−1.

1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,4-trifluorobenzene

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The title molecule was isolated as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.44 (qd, J=m, 1H), 7.11-7.03 (m, 1H), 5.53-5.45 (m, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-2,4,5-trichlorobenzene

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The title molecule was isolated as an off white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=2.1 Hz, 1H), 7.71 (s, 1H), 6.45-6.37 (m, 1H); EIMS m/z 340.0 ([M]+); IR (thin film) 1186, 764, 576 cm−1.

4-(1-Bromo-2,2,2-trifluoroethyl)-1-chloro-2-nitrobenzene

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The title molecule was isolated as an off white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 6.43-6.35 (m, 1H); EIMS m/z 317.0 ([M]+); IR (thin film) 2927, 1540, 1353, 1177, 766, 530 cm−1.

5-(1-Bromo-2,2,2-trifluoroethyl)-2-fluoro-1,3-dimethylbenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.32 (d, J=7.2 Hz, 2H), 6.15-6.07 (m, 1H), 3.23 (s, 6H); ESIMS m/z 284.1 ([M+H]+); IR (thin film) 2962, 1112, 500 cm−1.

4-(1-Bromo-2,2,2-trifluoroethyl)-1-fluoro-2-methylbenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.34-7.28 (m, 2H), 7.04-6.98 (m, 1H), 5.10-5.03 (m, 1H), 2.29 (s, 3H); EIMS m/z 270.1 ([M]+); IR (thin film) 2989, 1163 cm−1.

1-(1-Bromo-2,2,3,3,3-pentafluoropropyl)-3,5-dichlorobenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, DMSO-d6) δ 7.79 (t, J=2.0 Hz, 1H), 7.63 (S, 2H), 6.37-6.29 (m, 1H); EIMS m/z 356 ([M]+); IR (thin film) 1673, 1130, 715, 518 cm−1.

4-(1-Bromo-2,2,2-trifluoroethyl)-2-chloro-1-methylbenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.55-7.50 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 6.24-6.16 (m, 1H); IR (thin film) 2983, 1112, 749, 564 cm−1.

1,2-Dibromo-4-(1-bromo-2,2,2-trifluoroethyl)benzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.33-7.30 (m, 1H), 5.07-5.00 (m, 1H); EIMS m/z 393.8 ([M]+); IR (thin film) 2981, 1644, 1165 cm−1.

1-(1-Bromo-2,2,2-trifluoroethyl)-3-(trifluoromethoxy)benzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.65-7.60 (m, 2H), 7.56-7.50 (m, 2H), 6.35-6.27 (m, 1H); EIMS m/z 322 ([M]+); IR (thin film) 3413, 1161, 564 cm−1.

5-(1-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzonitrile

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The title molecule was isolated as a pale yellow liquid: 1H NMR (300 MHz, CDCl3) δ 8.15-8.12 (m, 1H), 8.00-7.98 (m, 1H), 7.69-7.63 (m, 1H), 6.31-6.26 (m, 1H); EIMS m/z 280.9 ([M]+).

1-Bromo-3-(1-bromo-2,2,2-trifluoroethyl)-5-chlorobenzene

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The title molecule was isolated as a pale yellow liquid: 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.74 (s, 1H), 7.65 (s, 1H), 6.26-6.20 (m, 1H); EIMS m/z 349.9 ([M]+); IR (thin film) 1114, 764 cm−1.

1-Bromo-3-(1-bromo-2,2,2-trifluoroethyl)-5-fluorobenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.32-7.29 (m, 1H), 7.22 (d, J=8.8 Hz, 1H), 1.06 (q, 1H); EIMS m/z 334.0 ([M]+); IR (thin film) 3087, 1168, 533 cm−1.

5-(1-Bromo-2,2,3,3,3-pentafluoropropyl)-1,2,3-trichlorobenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.85 (s, 2H), 6.38-6.29 (m, 1H); EIMS m/z 389.9 ([M]+); IR (thin film) 1208, 798, 560 cm−1.

4-(1-Bromo-2,2,2-trifluoroethyl)-2,6-difluorobenzonitrile

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The title molecule was isolated as a purple solid: mp 59-63° C.; 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 2H), 5.11-5.07 (m, 1H); ESIMS m/z 299.0 ([M+H]+).

1-(1-Bromo-2,2,2-trifluoroethyl)-3-(trifluoromethyl)benzene

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The title molecule was isolated as a colorless liquid: mp 59-63° C.; 1H NMR (300 MHz, CDCl3) δ 7.75-7.67 (m, 3H), 7.57-7.52 (m, 1H), 5.20-5.13 (m, 1H); ESIMS m/z 306.0 ([M]+); IR (thinfilm) 3436, 2925, 1265, 749 cm−1.

5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-difluoro-2-methoxybenzene

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The title molecule was isolated as a pale yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J=8.4 Hz, 2H), 5.03-4.98 (m, 1H), 4.04 (s, 3H); ESIMS m/z 304.1 ([M+H]+); IR (thinfilm) 1114, 613 cm−1.

5-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichloro-3-methylbenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.27 (s, 1H), 5.04-4.99 (m, 1H), 2.44 (s, 3H); EIMS m/z 320.0 ([M]+); IR (thinfilm) 2925, 1112, 752, 580 cm−1.

4-(1-Bromo-2,2-difluoropropyl)-1,2-dichlorobenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.76-7.70 (m, 2H), 7.54 (dd, J=8.4 1.8 Hz, 1H), 5.81-5.73 (m, 1H), 1.67 (d, J=18.9 Hz, 3H); EIMS m/z 304.0 ([M]+); IR (thinfilm) 1118, 800, 499 cm−1.

1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-ethylbenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J=5.6 Hz, 2H), 7.39 (s, 1H), 6.20-6.16 (m, 1H), 2.68-2.62 (m, 2H), 1.19 (t, J=7.6 Hz, 3H); EIMS m/z 300.0 ([M]+); IR (thinfilm) 2970, 1167, 716, 539 cm−1.

2-Bromo-5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichlorobenzene

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The title molecule was isolated as a colorless liquid: 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 2H), 6.27-6.21 (m, 1H); EIMS m/z 383.9 ([M]+); IR (thinfilm) 2924, 1114, 749, 534 cm−1.

1,3-Dibromo-5-(1-bromo-2,2,2-trifluoroethyl)-2-chlorobenzene

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The title molecule was isolated as a pale yellow liquid: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 2H), 6.27-6.19 (m, 1H); EIMS m/z 428.0 ([M]+).

Example 2: Preparation of N-Methyl-4-vinylbenzamide (AI9)

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Step 1. 4-Vinylbenzoyl chloride (AI10)

To a stirred solution of 4-vinylbenzoic acid (1 g, 6.75 mmol) in CH2Cl2 (20 mL) at 0° C. were added a catalytic amount of DMF and oxalyl chloride (1.27 g, 10.12 mmol) dropwise over a period of 15 minutes (min). The reaction mixture was stirred at 25° C. for 6 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride.

Step 2. N-Methyl-4-vinylbenzamide (AI9)

To 1 M N-methylamine in THF (13.5 mL, 13.5 mmol) at 0° C. were added TEA (1.34 mL, 10.12 mmol) and the acid chloride from Step 1 above in THF (10 mL), and the reaction mixture was stirred at 25° C. for 3 h. After the reaction was deemed complete by TLC, the reaction mixture was quenched with water and then was extracted with EtOAc (3×). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H); ESIMS m/z 161.95 ([M+H]+).

The following compounds were made in accordance with the procedures disclosed in accordance with Example 2.

N,N-Dimethyl-4-vinylbenzamide (AI11)

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The product was isolated as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 4H), 6.71 (m, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.31 (d, J=10.8 Hz, 1H), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m/z 176.01 ([M+H]+).

N-(2,2,3-Trifluoromethyl)-4-vinylbenzamide (AI12)

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The product was isolated as an off-white solid (900 mg, 60%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (br s, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.19 (m, 2H); ESIMS m/z 230.06 ([M+H]+).

Morpholino(4-vinylphenyl)methanone (AI13)

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The product was isolated as a white solid (850 mg, 60%): ESIMS m/z 218.12 ([M+H]+).

Example 3: Preparation of Ethyl 2-methyl-4-vinylbenzoate (AI14)

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Step 1. 4-Formyl-2-methylbenzoic acid (AI15)

To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at −78° C. was added n-BuLi (1.6 M solution in hexanes; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at −78° C. for 1 h then was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M−H]).

Step 2. Ethyl 4-formyl-2-methylbenzoate (AI16)

To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in EtOH (30 mL) was added H2SO4 and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).

Step 3. Ethyl 2-methyl-4-vinylbenzoate (AI14)

To a stirred solution of ethyl 4-formyl-2-methylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 mL) were added K2CO3 (3.01 g, 21.87 mmol) and methyltriphenyl phosphonium bromide (7.8 g, 21.87 mmol) at 25° C. Then the reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in n-Hexane) to afford the title compound as a solid (2.0 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191.10 ([M−H]); IR (thin film) 2980, 1716, 1257 cm−1.

Example 4: Preparation of tert-Butyl 2-chloro-4-vinylbenzoate (AI17)

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Step 1. tert-Butyl 4-bromo-2-chlorobenzoate (AI18)

To a stirred solution of 4-bromo-2-chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), TEA (3.2 g, 31.98 mmol) and DMAP (0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with water. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 2-3% EtOAc in n-hexane) to afford the title compound as a liquid (3.2 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.62 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+H]+); IR (thin film) 1728 cm−1.

The following compounds were made in accordance with the procedures disclosed in Step 1 of Example 4.

tert-Butyl 2-bromo-4-iodobenzoate (AI19)

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The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 382.10 ([M+H]+); IR (thin film) 1727 cm−1.

tert-Butyl 4-bromo-2-(trifluoromethyl)benzoate (AI20)

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The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 1.57 (s, 9H); ESIMS m/z 324.10 ([M+H]+); IR (thin film) 1725 cm−1.

Step 2. tert-Butyl 2-chloro-4-vinylbenzoate (AI17)

To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added Pd(PPh3)4 (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 5-6% EtOAc in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm−1.

The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 4.

tert-Butyl 2-bromo-4-vinylbenzoate (AI21)

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The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 2H), 7.36 (d, J=8.0 Hz, 1H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 282.10 ([M+H]+); IR (thin film) 2978, 1724, 1130 cm−1.

tert-Butyl 2-(trifluoromethyl)-4-vinylbenzoate (AI22)

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The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=6.4 Hz, 2H), 7.59 (d, J=7.6 Hz, 1H), 6.77 (dd, J=17.6, 10.8 Hz, 1H), 5.89 (d, J=17.6 Hz, 1H), 5.44 (d, J=10.8 Hz, 1H), 1.58 (s, 9H); ESIMS m/z 272.20 ([M+H]+); IR (thin film) 2982, 1727, 1159 cm−1.

Example 5: Preparation of tert-Butyl 2-cyano-4-vinylbenzoate (AI23)

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To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added CuCN (0.23 g, 2.65 mmol), and the reaction mixture was heated at 140° C. for 3 h. The reaction mixture was cooled to 25° C., diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm−1.

Example 6: Preparation of Ethyl 2-bromo-4-iodobenzoate (AI46)

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To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in EtOH (100 mL) was added H2SO4 (5 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc (2×100 mL) and washed with water (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

The following compounds were made in accordance with the procedures disclosed in Example 6.

Ethyl 4-bromo-2-chlorobenzoate (AI47)

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The title compound was isolated as an off-white solid (2.0 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=1.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 4.65 (q, J=7.2 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H).

Ethyl 4-bromo-2-methylbenzoate (AI48)

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The title compound was isolated as a pale yellow liquid (3.0 g, 83%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.40 (t, J=7.2 Hz, 3H)ESIMS m/z 229.11 ([M+H]+); IR (thin film) 1725 cm−1.

Ethyl 4-bromo-2-fluorolbenzoate (AI49)

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The title compound was isolated as a colorless liquid (9.0 g, 79%): 1H NMR (400 MHz, DMSO-d6) δ 7.84 (t, J=8.4 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); ESIMS m/z 246.99 ([M+H]+), IR (thin film) 1734 cm−1.

Example 7: Preparation of Ethyl 4-bromo-2-ethylbenzoate (AI50)

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To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with EtOAc. The combined EtOAc layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).

The title compound was synthesized from 4-bromo-2-ethylbenzoic acid in accordance to the procedure in Example 6, isolated as a colorless liquid (0.15 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=8.4 Hz, 1H), 7.47 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.06 (q, J=7.6 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 226.96 ([M−H]); IR (thin film) 3443, 1686, 568 cm−1.

Example 8: Preparation of Ethyl 2-bromo-4-vinylbenzoate (AI51)

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To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol) in THF/water (100 mL, 9:1) was added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), Cs2CO3 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for 20 min, then charged with PdCl2 (0.05 g, 0.28 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and filtered through a Celite® bed and washed with EtOAc. The filtrate was again extracted with EtOAc and the combined organic layers washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% EtOAc/petroleum ether) to afford the title compound as a light brown gummy material (2 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.4 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=3.6 Hz, 3H); ESIMS m/z 255.18 ([M+H]+); IR (thin film) 1729 cm−1.

The following compounds were made in accordance with the procedures disclosed in Example 8.

Ethyl 2-methyl-4-vinylbenzoate (AI52)

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The title compound was isolated as a colorless liquid (0.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.27 (m, 2H), 6.79 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 191.10 ([M+H]+); IR (thin film) 1717, 1257 cm−1.

Ethyl 2-fluoro-4-vinylbenzoate (AI53)

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The title compound was isolated as a pale yellow liquid (2.0 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J=8.0 Hz, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 6.82 (dd, J=17.6, 10.8 Hz, 1H), 6.09 (d, J=17.6 Hz, 1H), 5.50 (d, J=10.8 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); ESIMS m/z 195.19 ([M+H]+); IR (thin film) 1728 cm−1.

Example 9: Preparation of Ethyl 2-chloro-4-vinylbenzoate (AI54)

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To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and K2CO3 (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (2×50 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz,2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm−1.

The following compounds were made in accordance with the procedures disclosed in Example 9.

Ethyl 2-ethyl-4-vinylbenzoate (AI55)

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The title compound was isolated as a color less liquid (1.0 g, 66%): 1H NMR (300 MHz, CDCl3) δ 7.85 (m, 1H), 7.29 (m, 2H), 6.76 (d, J=10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.36 (d, J=10.5 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.10 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H); ESIMS m/z 205.26 ([M+H]+); IR (thin film) 1720, 1607, 1263 cm−1.

Methyl 2-methoxy-4-vinylbenzoate (AI56)

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The title compound was isolated as a pale yellow liquid (1.2 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.04 (d, J=1.2 Hz, 1H), 6.97 (s, 1H), 6.74 (dd, J=11.2, 11.2 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.39 (d, J=17.6 Hz, 1H) 3.93 (s, 3H), 3.91 (s, 3H); ESIMS m/z 193.18 ([M+H]+); IR (thin film) 1732 cm−1.

Ethyl 2-(methylthio)-4-vinylbenzoate

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The title compound was isolated as a brown liquid: 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=8.4 Hz, 1H), 7.23-7.18 (m, 2H), 6.78 (dd, J=17.7, 10.8, Hz, 1H), 5.89 (d, J=17.4 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.39-4.36 (m, 2H), 2.48 (s, 3H), 1.39 (t, J=6.9 Hz, 3H); ESIMS m/z 221.9 ([M+H]+); IR (thin film) 1708 cm−1.

Example 10: Preparation of (E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (AI24)

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To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (6.44 g, 21.0 mmol), CuCl (208 mg, 21 mmol) and 2,2bipyridyl (0.65 g, 4.1 mmol). The reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in petroleum ether) afforded the title compound as a solid (1.7 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 415.06 ([M−H]); IR (thin film) 1717, 1255, 1114 cm−1.

Compounds AI25, AI57-AI68 and AC1-AC5 (Table 1) were made in accordance with the procedures disclosed in Example 10.

(E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)-benzoic acid (AI25)

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The product was isolated as a pale brown gummy liquid (500 mg, 40%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (m, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.42 (s, 2H), 6.70 (d, J=16.0 Hz, 1H), 6.57 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 1.40 (t, J=7.6 Hz, 3H); ESIMS m/z 502.99 ([M−H]); IR (thin film) 1730, 1201, 1120, 749 cm−1.

(E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoate (AI57)

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1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.26 (s, 3H), 7.21 (d, J=8.4 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.47 (dd, J=,16.0, 8.0 Hz, 1H), 4.41 (q, J=6.8 Hz, 2H), 4.18 (m, 1H), 1.41 (t, J=6.8 Hz, 3H); ESIMS m/z 419.33 ([M−H]); IR (thin film) 1723, 1115, 802 cm−1.

(E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-bromobenzoate (AI58)

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1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 6.56 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.39 (m, 1H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 481.22 ([M−H]); IR (thin film) 1727, 1114, 801, 685 cm−1.

(E)-Ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI59)

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1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.36 (d, J=1.6 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 514.74 ([M−H]); IR (thin film) 1726, 1115, 808, 620 cm−1.

(E)-Ethyl 2-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI60)

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The title compound was isolated as a light brown gummy material: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).

(E)-Ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI61)

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1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.0 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.31 (d, J=1.6 Hz, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 470.73 ([M−H]); IR (thin film) 1726, 1115, 809, 3072 cm−1.

(E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoate (AI62)

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The title compound was isolated as a pale brown liquid (1.0 g, 46.3%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.41 (s, 2H) 6.65 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=7.6 Hz, 3H); ESIMS m/z 502.99 ([M−H]); IR (thin film) 1730, 1202, 1120, 750 cm−1.

(E)-Ethyl 2-chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI63)

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1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 2H), 7.34 (m, 1H), 7.24 (m, 1H), 6.57 (d, J=16.2 Hz, 1H), 6.45 (dd, J=16.2, 7.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm−1.

(E)-Ethyl 2-fluoro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI64)

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1H NMR (400 MHz, CDCl3) δ 7.93 (t, J=7.6 Hz, 1H), 7.34 (d, J=5.6 Hz, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.6 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J=7.6 Hz, 3H); ESIMS m/z 436.81 ([M−H]); IR (thin film) 1725 cm−1.

(E)-Ethyl 2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI65)

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1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.36 (m, 3H), 6.56 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.10 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 498.74 ([M−H]); IR (thin film) 1726, 1114, 820, 623 cm−1.

(E)-Ethyl 2-methyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI66)

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The title compound was isolated as a brown semi-solid: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.8 Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 432.90 ([M−H]); IR (thin film) 1715 cm−1.

(E)-Methyl 2-methoxy-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI67)

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1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.35 (d, J=6.0 Hz, 2H), 7.03 (d, J=1.2 Hz, 1H), 6.92 (s, 1H), 6.59 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.13 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H); ESIMS m/z 437.29 ([M+H]+); IR (thin film) 1724 cm−1.

(E)-Ethyl 2-ethyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI68)

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1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.35 (d, J=9.6 Hz, 2H), 7.26 (m, 1H), 7.24 (m, 1H), 6.60 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.01 (q, J=7.6 Hz 2H), 1.41 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 447.05 ([M−H]); IR (thin film) 1715, 1115, 817 cm−1.

(E)-Ethyl 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(methylthio)benzoate

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Isolated as a brown liquid: 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.1 Hz, 2H), 7.35-7.32 (m, 2H), 7.21-7.16 (m, 2H), 6.63 (d, J=15.8 Hz, 1H), 6.45 (dd, J=15.9, 7.8 Hz, 1H), 4.41-4.31 (m, 2H), 4.30-4.10 (m, 1H), 2.47 (s, 3H), 1.40 (t, J=7.5 Hz, 3H); ESIMS m/z 466.88 ([M+H]+); IR (thin film) 1705, 1114 cm−1.

(E)-Ethyl 2-bromo-4-(3-(3,5-difluoro-4-methoxyphenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoate

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The product was isolated as a pale yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.0 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.35-7.33 (m, 1H), 6.96-6.90 (m, 2H), 6.54 (d, J=15.6 Hz, 1H), 6.43 (dd, J=15.6, 8.0 Hz, 1H), 4.39 (q, J=6.8 Hz, 2H), 4.09-4.05 (m, 1H), 4.02 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); EIMS m/z 478.2 ([M]+); IR (thin film) 1727, 1113 cm−1.

Example 11: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI32)

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To a stirred solution of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added 11 N HCl (30 mL), and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with water and extracted with chloroform (CHCl3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude compound was washed with n-hexane to afford the title compound as a white solid (0.7 g, 50%): mp 142-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, J=16.0, 8.0 Hz, 1H), 6.78-6.74 (d, J=16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387.05 ([M−H]); IR (thin film) 3448, 1701, 1109, 777 cm−1.

The following compounds were made in accordance with the procedures disclosed in Example 11.

(E)-2-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI26)

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The product was isolated as a pale brown gummy liquid (1 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.50 (s, 3H); ESIMS m/z 422.67 ([M−H]).

(E)-2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI27)

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The product was isolated as an off-white semi-solid (1 g, 45%): 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 7.36 (m, 2H), 6.59 (d, J=15.6 Hz, 1H), 6.48 (dd, J=15.6, 7.6 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 442.72 ([M−H]); IR (thin film) 3472, 1704, 1113, 808 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI28)

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The product was isolated as a brown solid (1 g, 45%): mp 70-71° C.; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 484.75 ([M−H]); IR (thin film) 3468, 1700 cm−1.

(E)-2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI29)

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The product was isolated as an off-white solid (500 mg, 45%): mp 100-101° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.65 (br s, 1H), 7.42 (s, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 8.0 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 431.93 ([M−H]).

E)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI30)

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The product was isolated as a pale brown liquid (500 mg, 46%): 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58 (dd, J=16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.64 (s, 3H); ESIMS m/z 386.84 ([M−H]); IR (thin film) 3428, 1690, 1113, 780 cm−1.

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI31)

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The product was isolated as a white solid (500 mg, 50%): mp 91-93° C.; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.61 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M−H]).

(E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoic acid (AI33)

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The product was isolated as a white solid (500 mg, 45%): mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 474.87 ([M−H]).

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI69)

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The title compound was isolated as a brown solid (0.8 g, 28%): 1H NMR (400 MHz, CDCl3) δ 13.42 (br, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.94 (m, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.65 (m, 1H), 7.06 (dd, J=15.9, 9.0 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H), 4.91 (m, 1H); ESIMS m/z 484.75 ([M−H]); IR (thin film) 3469, 1700 cm−1.

(E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluo robut-1-enyl)benzoic acid (AI70)

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The title compound was isolated as a yellow liquid (0.3 g, crude): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.34 (m, 3H), 6.56 (d, J=15.9 Hz, 1H), 6.45 (dd, J=15.9, 7.6 Hz, 1H), 4.43 (m, 1H); ESIMS m/z 471.0 ([M−H]).

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-ethylbenzoic acid (AI71)

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The title compound was isolated as a brown gummy material (0.2 g, crude): 1H NMR (300 MHz, DMSO-d6) δ 12.5 (br, 1H), 7.85 (d, J=6.3 Hz, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.52 (m, 2H), 6.96 (dd, J=8.7, 8.7 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 4.80 (m, 1H), 4.06 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); ESIMS m/z 419.06 ([M−H]).

(E)-2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI72)

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The title compound was isolated as a yellow liquid (0.7 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=6.0 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.41 (s, 3H), 6.57 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm−1.

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI73)

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The title compound was isolated as a light brown gummy material (0.7 g, 38%): mp 91-93° C.; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.10 (d, J=16.0 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M−H]).

(E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoic acid (AI74)

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The title compound was isolated as a light brown liquid (0.3 g, crude): ESIMS m/z 393.15 ([M−H]).

(E)-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI75)

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The title compound was isolated as a light brown liquid (0.35 g, crude): ESIMS m/z 451.91 ([M−H]).

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(methylthio)benzoic acid

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1H NMR (400 MHz, CDCl3) δ 7.88-7.85 (m, 3H), 7.46 (d, J=6.8 Hz, 1H), 7.37 (s, 1H), 6.99 (dd, J=15.6, 8.8 Hz, 1H), 6.85 (d, J=16.0 Hz, 1H), 4.85-4.81 (m, 2H), 2.45 (s, 3H); ESIMS m/z 436.89 [(M−H)-]; IR (thinfilm) 3469, 1686, 1259, 714 cm−1.

(E)-2-Bromo-4-(3-(3,5-difluoro-4-methoxyphenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.48 (bs, 1H), 8.03 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.48 (d, J=9.3 Hz, 2H), 7.05 (dd, J=15.6, 9.0 Hz, 1H), 6.83 (d, J=15.9 Hz, 1H), 4.86-4.74 (m, 1H), 4.00 (s, 3H); EIMS m/z 451.18 ([M]+); IR (thin film) 3431, 1132 cm−1.

Prophetically, compounds AI34, AI36-AI41, AI44-AI45 (Table 1) could be made in accordance with the procedures disclosed in Example 10, or Examples 10 and 11.

Example 12: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-(2,2,2-trifluoroethyl)benzamide (AC6)

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To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, HOBt.H2O, EDC.HCl and DIPEA, and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with hexane:EtOAc afforded a white semi-solid (110 mg, 50%): 1H NMR (400 MHz, CDCl3) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([M−H]); IR (thin film) 1657, 1113, 804 cm−1.

Compounds AC7-AC38, AC40-AC58, AC110-AC112, AC117, and AC118 (Table 1) were made in accordance with the procedures disclosed in Example 12.

Example 13: Preparation of 4-((E)-3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-N-((pyrimidin-5-yl)methyl)benzamide (AC39)

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To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol) in CH2Cl2 (10 mL) was added drop wise trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of ethyl 4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (0.3 g, 0.71 mmol) in CH2Cl2 was added drop wise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound (0.18 g, 55%): mp 141-144° C.; 1H (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.40 (dd, J=16.0, 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H); ESIMS m/z 477.83 ([M−H]).

Example 14: Preparation of (E)-2-Chloro-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC64)

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To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28° C. for 30 min. A solution of (E)-ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (0.3 g, 0.58 mmol) in CH2Cl2 (5 mL) was added drop wise to the reaction mixture at 28° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 1N HCl solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.05 (t, J=5.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.23 (d, J=5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M−H]).

Compounds AC59-AC75 (Table 1) were made in accordance with the procedures disclosed in Example 14.

Example 15: Preparation of (E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (AC79)

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To a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (300 mg, 0.638 mmol) in CH2Cl2 (5.0 mL) was added 2-amino-N-(2,2,2-trifluoroethyl)acetamide (172. mg, 0.638 mmol) followed by PyBOP (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc/petroleum ether) afforded the title compound as an off-white solid (121 mg, 31%): 1H NMR (400 MHz, CDCl3) δ 8.69 (t, J=6.0 Hz, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=6.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.83 (t, J=8.0 Hz, 1H), 3.98 (m, 4H); ESIMS m/z 610.97 ([M+H]+); IR (thin film) 3303, 1658, 1166, 817 cm−1.

Compounds AC76-AC80, AC96-AC102, and AC113 (Table 1) were made in accordance with the procedures disclosed in Example 15.

Example 16: Preparation of (E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(1,1-dioxidothietan-3-yl)-2-fluorobenzamide (AC83)

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To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-N-(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/water (1:1, 5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% EtOAc/pet ether) afforded the title compound as an off white solid (70.0 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.07 (t, J=8.4 Hz, 1H), 7.39 (t, J=1.6 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J=1.6 Hz, 1H), 6.60 (d, J=16.8 Hz, 1H), 6.49 (dd, J=16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H; ESIMS m/z 493.83 ([M−H]); IR (thin film) 1527, 1113, 801, 1167, 1321 cm−1.

Compounds AC81-AC87 (Table 1) were made in accordance with the procedures disclosed in Example 16.

Example 17: Preparation of (E)-N-((5-Cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzamide (AC89)

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A solution of (E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (200 mg, 0.379 mmol) in phosphoryl chloride (POCl3, 2.0 mL) was stirred at ambient temperature for 10 min, then the resultant reaction mixture was heated to 50° C. for 1 h. The reaction mixture was quenched with ice water at 0° C. and extracted with EtOAc. The combined EtOAc layer was washed with saturated sodium bicarbonate (NaHCO3) solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 50% EtOAc/pet ether) afforded the title compound as a light brown gummy material (70.0 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.41 (dd, J=16.0, 7.6 Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H); ESIMS m/z 509.89 ([M+H]+); IR (thin film) 1666, 1166, 1112, 800 cm−1.

Example 18: Preparation of (E)-2-Bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzothioamide (AC90)

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To a stirred solution of (E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (336 mg, 0.830 mmol) in one portion. The resulting reaction mixture was stirred for 18 h. TLC showed the reaction was not complete, therefore additional Lawesson's reagent (168 mg, 0.415 mmol) was added and reaction stirred for 48 h. After the reaction was deemed complete by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compound as a yellow glassy oil (188 mg, 44.7%): 1H NMR (400 MHz, CDCl3) δ 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J=8.2, 1.7 Hz, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.38 (dd, J=15.9, 7.9 Hz, 1H), 4.89 (d, J=8.4, 5.5 Hz, 2H), 4.48 (qd, J=9.0, 6.0 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 656.9 ([M−H]).

Example 19: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenylthioamido)-N-(2,2,2-trifluoroethyl)acetamide (AC91)

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To a stirred solution of (E)-2-bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at ambient temperature was added Lawesson's reagent (64.5 mg, 0.160 mmol) in one portion. The resulting reaction mixture was stirred for 18 h, after which time, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compounds as a yellow oil (18.5 mg, 4.51%): 1H NMR (400 MHz, CDCl3) δ 8.18 (t, J=5.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.40 (s, 2H), 7.34 (dd, J=8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37 (dd, J=15.9, 7.9 Hz, 1H), 4.54 (d, J=4.9 Hz, 2H), 4.12 (m, 1H), 3.99 (qd, J=8.9, 6.5 Hz, 2H); ESIMS m/z 640.9 ([M−H]).

The following compound was made in accordance with the procedures disclosed in Example 19.

(E)-2-Bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC92)

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The product was isolated as a colorless oil (17.9 mg, 4.36%): 1H NMR (400 MHz, CDCl3) δ 9.16 (d, J=6.1 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.41 (m, 3H), 7.21 (t, J=5.6 Hz, 1H), 6.55 (d, J=15.9 Hz, 1H), 6.41 (dd, J=15.9, 7.8 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.45 (qd, J=9.0, 6.0 Hz, 2H), 4.12 (q, J=7.2 Hz, 1H); ESIMS m/z 640.9 ([M−H]).

Example 106: Preparation of Ethyl (Z)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate (AI76)

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The title compound was made in accordance with the procedure disclosed in Example 88 and was isolated as a yellow viscous oil (416 mg, 23%): 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.7 Hz, 1H), 7.35 (s, 2H), 7.12 (dd, J=8.0, 1.7 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.23-5.91 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.33-4.10 (m, 1H), 1.42 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −69.34 (d, J=8.3 Hz); EIMS m/z 514.10 ([M]); IR (thin film) 2983, 1727, 1247, 1204, 1116 cm−1.

Example 107: Preparation of (Z)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (AI77)

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To a stirred solution of (Z)-ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoate (360 mg, 0.70 mmol) in CH3CN (1.0 mL) was added iodotrimethylsilane (0.28 mL, 2.8 mmol). The reaction mixture was heated to reflux for 20 h, allowed to cool to ambient temperature and partitioned between CH2Cl2 and aqueous 10% sodium thiosulfate (Na2S2O3). The organic phase was washed once with aqueous 10% Na2S2O3 and dried over magnesium sulfate (MgSO4) and concentrated in vacuo. Passing the material through a silica plug with 10% EtOAc in hexanes, followed by 20% MeOH in CH2Cl2) as the eluting solvents afforded the title compound as a yellow foam (143 mg, 42%): mp 54-64° C.; 1H NMR (400 MHz, CDCl3) δ 11.36 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 7.14 (d, J=7.9 Hz, 1H), 6.85 (d, J=11.4 Hz, 1H), 6.15 (t, J=10.9 Hz, 1H), 4.36-4.09 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −69.30.

Example 108: Preparation of (Z)-2-Bromo-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC95)

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To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added carbonyldiimidazole (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aqueous 5% sodium bisulfate (NaHSO4) (2×) and once with saturated NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).

Example 109a: Preparation of (E)-2-Bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC114)

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(E)-tert-Butyl 4-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)piperidine-1-carboxylate (0.75 g, 1.11 mmol) was added to dioxane HCl (10 mL) at 0° C. and was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and triturated with diethylether to afford the compound as a light brown solid (0.6 g, 88%).

Example 109b: Preparation of (E)-N-(1-Acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC103)

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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in CH2Cl2 (10.0 mL) was added TEA (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine solution. The combined CH2Cl2 layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% Et2O/n-pentane to afford the title compound as a white solid (0.054 g, 50%).

Example 110: Preparation of (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)benzamide (AC104)

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To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in CH2Cl2 (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2Cl2. The combined CH2Cl2 layer was washed with 3N HCl and saturated NaHCO3 solution, the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% MeOH in CH2Cl2) to afford the title compound as an off white gummy material (0.035 g, 29.%).

Example 111: Preparation of (E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide (AC105)

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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added TEA (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution and brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).

Example 112: Preparation of (E)-2-Bromo-N-(1-methylpiperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC106)

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A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), formaldehyde (30% in water) (0.1 mL, 0.16 mmol) and AcOH (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at 0° C. and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain residue which was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with Et2O/pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).

Example 113: Preparation of ((E)-2-Bromo-N-(1-(cyanomethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC107)

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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).

Example 114: Preparation of (E)-2-Bromo-N-(1-(oxetan-3-yl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC108)

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A solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and AcOH (0.01 mL) in MeOH (5.0 mL) was stirred at ambient temperature for 30 min. After that NaBH3CN (0.022 g, 0.35 mmol) was added at 0° C. slowly lot wise over the period of 10 min and the reaction was stirred for 8 h at ambient temperature. The solvent was removed under reduced pressure to obtain a residue which was diluted with EtOAc and washed with saturated NaHCO3 solution and brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with Et2O/pentane to afford the title compound as an off-white solid (0.05 g, 23%).

Example 115: Preparation of (E)-2-Bromo-N-(1-(2-hydroxyethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC109)

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To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added TEA (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated brine solution. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).

Example 116: Preparation of (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamido)acetic acid (AI78)

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To a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetate (440 mg, 0.734 mmol) in CH2Cl2 (36.0 ml), was added TFA (4.0 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain residue which was washed with n-pentane to afford the title compound as an off-white solid (310 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 13.0 (s, 1H), 8.75 (t, J=5.7 Hz, 1H), 7.93 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 6.96 (dd, J=15.3, 9.3 Hz, 1H), 6.78 (d, J=15.3 Hz, 1H), 4.83 (m, 1H), 3.90 (d, J=5.7 Hz, 2H); ESIMS m/z 543.61 ([M+H]+); IR (thin film) 3429, 1635, 1114, 772 cm−1.

Example 117: Preparation of (E)-N-((6-Chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzothioamide (AC115)

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To the stirred solution of (E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100° C. for 1 h, then cooled to ambient temperature and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the product as yellow color solid (0.03 g, 49%).

Example 118: Preparation of (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-(trifluoromethoxy)benz amide (AC116)

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Step 1. 2-(Trifluoromethoxy)-4-vinylbenzoic acid (AI79)

To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and K2CO3 (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with EtOAc (2×50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure furnished the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.4 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J=17.4 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).

Step 2. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (AI80)

To a stirred solution of 2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356 g, 1.53 mmol) in 1N methyl pyrrolidine (5.0 mL) was added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g, 3.07 mmol), CuCl (0.03 g, 0.307 mmol) and 2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150° C. for 1 h. After the reaction was complete by TLC, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.3 g, 21%): 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J=16.0 Hz, 1H), 6.50 (dd, J=16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81 ([M−H]).

Step 3. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-2-(trifluoromethoxy)benzamide (AC116)

A mixture of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide (0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in CH2Cl2 (10.0 mL) were stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 20% EtOAc/pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47%). The following molecules were made in accordance with the procedures disclosed in Example 118, Step 2:

(E)-4-(3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzoic acid

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The title molecule was isolated as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ 12.90 (bs, 1H), 7.85 (s, 1H), 7.78-7.75 (m, 3H), 7.47-7.41 (m, 2H), 6.89 (dd, J=15.6, 9.2 Hz, 1H), 6.72 (d, J=15.6 Hz, 1H), 4.80-4.75 (m, 1H), 2.33 (s, 3H); ESIMS m/z 474.90 ([M−H]); IR (thin film) 3437, 1689, 1165, 579 cm−1.

(E)-4-(3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 13.5 (bs, 1H), 8.03 (s, 1H), 7.95-7.85 (m, 4H), 7.81 (d, J=7.8 Hz, 1H), 7.14 (dd, J=15.6, 9.6 Hz, 1H), 6.90 (d, J=15.9 Hz, 1H), 4.86-4.79 (m, 1H); ESIMS m/z 528.82 ([M−H]+); IR (thin film) 3437, 1707, 1153, 555 cm−1.

(E)-2-Bromo-4-(3-(3,5-dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (400 MHz, DMSO-d6) δ 13.90 (bs, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.84 (s, 2H), 7.74 (d, J=7.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.04 (dd, J=15.6, 8.8 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 4.80-4.78 (m, 1H); ESIMS m/z 538.74 ([M−H]); IR (thin film) 3424, 1695, 1168, 578 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3-fluoro-5-(trifluoromethyl)phenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (400 MHz, DMSO-d6) δ 13.3 (bs, 1H), 7.93 (s, 1H), 7.82-7.77 (m, 2H), 7.72-7.66 (m, 2H), 7.59 (d, J=8.0 Hz, 1H), 7.03 (dd, J=15.6, 9.2 Hz, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.94-4.90 (m, 1H); ESIMS m/z 469.02 ([M−H]); IR (thin film) 3444, 1704, 1172, 513 cm−1.

(E)-4-(3-(3,5-Bis(trifluoromethyl)phenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-bromobenzoic acid

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The title molecule was isolated as a brown solid: 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=7.6 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 2H), 7.73 (d, J=1.6 Hz, 1H), 7.42-7.40 (m, 1H), 6.62 (d, J=16.4 Hz, 1H), 6.55 (dd, J=16.0, 8.0 Hz, 1H), 4.40-4.30 (m, 1H); ESIMS m/z 518.94 ([M−H]); IR (thin film) 3447, 1705, 1171, 526 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3-(trifluoromethyl)phenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.50 (bs, 1H), 7.97-7.87 (m, 3H), 7.78-7.61 (m, 4H), 7.08 (dd, J=15.9, 9.3 Hz, 1H), 6.81 (d, J=15.9 Hz, 1H), 4.97-4.84 (m, 1H); ESIMS m/z 518.94 ([M−H]); IR (thin film) 3447, 1705, 1171, 526 cm−1.

(E)-2-Bromo-4-(3-(3-chloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a pale yellow gum: 1H NMR (300 MHz, DMSO-d6) δ 13.9 (s, 1H), 8.03 (s, 1H), 7.96-7.91 (m, 3H), 7.72 (d, J=8.1 Hz, 1H), 7.63-7.60 (m, 1H), 7.11 (dd, J=15.9, 9.6 Hz, 1H), 6.79 (d, J=15.9 Hz, 1H), 4.98-4.91 (m, 1H); ESIMS m/z 484.94 ([M−H]); IR (thin film) 3444, 1705, 1171, 764 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.61-7.59 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 7.30-7.24 (m, 1H), 6.59 (dd, J=16.2, 6.0 Hz, 1H), 6.48 (d, J=16.5 Hz, 1H), 4.26-4.21 (m, 1H); ESIMS m/z 469.0 ([M−H]); IR (thin film) 3444, 1699, 1327 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trifluorophenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.60 (bs, 1H), 7.97 (s, 2H), 7.72 (d, J=7.2 Hz, 1H), 7.41-7.31 (m, 2H), 7.04 (dd, J=15.6, 9.0 Hz, 1H), 6.71 (d, J=15.9 Hz, 1H), 4.15-4.11 (m, 1H); ESIMS m/z 438.8 ([M+H]+).

(E)-4-(4,4,4-Trifluoro-3-(2,3,4-trifluorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.63-7.60 (m, 1H), 7.47-7.44 (m, 1H), 7.02-7.01 (m, 1H), 5.10-4.90 (m, 1H).

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(2,3,4-trifluorophenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum and the crude acid was taken on directly to the next step: 1H NMR (300 MHz, DMSO-d6) δ 13.65 (bs, 1H), 7.95 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.62-7.59 (m, 2H), 7.50 (dd, J=15.6, 9.0 Hz, 1H), 6.95 (d, J=15.9 Hz, 1H), 4.86-4.74 (m, 1H); ESIMS m/z 436.92 ([M−H]); IR (thin film) 3445, 1641, 1116 cm−1.

(E)-4-(4,4,4-Trifluoro-3-(2,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.6 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=8.4 Hz, 3H), 7.83 (d, J=8.1 Hz, 1H), 7.17-7.03 (m, 2H), 5.16-5.05 (m, 1H); ESIMS m/z 476.9 ([M−H]); IR (thin film) 3436, 1651, 1116, 661 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(2,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ (300 MHz, DMSO-d6) δ 13.4 (s, 1H), 7.99 (d, J=10.2 Hz, 3H), 7.76 (d, J=8.1 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.09-6.91 (m, 2H), 5.11-5.05 (m, 1H); ESIMS m/z 486.8 ([M−H]); IR (thin film) 3436, 1651, 1115, 737 cm−1.

(E)-4-(3-(4-Chloro-3-nitrophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum and the crude acid was taken on directly to the next step: 1H NMR (300 MHz, DMSO-d6) 13.80 (bs, 1H), 8.33 (s, 1H), 7.94-7.81 (m, 5H), 7.75-7.72 (m, 1H), 7.06 (dd, J=15.9, 8.7 Hz, 1H), 6.90 (d, J=15.9 Hz, 1H), 5.02-4.81 (m, 1H).

(E)-2-Bromo-4-(3-(4-chloro-3-nitrophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) 13.50 (bs, 1H), 8.31 (s, 1H), 8.00-7.77 (m, 3H), 7.75-7.72 (m, 1H), 7.63-7.55 (m, 1H), 7.03 (dd, J=15.9, 9.0 Hz, 1H), 6.81 (d, J=15.9 Hz, 1H), 5.04-4.91 (m, 1H); ESIMS m/z 462.16 ([M−H]); IR (thin film) 3428, 1697, 1113, 749 cm−1.

(E)-4-(4,4,4-Trifluoro-3-(4-fluoro-3,5-dimethylphenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.80-7.75 (m, 1H), 7.27 (d, J=6.9 Hz, 2H), 6.96 (dd, J=15.6, 8.7 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.68-4.56 (m, 1H), 2.23 (s, 6H); ESIMS m/z 419.03 ([M−H]); IR (thin film) 3445, 2928, 1713, 1146 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(4-fluoro-3,5-dimethylphenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.61-7.58 (m, 1H), 7.26 (d, J=6.6 Hz, 2H), 6.93 (dd, J=15.9, 8.7 Hz, 1H), 6.87 (d, J=15.9 Hz, 1H), 4.59-4.53 (m, 1H), 2.23 (s, 6H); ESIMS m/z 428.97 ([M−H]); IR (thin film) 3473, 1701, 1111, 581 cm−1.

(E)-4-(4,4,4-Trifluoro-3-(4-fluoro-3-methylphenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.58 (bs, 1H), 7.98 (s, 1H), 7.92-7.90 (m, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.48-7.45 (m, 1H), 7.42-7.37 (m, 1H), 7.22-7.16 (m, 1H), 7.04 (dd, J=15.9, 8.7 Hz, 1H), 6.88 (d, J=15.9 Hz, 1H), 4.70-4.60 (m, 1H), 4.04-3.99 (m, 1H), 2.26 (s, 3H); ESIMS m/z 405.05 ([M−H]); IR (thin film) 3437, 1710, 1145 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(4-fluoro-3-methylphenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.39 (bs, 1H), 7.91 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.61-7.58 (m 1H), 7.47-7.44 (m, 1H), 7.38-7.36 (m, 1H), 7.18 (t, J=9.6 Hz, 1H), 6.95 (dd, J=15.6, 8.7 Hz, 1H), 6.76 (d, J=15.9 Hz, 1H), 4.67-4.61 (m, 1H), 2.25 (s, 3H); ESIMS m/z 415.0 ([M−H]); IR (thin film) 3435, 2989, 1700, 1260 cm−1.

(E)-4-(3-(3,5-Dichlorophenyl)-4,4,5,5,5-pentafluoropent-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown semi solid: 1H NMR (400 MHz, DMSO-d6) δ 13.70 (bs, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.72 (J=1.6 Hz, 2H), 7.66 (t, J=3.2 Hz, 1H), 7.15 (dd, J=15.6, 9.6 Hz, 1H), 6.91 (d, J=15.6 Hz, 1H), 4.86-4.78 (m, 1H); ESIMS m/z 491.0 ([M−H]); IR (thin film) 3446, 1712, 1141, 749 cm−1.

(E)-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,5,5,5-pentafluoropent-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.70 (s, 2H), 7.65-7.64 (m, 1H), 7.56-7.52 (m, 2H), 6.94 (d, J=9.2 Hz, 1H), 6.76 (d, J=16 Hz, 1H), 4.82-4.80 (m, 1H); ESIMS m/z 500.8 ([M−H]); IR (thin film) 3422, 1683, 1184, 750, 575 cm−1.

(E)-4-(3-(3,4-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.5 (bs, 1H), 8.01-7.99 (m, 2H), 7.94-7.91 (m, 1H), 7.85-7.78 (m, 2H), 7.53-7.50 (m, 1H), 7.09 (dd, J=15.6, 8.7 Hz, 1H), 6.89 (d, J=15.9 Hz, 1H), 4.85-4.78 (m, 1H); ESIMS m/z 528.8 ([M−H]); IR (thin film) 3437, 1722, 1168 cm−1.

(E)-2-Bromo-4-(3-(3,4-dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.38 (bs, 1H), 7.98-7.96 (m, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.63-7.61 (m, 1H), 7.51-7.49 (m, 1H), 7.01 (dd, J=15.9, 9.0 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 4.82-4.76 (m, 1H); ESIMS m/z 538.8 ([(M−H]); IR (thin film) 3446, 1699, 1166, 581 cm−1.

(E)-4-(4,4,4-Trifluoro-3-(3-(trifluoromethoxy)phenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown semi solid: 1H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.63-7.55 (m, 3H), 7.41 (d, J=7.5 Hz, 1H), 7.11 (dd, J=15.6, 9.0 Hz, 1H), 6.92 (d, J=15.9 Hz, 1H), 4.89-4.82 (m, 1H); ESIMS m/z 456.98 ([M−H]); IR (thin film) 3413, 1668, 1161 cm−1.

(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3-(trifluoromethoxy)phenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.59 (m, 3H), 7.44 (s, 1H), 7.40 (d, J=7.6 Hz, 2H), 6.88 (dd, J=15.6, 9.0 Hz, 1H), 6.73 (d, J=15.9 Hz, 1H), 4.85-4.82 (m, 1H); ESIMS m/z 466.93 ([M−H]); IR (thin film) 3437, 1703, 1111 cm−1.

(E)-4-(3-(3-Cyano-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.60 (bs, 1H), 8.21-8.19 (m, 1H), 8.01-7.91 (m, 3H), 7.81 (d, J=8.4 Hz, 1H), 7.12 (dd, J=15.9, 8.1 Hz, 1H), 6.91 (d, J=15.6 Hz, 1H), 4.92-4.86 (m, 1H); ESIMS m/z 416.27 ([M−H]); IR (thin film) 3429, 2238, 1713, 1116 cm−1.

(E)-2-Bromo-4-(3-(3-cyano-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.56 (bs, 1H), 8.21-8.18 (m, 1H), 8.00-7.95 (m, 2H), 7.73-7.59 (m, 3H), 7.03 (dd, J=15.9, 9.3 Hz, 1H), 6.79 (d, J=15.3 Hz, 1H), 4.87-4.84 (m, 1H); ESIMS m/z 426.0 ([M−H]).

(E)-2-Bromo-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.4 (s, 1H), 7.96 (d, J=1.2 Hz, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.74-7.68 (m, 2H), 7.63 (dd, J=8.1, 1.2 Hz, 1H), 7.57 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (dd, J=15.9, 9.3 Hz, 1H), 6.78 (dd, J=5.9 Hz, 1H), 4.84-4.78 (m, 1H); ESIMS m/z 451.0 ([M−H]); IR (thin film) 3445, 1704, 1113, 740 cm−1.

(E)-4-(3-(3-Bromo-5-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 13.50 (bs, 1H), 7.91 (s, 1H), 7.86-7.64 (m, 5H), 7.06 (dd, J=15.9, 9.0 Hz, 1H), 6.87 (d, J=15.9 Hz, 1H), 4.85-4.78 (m, 1H); ESIMS m/z 485.17 ([M−H]); IR (thin film) 3438, 1708, 1114, 774, 516 cm−1.

(E)-2-Bromo-4-(3-(3-bromo-5-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.38 (bs, 1H), 7.98 (s, 1H), 7.80-7.72 (m, 4H), 7.64-7.61 (m, 1H), 7.06 (dd, J=15.9, 9.3 Hz, 1H), 6.79 (d, J=15.6 Hz, 1H), 4.88-4.80 (m, 1H); ESIMS m/z 495.05 ([M−H]); IR (thin film) 3436, 1699, 1116, 750, 531 cm−1.

(E)-4-(3-(3-Bromo-5-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.6 (bs, 1H), 8.02 (s, 1H), 7.91-7.89 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.63-7.59 (m, 1H), 7.55 (d, J=9.3 Hz, 1H), 7.11 (dd, J=15.9, 9.0 Hz, 1H), 6.91 (d, J=15.9 Hz, 1H), 4.87-4.80 (m, 1H); ESIMS m/z 469.07 ([M−H]); IR (thin film) 3428, 1712, 1171, 523 cm−1.

(E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid

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The title molecule was isolated as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.18-8.03 (m, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.42 (s, 2H), 6.66 (d, J=15.9 Hz, 1H), 6.47 (dd, J=15.9, 8.0 Hz, 1H), 4.13 (p, J=8.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −68.65; ESIMS m/z 409.1 ([M−H]).

(E)-2-Bromo-4-(3-(3-chloro-4-methylphenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.30 (bs, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.62 (dd, J=1.5, 8.1 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 6.96 (dd, J=15.6, 8.7 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 4.73-4.61 (m, 1H), 2.35 (s, 3H); ESIMS m/z 431.77 ([M−H]−1); IR (thin film) 3435, 1701, 1111, 750 cm−1.

(E)-4-(3-(3-Chloro-4-methylphenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.50 (bs, 1H), 7.98 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.04 (dd, J=15.6, 8.4 Hz, 1H), 6.88 (d, J=15.6 Hz, 1H), 4.72-4.66 (m, 1H), 2.35 (s, 3H); ESIMS m/z 421.82 ([M−H]); IR (thin film) 3460, 2926, 1712, 1170, 750 cm−1.

(E)-4-(4,4,5,5,5-Pentafluoro-3-(3,4,5-trichlorophenyl)pent-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a dark brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.6 (bs, 1H), 8.03 (s, 1H), 7.95-7.86 (m, 3H), 7.81 (d, J=8.1 Hz, 1H), 7.16 (dd, J=15.3, 9.3 Hz, 1H), 6.92 (d, J=15.6 Hz, 1H), 4.95-4.88 (m, 1H); 19F NMR (300 MHz, DMSO-d6) δ −80.35, −58.02; ESIMS m/z 526.8 ([M+H]+).

(E)-2-Bromo-4-(4,4,5,5,5-pentafluoro-3-(3,4,5-trichlorophenyl)pent-1-en-1-yl)benzoic acid

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The title molecule was isolated as a dark brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.6 (bs, 1H), 7.94 (s, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.5 Hz 1H), 7.07 (dd, J=15.0, 8.7 Hz, 1H), 6.79 (d, J=15.6 Hz, 1H), 4.93-4.78 (m, 1H); ESIMS m/z 538.9 ([M+H]+); IR (thinfilm) 3420, 1602, 1123, 746 cm−1.

(E)-2-Bromo-4-(3-(4-cyano-3,5-difluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: ESIMS m/z 443.91 ([M−H]); IR (thin film) 3447, 2244, 1703, 1114 cm−1.

(E)-2-Chloro-4-(3-(3,5-dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (300 MHz, DMSO-d6) δ 13.39 (bs, 1H), 7.95-7.70 (m, 5H), 7.61 (d, J=8.1 Hz, 1H), 7.07 (dd, J=15.6, 9.3 Hz, 1H), 6.80 (d, J=15.6 Hz, 1H), 4.84-4.78 (m, 1H); ESIMS m/z 496.77 ([M−H]); IR (thin film) 3439, 2920, 1707, 1165 cm−1.

(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as an off white solid: mp 140-143° C.; 1H NMR (400 MHz, DMSO) δ13.60 (bs, 1H), 8.02 (s, 1H), 7.94-7.90 (m, 1H), 7.88-7.86 (m, 2H), 7.81-7.79 (m, 1H), 7.12 (dd, J=15.6, 8.8 Hz, 1H), 6.89 (d, J=15.6 Hz, 1H), 4.86-4.81 (m, 2H); ESIMS m/z 458.88 ([M−H]).

(E)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a light orange crystalline solid (875 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 12.35 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.55-7.41 (m, 4H), 7.24 (dd, J=8.3, 2.1 Hz, 1H), 6.64 (d, J=15.8 Hz, 1H), 6.51 (dd, J=15.9, 7.7 Hz, 1H), 4.15 (p, J=8.7 Hz, 1H); 19F NMR 376 MHz, CDCl3) δ −68.75; ESIMS m/z 375 ([M+H]+).

(E)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated was isolated as a brown gum: 1H NMR (400 MHz, DMSO-d6) δ 13.6 (s, 1H), 8.02 (s, 1H), 7.93-7.89 (m, 2H), 7.80 (d, J=7.6 Hz, 1H), 7.73 (d, J=8.4, Hz, 1H), 7.58 (dd, J=8.4, 2.0 Hz, 1H), 7.09 (dd, J=15.6, 8.8, Hz, 1H), 6.89 (d, J=15.6, Hz, 1H), 4.86-4.81 (m, 1H); ESIMS m/z 441.0 ([M−H]); IR (thinfilm) 3447, 1710, 1169, 749 cm−1.

(E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.6 (bs, 1H), 7.98 (s, 1H), 7.91 (d, J=7.8 Hz 1H), 7.75-7.66 (m, 1H), 7.10 (dd, J=15.6, 9.0 Hz, 1H), 6.89 (d, J=15.9 Hz 1H), 4.86-4.80 (m, 1H); ESIMS m/z 441.1 ([M−H]); IR (thinfilm) 3460, 2928, 1721, 1170, 764 cm−1.

(E)-4-(3-(3,4-Dichloro-5-methylphenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a pale yellow semi solid: 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs, 1H), 8.00 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.07 (dd, J=16.4, 9.6 Hz, 1H), 6.89 (d, J=15.6 Hz, 1H), 4.78-4.73 (m, 1H), 2.42 (s, 3H); ESIMS m/z 455.0 ([M−H]); IR (thin film) 1713, 1170, 750 cm−1.

(E)-2-Bromo-4-(3-(3,4-dichlorophenyl)-4,4-difluoropent-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (400 MHz, DMSO-d6) δ 13.3 (s, 1H), 7.92 (s, 1H), 7.77-7.71 (m, 2H), 7.68-7.63 (m, 1H), 7.61-7.60 (m, 1H), 7.60-7.58 (m, 1H), 6.98 (dd, J=15.6, 9.2 Hz, 1H), 6.65 (d, J=15.6 Hz, 1H), 4.83-4.80 (m, 1H), 1.59-1.54 (m, 3H); ESIMS m/z 448.8 ([M−H]).

(E)-2-Bromo-4-(3-(3-chloro-5-ethylphenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown liquid: 1H NMR (400 MHz, DMSO-d6) δ 13.4 (bs, 1H), 7.97 (s, 2H), 7.91 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.66-7.61 (m, 1H), 7.03 (dd, J=16.0, 8.4 Hz, 1H), 6.8 (d, J=15.6 Hz, 1H), 4.89-4.84 (m, 1H), 2.66-2.65 (m, 2H), 1.25 (t, J=9.2 Hz, 3H); ESIMS m/z 446.8 ([M+H]+).

(E)-2,6-Dimethyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.1 (s, 1H), 7.87 (s, 2H), 7.27 (s, 2H), 6.81 (dd, J=15.6, 8.7 Hz, 1H), 6.69 (d, J=15.3 Hz, 1H), 4.85-4.79 (m, 1H), 2.27 (s, 6H); ESIMS m/z 437.01 ([M−H]); IR (thin film) 3285, 1621, 1162, 954 cm−1.

(E)-2-Bromo-4-(3-(3,5-dibromo-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.40 (bs, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.94-7.89 (m, 2H), 7.66-7.60 (m, 2H), 7.10 (dd, J=8.7, 16.0 Hz, 1H), 6.96 (d, J=15.6 Hz, 1H), 4.82-4.80 (m, 1H); ESIMS m/z 574.7 ([M+H]+).

(E)-4-(3-(3,5-Dibromo-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.36 (bs, 1H) 8.05 (s, 2H), 7.95 (d, J=8.1 Hz, 1H), 7.87-7.67 (m, 2H), 7.14 (dd, J=9.0, 15.6 Hz, 1H), 6.96 (d, J=15.6 Hz, 1H), 4.88-4.82 (m, 1H); ESIMS m/z 564.58 ([M+H]+).

(E)-2-Bromo-4-(3-(4-bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.40 (bs, 1H), 7.98 (s, 1H), 7.87 (s, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.65-7.62 (m, 1H), 7.06 (dd, J=15.9, 9.3 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H), 4.87-4.80 (m, 1H); ESIMS m/z 518.9 ([M−H]).

(E)-4-(3-(4-Bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (300 MHz, DMSO-d6) δ 13.6 (bs, 1H) 8.03 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.88 (s, 2H), 7.81 (d, J=8.1 Hz, 1H), 7.13 (dd, J=16.2, 7.5 Hz, 1H), 6.91 (d, J=15.9 Hz, 1H), 4.89-4.83 (m, 1H); ESIMS m/z 532.0 ([M+H]+).

(E)-2-Bromo-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-4,4,4-trifluorobut-1-en-1-yl)benzoic acid

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The title molecule was isolated as a brown gum: 1H NMR (400 MHz, DMSO-d6) δ 13.36 (bs, 1H) 7.95 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.46 (s, 1H) 7.35-7.31 (m, 2H), 7.04 (dd, J=16.0, 8.8 Hz, 1H), 6.78 (d, J=16.4 Hz, 1H), 4.71-4.68 (m, 1H); ESIMS m/z 500.8 ([M−H]).

Example 20: Preparation of 5-vinyl-2,3-dihydro-1H-inden-1-one (BI1)

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To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) afforded the title compound as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J=7.4 Hz, 1H), 5.42 (d, J=6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]).

The following compound was made in accordance with the procedures disclosed in Example 20.

6-Vinyl-3,4-dihydronaphthalen-1(2H)-one (BI2)

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The product was isolated as an off-white solid (5 g, 48%): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=8.4 Hz, 1H), 7.48 (m, 2H), 6.82 (m, 1H), 6.02 (d, J=7.4 Hz, 1H), 5.44 (d, J=6.4 Hz, 1H), 2.95 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H); ESIMS m/z 173.14 ([M−H]); IR (thin film) 1681 cm−1.

Example 21: Preparation of (E)-5-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (BI3)

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5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (4 g, 11.7 mmol), 5-vinyl-2,3-dihydro-1H-inden-1-one (0.92 g, 5.8 mmol), CuCl (0.115 g, 1.171 mmol) and 2,2-bipyridyl (0.053 g, 0.34 mmol) in 1,2-dichlorobenzene (25 mL) were heated at 180° C. for 16 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) to afford the title compound as a liquid (1.28 g, 25%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 1H), 7.52 (m, 3H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+H]); IR (thin film) 1708.94, 1113.60, 807.77 cm−1.

The following compound was made in accordance with the procedures disclosed in Example 21.

(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-one (BI4)

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The product was isolated as a brown semi-solid (1.2 g, 16%): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.4 Hz, 1H), 7.54 (m, 3H), 7.30 (s, 1H), 6.68 (d, J=7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 400.84 ([M−H]); IR (thin film) 815, 1113, 1709 cm−1.

(E)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (BI5)

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The product was isolated as a pale yellow semi solid (1.2 g, 30%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 6.62 (d, J=16 Hz, 1H), 6.46 (m, 1H), 4.18 (m, 1H), 2.95 (m, 2H), 2.65 (m, 2H), 2.19 (m, 2H); ESIMS m/z 432.94 ([M−H]); IR (thin film) 1680, 1113, 808 cm−1.

Example 22: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-one (BI6)

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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.5 g, 1.24 mmol) in MeCN (20 mL), was added Selectfluor® (0.52 g, 1.48 mmol) and the reaction was heated to reflux temperature for 16 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and diluted with CH2Cl2. The solution was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (0.1 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.80 (m, 1H), 7.48 (m, 2H), 7.32 (m, 2H), 6.65 (d, J=16.0 Hz, 1H), 6.54 (dd, J=16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z 419.06 ([M−H]); IR (thin film) 1728, 1114, 817 cm−1.

Example 23: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-inden-1-amine (BC10)

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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and NaBH3CN (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCE, was washed with water and brine and dried over anhydrous Na2SO4. Concentration under reduced pressure gave the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 6.62 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 2H), 1.82 (m, 1H), 1.42 (m, 1H); ESIMS m/z 497.98 ([M−H]); IR (thin film) 3027, 1654, 815 cm−1.

Example 24: Preparation of 6-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one oxime (BI5a)

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To a stirred solution of ((E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (NaOAc, 0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 155-158° C.; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, J=16 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m/z 445.95 ([M−H]I).

Example 25: Preparation of (E)-5-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (BI5b)

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To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.39 mmol) in MeOH (10 mL) were added ammonium acetate (NH4OAc, 1.84 g, 23.9 mmol) and NaBH3CN (0.44 g, 7.17 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm−1.

The following compound was made in accordance with the procedures disclosed in Example 25.

(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-amine (BI7)

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The product was isolated as a light brown gummy material, taken as such to the next step (0.15 g, crude compound): ESIMS m/z 401.97 ([M−H]).

(E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1H-inden-1-amine (BI8)

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The product was isolated as a light brown gummy material, taken as such to the next step (0.15 g, crude compound): ESIMS m/z 420.15 ([M−H]).

(E)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-1,2,3,4-tetrahydronaphthalen-1-amine (BI9)

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The product was isolated as a pale yellow liquid (500 mg crude).

Example 26: Preparation of (E)-1-Methyl-3-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-enyl)-2,3-dihydro-1H-inden-1-yl)thiourea (BC1)

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To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in Et2O (5 mL) was added methylisothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.4 Hz, 1H), 5.91-5.70 (br, 2H), 4.05 (m, 1H), 3.05-2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H); ESIMS m/z 492.17 ([M+H]+); IR (thin film) 3211, 1569, 1113, 806 cm−1.

Compounds BC2-BC3 in Table 1 were made in accordance with the procedures disclosed in Example 26.

Example 27: Preparation of (E)-3,3,3-Trifluoro-N-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-yl)propanamide (BC4)

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To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-amine (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) were added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC.HCl (0.038 g, 0.35 mmol), HOBt.H2O (0.07 g, 0.46 mmol) and DIPEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J=16.0 Hz, 1H), 6.30 (dd, J=16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+H]+); IR (thin film) 3283, 1652, 1241, 811 cm−1.

Compounds BC5-BC9, BC11 in Table 1 were made in accordance with the procedures disclosed in Example 27.

Example 28: Preparation of tert-Butyl 5-vinylindoline-1-carboxylate (BI10)

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Step 1. 5-Bromo-indoline (BI11)

To 5-Bromo-1H-indole (2.5 g, 12.82 mmol) in AcOH (10.0 mL), NaBH3CN (2.38 g, 38.46 mmol) was added portion wise at 10° C. over the period of 20 min. After that the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with water and extracted with Et2O. The organic layer was washed with saturated NaHCO3, water and brine solution. The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).

Step 2. tert-Butyl-5-bromoindoline-1-carboxylate (BI12)

To a stirred solution of 5-bromo-indoline (3.0 g, 15 mmol) in MeCN (100 ml), was added DMAP (0.185 g, 1.522 mmol) and di-tert-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated on reduced pressure to obtain a residue which was diluted with Et2O and washed with water and brine solution (2×). The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as an off-white solid, which was used in the next step without further purification (3.0 g).

Step 3. tert-Butyl-5-vinylindoline-1-carboxylate (BI10)

A stirred solution of tert-butyl-5-bromoindoline-1-carboxylate (2.0 g, 6.73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) and K2CO3 (2.78 g, 20.2 mmol) in DMSO (50.0 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.49 g, 0.67 mmol) was added at ambient temperature, then the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and filtered through a Celite® bed under vacuum and washed with Et2O. The reaction mixture was extracted with Et2O. The combined Et2O layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% EtOAc/petroleum ether) to afford the title compound as an off-white solid (1.2 g, 73%): mp 85.5-88.6° C.; 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 3H), 6.69 (dd, J=17.4, 10.8 Hz, 1H), 5.64 (d, J=10.5 Hz, 1H), 5.13 (d, J=10.5 Hz, 1H), 4.00 (t, J=9.0 Hz, 2H), 3.10 (t, J=9.0 Hz, 2H), 1.55 (bs, 9H).

Example 29: Preparation of (E)-tert-Butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indoline-1-carboxylate (BI13)

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To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28 g, 5.23 mmol) in 1,2-dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.4 g, 10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% EtOAc/petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.21 (dd, J=16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J=8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M−H]); IR (thin film) 1168, 858 cm−1.

Example 30: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine (BI14)

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Step 1. (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (BI15)

To a stirred solution of (E)-tert-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-carboxylate (0.2 g, 0.4 mmol) in CH2Cl2 (10.0 mL) was added TFA (0.6 mL) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aq NaHCO3, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a light brown gummy material which was used in the next step without further purification (0.12 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.49 (d, J=15.6 Hz, 1H), 6.21 (dd, J=15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t, J=8.4 Hz, 2H), 3.05 (t, J=8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]+); IR (thin film) 3385, 1112, 816 cm−1.

Step 2. 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (BI16)

To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5° C., was added slowly NaNO2 in water and the reaction was allowed to stir at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J=8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm−1.

Step 3. (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-amine (BI14)

To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (0.1 g, 0.2 mmol) in MeOH(10.0 mL) was added zinc powder (77.5 mg) and NH4Cl (36.9 mg, 0.69 mmol) in water (2.0 mL). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with CH2Cl2 and the CH2Cl2 layer was washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% EtOAc/petroleum ether) to afford the title compound as a light brown gummy material (0.08 g): ESIMS m/z 404.86 ([M+H]+).

Example 31: Preparation of (E)-N-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1-yl)-3,3,3-trifluoropropanamide (BC12)

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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine (0.1 g, 0.247 mmol) in CH2Cl2 (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% EtOAc/petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCl3) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0, 1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm−1.

Example 32: Preparation of tert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17)

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Step 1. 5-Vinyl-1H-indole (BI18)

A mixture of 5-bromo-1H-indole (2.5 g, 12.82 mmol), potassium vinyltrifluoroborate (2.57 g, 19.2 mmol), Cs2CO3 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9:1, 75 ml) was degassed with argon for 20 min, then charged with PdCl2 (45.3 mg, 0.256 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to ambient temperature, filtered through Celite® bed and washed with EtOAc. The filtrate was again extracted with EtOAc, and the combined organic layer washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% EtOAc/petroleum ether) to afford the title compound as a light brown gummy material (1.5 g, 83%): 1H NMR (400 MHz, CDCl3) δ 8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H); ESIMS m/z 142.05 ([M−H]).

Step 2. tert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17)

To a stirred solution of 5-vinyl-1H-indole (0.7 g, 4.89 mmol) in MeCN (20 ml) was added DMAP (59.65 mg, 0.489 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.36 mmol), and the reaction was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue which was diluted with CH2Cl2 and washed with water and brine solution. The combined CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% EtOAc/petroleum ether) to afford the title compound as an off-white semi-solid (0.7 g, 59%): 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 7.60 (s, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.21 (m, 1H), 6.90 (dd, J=16.0, 10.8 Hz, 1H), 6.59 (s, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 242.10 ([M−H]); IR (thin film) 1630 cm−1.

Example 33: Preparation of (E)-tert-Butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole-1-carboxylate (BI19)

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To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% EtOAc/petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M−H]); IR (thin film) 1165, 854 cm−1.

Example 34: Preparation of (E)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indole (BI20)

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To a stirred solution of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole-1-carboxylate (0.2 g, 0.40 mmol) in CH2Cl2 (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown solid (0.2 g, 97%): mp 132.9-138.8° C.; 1H NMR (400 MHz, CDCl3) δ 11.19 (br, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+H]+).

Example 35: Preparation of 4-Nitrophenyl 2-((tert-butoxycarbonyl)amino)acetate (BI21)

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To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in CH2Cl2 (20.0 mL) was added N-Boc glycine (1.38 g, 7.91 mmol) and EDC HCl (2.05 g, 10.785 mmol) and the reaction was stirred at ambient temperature for 24 h. The reaction mixture was diluted with CH2Cl2 and washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown gummy material that was used in the next step without further purification (1.1 g): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.2 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).

Example 36: Preparation of (E)-tert-Butyl (2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)carbamate (BI22)

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To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole (0.1 g, 0.258 mmol) in MeCN (5.0 mL) was added 4-nitrophenyl 2-(tert-butoxycarbonylamino) acetate (0.114 g, 0.387 mmol), KF (0.03 g, 0.516 mmol), 18-crown-6-ether (0.075 g, 0.283 mmol) and DIPEA (0.0332 g, 0.258 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to obtain a residue which was diluted with CH2Cl2 and washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a light brown gummy material which was used in the next step without further purification (0.1 g): ESIMS m/z 545.23 ([M+H]+).

Example 37: Preparation of (E)-N-(2-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)

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Step 1. (E)-2-Amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone (BI23)

To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).

Step 2. (E)-N-(2-(5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)

To a stirred solution of (E)-2-amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl) ethanone (0.04 g, 0.09 mmol) in CH2Cl2 (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIPEA (29 mg, 0.225 mmol) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2, and the CH2Cl2 layer was washed with water and saturated brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; 10% EtOAc/petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%): mp 121-126° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 4H), 6.72 (d, J=3.6 Hz, 3H), 6.39 (m, 1H), 4.71 (t, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M−H]).

Example 38: Preparation of Ethyl 2-(1-oxo-6-vinylphthalazin-2(1H)-yl)acetate (BI24)

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Step 1. 5-Bromo-3-hydroxyisoindoline-1-one (BI25)

A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g, 0.08 mmol) and 2M aq NaOH (27 mL) were cooled to 0° C. 5-Bromoisoindoline-1,3-dione (5 g, 22 mmol) was added at the same temperature over the period of 30 min. The reaction mixture was stirred at 0° C. for 30 min and 3 h at ambient temperature. The reaction mixture was filtered and the filtrate was neutralized with concentrated HCl. The reaction mixture was diluted with ethanol and extracted with EtOAc. The combined EtOAc layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a brown solid, which was used in the next step without further purification (1.3 g): mp 258-261° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m, 1H), 6.44 (m, 1H), 5.88 (d, J=9.3 Hz, 1H); ESIMS m/z 225.83 ([M−H]); IR (thin film) 1684, 3246, 606 cm−1.

Step 2. 6-Bromophthalazine-1(2H)-one (BI26)

To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95° C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with Et2O and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).

Step 3. 6-Vinylphthalazine-1(2H)-one (BI27)

A solution of 6-bromophthalazine-1(2H)-one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at ambient temperature, and the reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered through Celite® bed under vacuum and washed with EtOAc. The reaction mixture was extracted with EtOAc and the combined EtOAc layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% EtOAc/petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm−1.

Step 4. Ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (BI24)

To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min. Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at ambient temperature and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted and extracted with EtOAc, and the EtOAc layer was washed with water and brine solution (2×). The separated EtOAc layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% EtOAc/petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]+); IR (thin film) 1750, 1660 cm−1.

Example 39: Preparation of (E)-Ethyl 2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)acetate (BI28)

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To a stirred solution of ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (0.07 g, 0.27 mmol) in 1,2-dichlorobenzene (1.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2fluorobenzene (0.17 g, 0.54 mmol), CuCl (0.005 g, 0.05 mmol) and 2,2-bipyridyl (0.016 g, 0.10 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 180° C. for 12 h. The reaction mixture was cooled to ambient temperature and filtered and the filtrated was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc/petroleum ether) to afford the title compound as a brown solid (40 mg, 29%): 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=8.4 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.37 (d, J=6.3 Hz, 2H), 6.76 (d, J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.96 (s, 2H), 4.29 (m, 3H), 1.31 (t, J=7.2 Hz, 3H); ESIMS m/z 503.0 ([M+H]+); IR (thin film) 1660, 1114, 817 cm−1.

Example 40: Preparation of (E)-2-(6-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)acetic acid (BI29)

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A solution of (E)-ethyl-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl) acetate (0.04 g, 0.07 mmol) in HCl (0.5 mL) and AcOH (0.5 mL) was heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the residue diluted with water. The aqueous layer was extracted with EtOAc and the separated EtOAc layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with Et2O-pentane mixture to afford the title compound as a brown solid (0.03 g): 1H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 1H), 8.43 (m, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.14 (m, 2H), 7.91 (m, 2H), 7.16 (dd, J=16.0, 8.0 Hz, 1H), 6.99 (d, J=16.0 Hz, 1H), 4.96 (m, 3H); ESIMS m/z 473.0 ([M−H]); IR (thin film) 1629, 1168, 817 cm−1.

Example 41: Preparation of (E)-2-(6-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1-oxophthalazin-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide (BC14)

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To a stirred solution of (E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in CH2Cl2 (20.0 ml) was added 2,2,2,-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIPEA (0.15 ml, 0.93 mmol) at ambient temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with 3N HCl (2×20 mL), NaHCO3 (2×20 mL) and brine solution (2×). The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% EtOAc/petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J=6.6 Hz, 1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]).

Example 42: Preparation of 2-(4-Vinylbenzyl)isoindoline-1,3-dione (CI1)

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To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resultant reaction mixture was heated at 70° C. for 16 h. The reaction mixture was diluted with water and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Recrystallization from MeOH afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm−1.

Example 43: Preparation of (E)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI2)

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Using the procedure of Example 10 with 2-(4-vinylbenzyl)isoindoline-1,3-dione and 1-(1-bromoethyl)-3,5-dichlorobenzene as the starting materials, the title compound was isolated as an off-white solid (0.3 g, 40-50%): mp 142-145° C.; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42 (m, 2H), 7.36 (m, 3H), 7.27 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 488.17 ([M−H]).

The following compound was made in accordance with the procedures disclosed in Example 43.

(E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI3)

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The title compound was isolated as an off white solid (0.3 g, 56%): mp 145-146° C.; 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.74 (m, 2H), 7.42-7.31 (m, 6H), 6.58 (d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 522.2 ([M−H]); IR (thin film) 1716, 1110, 712 cm−1.

Prophetically, compounds CI4-CI5 (Table 1) could be made in accordance with the procedures disclosed in Example 43.

Example 44: Preparation of (E)-(4-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (CI6)

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To a stirred solution of (E)-2-(4-(3-(3,5-dichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (1.2 g, 2.45 mmol) in EtOH was added hydrazine hydrate (0.61 g, 12 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.9 g) which was used without further purification.

The following compounds were made in accordance with the procedures disclosed in Example 44.

(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)methanamine (CI7)

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The title compound was isolated and used without further purification.

Prophetically, compounds CI8-CI9 (Table 1) could be made in accordance with the procedures disclosed in Example 44.

Example 45: Preparation of 4-(Bromomethyl)-3-chlorobenzonitrile (CI10)

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To a stirred solution of 3-chloro-4-methylbenzonitrile (5 g, 25.4 mmol) in CCl4 (50 mL) under an argon atmosphere was added NBS (5.16 g, 29 mmol), and the mixture was degassed for 30 min. To this was added AIBN (0.3 g, 1.8 mmol), and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, washed with water, and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (4.8 g, 68%): mp 87-88° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (s, 2H), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+H]+); IR (thin film) 2235, 752, 621 cm−1.

The following compounds were made in accordance with the procedures disclosed in Example 45.

4-(Bromomethyl)-3-(trifluoromethyl)benzonitrile (CI11)

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The title compound was isolated as an off-white gummy material (5 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 4.62 (s, 2H); ESIMS m/z 262.11 ([M−H]); IR (thin film) 2236, 1132, 617 cm−1.

3-Bromo-4-(bromomethyl)benzonitrile (CI12)

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The title compound was isolated as an off-white solid (5 g, 67%): mp 82-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.61 (m, 2H), 4.62 (s, 2H); EIMS m/z 272.90; IR (thin film) 2229, 618 cm−1.

4-(Bromomethyl)-3-fluorobenzonitrile (CI13)

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The title compound was isolated as an off-white solid (2 g, 60%): mp 79-81° C.; 1H NMR (400 MHz, CDCl3) δ 7.54 (t, J=8.0 Hz, 1H), 7.48 (dd, J=8.0 Hz, 8.0, 1H), 7.38 (dd, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 215.

Example 46: Preparation of 4-(Bromomethyl)-3-chlorobenzaldehyde (CI14)

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To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise DIBAl-H (1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).

The following compounds were made in accordance with the procedures disclosed in Example 46.

4-(Bromomethyl)-3-(trifluoromethyl)benzaldehyde (CI15)

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The title compound was isolated as a pale yellow low-melting solid (5 g, 60%): 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.19 (s, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 4.61 (s, 2H); ESIMS m/z 265.04 ([M−H]); IR (thin film) 1709, 1126, 649 cm−1.

3-Bromo-4-(bromomethyl)benzaldehyde (CI16)

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The title compound was isolated as a pale yellow solid (5 g, 62%): mp 94-95° C.; 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.05 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); EIMS m/z 275.90 ([M]+).

4-(Bromomethyl)-3-fluorobenzaldehyde (CI17)

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The title compound was isolated as an off-white solid (5 g, 61%): mp 43-45° C.; 1H NMR (400 MHz, CDCl3) δ 9.1 (s, 1H), 7.54 (t, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.38 (d, J=5 Hz, 1H), 4.5 (s, 2H); EIMS m/z 216 ([M]+).

Example 47: Preparation of 3-Chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI18)

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To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60° C. for 6 h. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). The solid obtained was separated by filtration and dried under vacuum to afford the title compound as a white solid (2.8 g, 60%): mp 123-126° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M−H]).

The following compounds were made in accordance with the procedures disclosed in Example 47.

4-((1,3-Dioxoisoindolin-2-yl)-3-(trifluoromethyl)benzaldehyde (CI19)

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The title compound was isolated as an off white solid (1 g, 62%): mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.15 (s, 1H), 7.91 (m, 2H), 7.80 (m, 3H), 7.27 (m, 1H), 5.19 (s, 2H); ESIMS m/z 332.03 ([M−H]).

3-Bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI20)

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The title compound was isolated as an off-white solid (0.5 g, 64%): mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 314.00 ([M-CHO]).

4-((1,3-Dioxoisoindolin-2-yl)-3-fluorobenzaldehyde (CI21)

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The title compound was isolated as a white solid (2 g, 60%): mp 154-156° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.9 (m, 2H), 7.75 (m, 2H), 7.6 (m, 2H), 7.5 (t, J=7.6 Hz, 1H), 5.05 (s, 2H); EIMS m/z 283.1 ([M]+).

Example 48: Preparation of 2-(2-Chloro-4-vinylbenzyl)isoindoline-1,3-dione (CI22)

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To a stirred solution of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2CO3 (1.68 g, 12.24 mmol) and methyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M−H]).

The following compounds were made in accordance with the procedures disclosed in Example 48.

2-(2-(Trifluoromethyl)-4-vinylbenzyl)isoindoline-1,3-dione (CI23)

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The title compound was isolated as a light brown solid (0.5 g, 60%): mp 134-135° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.71 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.65 (m, 1H), 5.80 (d, J=17.8 Hz, 1H), 5.19 (d, J=10.8 Hz, 1H), 5.09 (s, 2H); ESIMS m/z 332.10 ([M+H]+).

2-(2-Bromo-4-vinylbenzyl)isoindoline-1,3-dione (CI24)

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The title compound was isolated as an off white solid (0.5 g, 62%): mp 126-128° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.21 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.62 (m, 1H), 5.72 (d, J=17.8 Hz, 1H), 5.15 (d, J=10.8 Hz, 1H), 4.95 (s, 2H); EIMS m/z 341.10 ([M]+).

2-(2-Fluoro-4-vinylbenzyl)isoindoline-1,3-dione (CI25)

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The title compound was isolated as a white solid (0.5 g, 61%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.25 (m, 1H), 7.11 (m, 2H), 6.63 (m, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.28 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); EIMS m/z 282.08.

Example 49: Preparation of (E)-2-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI26)

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To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (3.48 g, 11.36 mmol), CuCl (112 mg, 1.13 mmol) and 2,2-bipyridyl (0.35 g). The resultant reaction mixture was degassed with argon for 30 min and then was stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07 ([M+H]+).

The following compounds were made in accordance with the procedures disclosed in Example 49.

(E)-2-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI27)

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The title compound was isolated as a pale white solid (0.2 g, 55%): mp 128-129° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 3H), 7.22 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 557.99 ([M+H]+).

(E)-2-(2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI28)

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The title compound was isolated as an off white solid (0.2 g, 54%): mp 177-180° C.; 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 2H), 7.77 (m, 2H), 7.42 (s, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.21 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 540.08 ([M−H]); IR (thin film) 1716 cm−1.

(E)-2-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI29)

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The title compound was isolated as an off-white solid (0.2 g, 59%): 1H NMR (400 MHz, CDCl3) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.47 (m, 3H), 7.21 (m, 3H), 6.50 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 7.6 Hz, 1H), 4.97 (s, 2H), 4.11 (m, 1H); ESIMS m/z 522.27 ([M−H]); IR (thin film) 3064, 1717, 1111, 715 cm−1.

(E)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione (CI30)

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The title compound was isolated as an off-white solid (0.2 g, 54%): mp 141-142° C.; 1H NMR (400 MHz, CDCl3) 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.19 (m, 1H), 6.60 (d, J=16.0 Hz, 1H), 6.39 (dd, J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.11 (m, 1H); ESIMS m/z 556.00 ([M−H]).

(E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-benzyl)isoindoline-1,3-dione (CI31)

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The title compound was isolated as an off-white solid (0.2 g, 56%): mp 130-132° C.; 1H NMR (400 MHz, CDCl3) δ 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 3H), 7.19 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.12 (m, 1H); ESIMS m/z 589.57 ([M−2H]).

(E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (CI32)

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The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp 160-162° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.62 (s, 1H), 7.39 (s, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.98 (s, 2H), 4.12 (m, 1H); ESIMS m/z 599.78 ([M−H]).

(E)-2-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3-dione (CI33)

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The title compound was isolated as an off-white solid (0.2 g, 55%): mp 72-74° C.; 1H NMR (400 MHz, CDCl3) δ 7.88 (m, 2H), 7.74 (m, 2H), 7.38 (s, 2H), 7.34 (m, 1H), 7.18 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 8.0 Hz, 1H), 4.91 (s, 2H), 4.08 (m, 1H); ESIMS m/z 539.89 ([M−H]); IR (thin film) 1773 cm−1.

Prophetically, compounds CI34-CI41 (Table 1) could be made in accordance with the procedures disclosed in Example 49.

Example 50: Preparation of (E)-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (CI42)

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To a stirred solution of (E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a gummy liquid (0.3 g), which was carried on to the next step without further purification.

The following compounds were made in accordance with the procedures disclosed in Example 50.

(E)-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI43)

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The product obtained in this reaction was carried on to the next step without further purification.

(E)-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI44)

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The product obtained in this reaction was carried on to the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 2H), 7.39 (m, 2H), 7.23 (m, 2H), 6.52 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 7.6 Hz, 1H), 4.12 (m, 1H), 3.90 (s, 2H); ESIMS m/z 391.90 ([M−H]); IR (thin film) 3370, 3280, 1111, 817 cm−1.

(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-phenyl)methanamine (CI45)

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The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.

(E)-(2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI46)

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The title compound was isolated as a gummy material: The product obtained in this reaction was carried on to the next step without further purification.

(E)-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI47)

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The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.

(E)-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI48)

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The title compound was isolated as a gummy material: 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.13 (m, 2H), 6.56 (d, J=16.0 Hz, 1H), 6.33 (dd, J=16.0, 7.6 Hz, 1H), 4.08 (m, 1H), 3.90 (s, 2H); ESIMS m/z 413.84 ([M+H]+); IR (thin film) 3368, 3274, 1114, 808 cm−1.

Prophetically, compounds CI49-CI57 (Table 1) could be made in accordance with the procedures disclosed in Example 50.

Example 51: Preparation of 3-Chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (CI58)

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To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9 mmol) in N,N-dimethylacetamide (DMA; 20 mL) was added K2CO3 (2.36 g, 17.16 mmol) and 2-aminopyridine (0.84 g, 8.58 mmol), and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.4 (m, 1H), 6.64 (d, J=3.9 Hz, 1H), 6.38 (d, J=6.3 Hz, 1H), 5.04 (br s, 1H), 4.71 (s, 2H); ESIMS m/z 246.97 ([M+H]+).

Example 52: Preparation of N-(2-Chloro-4-vinylbenzyl)pyridin-2-amine (CI59)

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To a stirred solution of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (1 g, 4. mmol) in 1,4-dioxane (20 mL) were added K2CO3 (0.84 g, 6.09 mmol) and methyl triphenyl phosphonium bromide (2.17 g, 6.09 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 10% EtOAc in n-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.42-7.40 (m, 3H), 7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J=6.3 Hz, 1H), 5.75 (d, J=13.2 Hz, 1H), 4.92 (br s, 1H), 4.60 (s, 2H); ESIMS m/z 245.05 ([M+H]+).

Example 53: Preparation of Ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (CI60)

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Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0° C., and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient temperature. The mixture was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as a liquid (1.3 g, 20%): 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.89 (s, 1H), 5.09 (s1H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+H]+); IR (thin film) 3381, 3306, 1742, 759, 523 cm−1.

Example 54: Preparation of (5-Bromo-3-chloropyridin-2-yl)methanamine hydrochloride (CI61)

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A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with Et2O and water. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]+).

Example 55: Preparation of 2-((5-Bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (CI62)

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To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added TEA (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]); IR (thin film) 3307, 1665, 1114, 813 cm−1.

Example 56: Preparation of 2-((3-Chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (CI63)

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To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d, J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).

Example 57: Preparation of (E)-2-((3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (CI64)

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To a stirred solution of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (0.35 g, 1.17 mmol) in 1,2-dichlorobenzene (10 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.8 g, 2.3 mmol), CuCl (23 mg, 0.12 mmol), 2,2-bipyridyl (0.073 g, 0.234 mmol), and the reaction mixture was heated at 180° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a liquid (0.4 g, 50%): mp 79-82° C.; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d, J=15.6 Hz, 1H), 6.32 (dd, J=15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m/z 559 ([M+H]+).

Example 58: Preparation of (E)-(3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (CI65)

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To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.

Example 59: Preparation of 4-(Bromomethyl)-1-naphthonitrile (CI66)

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To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min. AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm−1.

Example 60: Preparation of 4-(Bromomethyl)-1-naphthaldehyde (CI67)

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To a stirred solution of 4-(bromomethyl)-1-naphthonitrile (8 g, 33 mmol) in toluene (100 mL) at 0° C. was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0° C. for 1 h. 3 N HCl in water (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116° C.; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.35 (m, 1H), 8.22 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).

Example 61: Preparation of 4-((1,3-Dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (CI68)

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To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28. mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85° C. for 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192° C.; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.25 (m, 1H), 8.41 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm−1.

Example 62: Preparation of 2-((4-Vinylnaphthalen-1-yl)methyl) isoindoline-1,3-dione (CI69)

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To a stirred solution of 4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) were added K2CO3 (6 g, 42.8 mmol) and methyl triphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambient temperature. The reaction mixture was heated at 100° C. for 14 h and then was cooled to ambient temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (6 g, 67%): mp 146-147° C.; 1H NMR (400 MHz, CDCl3) δ 8.35 (m, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H), 5.21 (s, 2H); ESIMS m/z 314.13 ([M+H]+).

Example 63: Preparation of (E)-2-((4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (CI70)

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To a stirred solution of 2-((4-vinylnaphthalen-1-yl)methyl)isoindoline-1,3-dione (1.5 g, 4.79 mmol) in 1,2-dichlorobenzene (15 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,4,5-trichlorobenzene (3.2 g, 9.5 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol), and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (1.5 g, 56%): mp 158-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m, 2H), 7.46 (s, 2H), 7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m/z 572.08 ([M−H]).

Example 64: Preparation of (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (CI71)

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To a stirred solution of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.

Example 65: Preparation of 2-((4-Bromophenyl)amino)isoindoline-1,3-dione (CI72)

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To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in AcOH (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130° C. for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with satd aqueous NaHCO3 solution and filtered to give a solid. Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206° C.; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H); ESIMS m/z 314.95 ([M−H]).

Example 66: Preparation of 2-((4-Vinylphenyl)amino)isoindoline-1,3-dione (CI73)

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To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6. mmol) in 1,2-dimethoxyethane (20 mL) and water (4 mL) were added vinyl boronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd(PPh3)4 (0.219 g, 0.189 mmol). The resultant reaction mixture was heated at 150° C. in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, J=17.6 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H); ESIMS m/z 263.18 ([M−H]).

Example 67: Preparation of (E)-2-((4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)amino)isoindoline-1,3-dione (CI74)

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To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) were added CuCl (0.022 g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m/z 523.05 ([M−H]).

Example 68: Preparation of (E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine (CI75)

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To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenylamino)isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85° C. for 1 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification.

Example 69: Preparation of 2-(4-Vinylphenoxy)isoindoline-1,3-dione (CI76)

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To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2-hydroxyisoindoline-1,3-dione (3.63 g, 24.53 mmol), and CuCl (1.214 g 12.26 mmol) in 1,2-dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the resultant reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was diluted with water and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (2 g, 63%): mp 129-131° C.; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=2.0 Hz, 2H), 7.82 (d, J=3.2 Hz, 2H), 7.38 (d, J=2.0 Hz, 2H), 7.14 (d, J=2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, J=16.0 Hz, 1H), 5.22 (d, J=10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]+).

Example 70: Preparation of (E)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)isoindoline-1,3-dione (CI77)

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To a stirred solution of 2-(4-vinylphenoxy)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (10 mL) was added 1-(1-bromoethyl)-3,4,5-trichlorobenzene (769 mg, 2.26 mmol), CuCl (22 mg, 0.22 mmol) and 2,2-bipyridyl (35 mg, 0.44 mmol), and the resultant reaction mixture was degassed with argon for 30 min and heated to 180° C. for 24 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) to afford the title compound as a solid (0.29 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.62 (m, 2H), 7.50 (m, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 6.90 (m, 2H), 6.60 (m, 2H), 6.20 (m, 1H), 4.08 (m, 1H); ESIMS m/z 524.09 ([M−H]).

Example 71: Preparation of (E)-O-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (CI78)

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To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenoxy)isoindoline-1,3-dione (0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g, 1.9 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2. washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.08 g, 53%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02 (s, 1H), 4.08 (m, 1H); ESIMS m/z 394.94 ([M−H]).

Example 72: Preparation of (E)-N-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzyl)acetamide (CC1)

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To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in CH2Cl2 (10 mL) was added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 60%) mp 107-109° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).

Compounds CC2-CC6 in Table 1 were made in accordance with the procedures disclosed in Example 72. In addition, compound DC56 in Table 1 was made from compound DC55 in accordance with the procedures disclosed in Example 72.

Example 73: Preparation of (E)-N-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)acetamide (CC7)

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To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DMF (5 mL) was added 2,2,2-trifluoropropanoic acid (97 mg, 0.76 mmol), HOBt.H2O (174 mg, 1.14 mmol) and EDC.HCl (217 mg, 1.14 mmol) and DIPEA (196 mg, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; EtOAc in hexane (30-50% afforded the title compound as an off-white solid (0.2 g, 60%): mp 127-128° C.; 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.86 (br s, 1H), 4.51 (d, J=6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H); ESIMS m/z 436.03 ([M+H]+).

Compounds CC8-CC28 in Table 1 were made in accordance with the procedures disclosed in Example 73.

Example 74: Preparation of (E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide (CC29)

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Step 1: (E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)methanamine

(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in MeOH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm−1.

Step 2: (E)-N-(Pyridin-2-ylmethyl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide

(E)-1-(Pyridin-2-yl)-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2Cl2 (3 mL). To this was added TEA (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min. After 10 min, the reaction mixture was cooled to 0° C., and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h and then was washed with water and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J=10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M−H]); IR (thin film) 1645, 1115, 808 cm−1.

Example 75: Preparation of (E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylsulfonyl)propanamide (CC30)

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(E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-(methylthio)propanamide (0.15 g, 0.28 mmol) was treated with oxone (0.175 g, 0.569 mmol) in 1:1 acetone:water (20 mL) for 4 h at ambient temperature. The acetone was evaporated to obtain a white solid (0.095 g, 60%): mp 101-104° C.; 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.12 (br s, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H); ESIMS m/z 559.75 ([M−H]).

Example 76: Preparation of (E)-1-(2-Chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea (CC31)

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To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]).

Compounds CC32-CC35 in Table 1 were made in accordance with the procedures disclosed in Example 76.

Example 77: Preparation of (E)-3-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-1,1-dimethylurea (CC36)

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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]); IR (thin film) 3350, 1705, 1114, 808 cm−1.

Example 78: Preparation of (E)-1-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3-ethylthiourea (CC37)

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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethyl isothicyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91° C.; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8 Hz, 1H), 7.41 (d, J=7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J=16 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 6.0 (br s, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H); ESIMS m/z 515.01 ([M+H]+).

Compound CC38 in Table 1 was made in accordance with the procedures disclosed in Example 78.

Example 79: Preparation of (E)-tert-Butyl (2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)-3-ethylurea (CC39)

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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and di-tert-butyl dicarbonate (0.163 mL, 0.75 mmol), and the reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 10-20% EtOAc in hexane) afforded the title compound as a white solid (0.147 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H); ESIMS m/z 526.09 ([M−H]); IR (thin film) 3350, 1705, 1114, 808 cm−1.

Compound CC40 in Table 1 was made in accordance with the procedures disclosed in Example 79.

Example 80: Preparation of (E)-Methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)amino)-2-oxoacetate (CC41)

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To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]); IR (thin film) 1740, 1701, 1114, 808 cm−1.

Example 81: Preparation of (E)-N1-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-N2-(2,2,2-trifluoroethyl)oxalamide (CC42)

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To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g, 0.77 mmol) in CH2Cl2 (10 mL) was added dropwise trimethylaluminum (2 M solution in toluene; 0.39 mL, 0.77 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of (E)-methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-2-oxoacetate (0.2 g, 0.38 mmol) in CH2Cl2 (5 mL) was added dropwise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; 20%-40% EtOAc in n-hexane) to afford the title compound (0.13 g, 60%): mp 161-163° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.93 (m, 1H), 6.75 (m, 1H), 4.80 (m, 1H), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m/z 578.96 ([M−H]).

Example 82: Preparation of (E)-N-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)pyridin-2-amine (CC43)

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To a stirred solution of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3 g, 1.22 mmol) in 1,2-dichlorobenzene (5 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.83 g, 2.44 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). The resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s, 1H), 4.61 (d, J=6.4 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 505.39 ([M+H]+).

Example 83: Preparation of (E)-N-((3-Chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1-en-1-yl)pyridin-2-yl)methyl)-3,3,3-trifluoropropanamide (CC44)

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To a stirred solution of (E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (0.1 g, 0.2 mmol) in CH2Cl2 (5 mL) were added 3,3,3-trifluoropropanoic acid (45 mg, 0.350 mmol), EDC.HCl (67 mg, 0.350 mmol), HOBt.H2O (71 mg, 0.467 mmol) and DIPEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.68 (d, J=4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J=10.8 Hz, 2H); ESIMS m/z 536.88 ([M−H]); IR (thin film) 3320, 1674, 1114, 808.

Compound CC45 in Table 1 was made in accordance with the procedures disclosed in Example 83.

Example 84: Preparation of (E)-3,3,3-Trifluoro-N-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)propanamide (CC46)

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To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 (8 mL) were added 3,3,3-trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBt.H2O (52 mg, 0.33 mmol), EDC.HCl (0.065 g, 0.33 mmol) and DIPEA (0.044 g, 0.45 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H); ESIMS m/z 554.04 ([M−H]).

Compounds CC47-CC48 in Table 1 were made in accordance with the procedures disclosed in Example 84.

Example 85: Preparation of (E)-1-Ethyl-3-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)urea (CC49)

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To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 at 0° C. were added TEA (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).

Example 86: Preparation of (E)-N′-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)cyclopropanecarbohydrazide (CC50)

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To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydrazine (0.1 g, 0. 3 mmol) in CH2Cl2 (10 mL) was added DIPEA (65 mg, 0.51 mmol), HOBt.H2O (59 mg, 0.38 mmol), EDC.HCl (73 mg, 0.38 mmol) and cyclopropanecarbonyl chloride (0.024 g, 0.28 mmol), and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with satd aq NaHCO3 solution and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 5-25% EtOAc in petroleum ether) afforded the title compound as a solid (65 mg, 55%): mp 138-140° C.; 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J=8.4 Hz, 2H), 6.65 (d, J=15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, J=15.6, 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H); ESIMS m/z 461.32 ([M−H]).

Compound CC51 in Table 1 was made in accordance with the procedures disclosed in Example 86.

Example 87: Preparation of (E)-N-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenoxy)cyclopropanecarboxamide (CC52)

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To a stirred solution of (E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2Cl2 (5 mL) was added EDC.HCl (0.109 g, 0.569 mmol), HOBt.H2O (0.087 g, 0.569 mmol), DIPEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CHCl3 (35 mL) The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in hexane) afforded the title compound as a brown liquid (0.06 g, 34%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H), 1.90 (m, 1H), 1.30-1.10 (m, 4H); ESIMS m/z 464.87 ([M−H]).

Compound CC53 in Table 1 was made in accordance with the procedures disclosed in Example 87.

Example 88: Preparation of (Z)-3,3,3-Trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (CC54)

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A silicon borate vial was charged with (E)-3,3,3-trifluoro-N-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (133 mg, 0.269 mmol) and dimethyl sulfoxide (DMSO; 10 mL). The mixture was placed within 0.6 to 1 meter (m) of a bank of eight 115 watt Sylvania FR48T12/350BL/VHO/180 Fluorescent Tube Black Lights and four 115 watt Sylvania (daylight) F48T12/D/VHO Straight T12 Fluorescent Tube Lights for 72 h. The mixture was concentrated in vacuo and purified by reverse phase chromatography to give the title compound as a colorless oil (11 mg, 8%): 1H NMR (300 MHz, CDCl3) δ 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.89 (d, J=11.4 Hz, 1H), 6.07 (br s, 1H), 6.01 (m, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J=7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 162.44, 137.20, 135.38, 135.23, 134.82, 134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63, 76.70, 47.33 (q, J=28 Hz), 43.59, 42.12 (q, J=30 Hz); ESIMS m/z 504 ([M+H]+).

Compounds DC46, AC93. AC94 in Table 1 were made in accordance with the procedures disclosed in Example 88.

Example 89: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3-chlorobenzene (DI2)

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The title compound was synthesized in two steps via 1-(3-chlorophenyl)-2,2,2-trifluoroethanol (DI1, prepared as in Step 1, Method B in Example 1); isolated as a colorless viscous oil (1.5 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.42-7.35 (m, 3H), 5.02 (m, 1H), 2.65 (br s, 1H)) and Step 2 in Example 1 and isolated (0.14 g, 22%): 1H NMR (400 MHz, CDCl3) δ 7.50 (br s, 1H), 7.42-7.35 (m, 3H), 5.07 (m, 1H).

The following compounds were made in accordance with the procedures disclosed in Example 89.

(1-Bromo-2,2,2-trifluoroethyl)benzene (DI4)

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2,2,2-Trifluoro-1-phenylethanol (DI3) was isolated (10 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, 1H), 2.65 (d, J=7.1 Hz, 1H). The title compound (DI4) was isolated as a liquid (8.0 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q, J=7.5 Hz, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (DI20)

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1-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (DI19) was isolated an off white solid: 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 2H), 7.02 (s, 1H), 4.95 (m, 1H), 2.32 (s, 6H); ESIMS m/z 204 ([M]). The title compound (DI20) was isolated (3.0 g, 51%).

1-(1-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (DI22)

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1-(2,4-Dichlorophenyl)-2,2,2-trifluoroethanol (DI21) was isolated as an off white powder (5.3 g, 61%): mp 49-51° C.; 1H NMR (400 MHz, CDCl3) δ 7.62-7.66 (d, 1H), 7.42-7.44 (d, 1H), 7.32-7.36 (d, 1H), 5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+). The title compound (DI22) was isolated (3.2 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.72 (m, 1H), 7.4-7.42 (m, 1H), 7.3-7.38 (m, 1H), 5.7-5.8 (m, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (DI24)

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1-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (DI23) was isolated as a pale yellow oil (5.2 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.64 (d, 1H), 7.52-7.54 (m, 1H), 7.29-7.33 (t, 1H), 5.6-5.76 (m, 1H), 2.7 (s, 1H); ESIMS m/z 243.9 ([M]+). The title compound (DI24) was isolated as an oil (8.7 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.62-7.71 (m, 1H), 7.44-7.52 (m, 1H), 7.27-7.3 (s, 1H), 5.81-5.91 (m, 1H).

2-(1-Bromo-2,2,2-trifluoroethyl)-1,4-dichlorobenzene (DI26)

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1-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (DI25) was isolated as a yellow oil (4.1 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.68-7.7 (s, 1H), 7.3-7.37 (m, 2H), 5.51-5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+)). The title compound (DI26) was isolated (3.0 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.7-7.78 (m, 1H), 7.3-7.4 (m, 2H), 5.7-5.8 (m, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzene (DI28)

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1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI27) was isolated (3.8 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 3H), 5.25 (m, 1H), 3.2 (br, 1H); ESIMS m/z 312.2 ([M]+). The title compound (DI28) was prepared and carried on crude.

1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (DI30)

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2,2,2-Trifluoro-1-(2,3,5-trichlorophenyl)ethanol (DI29) was isolated as a white solid (4.0 g, 60%): mp 113-115° C.; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 1H), 7.50 (d, 1H), 5.60-5.70 (m, 1H), 2.75 (s, 1H); ESIMS m/z 278.0 ([M+]). The title compound (DI30) was isolated (2.9 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H), 7.50 (d, 1H), 5.72-5.82 (m, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluoromethyl)benzene (DI32)

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1-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI131) was isolated as a pale yellow oil (2.0 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 3H), 5.08 (m, 1H), 2.81 (s, 1H); ESIMS m/z 278.1 ([M]+). The title compound (DI132) was isolated oil (2.0 g, 40%): ESIMS m/z 342 ([M]+).

5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-methoxybenzene (DI34)

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1-(3,5-Dichloro-4-methoxyphenyl)-2,2,2-trifluoroethanol (DI33) was isolated as an off white solid (0.8 g, 60%); mp 92-95° C.: 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 5.00 (m, 1H), 3.89 (s, 3H), 2.64 (m, 1H); ESIMS m/z 274 ([M]+). The title compound (DI134) was isolated as a colorless liquid (0.6 g, 57%).

Example 90: Preparation of 1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-difluorobenzene (DI36)

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The title compound was synthesized in two steps via 1-(3,5-difluorophenyl)-2,2,2-trifluoroethanol (DI35, prepared as in Step 1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 2H), 6.88 (m, 1H), 5.06 (m, 1H), 2.66 (s, 1H); ESIMS m/z 212 ([M]+) and Step 2 in Example 1 and isolated (3.2 g, 50%); 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 2H), 6.86 (m, 1H), 5.03 (q, J=7.4 Hz, 1H).

The following compounds were made in accordance with the procedures disclosed in Example 90.

1-(1-Bromo-2,2,2-trifluoroethyl)-4-chlorobenzene (DI38)

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1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (DI37) was isolated as a colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.38 (m, 4H), 5.05 (m, 1H), 2.55 (s, 1H); ESIMS m/z 210 ([M]+). The title compound (DI38) was isolated (3.0 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 5.10 (q, J=7.2 Hz, 1H).

1-(1-Bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (DI40)

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2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol (DI39) was isolated as a pale yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.8 Hz, 2H), 6.95 (m, J=8.8 Hz, 2H), 5.00 (m, 1H), 3.82 (s, 3H), 2.44 (s, 1H); ESIMS m/z 206.1 ([M]+). The title compound (DI40) was isolated (3.8 g, 62%).

1-(1-Bromo-2,2,2-trifluoroethyl)-4-fluorobenzene (DI42)

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2,2,2-Trifluoro-1-(4-fluorophenyl)ethanol (DI41) was isolated as a colorless oil (5 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.48-7.45 (m, 2H), 7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI42) was prepared and carried on as crude intermediate.

1-(1-Bromo-2,2,2-trifluoroethyl)-4-methylbenzene (DI44)

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2,2,2-Trifluoro-1-(p-tolyl)ethanol (DI43) was isolated as colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.02 (m, 1H), 2.46 (m, 1H), 2.37 (s, 3H); ESIMS m/z 190 ([M]+). The title compound (DI44) was isolated (3.0 g, 45%).

1-(1-Bromo-2,2,2-trifluoroethyl)-3-fluorobenzene (DI46)

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2,2,2-Trifluoro-1-(3-fluorophenyl)ethanol (D145) was isolated as a colorless viscous oil (2.8 g, 93%): 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 5.06 (m, 1H), 2.60 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI46) was isolated (2.0 g, 61%).

1-(1-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzene (DI48)

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2,2,2-Trifluoro-1-(2-fluorophenyl)ethanol (DI47) was isolated as a colorless oil (2.5 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 1H), 7.43 (m, 1H), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H), 2.65 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI48) was isolated (2.0 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 5.40 (m, 1H); GCMS m/z 255 ([M−H]).

Example 91: Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5)

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To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).

The following compound was made in accordance with the procedures disclosed in Example 91.

5-Formyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI49)

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The title compound was isolated (2.8 g, 60%); 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.07 (d, 1H); IR (thin film) 3433, 3120, 1702, 1599, 1510 cm−1.

2-Chloro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI50)

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The title compound was isolated as an off white solid (3.0 g, 40%): mp 149-151° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.90 (m, 2H); ESIMS m/z 208.10 ([M+H]+).

5-Methyl-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI51)

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The title compound was isolated as a white solid (0.5 g, 74%): mp 109-111° C.; 1H NMR (400 MHz, D6-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.92 (d, J=9.2 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 2.30 (s, 3H); ESIMS m/z 188.13 ([M+H]+).

Example 92: Preparation of 5-Formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (DI52)

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To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reaction mixture was stirred at ambient temperature for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]); IR (thin film) 2238, 1705, 1551, 1314 cm−1.

Example 93: Preparation of 4-(3-Methyl-1H-1,2,4-triazol-1-yl)benzaldehyde (DI53)

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To a stirring solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol) in DMF (50 mL), were added K2CO3 (3.34 g, 40.32 mmol) and 3-methyl-1,2,4-trizole (3.34 g, 40.32 mmol) and the resultant reaction mixture was stirred at ambient temperature for 4 h. After completion of the reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a white solid (4.1 g, 60%): mp 125-128° C.; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.76 (s, 1H), 8.02 (d, 2H), 7.85 (d, 2H), 2.50 (s, 3H); ESIMS m/z 188.04 ([M+H]+).

The following compound was made in accordance with the procedures disclosed in Example 93.

4-(1H-1,2,4-triazol-1-yl)-3-(trifluoromethyl)benzaldehyde (DI54)

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The title compound was isolated as white solid (1.05 g, 60%): mp 81-83° C.; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.25 (d, J=7.2 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=7.2 Hz, 1H); ESIMS m/z 241.0 ([M]+).

4-(3-Nitro-1H-1,2,4-triazol-1-yl)benzaldehyde (DI55)

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The title compound was isolated as pale yellow solid (0.10 g, 23%): mp 159-161° C.; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.89 (s, 1H), 8.15 (m, 2H), 8.00 (m, 2H); ESIMS m/z 217.11 ([M−H]).

3-Bromo-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI56)

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The title compound was isolated as white solid (3.2 g, 51%): mp 126-128° C.; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.69 (s, 1H), 8.27 (M, 1H, 8.18 (s, 1H) 7.99 (d, J=9.2 Hz, 1H), 7.76 (d, J=9.2 Hz, 1H); ESIMS m/z 250.9 ([M]+).

5-Formyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (DI57)

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The title compound was isolated as white solid (0.13 g, 30%): mp 147-149° C.; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.89 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.24 (dd, J=8.6, 1.3 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 2.54 (s, 3H); ESIMS m/z 213.09 ([M+H]+); IR (thin film) 2239, 1697 cm−1.

3-Nitro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI58)

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The title compound was isolated as pale yellow solid (3.0 g, 60%): mp 116-118° C.; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.26 (d, J=6.9 Hz, 1H), 8.16 (s, 1H), 7.83 (d, J=6.9 Hz, 1H); ESIMS m/z 219.00 ([M+H]+).

Example 94: Preparation of 1-(4-Vinylphenyl)-1H-1,2,4-triazole (DI59)

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To a stirred solution of 4-[1,2,4]triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at room temperature. The resultant reaction mixture was heated to 70° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).

The following compound was made in accordance with the procedures disclosed in Example 94.

1-(2-Methyl-4-vinylphenyl)-1H-1,2,4-triazole (DI60)

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The title compound was isolated as an off white solid (1.5 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (m, 2H), 7.27 (d, J=8.7 Hz, 1H), 6.74 (m, 1H), 5.82 (d, J=17.3 Hz, 1H), 5.36 (d, J=10.0 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 186.14 ([M+H]+).

2-(1H-1,2,4-Triazol-1-yl)-5-vinylbenzonitrile (DI61)

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The title compound was isolated as an off-white solid (1.40 g, 71%): mp 126-129° C.; 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.18 (s, 1H), 7.82-7.84 (m, 1H), 7.72-7.80 (m, 2H), 6.70-6.80 (dd, J=17.6, 10.8 Hz, 1H), 5.90-5.95 (d, J=17.6 Hz, 1H), 5.50-5.70 (d, J=10.8 Hz, 1H); ESIMS m/z 197.03 ([M+H]+).

Example 95: Preparation of 2-(3-Nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI62)

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To a stirred solution of 5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultant reaction mixture was heated to 100° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%): mp 103-105° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, J=15.7 Hz, 1H), 5.56 (d, J=11.8 Hz, 1H); ESIMS m/z 240.27 ([M−H]); IR (thin film) 2240, 1514, 1312 cm−1.

The following compound was made in accordance with the procedures disclosed in Example 95.

1-(3-Chloro-4-vinylphenyl)-1H-1,2,4-triazole (DI63)

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The title compound was isolated as an off-white solid (2.3 g, 80%): mp 134-137° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.10 (m, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.47 (d, J=12.4 Hz, 1H); ESIMS m/z 206.04 ([M+H]+.

3-Methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI64)

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The title compound was isolated as a white solid (0.6 g, 60%): mp 109-111° C.; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.40-7.60 (m, 4H), 6.70-7.00 (dd, J=17.6, 10.8 Hz, 1H), 5.80 (d, J=17.6 Hz, 1H), 5.30 (d, J=17.6 Hz, 1H), 2.50 (s, 3H); ESIMS m/z 186.20 ([M+H]+).

1-(2-(Trifluoromethyl)-4-vinylphenyl)-1H-1,2,4-triazole (DI65)

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The title compound was isolated as a colorless oil (0.6 g, 60%): 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.70-6.90 (dd, J=17.6, 10.8 Hz, 1H), 5.90-6.00 (d, J=17.6 Hz, 1H), 5.50-5.80 (d, J=10.8 Hz 1H); ESIMS m/z 240.16 ([M+H]+).

3-Nitro-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI66)

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The title compound was isolated as a pale yellow solid (61 mg, 20%): mp 137-139° C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.68 (d, J=7.7 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 6.77 (dd, J=17.7, 10.8, 1H), 5.87 (d, J=17.7 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H); ESIMS m/z 217.28 ([M+H]+).

1-(2-Bromo-4-vinylphenyl)-1H-1,2,4-triazole (DI67)

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The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77° C.; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H) 7.42 (s, 2H), 6.70 (m, 1H), 5.83 (d, J=18 Hz, 1H), 5.42 (d, J=12 Hz, 1H); ESIMS m/z 249.1 ([M]+).

2-(3-Methyl-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI68)

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The title compound was isolated as an off-white solid (0.6 g, 60%): mp 96-97° C.; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.80 (s, 1H), 7.74 (m, 2H), 6.73 (dd, J=17.6 Hz, 10.8 Hz, 1H), 5.88 (d, J=17.6 Hz, 1H), 5.49 (d, J=10.8 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 211.10 ([M+H]+); IR (thin film) 2229 cm−1.

1-(2-Nitro-4-vinylphenyl)-1H-1,2,4-triazole (DI69)

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The title compound was isolated as a yellow solid (1.78 g, 60%): mp 102-104° C.; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.72-7.76 (d, J=8.0 Hz, 1H), 7.52-7.56 (d, J=17.6 Hz, 1H), 6.70-6.82 (dd, J=17.6, 10.8 Hz, 1H), 5.85-6.00 (d, J=17.6 Hz, 1H), 5.50-5.60 (d, J=10.8, Hz 1H); ESIMS m/z 217.0 ([M+H]+).

Example 96: Preparation of 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)

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Step 1. 5-Bromo-2-fluoro-3-methylbenzaldehyde

To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-BuLi (1.6 M in hexane) (19.9 mL, 31.91 mmol) at −78° C. slowly dropwise over the period of 10 min, the reaction mixture was stirred at −78° C. for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at −78° C., and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 mL) was added and stirred at −78° C. for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0° C. The aqueous layer was extracted with Et2O, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% EtOAc/pet ether) to afford the title compound as a white solid (3.6 g, 64%); mp 48-50° C.: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]).

Step 2. ((E)-5-Bromo-2-fluoro-3-methylbenzaldehyde oxime

To a stirred solution of 5-bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in ethanol (50.0 mL) were added NaOAc (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated on rotavapour to obtain crude compound, which was washed with water filtered and dried under vacuum to afford the title compound as a white solid: mp 126-127° C.; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 232.10 ([M+H]+).

Step 3. 5-Bromo-2-fluoro-3-methylbenzonitrile

A stirred solution of (E)-5-bromo-2-fluoro-3-methylbenzaldehyde oxime (0.5 g, 2.2 mmol) in acetic anhydride (5.0 mL) was heated to reflux for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound as a light brown gummy material (0.4 g, crude): ESIMS m/z 213.82 ([M+H]+).

Step 4. 5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71)

To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added K2CO3 (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc (2×100 mL). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% EtOAc/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.

Step 5. 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)

A mixture of 5-bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6 g, 2.3 mmol), K2CO3 (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc (2×100 mL). The combined EtOAc layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% EtOAc/pet ether) to afford the title compound as a pink solid (0.25 g, 52%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (d, J=17.6, 1H), 5.52 (d, J=10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm−1.

The following compound was made in accordance with the procedures disclosed in Steps 4 and 5 of Example 96.

1-(2-Fluoro-4-vinylphenyl)-1H-1,2,4-triazole (DI72)

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1-(4-Bromo-2-fluorophenyl)-1H-1,2,4-triazole (DI73) was isolated as a pale yellow solid (3.0 g, 75%): mp 113-116° C.; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H), 7.21 (m, 1H); ESIMS m/z 241.93 ([M]+). The title compound (DI72) was isolated as a yellow solid (1.0 g, 71%): mp 67-70° C.; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.13 (s, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 7.24 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.81 (d, J=17.6 Hz, 1H), 5.37 (d, J=10.8 Hz, 1H); ESIMS m/z 190.00 ([M+H]+).

Example 119: Preparation of 1-(1-(4-Vinylphenyl)-1H-1,2,4-triazol-5-yl)ethanone (DI78)

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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).

Example 120: Preparation of Cyclopropyl(1-(4-vinylphenyl)-1H-1,2,4-triazol-5-yl)methanone (DI79)

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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy N-methylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, 30%): mp 90-91° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 6.75 (dd, J=16.3, 10.7 Hz, 1H), 5.81 (d, J=16.3 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 3.22 (m, 1H), 1.27 (m, 2H), 1.18 (m, 2H); ESIMS m/z 240.18 ([M+H]+); IR (thin film) 2922, 1630 cm−1.

Example 121: Preparation of 5-(Methylthio)-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI80)

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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 50 mL of THF, was added n-BuLi (0.41 g, 6.4 mmol) at −78° C. and stirred for 30 min. To this dimethyldisulfide in THF (0.6 g, 6.43 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (0.6 g, 48%): mp 68-70° C.; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.05 (m, 4H), 6.75 (dd, J=16.4, 10.7 Hz, 1H), 5.81 (d, J=16.4 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 2.73 (s, 3H); ESIMS m/z 218.09 ([M+H]+).

Example 122: Preparation of 5-Methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI81)

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To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (0.5 g, 2.9 mmol) in 10 mL of THF, was added n-BuLi (0.22 g, 3.5 mmol) at −78° C. and stirred for 30 min. To this methyl iodide in THF (0.50 g, 3.5 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) afford the title compound as a pale brown liquid (250 mg, 46%): 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.55 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 6.76 (dd, J=18, 11 Hz, 1H), 5.83 (d, J=18 Hz, 1H), 5.38 (d, J=11 Hz, 1H), 2.55 (s, 3H); ESIMS m/z 186.13 ([M+H]+); IR (thin film) 1517, 1386, 1182, 847 cm−1.

Example 97: Preparation of (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC1)

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To a stirred solution of 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCl (64 mg, 0.65 mmol) and 2,2-bipyridyl (0.2 g, 1.3 mmol). The resultant reaction mixture was degassed with argon for 30 min, then stirred at 180° C. for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (t, J=1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).

Compounds DC2-DC37, DC44, DC45, DC47-49, DC50, DC51, DC54, DC58, DC60, DC62, and DC63-DC67 in Table 1 were made in accordance with the procedures disclosed in Example 97.

Example 98: Preparation of (E)-2-(3-Nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile (DC40)

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To a stirred solution of 2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2-dichlorobenzene (10 mL), were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (2.5 g, 7.5 mmol), CuCl (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh, 25-30% EtOAc in Pet ether) afforded the title compound as an off white solid (0.9 g, 50%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J=16.0 Hz, 1H), 6.56 (dd, J=16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 436.11 ([M-2H]).

Example 99: Preparation of (E)-2-(3-Amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzonitrile (DC41)

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To a stirred solution of (E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39 g, 5.98 mmol) and saturated aqueous NH4Cl solution (5 mL) and the resultant reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction (TLC), the reaction mass was concentrated under reduced pressure. The reaction mass was diluted with CH2Cl2, filtered through a Celite® bed, and the obtained filtrate concentrated under reduced pressure to afford the title compound as a solid (0.5 g, 89%): mp 72-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J=8.4 Hz, 1H), 6.42 (dd, J=15.6, 9.2 Hz, 1H), 6.83 (d, J=15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M−H]).

Compound DC38 in Table 1 was made in accordance with the procedures disclosed in Example 99. Also, compound DC55 in Table 1 was made from compound DC54 in accordance with the procedures disclosed in Example 99, with the exception of using ammonium formate in place of NH4Cl.

Example 100: Preparation of (E)-N-(1-(2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)-N-(cyclopropanecarbonyl)cycloprop anecarboxamide (DC42)

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To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.1 g, 0.21 mmol) in CH2Cl2 at ambient temperature, was added cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by preparative HPLC afforded the title compound as a solid (0.09 g, 79%): mp 104-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J=16.4 Hz, 1H), 6.51 (dd, J=7.6, 8.0 Hz, 1H), 4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H); ESIMS m/z 609.98 ([M+H]+); IR (thin film) 2234, 1714, 1114, 807 cm−1.

Example 101: Preparation of (E)-N-(1-(2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)cyclopropanecarboxamide (DC43)

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To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in CH2Cl2 at 0° C., were added TEA (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.

Compound DC39 in Table 1 was made in accordance with the procedures disclosed in Example 101.

Example 102: Preparation of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (DI74)

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To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with Et2O afforded the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M−H]).

Example 103: Preparation of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (DI75)

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Step 1. 1-(4-(1-(Trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (DI76)

To a stirred solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (4.5 g, 24.0 mmol) in CH2Cl2 at 0° C., were added TEA (3.7 g, 36.1 mmol) and trimethylsilyl trifluoromethanesulfonate (8 g, 36 mmol) and the resultant reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aqueous NaHCO3 solution and ether. The ether layer and was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.

Step 2. 1-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (DI75)

To a stirred solution of 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6 g, 23 mmol) and 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichlorobenzene (7.1 g, 34.7 mmol) in 1,2-dichlorobenzene (30 mL) was degassed with argon. To this CuCl (0.23 g, 2.31 mmol) and 2,2-bipyridyl (0.73 g, 4.63 mmol) was added to the above reaction mixture and the resultant reaction mixture was heated to 180° C. for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (SiO2; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31%): 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412. 14 ([M−H]).

Example 104: Preparation of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (DI77)

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To a solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (300 mg, 0.726 mmol) in THF cooled to 0° C. was added methylmagnesium bromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at 0° C., then the reaction mixture was quenched with sat aqueous NH4Cl solution and extracted with EtOAc. The combined EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (100 mg, 32%): 1H NMR (400 MHz, CDCl3) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, J=9.0 Hz, 2H, minor), 7.53 (d, J=9.0 Hz, 2H, minor), 7.40 (d, J=9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J=9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H, minor); ESIMS m/z 430.05 ([M+H]+).

Example 105: Preparation of (E)-1-(4-(4-(3,5-Dichlorophenyl)-5,5,5-trifluoropent-2-en-2-yl)phenyl)-1H-1,2,4-triazole (DC68)

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To a solution of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5-trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of p-toluenesulfonic acid and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to room temperature and dissolved in EtOAc. The solution was washed with sat aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).

Example 123: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzaldehyde (DC52)

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To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol) in toluene (10 mL) at −78° C. was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85 mL), and the reaction mixture was stirred at −78° C. for 20 min. The reaction mixture was quenched with the addition of 1 N HCl solution, then the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow oil.

Compound DC53 in Table 1 was made in accordance with the procedures disclosed in Example 123.

Example 124: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)aniline (DC57)

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To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in CH2Cl2 (10 mL) was added TEA (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at ambient temperature for 18 h. The CH2Cl2 layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).

Example 125: Preparation of (E)-5-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoic acid (DC61)

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A solution of (E)-ethyl 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100° C. for 18 h. The reaction was cooled to ambient temperature, resulting in a white solid precipitate. The precipitate was filtered to afford the title compound as a white solid (0.12 g, 60%).

Example 126: Preparation of (Z)-5-((E)-3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N′-hydroxy-2-(1H-1,2,4-triazol-1-yl)benzimidamide (DC59)

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A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol), NaOAc (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/water mixture (10 mL) was stirred at 70° C. for 8 h. The reaction was cooled to ambient temperature, and the ethanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off white solid.

Example 127: Preparation of (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC70)

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Step 1. (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one

To a solution of 1-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) in ethanol (20 mL) was added 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0° C. NaOH (0.22 g, 5.29 mmol) in water (10 mL) was then added and the reaction was allowed to stir for 2 h at 0° C. The reaction was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%); ESIMS m/z 430.05 ([M+H]+) 344.08

Step 2. (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (DC69)

To a solution of (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0° C. The reaction was slowly warmed to ambient temperature and allowed to stir for 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution was added and the reaction was stirred for an additional 4 h at ambient temperature. The reaction was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).

Step 3. (E)-1-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yl)phenyl)-1H-1,2,4-triazole (DC70)

To a solution of (E)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0° C. The reaction was allowed to stir at 0° C. for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed to ambient temperature and allowed to stir for 4 h. The reaction was quenched with aqueous NH4Cl solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (55 mg, 35%).

Example 128: Preparation of tert-Butyl (2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)carbamate

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To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (4.58 g, 22.6 mmol) in methylene chloride (50 mL) was added EDC HCl (4.75 g, 24.8 mmol) followed by 2,2,2-trifluoroethylamine (2.67 g, 27.0 mmol) and DMAP (3.03 g, 24.8 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then washed with aqueous 5% NaHSO4 (2×), aqueous 10% HCl (1×) and aqueous saturated NaHCO3 (2×). The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (2.97 g, 46%).

The following molecules were made in accordance with the procedures disclosed in Example 128:

(S)-tert-Butyl (1-oxo-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)carbamate

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The title molecule was isolated as a white solid: mp 108-111° C.; 1H NMR (400 MHz, CDCl3) δ 6.90 (s, 1H), 5.04 (m, 1H), 4.07 (m, 1H), 3.92 (m, 3H), 1.87 (m, 1H), 1.66 (m, 1H), 1.44 (s, 9H), 0.96 (t, J=7.4 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −72.54; 13C NMR (101 MHz, CDCl3) δ 173.05, 156.04, 124.03 (q, J=278.5 Hz), 80.30, 55.56, 40.43 (q, J=34.7 Hz), 28.19, 25.63, 9.80; [α]D=−33.3 (c, 10.1 mg/mL in CH2Cl2).

tert-Butyl (1-oxo-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)carbamate

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The title molecule was isolated as a white solid: mp 113-116° C.; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8.4 Hz, 1H), 5.43-5.25 (m, 1H), 4.16 (m, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 1.84 (dt, J=14.0, 7.0 Hz, 1H), 1.66 (dt, J=14.2, 7.3 Hz, 1H), 1.44 (s, 9H), 0.95 (t, J=7.3 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −72.51; 13C NMR (101 MHz, CDCl3) δ 172.94, 156.02, 124.47 (q, J=380.8 Hz), 80.33, 55.54, 40.46 (q, J=34.8 Hz), 28.19, 25.61, 9.79.

tert-Butyl (2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)ethyl)carbamate

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The title molecule was isolated as a white solid: mp 84-88° C.; 1H NMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 5.44 (t, J=5.8 Hz, 1H), 4.77-4.48 (m, 1H), 3.83 (d, J=5.9 Hz, 2H), 1.45 (s, 9H), 1.33 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −77.63; 13C NMR (101 MHz, CDCl3) δ 169.84, 156.33, 125.19 (q, J=280.9 Hz), 80.29, 46.20 (q, J=31.7 Hz), 44.15, 28.11, 13.88; EIMS m/z 270 ([M]+).

(R)-tert-Butyl (1-((2-fluoroethyl)amino)-1-oxopropan-2-yl)carbamate

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The title molecule was isolated as a white solid: mp 91-94° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.98 (bs, 1H), 6.87 (t, J=7.2 Hz, 1H), 4.47 (t, J=4.8 Hz, 1H), 4.32 (t, J=5.1 Hz, 1H), 3.97-3.92 (m, 1H), 3.41-3.37 (m, 1H), 3.33-3.28 (m, 1H), 1.37 (s, 9H), 1.16 (d, J=7.3 Hz, 3H); ESIMS m/z 235.0 ([M+H]+).

tert-Butyl (3-oxo-3-((2,2,2-trifluoroethyl)amino)propyl)carbamate

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The title molecule was isolated as a white solid: mp 123-125° C.; 1H NMR (400 MHz, CDCl3) δ 6.42-6.22 (m, 1H), 5.07 (s, 1H), 3.92 (qd, J=9.1, 6.4 Hz, 2H), 3.43 (q, J=6.2 Hz, 2H), 2.50 (t, J=6.0 Hz, 2H), 1.43 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −72.50; 13C NMR (101 MHz, CDCl3) δ 171.76, 156.30, 124.02 (q, J=278.5 Hz), 79.67, 40.53 (q, J=34.8 Hz), 36.41, 36.27, 28.31.

(R)-tert-Butyl (1-(ethylamino)-1-oxopropan-2-yl)carbamate

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The title molecule was isolated as a white solid: mp 88-93° C.; 1H NMR (400 MHz, CDCl3) δ 6.35 (s, 1H), 5.25-5.04 (m, 1H), 4.21-3.99 (m, 1H), 3.29 (dd, J=7.5, 5.9 Hz, 2H), 1.45 (s, 8H), 1.35 (d, J=7.0 Hz, 3H), 1.13 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.79, 155.51, 79.59, 49.97, 34.16, 28.25, 18.77, 14.60.

(R)-tert-Butyl (1-oxo-1-((3,3,3-trifluoropropyl)amino)propan-2-yl)carbamate

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The title molecule was isolated as an off white solid: mp 101-105° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.96 (bs, 1H), 6.90 (d, J=6.9 Hz, 1H), 3.91-3.86 (m, 1H), 3.34-3.19 (m, 2H), 2.50-2.32 (m, 2H), 1.37 (s, 9H), 1.15 (d, J=7.2 Hz, 3H).

(R)-tert-Butyl (1-oxo-1-((2,2,2-trifluoroethyl)amino)pentan-2-yl)carbamate

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The title molecule was isolated as a white solid: mp 107-122° C.; 1H NMR (400 MHz, CDCl3)) δ 6.90 (s, 1H), 5.00 (d, J=8.0 Hz, 1H), 4.12 (d, J=7.3 Hz, 1H), 3.99-3.76 (m, 2H), 1.87-1.73 (m, 1H), 1.65-1.52 (m, 1H), 1.44 (s, 9H), 1.38 (m, 2H), 0.94 (t, J=7.3 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ rotomer −72.55, −73.27; 13C NMR (101 MHz, CD3OD) δ rotomers 176.08, 157.86, minor 126.13 (q, J=279.8 Hz), major 125.83 (q, J=278.8 Hz), 80.65, 55.90, minor 42.27 (q, J=35.4 Hz), major 41.24 (q, J=35.4 Hz), 35.50, 28.73, 20.04, 14.03.

(R)-Benzyl (3-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)carbamate

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The title molecule was isolated as a white solid: mp 157-161° C.; 1H NMR (400 MHz, CDCl3) δ 7.46-7.31 (m, 5H), 6.57 (d, J=8.3 Hz, 1H), 5.34 (d, J=8.9 Hz, 1H), 5.11 (s, 2H), 4.02 (dq, J=16.1, 8.8, 7.7 Hz, 2H), 3.78 (td, J=9.0, 4.7 Hz, 1H), 2.15 (q, J=6.7 Hz, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −72.44.

Example 129: Preparation of N-(2,2,2-Trifluoroethyl) 1-amino-2-methylpropanecarboxamide hydrochloride

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To tert-butyl (2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)carbamate (2.61 g, 9.18 mmol) in methylene chloride (20 mL) was added 4 M HCl in dioxane (20 mL). The solution was stirred for 6 h at ambient temperature. The reaction mixture was concentrated in vacuo to afford the title compound as a white solid (2.18 g).

The following molecules were made in accordance with the procedures disclosed in Example 129:

(R)-1-Oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-aminium chloride

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The title molecule was isolated as a white solid: mp 210-213° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.22 (t, J=6.3 Hz, 1H), 8.37-8.27 (m, 3H), 4.07-3.95 (m, 2H), 3.95-3.84 (m, 1H), 1.38 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −70.75; [α]D=−6.6 (c, 5.0 mg/mL in MeOH).

1-Oxo-1-((2,2,2-trifluoroethyl)amino)butan-2-aminium chloride

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The title molecule was isolated as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.12 (t, J=5.7 Hz, 1H), 8.19 (s, 3H), 4.14-3.93 (m, 2H), 3.78 (t, J=6.0 Hz, 1H), 1.81-1.71 (m, 2H), 0.88 (t, J=7.2 Hz, 3H); ESIMS m/z 184.90 ([(M-TFA)+H]+); IR (thinfilm) 3269, 1681, 1158 cm−1.

2-Oxo-2-((1,1,1-trifluoropropan-2-yl)amino)ethanaminium chloride

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The title molecule was isolated as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J=8.7 Hz, 1H), 8.09 (bs, 3H), 4.71-4.59 (m, 1H), 3.64-3.62 (m, 2H), 1.27 (d, J=6.9 Hz, 3H); EIMS m/z 170.1 ([M]+).

(R)-1-((2-Fluoroethyl)amino)-1-oxopropan-2-aminium chloride

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The title molecule was isolated as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.76 (t, J=5.1 Hz, 1H), 8.21 (bs, 3H), 4.54 (t, J=5.1 Hz, 1H), 4.38 (t, J=4.8 Hz, 1H), 3.85-3.79 (m, 1H), 3.50-3.45 (m, 1H), 3.41-3.36 (m, 1H), 1.36 (d, J=7.2 Hz, 3H); ESIMS m/z 135.1 ([M+H]+); IR (thinfilm) 3331, 2983, 1660, 1161, 597 cm−1.

3-Oxo-3-((2,2,2-trifluoroethyl)amino)propan-1-aminium chloride

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The title molecule was isolated as a white solid: mp 193-197° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J=6.4 Hz, 1H), 8.16 (s, 3H), 3.99-3.79 (m, 2H), 2.98 (t, J=7.3 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −70.74.

(R)-1-(Ethylamino)-1-oxopropan-2-aminium chloride

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The title molecule was isolated as a white solid: mp 223-236° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J=5.4 Hz, 1H), 8.32 (s, 3H), 3.89-3.66 (m, 1H), 3.12 (p, J=7.0 Hz, 2H), 1.35 (d, J=6.9 Hz, 3H), 1.05 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 168.98, 48.08, 33.54, 17.16, 14.43.

(R)-1-Oxo-1-((3,3,3-trifluoropropyl)amino)propan-2-aminium chloride

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The title molecule was isolated as an off white solid: mp 128-131° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.62 (bs, 1H), 8.10 (bs, 3H), 3.82-3.79 (m, 1H), 3.50-3.38 (m, 2H), 2.50-2.37 (m, 2H), 1.34 (d, J=6.9 Hz, 3H).

(R)-1-Oxo-1-((2,2,2-trifluoroethyl)amino)pentan-2-aminium chloride

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The title molecule was isolated as a white solid: mp 204-210° C.; 1H NMR (400 MHz, CD3OD) δ 4.17-4.00 (m, 1H), 3.98-3.69 (m, 2H), 1.83 (dt, J=15.0, 7.5 Hz, 2H), 1.50-1.35 (m, 2H), 0.99 (t, J=7.3 Hz, 3H); 19F NMR (376 MHz, CD3OD) δ −73.90; 13C NMR (101 MHz, CD3OD) δ 170.97, 125.72 (q, J=277.9 Hz), 54.37, 41.30 (q, J=34.7 Hz), 34.65, 19.00, 13.94.

Example 130: Preparation of (R)-tert-Butyl 1-thioxo-1-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate

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To a stirred solution of (R)-tert-butyl 1-oxo-1-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (100 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added P2S5 (24 mg, 0.11 mmol) and hexamethyldisiloxane (HMDO) (0.13 mL, 0.59 mmol) at room temperature and the mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and another portion of P2S5 (24 mg, 0.11 mmol) was added and the resulting mixture was refluxed for 18 h. The volatiles were evaporated, pentane (25 mL) was added to the residue and stirred for 10-15 min. The pentane layer was decanted, concentrated in vacuo and the residue was passed through a short silica pad eluting with pentane followed by CH2Cl2 to give the title compound as colorless liquid (30 mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ 10.27 (t, J=5.4 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 4.57-4.35 (m, 3H), 1.32 (s, 9H), 1.25 (d, J=7.6 Hz, 3H); ESIMS m/z 286.2 ([M+H]+); IR (thin film) 3233, 1683, 1257 cm−1.

Example 131: Preparation of (R)-1-Thioxo-1-((2,2,2-trifluoroethyl)amino)propan-2-aminium 2,2,2-trifluoroacetate

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To a stirred solution of (R)-tert-butyl 1-thioxo-1-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (200 mg, 0.69 mmol) in CH2Cl2 (5 mL) was added TFA (0.5 mL) dropwise and the reaction mixture was stirred for 18 h. The volatiles were evaporated and the residue was triturated with pentane to give the title compound as colorless gum, which was taken to next step without further purification (200 mg): 1H NMR (300 MHz, DMSO-d6) δ 10.99 (bs, 1H), 8.23 (bs, 2H), 4.62-4.55 (m, 2H), 4.23-4.19 (m, 1H), 1.43 (d, J=8.4 Hz, 3H); ESIMS m/z 186.2 ([M+H]+); IR (thin film) 3445, 2967, 1168 cm−1.

The following molecule was made in accordance with the procedures disclosed in Example 131:

(S)-1-Oxo-1-((2,2,2-trifluoroethyl)amino)butan-2-aminium 2,2,2-trifluoroacetate

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The title molecule was isolated as a colorless gum: 1H NMR (300 MHz, DMSO-d6) δ 9.12 (t, J=5.7 Hz, 1H), 8.19 (bs, 2H), 4.14-3.93 (m, 2H), 3.80 (t, J=6.0 Hz, 1H), 1.81-1.71 (m, 2H), 0.88 (t, J=7.2 Hz, 3H); ESIMS m/z 185.00 ([M+H]+); IR (thin film) 3459, 1674, 1169 cm−1.

Example 132: Preparation of 2-Bromo-N—((S)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (F10 and F11)

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The title molecule was prepared as described in Example 15. The diastereomeric pairs were separated by chiral HPLC using Chiralpak® IA (4.6×250 mm) 5 μm column using 0.1% TFA in hexane and isopropanol as the mobile phase (isocratic 70:30) with a flow rate 1.0 mL/min at ambient temperature. Diastereomer F10 was collected at a retention time of 4.55 min and possessed an optical rotation of [α]D30=+35.6 (c, 0.5% in CH2Cl2). Diastereomer F11 was collected at 8.71 min and possessed an optical rotation of [α]D30=−82.0 (c, 0.5% in CH2Cl2). Characterization data for these molecules are listed in Table 2.

Example 133: Preparation of 2-Bromo-N—((R)-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (F12 and F13)

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The title molecule was prepared as described in Example 15. The diastereomeric pairs were separated by chiral HPLC using Chiralpak® IA (4.6×250 mm) 5 m column using 0.1% TFA in hexane and isopropanol as the mobile phase (isocratic 70:30) with a flow rate 1.0 mL/min at ambient temperature. Diastereomer F12 was collected at a retention time of 5.62 min and possessed an optical rotation of [α]D30=+59.4 (c, 1% in CH2Cl2). Diastereomer F13 was collected at 8.85 min and possessed an optical rotation of [α]D30=−44.0 (c, 1% in CH2Cl2). Characterization data for these molecules are listed in Table 2.

The following molecules was prepared in accordance with the procedures disclosed in Example 133:

N—((R)-1-Oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethy l)benzamide (F20A and F20B)

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Diastereomer F20A (isomer 1) was collected at a retention time of 4.13 min and possessed an optical rotation of [α]D25=+49.2 (c, 1.0% in CH2Cl2). Diastereomer F20B was collected at 4.88 min and possessed an optical rotation of [α]D25=−38.8 (c, 1.0% in CH2Cl2). Characterization data for these molecules are listed in Table 2.

F20A and F20B Stereochemical Assignment

F20A and F20B were dissolved in CDCl3 and placed in a 100 μm path length cell with BaF2 windows. IR and vibrational circular dichroism (VCD) spectra were recorded on a IR-2XTM VCD spectrometer (BioTools, Inc.) equipped with dual PEM accessory, with 4 cm−1 resolution. The sample and CDCl3 spectra were acquired for 21 h on an instrument optimized at 1400 cm−1. The solvent-subtracted IR and VCD spectra were collected.

Theoretical Calculations:

F20 with R,R- and S,R-configurations were built with Maestro (Schrodinger, LLC. New York, N.Y.). The conformational search was carried out with MacroModel (Schrodinger, LLC. New York, N.Y.) with MMFF94x force field to generate low-energy conformers. Single point calculation (SPE), geometry, frequency, and IR and VCD calculations were performed at the DFT level (B3LYP/lacvp**) in Jaguar (Schrodinger, LLC. New York, N.Y.). A scaling factor of 0.96 was applied to the frequency calculation. Analysis: for F20 with R,R- and S,R-configurations, the top 100 low-energy conformers generated with MacroModel were selected for DFT SPE calculations. These calculations resulted in the 8 and 4 conformers that have energies within 1 kcal/mol higher than the lowest energy conformer for R,R- and S,R-configurations, respectively. The frequency calculations were performed on these conformers to determine the IR and VCD spectra. The Boltzmann-weighted IR and VCD spectra of these conformers were compared with the observed IR and VCD spectra. Based on the overall agreement in VCD pattern between the observed and calculated spectra, the absolute configuration of F20A is assigned as R,R-configuration. The assignment was evaluated by CompareVOA program (BioTools). The confidence level of the assignment is 88% based on a database that includes 105 previous correct assignments for different chiral structures. However, the observed spectrum for F20B does not agree well with the calculated spectrum for S,R-configuration with a confidence level of 65%. But considering that the compound has only one chiral center, two possible configurations and F20A is of R,R-configuration, F20B can be with high confidence assigned as the S,R-configuration.

Example 134: Preparation of (E)-2-Methyl-N-(2-methyl-1-thioxo-1-(2,2,2-trifluoroethylamino)propan-2-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzothio amide (F31)

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To a stirred solution of (E)-2-methyl-N-(2-methyl-1-oxo-1-(2,2,2-trifluoroethylamino)propan-2-yl)-4-(4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (400 mg, 0.68 mmol) in CH2Cl2 (50 mL) was added P2S5 (75 mg, 0.34 mmol) and HMDO (0.25 mL, 1.12 mmol) at room temperature and the mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and another portion of P2S5 (75 mg, 0.34 mmol) was added and the resulting mixture was refluxed for 18 h. The volatiles were evaporated and the residue was purified by prep TLC to give the title compound as pale yellow gum (47 mg, 11%). Characterization data for this molecule is listed in Table 2.

Example 135: Preparation of (E)-2-Bromo-N-(2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamid e (F1)

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To (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (200 mg, 0.409 mmol) in MeCN (5 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol hydrate (63 mg, 0.411 mmol), HBTU (155 mg, 0.409 mmol), N-(2,2,2-trifluoroethyl) 1-amino-2-methyl-propanecarboxamide hydrochloride (180 mg, 0.816 mmol) and diisopropylethylamine (0.24 mL, 1.38 mmol). After 24 h the material was concentrated in vacuo. The crude product was purified by passing the crude reaction mixture through a silica frit and eluting with EtOAc/hexane (1:2). The recovered material was further purified by medium pressure chromatography on silica with EtOAc/hexane as the eluent to afford the title as a white foam (147 mg, 55%). Characterization data for this molecule is listed in Table 2.

Example 136: Preparation of 1-(3,5-Difluoro-4-methoxyphenyl)-2,2,2-trifluoroethanone

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Isopropyl magnesium chloride lithium chloride complex (22.0 mL, 28.02 mmol) was added dropwise to a stirred solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.0 g, 22.42 mmol) at −5° C. in THF (100 mL) and the reaction mixture was stirred at same temperature for 30 min. Methyl trifluoroacetate (3.67 g, 28.69 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 h. A 2 N HCl solution (200 mL) was added to quench the reaction and then it was extracted with diethylether. The combined organic layers were washed with brine, dried (Na2SO4) filtered and concentrated to afford the title compound (5.4 g, crude) as a yellow liquid. The material was taken to next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68-7.60 (m, 2H) 4.19 (s, 3H); ESIMS m/z 240.1 ([M]+).

The following molecule was prepared in accordance with the procedures disclosed in Example 136:

2,6-Difluoro-4-(2,2,2-trifluoroacetyl)benzonitrile

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1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H); EIMS m/z 235.1 ([M]+).

Example 137: Preparation of (E)-N-(1-((2-Fluoroethyl)amino)-1-oxopropan-2-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (P1618A)

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Step 1: (2R)-tert-Butyl 2-(4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzamido)propanoate

The title compound was prepared according to procedures outlined in Example 15: 1HNMR (400 MHz, DMSO d6) δ 8.73 (d, J=6.8 Hz, 1H), 7.92-7.90 (m, 3H), 7.61 (d, J=7.2 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.2, 9.2 Hz, 1H), 6.77 (d, J=15.2 Hz, 1H), 4.85-4.80 (m, 1H), 4.30-4.26 (m, 1H), 1.43 (s, 9H), 1.33 (d, J=6.8 Hz, 3H); ESIMS m/z 601.9 ([M−H]); IR (KBr) 3414, 1732, 1661, 1170, 748 cm−1.

Step 2: (2R)-(4-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzamido)propanoic acid

TFA (1 mL) was added to a stirred solution of tert-butyl 2-(2-bromo-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)propanoate (1.0 g, 1.63 mmol) in CH2Cl2 (20 mL) at 0° C. and the reaction mixture was stirred at ambient temperature for 18 h. The volatiles were evaporated under vacuum and the residue was triturated with pentane to afford the title compound as brown solid (0.65 g, 67%): 1HNMR (400 MHz, DMSO-d6) δ 12.60 (bs, 1H), 8.82 (d, J=8.0 Hz, 1H), 7.99 (s, 1H), 7.92-7.89 (m, 3H), 7.51 (d, J=8.0 Hz, 1H), 7.08 (dd, J=15.6, 8.8 Hz, 1H), 6.88 (d, J=15.6 Hz, 1H), 4.88-4.83 (m, 1H), 4.41-4.34 (m, 1H), 1.34 (d, J=7.2 Hz, 3H); ESIMS: m/z 545.7 ([M−H]+); IR (KBr) 3410, 3281, 2928, 1728, 1172, 744 cm−1.

Step 3. (E)-N-(1-((2-Fluoroethyl)amino)-1-oxopropan-2-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (P1618)

DIPEA (0.60 mL, 1.08 mmol), PyBOP (180 mg, 0.36 mmol) 2-(4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzamido)propanoic acid (35 mg, 0.36 mmol) were added to a stirred solution of compound 1 (200 mg, 0.36 mmol) in CH2Cl2 (10 mL) at ambient temperature and the reaction mixture was stirred for 18 h. The reaction mixture was diluted CH2Cl2, washed with 1N HCl, followed by a saturated NaHCO3 solution, water and brine. The organic phase was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 10% EtOAc in petroleum ether to afford the title compound as a brown solid (85 mg, 39%).

The following molecule was prepared in accordance with the procedures disclosed in Example 137, Step 1:

tert-Butyl 2-(2-bromo-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)propanoate

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1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.91-7.90 (m, 3H), 7.50 (d, J=7.6 Hz, 1H), 7.07 (dd, J=16.0, 8.8 Hz, 1H), 6.88 (d, J=15.2 Hz, 1H), 4.88-4.83 (m, 1H), 4.31-4.27 (m, 1H), 1.42 (s, 9H), 1.32 (d, J=7.6 Hz, 3H); ESIMS m/z 611.7 ([M−H]); IR (KBr) 3296, 2932, 1732, 1162, 743, 556 cm−1.

(E)-tert-Butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetate

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Isolated as a (620 mg, 72%) pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (t, J=6.0 Hz, 1H), 7.93-7.91 (m, 3H), 7.62 (d, J=6.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.00 (dd, J=15.6, 9.2 Hz, 1H), 6.77 (d, J=16.0 Hz, 1H), 4.86-4.81 (m, 1H), 3.86-3.85 (m, 2H), 1.33 (s, 9H). ESIMS m/z 599.87 ([M+H]+).

The following molecule was prepared in accordance with the procedures disclosed in Example 137, Step 2:

2-(2-Bromo-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)propanoic acid

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1HNMR (400 MHz, DMSO-d6): δ 12.62 (bs, 1H), 8.73 (d, J=9.6 Hz, 1H), 7.93-7.91 (m, 3H), 7.61 (d, J=8.1 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.01 (dd, J=15.6, 9.0 Hz, 1H), 6.78 (d, J=15.9 Hz, 1H), 4.89-4.79 (m, 1H), 4.42-4.32 (m, 1H), 1.36 (d, J=7.2 Hz, 3H); ESIMS: m/z 558.0 ([M+H]+); IR (KBr) 3418, 1650, 1115, 747, 560 cm−1.

(E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)acetic acid

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Isolated as an (550 mg, 97%) off white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.56 (bs, 1H), 8.73 (t, J=5.4 Hz, 1H), 7.93-7.91 (m, 3H), 7.62 (d, J=9.3 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.01 (dd, J=15.9, 9.0 Hz, 1H), 6.78 (d, J=15.9 Hz, 1H), 4.89-4.80 (m, 1H), 3.90-3.88 (m, 2H). ESIMS m/z 541.82 ([M−H]).

Example 138: Preparation of (E)-2-Chloro-5-hydroxy-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide

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Step 1. Methyl 4-bromo-2-chloro-5-methoxybenzoate

A 25 mL round bottomed flask equipped with a magnetic stir bar was charged with 4-bromo-2-chloro-5-methoxybenzoic acid (JACS, 1963, 730-2; 1.25 g, 4.72 mmol), 20% MeOH/EtOAc (25 mL) and cooled in an ice-water bath. Trimethylsilyldiazomethane (TMSCHN2 2 M in hexanes, 2.6 mL, 5.20 mmol) was added dropwise via an addition funnel. The reaction continued to stir for 1 h then it was concentrated to afford the title compound as a white solid (1.31 g, 100%): mp 78-79° C.; 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.36 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H); EIMS m/z 280 ([M]+).

Step 2. 2-Chloro-5-methoxy-4-vinylbenzoic acid

A 25 mL round bottomed flask was charged with methyl 4-bromo-2-chloro-5-methoxybenzoate (640 mg, 2.29 mmol), K2CO3 (665 mg, 4.81 mmol), potassium trifluoro(vinyl)borate (920 mg, 6.87 mmol), PdCl2(dppf) (84 mg, 0.11 mmol) and anhydrous DMSO (15 mL) and stirred at 80° C. for 2 h. The reaction was allowed to cool, water (150 mL) was added and then extracted several times with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a brown residue. The crude product was purified via flash chromatography eluting with 15% Et2O/hexanes to give methyl 2-chloro-5-methoxy-4-vinylbenzoate as a yellow oil (440 mg, 85%). To a 25 mL round bottomed flask containing methyl 2-chloro-5-methoxy-4-vinylbenzoate (440 mg, 1.94 mmol) and MeOH (10 mL) was added 1N NaOH (2 mL, 2.04 mmol) and reaction stirred at ambient temperature for 18 h. The reaction mixture was concentrated to give a solid residue. The residue was dissolved in water and extracted 1× with 50% Et2O/hexanes. The aqueous layer was made acidic with 2N HCl and extracted 2× with CH2Cl2, dried over MgSO4, filtered and concentrated to afford the title compound as a white solid (0.39 g, 94%): 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=0.5 Hz, 1H), 7.52 (s, 1H), 6.98 (ddd, J=17.7, 11.2, 0.6 Hz, 1H), 5.87 (dd, J=17.7, 1.1 Hz, 1H), 5.45 (dd, J=11.2, 1.1 Hz, 1H), 3.90 (s, 3H).

Step 3. (E)-2-Chloro-5-methoxy-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid

A 50 mL 3 neck round bottomed flask was charged with 2-chloro-5-methoxy-4-vinylbenzoic acid (390 mg, 1.84 mmol)), 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (754 mg, 2.20 mmol) and anhydrous N-methyl pyrrolidinone (10 mL). Nitrogen was bubbled into the reaction mixture for 15 min. After which time, 2,2′-dipyridyl (57.3 mg, 0.37 mmol) and CuBr (11.7 mg, 0.18 mmol) were added and reaction mixture stirred at 150° C. for 1 h. Reaction mixture was allowed to cool, water (300 mL) was added and extracted several times with Et2O. Organic layer was washed repeatedly with water, dried over MgSO4, filtered and concentrated to afford—the title compound as a light brown foam (870 mg, 100%). This material was 95% pure by LC/MS; ESIMS m/z 473 ([M−H]). This material was used without further purification.

Step 4. (E)-2-Chloro-5-methoxy-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide

A 50 mL round bottomed flask was charged with (E)-2-chloro-5-methoxy-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (780 mg, 1.65 mmol)), di(1H-imidazol-1-yl)methanone (267 mg, 1.65 mmol) and anhydrous THF (30 mL). The resulting mixture was heated at reflux until it ceased giving off gas. 2-Amino-N-(2,2,2-trifluoroethyl)acetamide HCl (257 mg, 1.65 mmol) was added in one portion and the reaction mixture continued to stir at reflux for 18 h. The reaction mixture was concentrated to dryness and the residue was taken up in Et2O (50 mL) and 0.1N HCl (10 mL). The layers were separated. The aqueous layer was extracted 2× with Et2O. The Et2O layers were combined and washed 1× with aqueous NaHCO3, 1× with brine, dried over MgSO4, filtered and concentrated to give a brown oil. The crude product was purified via flash chromatography eluting with 30-40% EtOAc/hexanes to afford the title compound—as an off white foam (280 mg, 28%): 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.41 (s, 2H), 7.29 (s, 1H), 7.28 (s, 1H), 6.84 (m, 2H), 6.43 (dd, J=16.0, 8.3 Hz, 1H), 4.25 (d, J=5.4 Hz, 2H), 4.10 (m, 1H), 3.97 (qd, J=9.0, 6.4 Hz, 2H), 3.87 (s, 3H); ESIMS m/z 613.1 ([M+H]+).

Step 5. (E)-2-Chloro-5-hydroxy-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide

A 25 mL round bottomed flask was charged with (E)-2-chloro-5-methoxy-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (57 mg, 0.093 mmol) and CH2Cl2 (3 mL). The reaction mixture was cooled to −78° C. and boron tribromide (BBr3, 1.0M solution in CH2Cl2, 0.33 mL, 0.326 mmol) was added slowly via syringe. The reaction allowed to warm to ambient temperature and stirred for 18 h. An additional 0.3-0.4 mL of BBr3 was added at ambient temperature and continued to stir for 3 h. The reaction mixture was added to aqueous NaHCO3 and extracted 3× with CH2Cl2. The CH2Cl2 layers were combined and dried over MgSO4, filtered and concentrated to give an oil. The crude material was purified via flash chromatography eluting with 50% EtOAc/hexanes to afford the title compound as a white solid (18 mg, 33%): mp 190° C. (dec.); 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.06 (d, J=7.0 Hz, 1H), 7.71 (m, 1H), 7.44 (d, J=2.8 Hz, 2H), 7.37 (s, 1H), 7.20 (s, 1H), 6.82 (d, J=15.9 Hz, 1H), 6.50 (m, 1H), 4.14 (m, 3H), 3.89 (m, 2H); ESIMS m/z 599 ([M+H]+).

Example 139: Preparation of 1-(3,4-Dichlorophenyl)-2,2-difluoropropan-1-one

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To a magnetically stirred solution of 4-bromo-1,2-dichlorobenzene (5.64 g, 24.98 mmol) in dry Et2O (109 mL) was added n-BuLi (10.86 mL, 24.98 mmol) via an addition funnel under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 30 min, A solution of ethyl 2,2-difluoropropanoate (3.0 g, 21.7 mmol) in Et2O (10 mL) was added dropwise over 15 min and allowed to stir for 1 h. The reaction was then carefully quenched with 1 N HCl (4 mL) and allowed to warm to 23° C. The solution was dilute with Et2O and washed with water. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the resulting material was purified via flash column chromatography using 100% hexanes to 5% acetone/95% hexanes as eluent. The relevant fractions were concentrated under reduced pressure to afford the title compound as a colorless oil (3.89 g, 71%): 1H NMR (400 MHz, CDCl3) δ 8.21-8.18 (m, 1H), 7.99-7.93 (m, 1H), 7.59 (dd, J=8.4, 4.2 Hz, 1H), 1.89 (t, J=19.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −92.08-−93.21 (m); EISMS m/z 240 ([M−H]+).

Example 140: (E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-vinylbenzoic acid

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To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (600 mg, 1.23 mmol) in dry toluene (10 mL) was added tributyl(vinyl)stannane (470 mg, 1.48 mmol) and the mixture was degassed with argon for 15 min. Pd(PPh3)4 (72 mg, 0.06 mmol) was added and the reaction mixture was refluxed for 2 h. The reaction mixture was brought to ambient temperature, water was added and the mixture extracted with EtOAc. The organic layer was washed with 2N HCl and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica eluting with 30% EtOAc in petroleum ether to afford the title compound as brown solid (295 mg, 55%): 1H NMR (300 MHz, DMSO-d6) δ 13.05 (bs, 1H), 7.91 (s, 2H), 7.81-7.75 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.48 (dd, J=17.4, 10.8 Hz, 1H), 7.03 (dd, J=15.9, 8.7 Hz, 1H), 6.84 (d, J=15.6 Hz, 1H), 5.88 (d, J=16.5 Hz, 1H), 5.39 (d, J=12.3 Hz, 1H), 4.89-4.82 (m, 1H); ESIMS m/z 432.18 ([M−H]); IR (thinfilm) 3418, 1689, 1114, 747 cm−1.

Example 141: (E)-2-Iodo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid

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Per Buchwald, et al.; JACS, 2002, 124, 14844-14845, potassium iodide (KI, 273 mg, 1.64 mmol), CuI (31 mg, 0.16 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (catalytic amount) were added to a solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) in 1,4-dioxane (8 mL). The mixture in an Ace pressure tube was heated at 100° C. for 3 h. The reaction mixture was brought to ambient temperature and filtered through a Celite® pad. The filtrate was concentrated and residue was diluted with EtOAc and washed with 1N HCl followed by brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica eluting with 25% EtOAc in petroleum ether to afford the title compound as brown semi solid (240 mg, 55%): 1H NMR (400 MHz, DMSO-d6) δ 13.3 (bs, 1H), 8.21 (s, 1H), 7.91 (s, 2H), 7.71-7.64 (m, 2H), 7.01 (dd, J=15.6, 9.2 Hz, 1H), 6.75 (d, J=15.6 Hz, 1H), 4.85-4.81 (m, 1H); ESIMS m/z 532.8 ([M−H]); IR (thinfilm) 3436, 1699, 1113, 750 cm−1.

Example 142: Preparation of (E)-2-Bromo-N-(2-methyl-1-(neopentylamino)-1-oxopropan-2-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide

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Step 1. (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamido)-2-methylpropanoic acid

A 25 mL round bottomed flask equipped with a magnetic stir bar and reflux condenser was charged with (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (400 mg, 0.82 mmol) and 1,2-dichloroethane (DCE) (5 mL). Thionyl chloride (0.12 mL, 1.64 mmol) was added neat in one portion and the resulting reaction mixture was heated at reflux for 2 h. After which time, reaction mixture was allowed to cool and concentrated to give the crude acid chloride which was used without further purification. To a solution containing NaHCO3 (68.8 mg, 0.82 mmol), 2-amino-2-methylpropanoic acid (84 mg, 0.82 mmol) and dodecyltrimethylammonium bromide (2.52 mg, 8.19 μmol) in 10 mL of THF was added to the acid chloride in THF (1 mL). The resulting mixture was heated at reflux for 18 h. Reaction mixture was allowed to cool and added to water, made acidic with 0.1N HCl, extracted (3×) with Et2O, washed (1×) with brine, dried over MgSO4, filtered and evaporated to afford the title compound as a light brown foam (400 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=1.6 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.40 (s, 2H), 7.37 (dd, J=8.1, 1.6 Hz, 1H), 6.63 (s, 1H), 6.53 (d, J=15.9 Hz, 1H), 6.38 (dd, J=15.9, 7.9 Hz, 1H), 4.10 (p, J=8.3 Hz, 1H), 1.73 (s, 6H). This material is used without further purification.

Step 2. (E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-4,4-dimethyloxazol-5(4H)-one

A 25 mL round bottomed flask was charged with (E)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamido)-2-methylpropanoic acid (400 mg, 0.70 mmol), CH2Cl2 (10 mL) and stirred at 0° C. EDC. HCl (134 mg, 0.70 mmol) was added in one portion as a solid and the reaction mixture was allowed to warm toward ambient temperature and continued to stir for 1 h. The reaction was diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered and evaporated to give a dark oil. The crude product was purified via flash chromatography eluting with 50% hexanes/CH2Cl2 to afford the title compound as an off white foam (220 mg, 57): 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.1 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.42 (d, J=7.8 Hz, 3H), 6.56 (d, J=15.9 Hz, 1H), 6.45 (dd, J=15.9, 7.7 Hz, 1H), 4.12 (p, J=8.5 Hz, 1H), 1.57 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −68.55; ESIMS m/z 554 ([M−H]).

Step 3. (E)-2-Bromo-N-(2-methyl-1-(neopentylamino)-1-oxopropan-2-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide

A 10 mL round bottomed flask was charged with (E)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-4,4-dimethyloxazol-5(4H)-one (90 mg, 0.16 mmol) and CH2Cl2 (2 mL). 2,2-Dimethylpropan-1-amine (28.2 mg, 0.324 mmol) was added neat via pipette and the reaction stirred at ambient temperature for 18 h. The reaction mixture was evaporated to give an oil. The crude product was purified via flash chromatography eluting with 20% EtOAc/hexanes to afford the title compound as a white foam (90 mg, 86%): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.40 (s, 2H), 7.36 (dd, J=8.1, 1.6 Hz, 1H), 6.66 (d, J=10.0 Hz, 2H), 6.53 (d, J=15.9 Hz, 1H), 6.38 (dd, J=15.9, 7.8 Hz, 1H), 4.11 (m, 1H), 3.12 (d, J=6.2 Hz, 2H), 1.72 (s, 6H), 0.93 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −68.62; ESIMS m/z 643.19 ([M+H]+).

Example 143: Preparation of 3,5-Dibromo-4-chlorobenzaldehyde

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Step 1. Methyl 4-amino-3,5-dibromobenzoate: conc

H2SO4 (1.35 mL, 25.48 mmol) was added dropwise to a stirred solution of 4-amino-3,5-dibromobenzoic acid (5.0 g, 16.99 mmol) in MeOH (50 mL) at ambient temperature and the reaction mixture was then stirred at 80° C. for 8 h. The reaction mixture was brought to ambient temperature, volatiles were evaporated and ice cold water was added to the residue and which was then extracted with EtOAc. The organic layer was washed with an aqueous NaHCO3 solution followed by brine and water. The solution was then dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (5.0 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 2H), 6.20 (bs, 2H), 3.78 (s, 3H); ESIMS m/z 307.0 ([M]+); IR (thin film) 3312, 2953, 1726, 595 cm−1.

Step 2. Methyl 3,5-dibromo-4-chlorobenzoate

CuCl2 (2.82 g, 21.0 mmol) in MeCN (30 mL) was stirred at 80° C. for 30 min. To this mixture tert-butylnitrite (2.7 mL, 23 mmol) was then added dropwise at same temperature and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dibromobenzoate (5.0 g, 16 mmol) in MeCN (30 mL) was added dropwise to the reaction mixture and then stirred at 80° C. for 30 min. The reaction mixture was brought to ambient temperature and an aqueous ammonia solution (20 mL) was added to the reaction mixture and extracted with petroleum ether. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (4.5 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 2H), 3.94 (s, 3H); ESIMS m/z 326 ([M]+); IR (thin film) 1732, 746 cm−1.

Step 3. (3,5-Dibromo-4-chlorophenyl)methanol

NaBH4 (1.53 g, 40.65 mmol) was added portionwise to a stirred solution of methyl 3,5-dibromo-4-chlorobenzoate (4.45 g, 13.6 mmol) in MeOH (50 mL) at 0° C. The reaction mixture was then stirred at ambient temperature for 8 h. The volatiles were evaporated and the residue was diluted with CH2Cl2 and washed with brine followed by water. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (3.3 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 2H), 5.49 (bs, 1H), 4.48 (d, J=4.5 Hz, 2H); ESIMS m/z 297.9 ([M]+); IR (thin film) 3460, 747, 534 cm−1.

Step 4. 3,5-Dibromo-4-chlorobenzaldehyde

Pyridinium chlorochromate (PCC, 3.44 g, 15.9 mmol) was added in one portion to a stirred solution of (3,5-dibromo-4-chlorophenyl)methanol (3.2 g, 11.0 mmol) in CHCl3 (40 mL) at ambient temperature and the reaction mixture was stirred overnight. The reaction mixture was filtered through Celite®, the Celite® pad was washed with CHCl3 and the filtrate was concentrated to afford the title compound as an off white solid (2.0 g, 62%): mp 110-113° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.27 (s, 2H); ESIMS m/z 297.0 ([M]+).

Example 144: Preparation of 4-Bromo-3,5-dichlorobenzaldehyde

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Step 1. Methyl 4-amino-3, 5-dichlorobenzoate: conc

H2SO4 (2.5 mL, 97.04 mmol) was added drop wise to a stirred solution of 4-amino-3,5-dichlorobenzoic acid (10.0 g, 48.54 mmol) in MeOH (150 mL) at 0° C. and the reaction mixture was then stirred at 80° C. for 8 h. The volatiles were evaporated; ice cold water was added to the residue and which was then extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a white solid (7.5 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 2H), 3.96 (s, 3H); ESIMS m/z 282 ([M]+); IR (KBr): 1733, 762, 514 cm−1.

Step 2. Methyl 4-bromo-3, 5-dichlorobenzoate

CuBr2 (7.5 g, 34.08 mmol) in MeCN (50 mL) was stirred at 80° C. for 30 min. To this solution tert-butylnitrite (6.5 mL, 54.55 mmol) was added dropwise at the same temperature and the mixture was stirred for another 10 min. Methyl 4-amino-3,5-dichlorobenzoate in MeCN (30 mL) was added dropwise to the reaction mixture which was then stirred at 80° C. for 30 min. The reaction mixture was brought to ambient temperature. Aqueous ammonia solution (20 mL) was added and extracted with petroleum ether. The organic layer was washed with brine followed by water. The organic solution was dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (7.5 g, 77%): 1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 2H), 3.94 (s, 3H); ESIMS m/z 282 ([M]+); IR (thin film) 1733, 762, 514 cm−1.

Step 3. (4-Bromo-3,5-dichlorophenyl)methanol

DIBAL-H (1M in toluene, 66 mL, and 66.0 mmol) was added dropwise to a stirred solution of methyl 4-bromo-3, 5-dichlorobenzoate (7.5 g, 26.0 mmol) in THF (50 mL) at −78° C. The reaction mixture was brought to ambient temperature and stirred for 6 h. The reaction mixture was poured into ice-water and extracted with CH2Cl2. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated to afford a mixture of (4-bromo-3,5-dichlorophenyl)methanol and 4-bromo-3,5-dichlorobenzaldehyde (6.0 g) as an off white solid which was taken to next step without purification.

Step 4. 4-Bromo-3, 5-dichlorobenzaldehyde

PCC (7.5 g, 35.16 mmol) was added in one portion to a stirred solution containing a mixture of (4-bromo-3,5-dichlorophenyl)methanol and 4-bromo-3,5-dichlorobenzaldehyde (6.0 g) in CHCl3 (40 mL) at ambient temperature and the reaction mixture was stirred overnight. The reaction mixture was filtered through celite. The celite pad was washed with CHCl3. The filtrate was concentrated to afford the title compound as an off white solid (3.5 g, 67%): mp 125-128° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.10 (s, 2H); ESIMS m/z 252 ([M]+).

Example 145: 3-Chloro-5-ethylbenzaldehyde

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PdCl2(dppf)(37 mg, 0.046 mmol), potassium phosphate (1.93 g, 9.11 mmol) and triethylborane (1M in hexane, 0.45 g, 4.56 mmol) were added to a solution of 3-bromo-5-chloro-benzaldehyde (1.0 g, 4.56 mmol) in THF (20 mL) at ambient temperature and the mixture was refluxed for 12 h. The reaction mixture was brought to ambient temperature, diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 2% EtOAc in petroleum ether to afford the title compound (330 mg, 41%) as a pale yellow liquid: 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.75 (d, J=1.6 Hz 1H), 7.73 (s, 1H), 7.65 (s, 1H), 2.74-2.68 (m, 2H), 1.23 (t, J=7.6 Hz, 3H); ESIMS m/z 168.0 ([M]+); IR (thin film) 3071, 1699, 692 cm−1.

Example 146: (E)-2-Amino-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide

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Step 1. (E)-Ethyl 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitrobenzoate

5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.5 g, 10.8 mmol), CuCl (54 mg, 0.54 mmol) and 2,2-bipyridyl (169 mg, 1.08 mmol) were added to a stirred solution of ethyl 2-nitro-4-vinylbenzoate (1.2 g, 5.42 mmol) in 1,2-dichlorobenzene (12 mL) at ambient temperature and the mixture was then stirred at 180° C. for 18 h. The reaction mixture was then cooled to ambient temperature, adsorbed on silica gel and purified by column chromatography eluting with 10% EtOAc in petroleum ether to afford the title compound (1.3 g, 53%) as a brown liquid: 1H NMR (DMSO-d6, 300 MHz) δ 8.31 (s, 1H), 8.02-7.95 (m, 1H), 7.88-7.85 (m, 3H), 7.20 (dd, J=15.9, 9.3 Hz, 1H), 6.91 (d, J=15.6 Hz, 1H), 4.91-4.85 (m, 1H), 4.34-4.27 (m, 2H), 1.27 (t, J=6.6 Hz, 3H); ESIMS m/z 463.8 ([M−H]); IR (KBr) 3439, 2985, 1731, 1251 cm−1.

Step 2. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitrobenzoic acid

Concentrated HCl (16.0 mL) was added dropwise to a stirred solution of (E)-ethyl 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitrobenzoate (800 mg, 1.72 mmol) in 1,4-dioxane (8.0 mL) at 0° C. and the reaction mixture was refluxed for 36 h. The volatiles were evaporated; the residue was diluted with EtOAc and washed with brine and water. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% EtOAc in petroleum ether to afford the title compound as a yellow solid (390 mg, 52%): 1H NMR (400 MHz, DMSO-d6) δ 13.9 (bs, 1H), 8.22 (s, 1H), 7.93-7.91 (m, 1H), 7.86-7.84 (m, 3H), 7.16 (dd, J=15.6, 9.2 Hz, 1H), 6.89 (d, J=15.6 Hz, 1H), 4.89-4.85 (m, 1H). ESIMS m/z 435.9 ([M−H]); IR (KBr) 3445, 2924, 1708, 1541, 817 cm−1.

Step 3. (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitro-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide

2-Amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (96 mg, 0.35 mmol), PyBOP (165 mg, 0.32 mmol) and DIPEA (0.1 mL, 0.57 mmol) were added to a stirred solution of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitrobenzoic acid (130 mg, 0.29 mmol) in CH2Cl2 (3 mL) and the reaction mixture was stirred at ambient temperature for 8 h. Water was added to reaction mixture and extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% EtOAc in petroleum ether to afford the title compound as a yellow solid (120 mg, 74%): 1H NMR (300 MHz, DMSO-d6) δ 9.04 (t, J=5.7 Hz, 1H), 8.60 (t, J=6.0 Hz, 1H), 8.25 (s, 1H), 7.97-7.94 (m, 1H), 7.87 (d, J=6.3 Hz, 2H), 7.69 (d, J=7.5 Hz, 1H), 7.15 (dd, J=15.9, 9.3 Hz, 1H), 6.89 (d, J=15.9 Hz, 1H), 4.88-4.83 (m, 1H), 3.98-3.89 (m, 4H); ESIMS m/z 575.87 ([M+H]+); IR (KBr) 3430, 2925, 1663, 1168, 832 cm−1.

Step 4. (E)-2-Amino-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide

Iron powder (81.8 mg, 1.46 mmol) and NH4Cl (104 mg, 1.94 mmol) was added to a stirred solution of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-nitro-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide (280 mg, 0.486 mmol) in EtOH: water (6 mL, 1:1) at ambient temperature and the mixture was stirred at reflux for 90 min. The reaction mixture was cooled to ambient temperature and filtered through celite. The filtrate was concentrated and the residue was dissolved in EtOAc and washed with saturated NaHCO3 solution, brine and water. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (10-200 mesh) eluting with 35% EtOAc in petroleum ether to afford the titled compound as a yellow solid (215 mg, 81%).

Example 147: (E)-2-Bromo-4-(3-(3,5-dichloro-4-hydroxyphenyl)-4,4,4-trifluorobut-1-enyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide

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DIPEA (0.20 mL, 1.26 mmol), PyBOP (245 mg, 0.47 mmol) and 2-amino-N-(2,2,2-trifluoroethyl)acetamide (90 mg, 0.47 mmol) were added to a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-hydroxyphenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (200 mg, 0.42 mmol, 66% purity) in CH2Cl2 (5 mL) at ambient temperature. The resulting mixture was then stirred for 12 h. The reaction mixture was diluted with CH2Cl2, washed with 1N HCl, followed by saturated sodium bicarbonate solution, brine solution and water. The organic layer was dried (Na2SO4), filtered, concentrated under vacuum. The residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% EtOAc in petroleum ether to give the title compound as light green solid (130 mg, 52%).

Example 148: Preparation of (R)-2-Amino-3-methyl-N-(2,2,2-trifluoroethyl)butanamide

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A Parr shaker flask charged with (R)-benzyl (3-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)-butan-2-yl)carbamate (4.95 g, 14.9 mmol) in 100 mL of EtOAc and 25 mL of EtOH was treated with 175 mg of 10% Pd/C. The mixture was placed under 40 psi of hydrogen and shaken for 6 h. An additional 65 mg of 10% Pd/C was added to the reaction mixture which was then placed under 40 psi of hydrogen and shaken for 3.5 h. The reaction solution was then filtered through a pad of celite, concentrated in vacuo and purified by sublimation (75 to 85° C., 200-230 millibar) to afford the title compound as a white solid (1.92 g, 65%): mp 43-47° C.; 1H NMR (400 MHz, CDCl3) δ 8.04-7.74 (m, 1H), 3.92 (ddd, J=16.0, 9.3, 6.8 Hz, 1H), 3.84-3.60 (m, 1H), 3.23 (d, J=3.8 Hz, 1H), 2.23 (ddd, J=10.7, 7.0, 3.5 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.75 (d, J=6.9 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −72.70.

Example 149: Preparation of (E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(methylsulfonyl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide

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Oxone (320 mg, 0.50 mmol) was added to a stirred solution of (E)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(methylthio)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide (150 mg, 0.25 mmol) in acetone-water (10 mL, 1:1) at ambient temperature and the reaction mixture was stirred for 18 h. The reaction mixture was then extracted with CH2Cl2. The organic layer was washed with brine and water, dried (Na2SO4), filtered, concentrated and the residue was triturated with pentane-Et2O (1:1) to afford the title compound as an off white solid (85 mg, 56%): 1H NMR (300 MHz, DMSO-d6) δ 9.01 (t, J=6.0, 1H), 8.37 (t, J=6.4 Hz, 1H), 8.08 (s, 1H), 8.01-7.96 (m, 1H), 7.88-7.86 (m, 2H), 7.64 (d, J=7.6 Hz, 1H), 7.05 (dd, J=16.4, 8.8 Hz, 1H), 6.91 (d, J=15.6 Hz, 1H), 4.87-4.80 (m, 1H), 3.98-3.91 (m, 4H), 3.38 (s, 3H); ESIMS m/z 608.85 ([M+H]+); IR (thin film) 337, 416, 721, 164, 768 cm−1.

The following prophetic molecules could be made in accordance with the procedures disclosed in this application:

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NumberStructure
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The following prophetic molecules could be made in accordance with the procedures disclosed in this application:

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Cmpd No.R1R2R3R4R6R8R10W1(C1-C8) alkylW2R15
P46FFFHCF3HBrOCH2OCH2CF3
P47FFFHCF3HClOCH2OCH2CF3
P48FFFHCF3HCF3OCH2OCH2CF3
P49FFFHCF3HCH3OCH2OCH2CF3
P50FFFHCF3HBrOCH2SCH2CF3
P51FFFHCF3HClOCH2SCH2CF3
P52FFFHCF3HCF3OCH2SCH2CF3
P53FFFHCF3HCH3OCH2SCH2CF3
P54FFFHCF3HBrSCH2OCH2CF3
P55FFFHCF3HClSCH2OCH2CF3
P56FFFHCF3HCF3SCH2OCH2CF3
P57FFFHCF3HCH3SCH2OCH2CF3
P58FFFHCF3HBrOCH2OCH2CHF2
P59FFFHCF3HClOCH2OCH2CHF2
P60FFFHCF3HCF3OCH2OCH2CHF2
P61FFFHCF3HCH3OCH2OCH2CHF2
P62FFFHCF3CF3BrOCH2OCH2CF3
P63FFFHCF3CF3ClOCH2OCH2CF3
P64FFFHCF3CF3CF3OCH2OCH2CF3
P65FFFHCF3CF3CH3OCH2OCH2CF3
P66FFFHCF2CF3HBrOCH2OCH2CF3
P67FFFHCF2CF3HClOCH2OCH2CF3
P68FFFHCF2CF3HCF3OCH2OCH2CF3
P69FFFHCF2CF3HCH3OCH2OCH2CF3
P70FFFHCF3HBrOCH2OCH(CH3)CF3
P71FFFHCF3HClOCH2OCH(CH3)CF3
P72FFFHCF3HCF3OCH2OCH(CH3)CF3
P73FFFHCF3HCH3OCH2OCH(CH3)CF3
P74FFFHCF3CF3BrOCH(CH3)OCH2CF3
P75FFFHCF3CF3ClOCH(CH3)OCH2CF3
P76FFFHCF3CF3CF3OCH(CH3)OCH2CF3
P77FFFHCF3CF3CH3OCH(CH3)OCH2CF3
P78FFFHCF2CF3HBrOCH(CH3)OCH2CF3
P79FFFHCF2CF3HClOCH(CH3)OCH2CF3
P80FFFHCF2CF3HCF3OCH(CH3)OCH2CF3
P81FFFHCF2CF3HCH3OCH(CH3)OCH2CF3
P82FFFHCF3HBrOCH(CH3)OCH2CF3
P83FFFHCF3HClOCH(CH3)OCH2CF3
P84FFFHCF3HCF3OCH(CH3)OCH2CF3
P85FFFHCF3HCH3OCH(CH3)OCH2CF3
P86FFFHCF3HBrOCH(CH3)SCH2CF3
P87FFFHCF3HClOCH(CH3)SCH2CF3
P88FFFHCF3HCF3OCH(CH3)SCH2CF3
P89FFFHCF3HCH3OCH(CH3)SCH2CF3
P90FFFHCF3HBrSCH(CH3)OCH2CF3
P91FFFHCF3HClSCH(CH3)OCH2CF3
P92FFFHCF3HCF3SCH(CH3)OCH2CF3
P93FFFHCF3HCH3SCH(CH3)OCH2CF3
P94FFFHCF3HBrOCH(CH3)OCH2CHF2
P95FFFHCF3HClOCH(CH3)OCH2CHF2
P96FFFHCF3HCF3OCH(CH3)OCH2CHF2
P97FFFHCF3HCH3OCH(CH3)OCH2CHF2
P98FFFHCF3HBrOCH(CH3)OCH(CH3)CF3
P99FFFHCF3HClOCH(CH3)OCH(CH3)CF3
P100FFFHCF3HCF3OCH(CH3)OCH(CH3)CF3
P101FFFHCF3HCH3OCH(CH3)OCH(CH3)CF3
P102FFFHCF3HBrOCH(CH3)OCH2CH2CF3
P103FFFHCF3HClOCH(CH3)OCH2CH2CF3
P104FFFHCF3HCF3OCH(CH3)OCH2CH2CF3
P105FFFHCF3HCH3OCH(CH3)OCH2CH2CF3
P106FFFHCF3HBrOCH(CH2CH3)OCH2CF3
P107FFFHCF3HClOCH(CH2CH3)OCH2CF3
P108FFFHCF3HCF3OCH(CH2CH3)OCH2CF3
P109FFFHCF3HCH3OCH(CH2CH3)OCH2CF3
P110FFFHCF3HBrOC(CH3)2OCH2CF3
P111FFFHCF3HClOC(CH3)2OCH2CF3
P112FFFHCF3HCF3OC(CH3)2OCH2CF3
P113FFFHCF3HCH3OC(CH3)2OCH2CF3
P114FFFHCF3HBrOCH2CH2OCH2CF3
P115FFFHCF3HClOCH2CH2OCH2CF3
P116FFFHCF3HCF3OCH2CH2OCH2CF3
P117FFFHCF3HCH3OCH2CH2OCH2CF3
P118ClClHClCF3HBrOCH2OCH2CF3
P119ClClHClCF3HClOCH2OCH2CF3
P120ClClHClCF3HCF3OCH2OCH2CF3
P121ClClHClCF3HCH3OCH2OCH2CF3
P122ClClHClCF3HBrOCH2SCH2CF3
P123ClClHClCF3HClOCH2SCH2CF3
P124ClClHClCF3HCF3OCH2SCH2CF3
P125ClClHClCF3HCH3OCH2SCH2CF3
P126ClClHClCF3HBrSCH2OCH2CF3
P127ClClHClCF3HClSCH2OCH2CF3
P128ClClHClCF3HCF3SCH2OCH2CF3
P129ClClHClCF3HCH3SCH2OCH2CF3
P130ClClHClCF3HBrOCH2OCH2CHF2
P131ClClHClCF3HClOCH2OCH2CHF2
P132ClClHClCF3HCF3OCH2OCH2CHF2
P133ClClHClCF3HCH3OCH2OCH2CHF2
P134ClClHClCF3CF3BrOCH2OCH2CF3
P135ClClHClCF3CF3ClOCH2OCH2CF3
P136ClClHClCF3CF3CF3OCH2OCH2CF3
P137ClClHClCF3CF3CH3OCH2OCH2CF3
P138ClClHClCF2CF3HBrOCH2OCH2CF3
P139ClClHClCF2CF3HClOCH2OCH2CF3
P140ClClHClCF2CF3HCF3OCH2OCH2CF3
P141ClClHClCF2CF3HCH3OCH2OCH2CF3
P142ClClHClCF3HBrOCH2OCH(CH3)CF3
P143ClClHClCF3HClOCH2OCH(CH3)CF3
P144ClClHClCF3HCF3OCH2OCH(CH3)CF3
P145ClClHClCF3HCH3OCH2OCH(CH3)CF3
P146ClClHClCF3CF3BrOCH(CH3)OCH2CF3
P147ClClHClCF3CF3ClOCH(CH3)OCH2CF3
P148ClClHClCF3CF3CF3OCH(CH3)OCH2CF3
P149ClClHClCF3CF3CH3OCH(CH3)OCH2CF3
P150ClClHClCF2CF3HBrOCH(CH3)OCH2CF3
P151ClClHClCF2CF3HClOCH(CH3)OCH2CF3
P152ClClHClCF2CF3HCF3OCH(CH3)OCH2CF3
P153ClClHClCF2CF3HCH3OCH(CH3)OCH2CF3
P154ClClHClCF3HBrOCH(CH3)OCH2CF3
P155ClClHClCF3HClOCH(CH3)OCH2CF3
P156ClClHClCF3HCF3OCH(CH3)OCH2CF3
P157ClClHClCF3HCH3OCH(CH3)OCH2CF3
P158ClClHClCF3HBrOCH(CH3)SCH2CF3
P159ClClHClCF3HClOCH(CH3)SCH2CF3
P160ClClHClCF3HCF3OCH(CH3)SCH2CF3
P161ClClHClCF3HCH3OCH(CH3)SCH2CF3
P162ClClHClCF3HBrSCH(CH3)OCH2CF3
P163ClClHClCF3HClSCH(CH3)OCH2CF3
P164ClClHClCF3HCF3SCH(CH3)OCH2CF3
P165ClClHClCF3HCH3SCH(CH3)OCH2CF3
P166ClClHClCF3HBrOCH(CH3)OCH2CHF2
P167ClClHClCF3HClOCH(CH3)OCH2CHF2
P168ClClHClCF3HCF3OCH(CH3)OCH2CHF2
P169ClClHClCF3HCH3OCH(CH3)OCH2CHF2
P170ClClHClCF3HBrOCH(CH3)OCH(CH3)CF3
P171ClClHClCF3HClOCH(CH3)OCH(CH3)CF3
P172ClClHClCF3HCF3OCH(CH3)OCH(CH3)CF3
P173ClClHClCF3HCH3OCH(CH3)OCH(CH3)CF3
P174ClClHClCF3HBrOCH(CH3)OCH2CH2CF3
P175ClClHClCF3HClOCH(CH3)OCH2CH2CF3
P176ClClHClCF3HCF3OCH(CH3)OCH2CH2CF3
P177ClClHClCF3HCH3OCH(CH3)OCH2CH2CF3
P178ClClHClCF3HBrOCH(CH2CH3)OCH2CF3
P179ClClHClCF3HClOCH(CH2CH3)OCH2CF3
P180ClClHClCF3HCF3OCH(CH2CH3)OCH2CF3
P181ClClHClCF3HCH3OCH(CH2CH3)OCH2CF3
P182ClClHClCF3HBrOC(CH3)2OCH2CF3
P183ClClHClCF3HClOC(CH3)2OCH2CF3
P184ClClHClCF3HCF3OC(CH3)2OCH2CF3
P185ClClHClCF3HCH3OC(CH3)2OCH2CF3
P186ClClHClCF3HBrOCH2CH2OCH2CF3
P187ClClHClCF3HClOCH2CH2OCH2CF3
P188ClClHClCF3HCF3OCH2CH2OCH2CF3
P189ClClHClCF3HCH3OCH2CH2OCH2CF3
P190HHHOCF3CF3HBrOCH2OCH2CF3
P191HHHOCF3CF3HClOCH2OCH2CF3
P192HHHOCF3CF3HCF3OCH2OCH2CF3
P193HHHOCF3CF3HCH3OCH2OCH2CF3
P194HHHOCF3CF3HBrOCH2SCH2CF3
P195HHHOCF3CF3HClOCH2SCH2CF3
P196HHHOCF3CF3HCF3OCH2SCH2CF3
P197HHHOCF3CF3HCH3OCH2SCH2CF3
P198HHHOCF3CF3HBrSCH2OCH2CF3
P199HHHOCF3CF3HClSCH2OCH2CF3
P200HHHOCF3CF3HCF3SCH2OCH2CF3
P201HHHOCF3CF3HCH3SCH2OCH2CF3
P202HHHOCF3CF3HBrOCH2OCH2CHF2
P203HHHOCF3CF3HClOCH2OCH2CHF2
P204HHHOCF3CF3HCF3OCH2OCH2CHF2
P205HHHOCF3CF3HCH3OCH2OCH2CHF2
P206HHHOCF3CF3CF3BrOCH2OCH2CF3
P207HHHOCF3CF3CF3ClOCH2OCH2CF3
P208HHHOCF3CF3CF3CF3OCH2OCH2CF3
P209HHHOCF3CF3CF3CH3OCH2OCH2CF3
P210HHHOCF3CF2CF3HBrOCH2OCH2CF3
P211HHHOCF3CF2CF3HClOCH2OCH2CF3
P212HHHOCF3CF2CF3HCF3OCH2OCH2CF3
P213HHHOCF3CF2CF3HCH3OCH2OCH2CF3
P214HHHOCF3CF3HBrOCH2OCH(CH3)CF3
P215HHHOCF3CF3HClOCH2OCH(CH3)CF3
P216HHHOCF3CF3HCF3OCH2OCH(CH3)CF3
P217HHHOCF3CF3HCH3OCH2OCH(CH3)CF3
P218HHHOCF3CF3CF3BrOCH(CH3)OCH2CF3
P219HHHOCF3CF3CF3ClOCH(CH3)OCH2CF3
P220HHHOCF3CF3CF3CF3OCH(CH3)OCH2CF3
P221HHHOCF3CF3CF3CH3OCH(CH3)OCH2CF3
P222HHHOCF3CF2CF3HBrOCH(CH3)OCH2CF3
P223HHHOCF3CF2CF3HClOCH(CH3)OCH2CF3
P224HHHOCF3CF2CF3HCF3OCH(CH3)OCH2CF3
P225HHHOCF3CF2CF3HCH3OCH(CH3)OCH2CF3
P226HHHOCF3CF3HBrOCH(CH3)OCH2CF3
P227HHHOCF3CF3HClOCH(CH3)OCH2CF3
P228HHHOCF3CF3HCF3OCH(CH3)OCH2CF3
P229HHHOCF3CF3HCH3OCH(CH3)OCH2CF3
P230HHHOCF3CF3HBrOCH(CH3)SCH2CF3
P231HHHOCF3CF3HClOCH(CH3)SCH2CF3
P232HHHOCF3CF3HCF3OCH(CH3)SCH2CF3
P233HHHOCF3CF3HCH3OCH(CH3)SCH2CF3
P234HHHOCF3CF3HBrSCH(CH3)OCH2CF3
P235HHHOCF3CF3HClSCH(CH3)OCH2CF3
P236HHHOCF3CF3HCF3SCH(CH3)OCH2CF3
P237HHHOCF3CF3HCH3SCH(CH3)OCH2CF3
P238HHHOCF3CF3HBrOCH(CH3)OCH2CHF2
P239HHHOCF3CF3HClOCH(CH3)OCH2CHF2
P240HHHOCF3CF3HCF3OCH(CH3)OCH2CHF2
P241HHHOCF3CF3HCH3OCH(CH3)OCH2CHF2
P242HHHOCF3CF3HBrOCH(CH3)OCH(CH3)CF3
P243HHHOCF3CF3HClOCH(CH3)OCH(CH3)CF3
P244HHHOCF3CF3HCF3OCH(CH3)OCH(CH3)CF3
P245HHHOCF3CF3HCH3OCH(CH3)OCH(CH3)CF3
P246HHHOCF3CF3HBrOCH(CH3)OCH2CH2CF3
P247HHHOCF3CF3HClOCH(CH3)OCH2CH2CF3
P248HHHOCF3CF3HCF3OCH(CH3)OCH2CH2CF3
P249HHHOCF3CF3HCH3OCH(CH3)OCH2CH2CF3
P250HHHOCF3CF3HBrOCH(CH2CH3)OCH2CF3
P251HHHOCF3CF3HClOCH(CH2CH3)OCH2CF3
P252HHHOCF3CF3HCF3OCH(CH2CH3)OCH2CF3
P253HHHOCF3CF3HCH3OCH(CH2CH3)OCH2CF3
P254HHHOCF3CF3HBrOC(CH3)2OCH2CF3
P255HHHOCF3CF3HClOC(CH3)2OCH2CF3
P256HHHOCF3CF3HCF3OC(CH3)2OCH2CF3
P257HHHOCF3CF3HCH3OC(CH3)2OCH2CF3
P258HHHOCF3CF3HBrOCH2CH2OCH2CF3
P259HHHOCF3CF3HClOCH2CH2OCH2CF3
P260HHHOCF3CF3HCF3OCH2CH2OCH2CF3
P261HHHOCF3CF3HCH3OCH2CH2OCH2CF3
P262HFHBrCF3HBrOCH2OCH2CF3
P263HFHBrCF3HClOCH2OCH2CF3
P264HFHBrCF3HCF3OCH2OCH2CF3
P265HFHBrCF3HCH3OCH2OCH2CF3
P266HFHBrCF3HBrOCH2SCH2CF3
P267HFHBrCF3HClOCH2SCH2CF3
P268HFHBrCF3HCF3OCH2SCH2CF3
P269HFHBrCF3HCH3OCH2SCH2CF3
P270HFHBrCF3HBrSCH2OCH2CF3
P271HFHBrCF3HClSCH2OCH2CF3
P272HFHBrCF3HCF3SCH2OCH2CF3
P273HFHBrCF3HCH3SCH2OCH2CF3
P274HFHBrCF3HBrOCH2OCH2CHF2
P275HFHBrCF3HClOCH2OCH2CHF2
P276HFHBrCF3HCF3OCH2OCH2CHF2
P277HFHBrCF3HCH3OCH2OCH2CHF2
P278HFHBrCF3CF3BrOCH2OCH2CF3
P279HFHBrCF3CF3ClOCH2OCH2CF3
P280HFHBrCF3CF3CF3OCH2OCH2CF3
P281HFHBrCF3CF3CH3OCH2OCH2CF3
P282HFHBrCF2CF3HBrOCH2OCH2CF3
P283HFHBrCF2CF3HClOCH2OCH2CF3
P284HFHBrCF2CF3HCF3OCH2OCH2CF3
P285HFHBrCF2CF3HCH3OCH2OCH2CF3
P286HFHBrCF3HBrOCH2OCH(CH3)CF3
P287HFHBrCF3HClOCH2OCH(CH3)CF3
P288HFHBrCF3HCF3OCH2OCH(CH3)CF3
P289HFHBrCF3HCH3OCH2OCH(CH3)CF3
P290HFHBrCF3CF3BrOCH(CH3)OCH2CF3
P291HFHBrCF3CF3ClOCH(CH3)OCH2CF3
P292HFHBrCF3CF3CF3OCH(CH3)OCH2CF3
P293HFHBrCF3CF3CH3OCH(CH3)OCH2CF3
P294HFHBrCF2CF3HBrOCH(CH3)OCH2CF3
P295HFHBrCF2CF3HClOCH(CH3)OCH2CF3
P296HFHBrCF2CF3HCF3OCH(CH3)OCH2CF3
P297HFHBrCF2CF3HCH3OCH(CH3)OCH2CF3
P298HFHBrCF3HBrOCH(CH3)OCH2CF3
P299HFHBrCF3HClOCH(CH3)OCH2CF3
P300HFHBrCF3HCF3OCH(CH3)OCH2CF3
P301HFHBrCF3HCH3OCH(CH3)OCH2CF3
P302HFHBrCF3HBrOCH(CH3)SCH2CF3
P303HFHBrCF3HClOCH(CH3)SCH2CF3
P304HFHBrCF3HCF3OCH(CH3)SCH2CF3
P305HFHBrCF3HCH3OCH(CH3)SCH2CF3
P306HFHBrCF3HBrSCH(CH3)OCH2CF3
P307HFHBrCF3HClSCH(CH3)OCH2CF3
P308HFHBrCF3HCF3SCH(CH3)OCH2CF3
P309HFHBrCF3HCH3SCH(CH3)OCH2CF3
P310HFHBrCF3HBrOCH(CH3)OCH2CHF2
P311HFHBrCF3HClOCH(CH3)OCH2CHF2
P312HFHBrCF3HCF3OCH(CH3)OCH2CHF2
P313HFHBrCF3HCH3OCH(CH3)OCH2CHF2
P314HFHBrCF3HBrOCH(CH3)OCH(CH3)CF3
P315HFHBrCF3HClOCH(CH3)OCH(CH3)CF3
P316HFHBrCF3HCF3OCH(CH3)OCH(CH3)CF3
P317HFHBrCF3HCH3OCH(CH3)OCH(CH3)CF3
P318HFHBrCF3HBrOCH(CH3)OCH2CH2CF3
P319HFHBrCF3HClOCH(CH3)OCH2CH2CF3
P320HFHBrCF3HCF3OCH(CH3)OCH2CH2CF3
P321HFHBrCF3HCH3OCH(CH3)OCH2CH2CF3
P322HFHBrCF3HBrOCH(CH2CH3)OCH2CF3
P323HFHBrCF3HClOCH(CH2CH3)OCH2CF3
P324HFHBrCF3HCF3OCH(CH2CH3)OCH2CF3
P325HFHBrCF3HCH3OCH(CH2CH3)OCH2CF3
P326HFHBrCF3HBrOC(CH3)2OCH2CF3
P327HFHBrCF3HClOC(CH3)2OCH2CF3
P328HFHBrCF3HCF3OC(CH3)2OCH2CF3
P329HFHBrCF3HCH3OC(CH3)2OCH2CF3
P330HFHBrCF3HBrOCH2CH2OCH2CF3
P331HFHBrCF3HClOCH2CH2OCH2CF3
P332HFHBrCF3HCF3OCH2CH2OCH2CF3
P333HFHBrCF3HCH3OCH2CH2OCH2CF3
P334HCH3ClHCF3HBrOCH2OCH2CF3
P335HCH3ClHCF3HClOCH2OCH2CF3
P336HCH3ClHCF3HCF3OCH2OCH2CF3
P337HCH3ClHCF3HCH3OCH2OCH2CF3
P338HCH3ClHCF3HBrOCH2SCH2CF3
P339HCH3ClHCF3HClOCH2SCH2CF3
P340HCH3ClHCF3HCF3OCH2SCH2CF3
P341HCH3ClHCF3HCH3OCH2SCH2CF3
P342HCH3ClHCF3HBrSCH2OCH2CF3
P343HCH3ClHCF3HClSCH2OCH2CF3
P344HCH3ClHCF3HCF3SCH2OCH2CF3
P345HCH3ClHCF3HCH3SCH2OCH2CF3
P346HCH3ClHCF3HBrOCH2OCH2CHF2
P347HCH3ClHCF3HClOCH2OCH2CHF2
P348HCH3ClHCF3HCF3OCH2OCH2CHF2
P349HCH3ClHCF3HCH3OCH2OCH2CHF2
P350HCH3ClHCF3CF3BrOCH2OCH2CF3
P351HCH3ClHCF3CF3ClOCH2OCH2CF3
P352HCH3ClHCF3CF3CF3OCH2OCH2CF3
P353HCH3ClHCF3CF3CH3OCH2OCH2CF3
P354HCH3ClHCF2CF3HBrOCH2OCH2CF3
P355HCH3ClHCF2CF3HClOCH2OCH2CF3
P356HCH3ClHCF2CF3HCF3OCH2OCH2CF3
P357HCH3ClHCF2CF3HCH3OCH2OCH2CF3
P358HCH3ClHCF3HBrOCH2OCH(CH3)CF3
P359HCH3ClHCF3HClOCH2OCH(CH3)CF3
P360HCH3ClHCF3HCF3OCH2OCH(CH3)CF3
P361HCH3ClHCF3HCH3OCH2OCH(CH3)CF3
P362HCH3ClHCF3CF3BrOCH(CH3)OCH2CF3
P363HCH3ClHCF3CF3ClOCH(CH3)OCH2CF3
P364HCH3ClHCF3CF3CF3OCH(CH3)OCH2CF3
P365HCH3ClHCF3CF3CH3OCH(CH3)OCH2CF3
P366HCH3ClHCF2CF3HBrOCH(CH3)OCH2CF3
P367HCH3ClHCF2CF3HClOCH(CH3)OCH2CF3
P368HCH3ClHCF2CF3HCF3OCH(CH3)OCH2CF3
P369HCH3ClHCF2CF3HCH3OCH(CH3)OCH2CF3
P370HCH3ClHCF3HBrOCH(CH3)OCH2CF3
P371HCH3ClHCF3HClOCH(CH3)OCH2CF3
P372HCH3ClHCF3HCF3OCH(CH3)OCH2CF3
P373HCH3ClHCF3HCH3OCH(CH3)OCH2CF3
P374HCH3ClHCF3HBrOCH(CH3)SCH2CF3
P375HCH3ClHCF3HClOCH(CH3)SCH2CF3
P376HCH3ClHCF3HCF3OCH(CH3)SCH2CF3
P377HCH3ClHCF3HCH3OCH(CH3)SCH2CF3
P378HCH3ClHCF3HBrSCH(CH3)OCH2CF3
P379HCH3ClHCF3HClSCH(CH3)OCH2CF3
P380HCH3ClHCF3HCF3SCH(CH3)OCH2CF3
P381HCH3ClHCF3HCH3SCH(CH3)OCH2CF3
P382HCH3ClHCF3HBrOCH(CH3)OCH2CHF2
P383HCH3ClHCF3HClOCH(CH3)OCH2CHF2
P384HCH3ClHCF3HCF3OCH(CH3)OCH2CHF2
P385HCH3ClHCF3HCH3OCH(CH3)OCH2CHF2
P386HCH3ClHCF3HBrOCH(CH3)OCH(CH3)CF3
P387HCH3ClHCF3HClOCH(CH3)OCH(CH3)CF3
P388HCH3ClHCF3HCF3OCH(CH3)OCH(CH3)CF3
P389HCH3ClHCF3HCH3OCH(CH3)OCH(CH3)CF3
P390HCH3ClHCF3HBrOCH(CH3)OCH2CH2CF3
P391HCH3ClHCF3HClOCH(CH3)OCH2CH2CF3
P392HCH3ClHCF3HCF3OCH(CH3)OCH2CH2CF3
P393HCH3ClHCF3HCH3OCH(CH3)OCH2CH2CF3
P394HCH3ClHCF3HBrOCH(CH2CH3)OCH2CF3
P395HCH3ClHCF3HClOCH(CH2CH3)OCH2CF3
P396HCH3ClHCF3HCF3OCH(CH2CH3)OCH2CF3
P397HCH3ClHCF3HCH3OCH(CH2CH3)OCH2CF3
P398HCH3ClHCF3HBrOC(CH3)2OCH2CF3
P399HCH3ClHCF3HClOC(CH3)2OCH2CF3
P400HCH3ClHCF3HCF3OC(CH3)2OCH2CF3
P401HCH3ClHCF3HCH3OC(CH3)2OCH2CF3
P402HCH3ClHCF3HBrOCH2CH2OCH2CF3
P403HCH3ClHCF3HClOCH2CH2OCH2CF3
P404HCH3ClHCF3HCF3OCH2CH2OCH2CF3
P405HCH3ClHCF3HCH3OCH2CH2OCH2CF3
P406HClCH3HCF3HBrOCH2OCH2CF3
P407HClCH3HCF3HClOCH2OCH2CF3
P408HClCH3HCF3HCF3OCH2OCH2CF3
P409HClCH3HCF3HCH3OCH2OCH2CF3
P410HClCH3HCF3HBrOCH2SCH2CF3
P411HClCH3HCF3HClOCH2SCH2CF3
P412HClCH3HCF3HCF3OCH2SCH2CF3
P413HClCH3HCF3HCH3OCH2SCH2CF3
P414HClCH3HCF3HBrSCH2OCH2CF3
P415HClCH3HCF3HClSCH2OCH2CF3
P416HClCH3HCF3HCF3SCH2OCH2CF3
P417HClCH3HCF3HCH3SCH2OCH2CF3
P418HClCH3HCF3HBrOCH2OCH2CHF2
P419HClCH3HCF3HClOCH2OCH2CHF2
P420HClCH3HCF3HCF3OCH2OCH2CHF2
P421HClCH3HCF3HCH3OCH2OCH2CHF2
P422HClCH3HCF3CF3BrOCH2OCH2CF3
P423HClCH3HCF3CF3ClOCH2OCH2CF3
P424HClCH3HCF3CF3CF3OCH2OCH2CF3
P425HClCH3HCF3CF3CH3OCH2OCH2CF3
P426HClCH3HCF2CF3HBrOCH2OCH2CF3
P427HClCH3HCF2CF3HClOCH2OCH2CF3
P428HClCH3HCF2CF3HCF3OCH2OCH2CF3
P429HClCH3HCF2CF3HCH3OCH2OCH2CF3
P430HClCH3HCF3HBrOCH2OCH(CH3)CF3
P431HClCH3HCF3HClOCH2OCH(CH3)CF3
P432HClCH3HCF3HCF3OCH2OCH(CH3)CF3
P433HClCH3HCF3HCH3OCH2OCH(CH3)CF3
P434HClCH3HCF3CF3BrOCH(CH3)OCH2CF3
P435HClCH3HCF3CF3ClOCH(CH3)OCH2CF3
P436HClCH3HCF3CF3CF3OCH(CH3)OCH2CF3
P437HClCH3HCF3CF3CH3OCH(CH3)OCH2CF3
P438HClCH3HCF2CF3HBrOCH(CH3)OCH2CF3
P439HClCH3HCF2CF3HClOCH(CH3)OCH2CF3
P440HClCH3HCF2CF3HCF3OCH(CH3)OCH2CF3
P441HClCH3HCF2CF3HCH3OCH(CH3)OCH2CF3
P442HClCH3HCF3HBrOCH(CH3)OCH2CF3
P443HClCH3HCF3HClOCH(CH3)OCH2CF3
P444HClCH3HCF3HCF3OCH(CH3)OCH2CF3
P445HClCH3HCF3HCH3OCH(CH3)OCH2CF3
P446HClCH3HCF3HBrOCH(CH3)SCH2CF3
P447HClCH3HCF3HClOCH(CH3)SCH2CF3
P448HClCH3HCF3HCF3OCH(CH3)SCH2CF3
P449HClCH3HCF3HCH3OCH(CH3)SCH2CF3
P450HClCH3HCF3HBrSCH(CH3)OCH2CF3
P451HClCH3HCF3HClSCH(CH3)OCH2CF3
P452HClCH3HCF3HCF3SCH(CH3)OCH2CF3
P453HClCH3HCF3HCH3SCH(CH3)OCH2CF3
P454HClCH3HCF3HBrOCH(CH3)OCH2CHF2
P455HClCH3HCF3HClOCH(CH3)OCH2CHF2
P456HClCH3HCF3HCF3OCH(CH3)OCH2CHF2
P457HClCH3HCF3HCH3OCH(CH3)OCH2CHF2
P458HClCH3HCF3HBrOCH(CH3)OCH(CH3)CF3
P459HClCH3HCF3HClOCH(CH3)OCH(CH3)CF3
P460HClCH3HCF3HCF3OCH(CH3)OCH(CH3)CF3
P461HClCH3HCF3HCH3OCH(CH3)OCH(CH3)CF3
P462HClCH3HCF3HBrOCH(CH3)OCH2CH2CF3
P463HClCH3HCF3HClOCH(CH3)OCH2CH2CF3
P464HClCH3HCF3HCF3OCH(CH3)OCH2CH2CF3
P465HClCH3HCF3HCH3OCH(CH3)OCH2CH2CF3
P466HClCH3HCF3HBrOCH(CH2CH3)OCH2CF3
P467HClCH3HCF3HClOCH(CH2CH3)OCH2CF3
P468HClCH3HCF3HCF3OCH(CH2CH3)OCH2CF3
P469HClCH3HCF3HCH3OCH(CH2CH3)OCH2CF3
P470HClCH3HCF3HBrOC(CH3)2OCH2CF3
P471HClCH3HCF3HClOC(CH3)2OCH2CF3
P472HClCH3HCF3HCF3OC(CH3)2OCH2CF3
P473HClCH3HCF3HCH3OC(CH3)2OCH2CF3
P474HClCH3HCF3HBrOCH2CH2OCH2CF3
P475HClCH3HCF3HClOCH2CH2OCH2CF3
P476HClCH3HCF3HCF3OCH2CH2OCH2CF3
P477HClCH3HCF3HCH3OCH2CH2OCH2CF3
P478HCH3FCH3CF3HBrOCH2OCH2CF3
P479HCH3FCH3CF3HClOCH2OCH2CF3
P480HCH3FCH3CF3HCF3OCH2OCH2CF3
P481HCH3FCH3CF3HCH3OCH2OCH2CF3
P482HCH3FCH3CF3HBrOCH2SCH2CF3
P483HCH3FCH3CF3HClOCH2SCH2CF3
P484HCH3FCH3CF3HCF3OCH2SCH2CF3
P485HCH3FCH3CF3HCH3OCH2SCH2CF3
P486HCH3FCH3CF3HBrSCH2OCH2CF3
P487HCH3FCH3CF3HClSCH2OCH2CF3
P488HCH3FCH3CF3HCF3SCH2OCH2CF3
P489HCH3FCH3CF3HCH3SCH2OCH2CF3
P490HCH3FCH3CF3HBrOCH2OCH2CHF2
P491HCH3FCH3CF3HClOCH2OCH2CHF2
P492HCH3FCH3CF3HCF3OCH2OCH2CHF2
P493HCH3FCH3CF3HCH3OCH2OCH2CHF2
P494HCH3FCH3CF3CF3BrOCH2OCH2CF3
P495HCH3FCH3CF3CF3ClOCH2OCH2CF3
P496HCH3FCH3CF3CF3CF3OCH2OCH2CF3
P497HCH3FCH3CF3CF3CH3OCH2OCH2CF3
P498HCH3FCH3CF2CF3HBrOCH2OCH2CF3
P499HCH3FCH3CF2CF3HClOCH2OCH2CF3
P500HCH3FCH3CF2CF3HCF3OCH2OCH2CF3
P501HCH3FCH3CF2CF3HCH3OCH2OCH2CF3
P502HCH3FCH3CF3HBrOCH2OCH(CH3)CF3
P503HCH3FCH3CF3HClOCH2OCH(CH3)CF3
P504HCH3FCH3CF3HCF3OCH2OCH(CH3)CF3
P505HCH3FCH3CF3HCH3OCH2OCH(CH3)CF3
P506HCH3FCH3CF3CF3BrOCH(CH3)OCH2CF3
P507HCH3FCH3CF3CF3ClOCH(CH3)OCH2CF3
P508HCH3FCH3CF3CF3CF3OCH(CH3)OCH2CF3
P509HCH3FCH3CF3CF3CH3OCH(CH3)OCH2CF3
P510HCH3FCH3CF2CF3HBrOCH(CH3)OCH2CF3
P511HCH3FCH3CF2CF3HClOCH(CH3)OCH2CF3
P512HCH3FCH3CF2CF3HCF3OCH(CH3)OCH2CF3
P513HCH3FCH3CF2CF3HCH3OCH(CH3)OCH2CF3
P514HCH3FCH3CF3HBrOCH(CH3)OCH2CF3
P515HCH3FCH3CF3HClOCH(CH3)OCH2CF3
P516HCH3FCH3CF3HCF3OCH(CH3)OCH2CF3
P517HCH3FCH3CF3HCH3OCH(CH3)OCH2CF3
P518HCH3FCH3CF3HBrOCH(CH3)SCH2CF3
P519HCH3FCH3CF3HClOCH(CH3)SCH2CF3
P520HCH3FCH3CF3HCF3OCH(CH3)SCH2CF3
P521HCH3FCH3CF3HCH3OCH(CH3)SCH2CF3
P522HCH3FCH3CF3HBrSCH(CH3)OCH2CF3
P523HCH3FCH3CF3HClSCH(CH3)OCH2CF3
P524HCH3FCH3CF3HCF3SCH(CH3)OCH2CF3
P525HCH3FCH3CF3HCH3SCH(CH3)OCH2CF3
P526HCH3FCH3CF3HBrOCH(CH3)OCH2CHF2
P527HCH3FCH3CF3HClOCH(CH3)OCH2CHF2
P528HCH3FCH3CF3HCF3OCH(CH3)OCH2CHF2
P529HCH3FCH3CF3HCH3OCH(CH3)OCH2CHF2
P530HCH3FCH3CF3HBrOCH(CH3)OCH(CH3)CF3
P531HCH3FCH3CF3HClOCH(CH3)OCH(CH3)CF3
P532HCH3FCH3CF3HCF3OCH(CH3)OCH(CH3)CF3
P533HCH3FCH3CF3HCH3OCH(CH3)OCH(CH3)CF3
P534HCH3FCH3CF3HBrOCH(CH3)OCH2CH2CF3
P535HCH3FCH3CF3HClOCH(CH3)OCH2CH2CF3
P536HCH3FCH3CF3HCF3OCH(CH3)OCH2CH2CF3
P537HCH3FCH3CF3HCH3OCH(CH3)OCH2CH2CF3
P538HCH3FCH3CF3HBrOCH(CH2CH3)OCH2CF3
P539HCH3FCH3CF3HClOCH(CH2CH3)OCH2CF3
P540HCH3FCH3CF3HCF3OCH(CH2CH3)OCH2CF3
P541HCH3FCH3CF3HCH3OCH(CH2CH3)OCH2CF3
P542HCH3FCH3CF3HBrOC(CH3)2OCH2CF3
P543HCH3FCH3CF3HClOC(CH3)2OCH2CF3
P544HCH3FCH3CF3HCF3OC(CH3)2OCH2CF3
P545HCH3FCH3CF3HCH3OC(CH3)2OCH2CF3
P546HCH3FCH3CF3HBrOCH2CH2OCH2CF3
P547HCH3FCH3CF3HClOCH2CH2OCH2CF3
P548HCH3FCH3CF3HCF3OCH2CH2OCH2CF3
P549HCH3FCH3CF3HCH3OCH2CH2OCH2CF3
P550HClHBrCF3HBrOCH2OCH2CF3
P551HClHBrCF3HClOCH2OCH2CF3
P552HClHBrCF3HCF3OCH2OCH2CF3
P553HClHBrCF3HCH3OCH2OCH2CF3
P554HClHBrCF3HBrOCH2SCH2CF3
P555HClHBrCF3HClOCH2SCH2CF3
P556HClHBrCF3HCF3OCH2SCH2CF3
P557HClHBrCF3HCH3OCH2SCH2CF3
P558HClHBrCF3HBrSCH2OCH2CF3
P559HClHBrCF3HClSCH2OCH2CF3
P560HClHBrCF3HCF3SCH2OCH2CF3
P561HClHBrCF3HCH3SCH2OCH2CF3
P562HClHBrCF3HBrOCH2OCH2CHF2
P563HClHBrCF3HClOCH2OCH2CHF2
P564HClHBrCF3HCF3OCH2OCH2CHF2
P565HClHBrCF3HCH3OCH2OCH2CHF2
P566HClHBrCF3CF3BrOCH2OCH2CF3
P567HClHBrCF3CF3ClOCH2OCH2CF3
P568HClHBrCF3CF3CF3OCH2OCH2CF3
P569HClHBrCF3CF3CH3OCH2OCH2CF3
P570HClHBrCF2CF3HBrOCH2OCH2CF3
P571HClHBrCF2CF3HClOCH2OCH2CF3
P572HClHBrCF2CF3HCF3OCH2OCH2CF3
P573HClHBrCF2CF3HCH3OCH2OCH2CF3
P574HClHBrCF3HBrOCH2OCH(CH3)CF3
P575HClHBrCF3HClOCH2OCH(CH3)CF3
P576HClHBrCF3HCF3OCH2OCH(CH3)CF3
P577HClHBrCF3HCH3OCH2OCH(CH3)CF3
P578HClHBrCF3CF3BrOCH(CH3)OCH2CF3
P579HClHBrCF3CF3ClOCH(CH3)OCH2CF3
P580HClHBrCF3CF3CF3OCH(CH3)OCH2CF3
P581HClHBrCF3CF3CH3OCH(CH3)OCH2CF3
P582HClHBrCF2CF3HBrOCH(CH3)OCH2CF3
P583HClHBrCF2CF3HClOCH(CH3)OCH2CF3
P584HClHBrCF2CF3HCF3OCH(CH3)OCH2CF3
P585HClHBrCF2CF3HCH3OCH(CH3)OCH2CF3
P586HClHBrCF3HBrOCH(CH3)OCH2CF3
P587HClHBrCF3HClOCH(CH3)OCH2CF3
P588HClHBrCF3HCF3OCH(CH3)OCH2CF3
P589HClHBrCF3HCH3OCH(CH3)OCH2CF3
P590HClHBrCF3HBrOCH(CH3)SCH2CF3
P591HClHBrCF3HClOCH(CH3)SCH2CF3
P592HClHBrCF3HCF3OCH(CH3)SCH2CF3
P593HClHBrCF3HCH3OCH(CH3)SCH2CF3
P594HClHBrCF3HBrSCH(CH3)OCH2CF3
P595HClHBrCF3HClSCH(CH3)OCH2CF3
P596HClHBrCF3HCF3SCH(CH3)OCH2CF3
P597HClHBrCF3HCH3SCH(CH3)OCH2CF3
P598HClHBrCF3HBrOCH(CH3)OCH2CHF2
P599HClHBrCF3HClOCH(CH3)OCH2CHF2
P600HClHBrCF3HCF3OCH(CH3)OCH2CHF2
P601HClHBrCF3HCH3OCH(CH3)OCH2CHF2
P602HClHBrCF3HBrOCH(CH3)OCH(CH3)CF3
P603HClHBrCF3HClOCH(CH3)OCH(CH3)CF3
P604HClHBrCF3HCF3OCH(CH3)OCH(CH3)CF3
P605HClHBrCF3HCH3OCH(CH3)OCH(CH3)CF3
P606HClHBrCF3HBrOCH(CH3)OCH2CH2CF3
P607HClHBrCF3HClOCH(CH3)OCH2CH2CF3
P608HClHBrCF3HCF3OCH(CH3)OCH2CH2CF3
P609HClHBrCF3HCH3OCH(CH3)OCH2CH2CF3
P610HClHBrCF3HBrOCH(CH2CH3)OCH2CF3
P611HClHBrCF3HClOCH(CH2CH3)OCH2CF3
P612HClHBrCF3HCF3OCH(CH2CH3)OCH2CF3
P613HClHBrCF3HCH3OCH(CH2CH3)OCH2CF3
P614HClHBrCF3HBrOC(CH3)2OCH2CF3
P615HClHBrCF3HClOC(CH3)2OCH2CF3
P616HClHBrCF3HCF3OC(CH3)2OCH2CF3
P617HClHBrCF3HCH3OC(CH3)2OCH2CF3
P618HClHBrCF3HBrOCH2CH2OCH2CF3
P619HClHBrCF3HClOCH2CH2OCH2CF3
P620HClHBrCF3HCF3OCH2CH2OCH2CF3
P621HClHBrCF3HCH3OCH2CH2OCH2CF3
P622HHBrBrCF3HBrOCH2OCH2CF3
P623HHBrBrCF3HClOCH2OCH2CF3
P624HHBrBrCF3HCF3OCH2OCH2CF3
P625HHBrBrCF3HCH3OCH2OCH2CF3
P626HHBrBrCF3HBrOCH2SCH2CF3
P627HHBrBrCF3HClOCH2SCH2CF3
P628HHBrBrCF3HCF3OCH2SCH2CF3
P629HHBrBrCF3HCH3OCH2SCH2CF3
P630HHBrBrCF3HBrSCH2OCH2CF3
P631HHBrBrCF3HClSCH2OCH2CF3
P632HHBrBrCF3HCF3SCH2OCH2CF3
P633HHBrBrCF3HCH3SCH2OCH2CF3
P634HHBrBrCF3HBrOCH2OCH2CHF2
P635HHBrBrCF3HClOCH2OCH2CHF2
P636HHBrBrCF3HCF3OCH2OCH2CHF2
P637HHBrBrCF3HCH3OCH2OCH2CHF2
P638HHBrBrCF3CF3BrOCH2OCH2CF3
P639HHBrBrCF3CF3ClOCH2OCH2CF3
P640HHBrBrCF3CF3CF3OCH2OCH2CF3
P641HHBrBrCF3CF3CH3OCH2OCH2CF3
P642HHBrBrCF2CF3HBrOCH2OCH2CF3
P643HHBrBrCF2CF3HClOCH2OCH2CF3
P644HHBrBrCF2CF3HCF3OCH2OCH2CF3
P645HHBrBrCF2CF3HCH3OCH2OCH2CF3
P646HHBrBrCF3HBrOCH2OCH(CH3)CF3
P647HHBrBrCF3HClOCH2OCH(CH3)CF3
P648HHBrBrCF3HCF3OCH2OCH(CH3)CF3
P649HHBrBrCF3HCH3OCH2OCH(CH3)CF3
P650HHBrBrCF3CF3BrOCH(CH3)OCH2CF3
P651HHBrBrCF3CF3ClOCH(CH3)OCH2CF3
P652HHBrBrCF3CF3CF3OCH(CH3)OCH2CF3
P653HHBrBrCF3CF3CH3OCH(CH3)OCH2CF3
P654HHBrBrCF2CF3HBrOCH(CH3)OCH2CF3
P655HHBrBrCF2CF3HClOCH(CH3)OCH2CF3
P656HHBrBrCF2CF3HCF3OCH(CH3)OCH2CF3
P657HHBrBrCF2CF3HCH3OCH(CH3)OCH2CF3
P658HHBrBrCF3HBrOCH(CH3)OCH2CF3
P659HHBrBrCF3HClOCH(CH3)OCH2CF3
P660HHBrBrCF3HCF3OCH(CH3)OCH2CF3
P661HHBrBrCF3HCH3OCH(CH3)OCH2CF3
P662HHBrBrCF3HBrOCH(CH3)SCH2CF3
P663HHBrBrCF3HClOCH(CH3)SCH2CF3
P664HHBrBrCF3HCF3OCH(CH3)SCH2CF3
P665HHBrBrCF3HCH3OCH(CH3)SCH2CF3
P666HHBrBrCF3HBrSCH(CH3)OCH2CF3
P667HHBrBrCF3HClSCH(CH3)OCH2CF3
P668HHBrBrCF3HCF3SCH(CH3)OCH2CF3
P669HHBrBrCF3HCH3SCH(CH3)OCH2CF3
P670HHBrBrCF3HBrOCH(CH3)OCH2CHF2
P671HHBrBrCF3HClOCH(CH3)OCH2CHF2
P672HHBrBrCF3HCF3OCH(CH3)OCH2CHF2
P673HHBrBrCF3HCH3OCH(CH3)OCH2CHF2
P674HHBrBrCF3HBrOCH(CH3)OCH(CH3)CF3
P675HHBrBrCF3HClOCH(CH3)OCH(CH3)CF3
P676HHBrBrCF3HCF3OCH(CH3)OCH(CH3)CF3
P677HHBrBrCF3HCH3OCH(CH3)OCH(CH3)CF3
P678HHBrBrCF3HBrOCH(CH3)OCH2CH2CF3
P679HHBrBrCF3HClOCH(CH3)OCH2CH2CF3
P680HHBrBrCF3HCF3OCH(CH3)OCH2CH2CF3
P681HHBrBrCF3HCH3OCH(CH3)OCH2CH2CF3
P682HHBrBrCF3HBrOCH(CH2CH3)OCH2CF3
P683HHBrBrCF3HClOCH(CH2CH3)OCH2CF3
P684HHBrBrCF3HCF3OCH(CH2CH3)OCH2CF3
P685HHBrBrCF3HCH3OCH(CH2CH3)OCH2CF3
P686HHBrBrCF3HBrOC(CH3)2OCH2CF3
P687HHBrBrCF3HClOC(CH3)2OCH2CF3
P688HHBrBrCF3HCF3OC(CH3)2OCH2CF3
P689HHBrBrCF3HCH3OC(CH3)2OCH2CF3
P690HHBrBrCF3HBrOCH2CH2OCH2CF3
P691HHBrBrCF3HClOCH2CH2OCH2CF3
P692HHBrBrCF3HCF3OCH2CH2OCH2CF3
P693HHBrBrCF3HCH3OCH2CH2OCH2CF3
P694HHClNO2CF3HBrOCH2OCH2CF3
P695HHClNO2CF3HClOCH2OCH2CF3
P696HHClNO2CF3HCF3OCH2OCH2CF3
P697HHClNO2CF3HCH3OCH2OCH2CF3
P698HHClNO2CF3HBrOCH2SCH2CF3
P699HHClNO2CF3HClOCH2SCH2CF3
P700HHClNO2CF3HCF3OCH2SCH2CF3
P701HHClNO2CF3HCH3OCH2SCH2CF3
P702HHClNO2CF3HBrSCH2OCH2CF3
P703HHClNO2CF3HClSCH2OCH2CF3
P704HHClNO2CF3HCF3SCH2OCH2CF3
P705HHClNO2CF3HCH3SCH2OCH2CF3
P706HHClNO2CF3HBrOCH2OCH2CHF2
P707HHClNO2CF3HClOCH2OCH2CHF2
P708HHClNO2CF3HCF3OCH2OCH2CHF2
P709HHClNO2CF3HCH3OCH2OCH2CHF2
P710HHClNO2CF3CF3BrOCH2OCH2CF3
P711HHClNO2CF3CF3ClOCH2OCH2CF3
P712HHClNO2CF3CF3CF3OCH2OCH2CF3
P713HHClNO2CF3CF3CH3OCH2OCH2CF3
P714HHClNO2CF2CF3HBrOCH2OCH2CF3
P715HHClNO2CF2CF3HClOCH2OCH2CF3
P716HHClNO2CF2CF3HCF3OCH2OCH2CF3
P717HHClNO2CF2CF3HCH3OCH2OCH2CF3
P718HHClNO2CF3HBrOCH2OCH(CH3)CF3
P719HHClNO2CF3HClOCH2OCH(CH3)CF3
P720HHClNO2CF3HCF3OCH2OCH(CH3)CF3
P721HHClNO2CF3HCH3OCH2OCH(CH3)CF3
P722HHClNO2CF3CF3BrOCH(CH3)OCH2CF3
P723HHClNO2CF3CF3ClOCH(CH3)OCH2CF3
P724HHClNO2CF3CF3CF3OCH(CH3)OCH2CF3
P725HHClNO2CF3CF3CH3OCH(CH3)OCH2CF3
P726HHClNO2CF2CF3HBrOCH(CH3)OCH2CF3
P727HHClNO2CF2CF3HClOCH(CH3)OCH2CF3
P728HHClNO2CF2CF3HCF3OCH(CH3)OCH2CF3
P729HHClNO2CF2CF3HCH3OCH(CH3)OCH2CF3
P730HHClNO2CF3HBrOCH(CH3)OCH2CF3
P731HHClNO2CF3HClOCH(CH3)OCH2CF3
P732HHClNO2CF3HCF3OCH(CH3)OCH2CF3
P733HHClNO2CF3HCH3OCH(CH3)OCH2CF3
P734HHClNO2CF3HBrOCH(CH3)SCH2CF3
P735HHClNO2CF3HClOCH(CH3)SCH2CF3
P736HHClNO2CF3HCF3OCH(CH3)SCH2CF3
P737HHClNO2CF3HCH3OCH(CH3)SCH2CF3
P738HHClNO2CF3HBrSCH(CH3)OCH2CF3
P739HHClNO2CF3HClSCH(CH3)OCH2CF3
P740HHClNO2CF3HCF3SCH(CH3)OCH2CF3
P741HHClNO2CF3HCH3SCH(CH3)OCH2CF3
P742HHClNO2CF3HBrOCH(CH3)OCH2CHF2
P743HHClNO2CF3HClOCH(CH3)OCH2CHF2
P744HHClNO2CF3HCF3OCH(CH3)OCH2CHF2
P745HHClNO2CF3HCH3OCH(CH3)OCH2CHF2
P746HHClNO2CF3HBrOCH(CH3)OCH(CH3)CF3
P747HHClNO2CF3HClOCH(CH3)OCH(CH3)CF3
P748HHClNO2CF3HCF3OCH(CH3)OCH(CH3)CF3
P749HHClNO2CF3HCH3OCH(CH3)OCH(CH3)CF3
P750HHClNO2CF3HBrOCH(CH3)OCH2CH2CF3
P751HHClNO2CF3HClOCH(CH3)OCH2CH2CF3
P752HHClNO2CF3HCF3OCH(CH3)OCH2CH2CF3
P753HHClNO2CF3HCH3OCH(CH3)OCH2CH2CF3
P754HHClNO2CF3HBrOCH(CH2CH3)OCH2CF3
P755HHClNO2CF3HClOCH(CH2CH3)OCH2CF3
P756HHClNO2CF3HCF3OCH(CH2CH3)OCH2CF3
P757HHClNO2CF3HCH3OCH(CH2CH3)OCH2CF3
P758HHClNO2CF3HBrOC(CH3)2OCH2CF3
P759HHClNO2CF3HClOC(CH3)2OCH2CF3
P760HHClNO2CF3HCF3OC(CH3)2OCH2CF3
P761HHClNO2CF3HCH3OC(CH3)2OCH2CF3
P762HHClNO2CF3HBrOCH2CH2OCH2CF3
P763HHClNO2CF3HClOCH2CH2OCH2CF3
P764HHClNO2CF3HCF3OCH2CH2OCH2CF3
P765HHClNO2CF3HCH3OCH2CH2OCH2CF3
P766HHFCNCF3HBrOCH2OCH2CF3
P767HHFCNCF3HClOCH2OCH2CF3
P768HHFCNCF3HCF3OCH2OCH2CF3
P769HHFCNCF3HCH3OCH2OCH2CF3
P770HHFCNCF3HBrOCH2SCH2CF3
P771HHFCNCF3HClOCH2SCH2CF3
P772HHFCNCF3HCF3OCH2SCH2CF3
P773HHFCNCF3HCH3OCH2SCH2CF3
P774HHFCNCF3HBrSCH2OCH2CF3
P775HHFCNCF3HClSCH2OCH2CF3
P776HHFCNCF3HCF3SCH2OCH2CF3
P777HHFCNCF3HCH3SCH2OCH2CF3
P778HHFCNCF3HBrOCH2OCH2CHF2
P779HHFCNCF3HClOCH2OCH2CHF2
P780HHFCNCF3HCF3OCH2OCH2CHF2
P781HHFCNCF3HCH3OCH2OCH2CHF2
P782HHFCNCF3CF3BrOCH2OCH2CF3
P783HHFCNCF3CF3ClOCH2OCH2CF3
P784HHFCNCF3CF3CF3OCH2OCH2CF3
P785HHFCNCF3CF3CH3OCH2OCH2CF3
P786HHFCNCF2CF3HBrOCH2OCH2CF3
P787HHFCNCF2CF3HClOCH2OCH2CF3
P788HHFCNCF2CF3HCF3OCH2OCH2CF3
P789HHFCNCF2CF3HCH3OCH2OCH2CF3
P790HHFCNCF3HBrOCH2OCH(CH3)CF3
P791HHFCNCF3HClOCH2OCH(CH3)CF3
P792HHFCNCF3HCF3OCH2OCH(CH3)CF3
P793HHFCNCF3HCH3OCH2OCH(CH3)CF3
P794HHFCNCF3CF3BrOCH(CH3)OCH2CF3
P795HHFCNCF3CF3ClOCH(CH3)OCH2CF3
P796HHFCNCF3CF3CF3OCH(CH3)OCH2CF3
P797HHFCNCF3CF3CH3OCH(CH3)OCH2CF3
P798HHFCNCF2CF3HBrOCH(CH3)OCH2CF3
P799HHFCNCF2CF3HClOCH(CH3)OCH2CF3
P800HHFCNCF2CF3HCF3OCH(CH3)OCH2CF3
P801HHFCNCF2CF3HCH3OCH(CH3)OCH2CF3
P802HHFCNCF3HBrOCH(CH3)OCH2CF3
P803HHFCNCF3HClOCH(CH3)OCH2CF3
P804HHFCNCF3HCF3OCH(CH3)OCH2CF3
P805HHFCNCF3HCH3OCH(CH3)OCH2CF3
P806HHFCNCF3HBrOCH(CH3)SCH2CF3
P807HHFCNCF3HClOCH(CH3)SCH2CF3
P808HHFCNCF3HCF3OCH(CH3)SCH2CF3
P809HHFCNCF3HCH3OCH(CH3)SCH2CF3
P810HHFCNCF3HBrSCH(CH3)OCH2CF3
P811HHFCNCF3HClSCH(CH3)OCH2CF3
P812HHFCNCF3HCF3SCH(CH3)OCH2CF3
P813HHFCNCF3HCH3SCH(CH3)OCH2CF3
P814HHFCNCF3HBrOCH(CH3)OCH2CHF2
P815HHFCNCF3HClOCH(CH3)OCH2CHF2
P816HHFCNCF3HCF3OCH(CH3)OCH2CHF2
P817HHFCNCF3HCH3OCH(CH3)OCH2CHF2
P818HHFCNCF3HBrOCH(CH3)OCH(CH3)CF3
P819HHFCNCF3HClOCH(CH3)OCH(CH3)CF3
P820HHFCNCF3HCF3OCH(CH3)OCH(CH3)CF3
P821HHFCNCF3HCH3OCH(CH3)OCH(CH3)CF3
P822HHFCNCF3HBrOCH(CH3)OCH2CH2CF3
P823HHFCNCF3HClOCH(CH3)OCH2CH2CF3
P824HHFCNCF3HCF3OCH(CH3)OCH2CH2CF3
P825HHFCNCF3HCH3OCH(CH3)OCH2CH2CF3
P826HHFCNCF3HBrOCH(CH2CH3)OCH2CF3
P827HHFCNCF3HClOCH(CH2CH3)OCH2CF3
P828HHFCNCF3HCF3OCH(CH2CH3)OCH2CF3
P829HHFCNCF3HCH3OCH(CH2CH3)OCH2CF3
P830HHFCNCF3HBrOC(CH3)2OCH2CF3
P831HHFCNCF3HClOC(CH3)2OCH2CF3
P832HHFCNCF3HCF3OC(CH3)2OCH2CF3
P833HHFCNCF3HCH3OC(CH3)2OCH2CF3
P834HHFCNCF3HBrOCH2CH2OCH2CF3
P835HHFCNCF3HClOCH2CH2OCH2CF3
P836HHFCNCF3HCF3OCH2CH2OCH2CF3
P837HHFCNCF3HCH3OCH2CH2OCH2CF3
P838HClOCF3ClCF3HBrOCH2OCH2CF3
P839HClOCF3ClCF3HClOCH2OCH2CF3
P840HClOCF3ClCF3HCF3OCH2OCH2CF3
P841HClOCF3ClCF3HCH3OCH2OCH2CF3
P842HClOCF3ClCF3HBrOCH2SCH2CF3
P843HClOCF3ClCF3HClOCH2SCH2CF3
P844HClOCF3ClCF3HCF3OCH2SCH2CF3
P845HClOCF3ClCF3HCH3OCH2SCH2CF3
P846HClOCF3ClCF3HBrSCH2OCH2CF3
P847HClOCF3ClCF3HClSCH2OCH2CF3
P848HClOCF3ClCF3HCF3SCH2OCH2CF3
P849HClOCF3ClCF3HCH3SCH2OCH2CF3
P850HClOCF3ClCF3HBrOCH2OCH2CHF2
P851HClOCF3ClCF3HClOCH2OCH2CHF2
P852HClOCF3ClCF3HCF3OCH2OCH2CHF2
P853HClOCF3ClCF3HCH3OCH2OCH2CHF2
P854HClOCF3ClCF3CF3BrOCH2OCH2CF3
P855HClOCF3ClCF3CF3ClOCH2OCH2CF3
P856HClOCF3ClCF3CF3CF3OCH2OCH2CF3
P857HClOCF3ClCF3CF3CH3OCH2OCH2CF3
P858HClOCF3ClCF2CF3HBrOCH2OCH2CF3
P859HClOCF3ClCF2CF3HClOCH2OCH2CF3
P860HClOCF3ClCF2CF3HCF3OCH2OCH2CF3
P861HClOCF3ClCF2CF3HCH3OCH2OCH2CF3
P862HClOCF3ClCF3HBrOCH2OCH(CH3)CF3
P863HClOCF3ClCF3HClOCH2OCH(CH3)CF3
P864HClOCF3ClCF3HCF3OCH2OCH(CH3)CF3
P865HClOCF3ClCF3HCH3OCH2OCH(CH3)CF3
P866HClOCF3ClCF3CF3BrOCH(CH3)OCH2CF3
P867HClOCF3ClCF3CF3ClOCH(CH3)OCH2CF3
P868HClOCF3ClCF3CF3CF3OCH(CH3)OCH2CF3
P869HClOCF3ClCF3CF3CH3OCH(CH3)OCH2CF3
P870HClOCF3ClCF2CF3HBrOCH(CH3)OCH2CF3
P871HClOCF3ClCF2CF3HClOCH(CH3)OCH2CF3
P872HClOCF3ClCF2CF3HCF3OCH(CH3)OCH2CF3
P873HClOCF3ClCF2CF3HCH3OCH(CH3)OCH2CF3
P874HClOCF3ClCF3HBrOCH(CH3)OCH2CF3
P875HClOCF3ClCF3HClOCH(CH3)OCH2CF3
P876HClOCF3ClCF3HCF3OCH(CH3)OCH2CF3
P877HClOCF3ClCF3HCH3OCH(CH3)OCH2CF3
P878HClOCF3ClCF3HBrOCH(CH3)SCH2CF3
P879HClOCF3ClCF3HClOCH(CH3)SCH2CF3
P880HClOCF3ClCF3HCF3OCH(CH3)SCH2CF3
P881HClOCF3ClCF3HCH3OCH(CH3)SCH2CF3
P882HClOCF3ClCF3HBrSCH(CH3)OCH2CF3
P883HClOCF3ClCF3HClSCH(CH3)OCH2CF3
P884HClOCF3ClCF3HCF3SCH(CH3)OCH2CF3
P885HClOCF3ClCF3HCH3SCH(CH3)OCH2CF3
P886HClOCF3ClCF3HBrOCH(CH3)OCH2CHF2
P887HClOCF3ClCF3HClOCH(CH3)OCH2CHF2
P888HClOCF3ClCF3HCF3OCH(CH3)OCH2CHF2
P889HClOCF3ClCF3HCH3OCH(CH3)OCH2CHF2
P890HClOCF3ClCF3HBrOCH(CH3)OCH(CH3)CF3
P891HClOCF3ClCF3HClOCH(CH3)OCH(CH3)CF3
P892HClOCF3ClCF3HCF3OCH(CH3)OCH(CH3)CF3
P893HClOCF3ClCF3HCH3OCH(CH3)OCH(CH3)CF3
P894HClOCF3ClCF3HBrOCH(CH3)OCH2CH2CF3
P895HClOCF3ClCF3HClOCH(CH3)OCH2CH2CF3
P896HClOCF3ClCF3HCF3OCH(CH3)OCH2CH2CF3
P897HClOCF3ClCF3HCH3OCH(CH3)OCH2CH2CF3
P898HClOCF3ClCF3HBrOCH(CH2CH3)OCH2CF3
P899HClOCF3ClCF3HClOCH(CH2CH3)OCH2CF3
P900HClOCF3ClCF3HCF3OCH(CH2CH3)OCH2CF3
P901HClOCF3ClCF3HCH3OCH(CH2CH3)OCH2CF3
P902HClOCF3ClCF3HBrOC(CH3)2OCH2CF3
P903HClOCF3ClCF3HClOC(CH3)2OCH2CF3
P904HClOCF3ClCF3HCF3OC(CH3)2OCH2CF3
P905HClOCF3ClCF3HCH3OC(CH3)2OCH2CF3
P906HClOCF3ClCF3HBrOCH2CH2OCH2CF3
P907HClOCF3ClCF3HClOCH2CH2OCH2CF3
P908HClOCF3ClCF3HCF3OCH2CH2OCH2CF3
P909HClOCF3ClCF3HCH3OCH2CH2OCH2CF3
P910HClCNClCF3HBrOCH2OCH2CF3
P911HClCNClCF3HClOCH2OCH2CF3
P912HClCNClCF3HCF3OCH2OCH2CF3
P913HClCNClCF3HCH3OCH2OCH2CF3
P914HClCNClCF3HBrOCH2SCH2CF3
P915HClCNClCF3HClOCH2SCH2CF3
P916HClCNClCF3HCF3OCH2SCH2CF3
P917HClCNClCF3HCH3OCH2SCH2CF3
P918HClCNClCF3HBrSCH2OCH2CF3
P919HClCNClCF3HClSCH2OCH2CF3
P920HClCNClCF3HCF3SCH2OCH2CF3
P921HClCNClCF3HCH3SCH2OCH2CF3
P922HClCNClCF3HBrOCH2OCH2CHF2
P923HClCNClCF3HClOCH2OCH2CHF2
P924HClCNClCF3HCF3OCH2OCH2CHF2
P925HClCNClCF3HCH3OCH2OCH2CHF2
P926HClCNClCF3CF3BrOCH2OCH2CF3
P927HClCNClCF3CF3ClOCH2OCH2CF3
P928HClCNClCF3CF3CF3OCH2OCH2CF3
P929HClCNClCF3CF3CH3OCH2OCH2CF3
P930HClCNClCF2CF3HBrOCH2OCH2CF3
P931HClCNClCF2CF3HClOCH2OCH2CF3
P932HClCNClCF2CF3HCF3OCH2OCH2CF3
P933HClCNClCF2CF3HCH3OCH2OCH2CF3
P934HClCNClCF3HBrOCH2OCH(CH3)CF3
P935HClCNClCF3HClOCH2OCH(CH3)CF3
P936HClCNClCF3HCF3OCH2OCH(CH3)CF3
P937HClCNClCF3HCH3OCH2OCH(CH3)CF3
P938HClCNClCF3CF3BrOCH(CH3)OCH2CF3
P939HClCNClCF3CF3ClOCH(CH3)OCH2CF3
P940HClCNClCF3CF3CF3OCH(CH3)OCH2CF3
P941HClCNClCF3CF3CH3OCH(CH3)OCH2CF3
P942HClCNClCF2CF3HBrOCH(CH3)OCH2CF3
P943HClCNClCF2CF3HClOCH(CH3)OCH2CF3
P944HClCNClCF2CF3HCF3OCH(CH3)OCH2CF3
P945HClCNClCF2CF3HCH3OCH(CH3)OCH2CF3
P946HClCNClCF3HBrOCH(CH3)OCH2CF3
P947HClCNClCF3HClOCH(CH3)OCH2CF3
P948HClCNClCF3HCF3OCH(CH3)OCH2CF3
P949HClCNClCF3HCH3OCH(CH3)OCH2CF3
P950HClCNClCF3HBrOCH(CH3)SCH2CF3
P951HClCNClCF3HClOCH(CH3)SCH2CF3
P952HClCNClCF3HCF3OCH(CH3)SCH2CF3
P953HClCNClCF3HCH3OCH(CH3)SCH2CF3
P954HClCNClCF3HBrSCH(CH3)OCH2CF3
P955HClCNClCF3HClSCH(CH3)OCH2CF3
P956HClCNClCF3HCF3SCH(CH3)OCH2CF3
P957HClCNClCF3HCH3SCH(CH3)OCH2CF3
P958HClCNClCF3HBrOCH(CH3)OCH2CHF2
P959HClCNClCF3HClOCH(CH3)OCH2CHF2
P960HClCNClCF3HCF3OCH(CH3)OCH2CHF2
P961HClCNClCF3HCH3OCH(CH3)OCH2CHF2
P962HClCNClCF3HBrOCH(CH3)OCH(CH3)CF3
P963HClCNClCF3HClOCH(CH3)OCH(CH3)CF3
P964HClCNClCF3HCF3OCH(CH3)OCH(CH3)CF3
P965HClCNClCF3HCH3OCH(CH3)OCH(CH3)CF3
P966HClCNClCF3HBrOCH(CH3)OCH2CH2CF3
P967HClCNClCF3HClOCH(CH3)OCH2CH2CF3
P968HClCNClCF3HCF3OCH(CH3)OCH2CH2CF3
P969HClCNClCF3HCH3OCH(CH3)OCH2CH2CF3
P970HClCNClCF3HBrOCH(CH2CH3)OCH2CF3
P971HClCNClCF3HClOCH(CH2CH3)OCH2CF3
P972HClCNClCF3HCF3OCH(CH2CH3)OCH2CF3
P973HClCNClCF3HCH3OCH(CH2CH3)OCH2CF3
P974HClCNClCF3HBrOC(CH3)2OCH2CF3
P975HClCNClCF3HClOC(CH3)2OCH2CF3
P976HClCNClCF3HCF3OC(CH3)2OCH2CF3
P977HClCNClCF3HCH3OC(CH3)2OCH2CF3
P978HClCNClCF3HBrOCH2CH2OCH2CF3
P979HClCNClCF3HClOCH2CH2OCH2CF3
P980HClCNClCF3HCF3OCH2CH2OCH2CF3
P981HClCNClCF3HCH3OCH2CH2OCH2CF3
P982HCH3HBrCF3HBrOCH2OCH2CF3
P983HCH3HBrCF3HClOCH2OCH2CF3
P984HCH3HBrCF3HCF3OCH2OCH2CF3
P985HCH3HBrCF3HCH3OCH2OCH2CF3
P986HCH3HBrCF3HBrOCH2SCH2CF3
P987HCH3HBrCF3HClOCH2SCH2CF3
P988HCH3HBrCF3HCF3OCH2SCH2CF3
P989HCH3HBrCF3HCH3OCH2SCH2CF3
P990HCH3HBrCF3HBrSCH2OCH2CF3
P991HCH3HBrCF3HClSCH2OCH2CF3
P992HCH3HBrCF3HCF3SCH2OCH2CF3
P993HCH3HBrCF3HCH3SCH2OCH2CF3
P994HCH3HBrCF3HBrOCH2OCH2CHF2
P995HCH3HBrCF3HClOCH2OCH2CHF2
P996HCH3HBrCF3HCF3OCH2OCH2CHF2
P997HCH3HBrCF3HCH3OCH2OCH2CHF2
P998HCH3HBrCF3CF3BrOCH2OCH2CF3
P999HCH3HBrCF3CF3ClOCH2OCH2CF3
P1000HCH3HBrCF3CF3CF3OCH2OCH2CF3
P1001HCH3HBrCF3CF3CH3OCH2OCH2CF3
P1002HCH3HBrCF2CF3HBrOCH2OCH2CF3
P1003HCH3HBrCF2CF3HClOCH2OCH2CF3
P1004HCH3HBrCF2CF3HCF3OCH2OCH2CF3
P1005HCH3HBrCF2CF3HCH3OCH2OCH2CF3
P1006HCH3HBrCF3HBrOCH2OCH(CH3)CF3
P1007HCH3HBrCF3HClOCH2OCH(CH3)CF3
P1008HCH3HBrCF3HCF3OCH2OCH(CH3)CF3
P1009HCH3HBrCF3HCH3OCH2OCH(CH3)CF3
P1010HCH3HBrCF3CF3BrOCH(CH3)OCH2CF3
P1011HCH3HBrCF3CF3ClOCH(CH3)OCH2CF3
P1012HCH3HBrCF3CF3CF3OCH(CH3)OCH2CF3
P1013HCH3HBrCF3CF3CH3OCH(CH3)OCH2CF3
P1014HCH3HBrCF2CF3HBrOCH(CH3)OCH2CF3
P1015HCH3HBrCF2CF3HClOCH(CH3)OCH2CF3
P1016HCH3HBrCF2CF3HCF3OCH(CH3)OCH2CF3
P1017HCH3HBrCF2CF3HCH3OCH(CH3)OCH2CF3
P1018HCH3HBrCF3HBrOCH(CH3)OCH2CF3
P1019HCH3HBrCF3HClOCH(CH3)OCH2CF3
P1020HCH3HBrCF3HCF3OCH(CH3)OCH2CF3
P1021HCH3HBrCF3HCH3OCH(CH3)OCH2CF3
P1022HCH3HBrCF3HBrOCH(CH3)SCH2CF3
P1023HCH3HBrCF3HClOCH(CH3)SCH2CF3
P1024HCH3HBrCF3HCF3OCH(CH3)SCH2CF3
P1025HCH3HBrCF3HCH3OCH(CH3)SCH2CF3
P1026HCH3HBrCF3HBrSCH(CH3)OCH2CF3
P1027HCH3HBrCF3HClSCH(CH3)OCH2CF3
P1028HCH3HBrCF3HCF3SCH(CH3)OCH2CF3
P1029HCH3HBrCF3HCH3SCH(CH3)OCH2CF3
P1030HCH3HBrCF3HBrOCH(CH3)OCH2CHF2
P1031HCH3HBrCF3HClOCH(CH3)OCH2CHF2
P1032HCH3HBrCF3HCF3OCH(CH3)OCH2CHF2
P1033HCH3HBrCF3HCH3OCH(CH3)OCH2CHF2
P1034HCH3HBrCF3HBrOCH(CH3)OCH(CH3)CF3
P1035HCH3HBrCF3HClOCH(CH3)OCH(CH3)CF3
P1036HCH3HBrCF3HCF3OCH(CH3)OCH(CH3)CF3
P1037HCH3HBrCF3HCH3OCH(CH3)OCH(CH3)CF3
P1038HCH3HBrCF3HBrOCH(CH3)OCH2CH2CF3
P1039HCH3HBrCF3HClOCH(CH3)OCH2CH2CF3
P1040HCH3HBrCF3HCF3OCH(CH3)OCH2CH2CF3
P1041HCH3HBrCF3HCH3OCH(CH3)OCH2CH2CF3
P1042HCH3HBrCF3HBrOCH(CH2CH3)OCH2CF3
P1043HCH3HBrCF3HClOCH(CH2CH3)OCH2CF3
P1044HCH3HBrCF3HCF3OCH(CH2CH3)OCH2CF3
P1045HCH3HBrCF3HCH3OCH(CH2CH3)OCH2CF3
P1046HCH3HBrCF3HBrOC(CH3)2OCH2CF3
P1047HCH3HBrCF3HClOC(CH3)2OCH2CF3
P1048HCH3HBrCF3HCF3OC(CH3)2OCH2CF3
P1049HCH3HBrCF3HCH3OC(CH3)2OCH2CF3
P1050HCH3HBrCF3HBrOCH2CH2OCH2CF3
P1051HCH3HBrCF3HClOCH2CH2OCH2CF3
P1052HCH3HBrCF3HCF3OCH2CH2OCH2CF3
P1053HCH3HBrCF3HCH3OCH2CH2OCH2CF3
P1054HHFCH3CF3HBrOCH2OCH2CF3
P1055HHFCH3CF3HClOCH2OCH2CF3
P1056HHFCH3CF3HCF3OCH2OCH2CF3
P1057HHFCH3CF3HCH3OCH2OCH2CF3
P1058HHFCH3CF3HBrOCH2SCH2CF3
P1059HHFCH3CF3HClOCH2SCH2CF3
P1060HHFCH3CF3HCF3OCH2SCH2CF3
P1061HHFCH3CF3HCH3OCH2SCH2CF3
P1062HHFCH3CF3HBrSCH2OCH2CF3
P1063HHFCH3CF3HClSCH2OCH2CF3
P1064HHFCH3CF3HCF3SCH2OCH2CF3
P1065HHFCH3CF3HCH3SCH2OCH2CF3
P1066HHFCH3CF3HBrOCH2OCH2CHF2
P1067HHFCH3CF3HClOCH2OCH2CHF2
P1068HHFCH3CF3HCF3OCH2OCH2CHF2
P1069HHFCH3CF3HCH3OCH2OCH2CHF2
P1070HHFCH3CF3CF3BrOCH2OCH2CF3
P1071HHFCH3CF3CF3ClOCH2OCH2CF3
P1072HHFCH3CF3CF3CF3OCH2OCH2CF3
P1073HHFCH3CF3CF3CH3OCH2OCH2CF3
P1074HHFCH3CF2CF3HBrOCH2OCH2CF3
P1075HHFCH3CF2CF3HClOCH2OCH2CF3
P1076HHFCH3CF2CF3HCF3OCH2OCH2CF3
P1077HHFCH3CF2CF3HCH3OCH2OCH2CF3
P1078HHFCH3CF3HBrOCH2OCH(CH3)CF3
P1079HHFCH3CF3HClOCH2OCH(CH3)CF3
P1080HHFCH3CF3HCF3OCH2OCH(CH3)CF3
P1081HHFCH3CF3HCH3OCH2OCH(CH3)CF3
P1082HHFCH3CF3CF3BrOCH(CH3)OCH2CF3
P1083HHFCH3CF3CF3ClOCH(CH3)OCH2CF3
P1084HHFCH3CF3CF3CF3OCH(CH3)OCH2CF3
P1085HHFCH3CF3CF3CH3OCH(CH3)OCH2CF3
P1086HHFCH3CF2CF3HBrOCH(CH3)OCH2CF3
P1087HHFCH3CF2CF3HClOCH(CH3)OCH2CF3
P1088HHFCH3CF2CF3HCF3OCH(CH3)OCH2CF3
P1089HHFCH3CF2CF3HCH3OCH(CH3)OCH2CF3
P1090HHFCH3CF3HBrOCH(CH3)OCH2CF3
P1091HHFCH3CF3HClOCH(CH3)OCH2CF3
P1092HHFCH3CF3HCF3OCH(CH3)OCH2CF3
P1093HHFCH3CF3HCH3OCH(CH3)OCH2CF3
P1094HHFCH3CF3HBrOCH(CH3)SCH2CF3
P1095HHFCH3CF3HClOCH(CH3)SCH2CF3
P1096HHFCH3CF3HCF3OCH(CH3)SCH2CF3
P1097HHFCH3CF3HCH3OCH(CH3)SCH2CF3
P1098HHFCH3CF3HBrSCH(CH3)OCH2CF3
P1099HHFCH3CF3HClSCH(CH3)OCH2CF3
P1100HHFCH3CF3HCF3SCH(CH3)OCH2CF3
P1101HHFCH3CF3HCH3SCH(CH3)OCH2CF3
P1102HHFCH3CF3HBrOCH(CH3)OCH2CHF2
P1103HHFCH3CF3HClOCH(CH3)OCH2CHF2
P1104HHFCH3CF3HCF3OCH(CH3)OCH2CHF2
P1105HHFCH3CF3HCH3OCH(CH3)OCH2CHF2
P1106HHFCH3CF3HBrOCH(CH3)OCH(CH3)CF3
P1107HHFCH3CF3HClOCH(CH3)OCH(CH3)CF3
P1108HHFCH3CF3HCF3OCH(CH3)OCH(CH3)CF3
P1109HHFCH3CF3HCH3OCH(CH3)OCH(CH3)CF3
P1110HHFCH3CF3HBrOCH(CH3)OCH2CH2CF3
P1111HHFCH3CF3HClOCH(CH3)OCH2CH2CF3
P1112HHFCH3CF3HCF3OCH(CH3)OCH2CH2CF3
P1113HHFCH3CF3HCH3OCH(CH3)OCH2CH2CF3
P1114HHFCH3CF3HBrOCH(CH2CH3)OCH2CF3
P1115HHFCH3CF3HClOCH(CH2CH3)OCH2CF3
P1116HHFCH3CF3HCF3OCH(CH2CH3)OCH2CF3
P1117HHFCH3CF3HCH3OCH(CH2CH3)OCH2CF3
P1118HHFCH3CF3HBrOC(CH3)2OCH2CF3
P1119HHFCH3CF3HClOC(CH3)2OCH2CF3
P1120HHFCH3CF3HCF3OC(CH3)2OCH2CF3
P1121HHFCH3CF3HCH3OC(CH3)2OCH2CF3
P1122HHFCH3CF3HBrOCH2CH2OCH2CF3
P1123HHFCH3CF3HClOCH2CH2OCH2CF3
P1124HHFCH3CF3HCF3OCH2CH2OCH2CF3
P1125HHFCH3CF3HCH3OCH2CH2OCH2CF3
P1126HHFClCF3HClOCH2OCH2CF3
P1127HHFClCF3HCF3OCH2OCH2CF3
P1128HHFClCF3HCH3OCH2OCH2CF3
P1129HHFClCF3HBrOCH2SCH2CF3
P1130HHFClCF3HClOCH2SCH2CF3
P1131HHFClCF3HCF3OCH2SCH2CF3
P1132HHFClCF3HCH3OCH2SCH2CF3
P1133HHFClCF3HBrSCH2OCH2CF3
P1134HHFClCF3HClSCH2OCH2CF3
P1135HHFClCF3HCF3SCH2OCH2CF3
P1136HHFClCF3HCH3SCH2OCH2CF3
P1137HHFClCF3HBrOCH2OCH2CHF2
P1138HHFClCF3HClOCH2OCH2CHF2
P1139HHFClCF3HCF3OCH2OCH2CHF2
P1140HHFClCF3HCH3OCH2OCH2CHF2
P1141HHFClCF3CF3BrOCH2OCH2CF3
P1142HHFClCF3CF3ClOCH2OCH2CF3
P1143HHFClCF3CF3CF3OCH2OCH2CF3
P1144HHFClCF3CF3CH3OCH2OCH2CF3
P1145HHFClCF2CF3HBrOCH2OCH2CF3
P1146HHFClCF2CF3HClOCH2OCH2CF3
P1147HHFClCF2CF3HCF3OCH2OCH2CF3
P1148HHFClCF2CF3HCH3OCH2OCH2CF3
P1149HHFClCF3HBrOCH2OCH(CH3)CF3
P1150HHFClCF3HClOCH2OCH(CH3)CF3
P1151HHFClCF3HCF3OCH2OCH(CH3)CF3
P1152HHFClCF3HCH3OCH2OCH(CH3)CF3
P1153HHFClCF3CF3BrOCH(CH3)OCH2CF3
P1154HHFClCF3CF3ClOCH(CH3)OCH2CF3
P1155HHFClCF3CF3CF3OCH(CH3)OCH2CF3
P1156HHFClCF3CF3CH3OCH(CH3)OCH2CF3
P1157HHFClCF2CF3HBrOCH(CH3)OCH2CF3
P1158HHFClCF2CF3HClOCH(CH3)OCH2CF3
P1159HHFClCF2CF3HCF3OCH(CH3)OCH2CF3
P1160HHFClCF2CF3HCH3OCH(CH3)OCH2CF3
P1161HHFClCF3HBrOCH(CH3)OCH2CF3
P1162HHFClCF3HClOCH(CH3)OCH2CF3
P1163HHFClCF3HCF3OCH(CH3)OCH2CF3
P1164HHFClCF3HCH3OCH(CH3)OCH2CF3
P1165HHFClCF3HBrOCH(CH3)SCH2CF3
P1166HHFClCF3HClOCH(CH3)SCH2CF3
P1167HHFClCF3HCF3OCH(CH3)SCH2CF3
P1168HHFClCF3HCH3OCH(CH3)SCH2CF3
P1169HHFClCF3HBrSCH(CH3)OCH2CF3
P1170HHFClCF3HClSCH(CH3)OCH2CF3
P1171HHFClCF3HCF3SCH(CH3)OCH2CF3
P1172HHFClCF3HCH3SCH(CH3)OCH2CF3
P1173HHFClCF3HBrOCH(CH3)OCH2CHF2
P1174HHFClCF3HClOCH(CH3)OCH2CHF2
P1175HHFClCF3HCF3OCH(CH3)OCH2CHF2
P1176HHFClCF3HCH3OCH(CH3)OCH2CHF2
P1177HHFClCF3HBrOCH(CH3)OCH(CH3)CF3
P1178HHFClCF3HClOCH(CH3)OCH(CH3)CF3
P1179HHFClCF3HCF3OCH(CH3)OCH(CH3)CF3
P1180HHFClCF3HCH3OCH(CH3)OCH(CH3)CF3
P1181HHFClCF3HBrOCH(CH3)OCH2CH2CF3
P1182HHFClCF3HClOCH(CH3)OCH2CH2CF3
P1183HHFClCF3HCF3OCH(CH3)OCH2CH2CF3
P1184HHFClCF3HCH3OCH(CH3)OCH2CH2CF3
P1185HHFClCF3HBrOCH(CH2CH3)OCH2CF3
P1186HHFClCF3HClOCH(CH2CH3)OCH2CF3
P1187HHFClCF3HCF3OCH(CH2CH3)OCH2CF3
P1188HHFClCF3HCH3OCH(CH2CH3)OCH2CF3
P1189HHFClCF3HBrOC(CH3)2OCH2CF3
P1190HHFClCF3HClOC(CH3)2OCH2CF3
P1191HHFClCF3HCF3OC(CH3)2OCH2CF3
P1192HHFClCF3HCH3OC(CH3)2OCH2CF3
P1193HHFClCF3HBrOCH2CH2OCH2CF3
P1194HHFClCF3HClOCH2CH2OCH2CF3
P1195HHFClCF3HCF3OCH2CH2OCH2CF3
P1196HHFClCF3HCH3OCH2CH2OCH2CF3
P1197HFFFCF3HBrOCH2OCH2CF3
P1198HFFFCF3HClOCH2OCH2CF3
P1199HFFFCF3HCF3OCH2OCH2CF3
P1200HFFFCF3HCH3OCH2OCH2CF3
P1201HFFFCF3HBrOCH2SCH2CF3
P1202HFFFCF3HClOCH2SCH2CF3
P1203HFFFCF3HCF3OCH2SCH2CF3
P1204HFFFCF3HCH3OCH2SCH2CF3
P1205HFFFCF3HBrSCH2OCH2CF3
P1206HFFFCF3HClSCH2OCH2CF3
P1207HFFFCF3HCF3SCH2OCH2CF3
P1208HFFFCF3HCH3SCH2OCH2CF3
P1209HFFFCF3HBrOCH2OCH2CHF2
P1210HFFFCF3HClOCH2OCH2CHF2
P1211HFFFCF3HCF3OCH2OCH2CHF2
P1212HFFFCF3HCH3OCH2OCH2CHF2
P1213HFFFCF3CF3BrOCH2OCH2CF3
P1214HFFFCF3CF3ClOCH2OCH2CF3
P1215HFFFCF3CF3CF3OCH2OCH2CF3
P1216HFFFCF3CF3CH3OCH2OCH2CF3
P1217HFFFCF2CF3HBrOCH2OCH2CF3
P1218HFFFCF2CF3HClOCH2OCH2CF3
P1219HFFFCF2CF3HCF3OCH2OCH2CF3
P1220HFFFCF2CF3HCH3OCH2OCH2CF3
P1221HFFFCF3HBrOCH2OCH(CH3)CF3
P1222HFFFCF3HClOCH2OCH(CH3)CF3
P1223HFFFCF3HCF3OCH2OCH(CH3)CF3
P1224HFFFCF3HCH3OCH2OCH(CH3)CF3
P1225HFFFCF3CF3BrOCH(CH3)OCH2CF3
P1226HFFFCF3CF3ClOCH(CH3)OCH2CF3
P1227HFFFCF3CF3CF3OCH(CH3)OCH2CF3
P1228HFFFCF3CF3CH3OCH(CH3)OCH2CF3
P1229HFFFCF2CF3HBrOCH(CH3)OCH2CF3
P1230HFFFCF2CF3HClOCH(CH3)OCH2CF3
P1231HFFFCF2CF3HCF3OCH(CH3)OCH2CF3
P1232HFFFCF2CF3HCH3OCH(CH3)OCH2CF3
P1233HFFFCF3HBrOCH(CH3)OCH2CF3
P1234HFFFCF3HClOCH(CH3)OCH2CF3
P1235HFFFCF3HCF3OCH(CH3)OCH2CF3
P1236HFFFCF3HCH3OCH(CH3)OCH2CF3
P1237HFFFCF3HBrOCH(CH3)SCH2CF3
P1238HFFFCF3HClOCH(CH3)SCH2CF3
P1239HFFFCF3HCF3OCH(CH3)SCH2CF3
P1240HFFFCF3HCH3OCH(CH3)SCH2CF3
P1241HFFFCF3HBrSCH(CH3)OCH2CF3
P1242HFFFCF3HClSCH(CH3)OCH2CF3
P1243HFFFCF3HCF3SCH(CH3)OCH2CF3
P1244HFFFCF3HCH3SCH(CH3)OCH2CF3
P1245HFFFCF3HBrOCH(CH3)OCH2CHF2
P1246HFFFCF3HClOCH(CH3)OCH2CHF2
P1247HFFFCF3HCF3OCH(CH3)OCH2CHF2
P1248HFFFCF3HCH3OCH(CH3)OCH2CHF2
P1249HFFFCF3HBrOCH(CH3)OCH(CH3)CF3
P1250HFFFCF3HClOCH(CH3)OCH(CH3)CF3
P1251HFFFCF3HCF3OCH(CH3)OCH(CH3)CF3
P1252HFFFCF3HCH3OCH(CH3)OCH(CH3)CF3
P1253HFFFCF3HBrOCH(CH3)OCH2CH2CF3
P1254HFFFCF3HClOCH(CH3)OCH2CH2CF3
P1255HFFFCF3HCF3OCH(CH3)OCH2CH2CF3
P1256HFFFCF3HCH3OCH(CH3)OCH2CH2CF3
P1257HFFFCF3HBrOCH(CH2CH3)OCH2CF3
P1258HFFFCF3HClOCH(CH2CH3)OCH2CF3
P1259HFFFCF3HCF3OCH(CH2CH3)OCH2CF3
P1260HFFFCF3HCH3OCH(CH2CH3)OCH2CF3
P1261HFFFCF3HBrOC(CH3)2OCH2CF3
P1262HFFFCF3HClOC(CH3)2OCH2CF3
P1263HFFFCF3HCF3OC(CH3)2OCH2CF3
P1264HFFFCF3HCH3OC(CH3)2OCH2CF3
P1265HFFFCF3HBrOCH2CH2OCH2CF3
P1266HFFFCF3HClOCH2CH2OCH2CF3
P1267HFFFCF3HCF3OCH2CH2OCH2CF3
P1268HFFFCF3HCH3OCH2CH2OCH2CF3
P1269HCF3HCF3CF3HBrOCH2OCH2CF3
P1270HCF3HCF3CF3HClOCH2OCH2CF3
P1271HCF3HCF3CF3HCF3OCH2OCH2CF3
P1272HCF3HCF3CF3HCH3OCH2OCH2CF3
P1273HCF3HCF3CF3HBrOCH2SCH2CF3
P1274HCF3HCF3CF3HClOCH2SCH2CF3
P1275HCF3HCF3CF3HCF3OCH2SCH2CF3
P1276HCF3HCF3CF3HCH3OCH2SCH2CF3
P1277HCF3HCF3CF3HBrSCH2OCH2CF3
P1278HCF3HCF3CF3HClSCH2OCH2CF3
P1279HCF3HCF3CF3HCF3SCH2OCH2CF3
P1280HCF3HCF3CF3HCH3SCH2OCH2CF3
P1281HCF3HCF3CF3HBrOCH2OCH2CHF2
P1282HCF3HCF3CF3HClOCH2OCH2CHF2
P1283HCF3HCF3CF3HCF3OCH2OCH2CHF2
P1284HCF3HCF3CF3HCH3OCH2OCH2CHF2
P1285HCF3HCF3CF3CF3BrOCH2OCH2CF3
P1286HCF3HCF3CF3CF3ClOCH2OCH2CF3
P1287HCF3HCF3CF3CF3CF3OCH2OCH2CF3
P1288HCF3HCF3CF3CF3CH3OCH2OCH2CF3
P1289HCF3HCF3CF2CF3HBrOCH2OCH2CF3
P1290HCF3HCF3CF2CF3HClOCH2OCH2CF3
P1291HCF3HCF3CF2CF3HCF3OCH2OCH2CF3
P1292HCF3HCF3CF2CF3HCH3OCH2OCH2CF3
P1293HCF3HCF3CF3HBrOCH2OCH(CH3)CF3
P1294HCF3HCF3CF3HClOCH2OCH(CH3)CF3
P1295HCF3HCF3CF3HCF3OCH2OCH(CH3)CF3
P1296HCF3HCF3CF3HCH3OCH2OCH(CH3)CF3
P1297HCF3HCF3CF3CF3BrOCH(CH3)OCH2CF3
P1298HCF3HCF3CF3CF3ClOCH(CH3)OCH2CF3
P1299HCF3HCF3CF3CF3CF3OCH(CH3)OCH2CF3
P1300HCF3HCF3CF3CF3CH3OCH(CH3)OCH2CF3
P1301HCF3HCF3CF2CF3HBrOCH(CH3)OCH2CF3
P1302HCF3HCF3CF2CF3HClOCH(CH3)OCH2CF3
P1303HCF3HCF3CF2CF3HCF3OCH(CH3)OCH2CF3
P1304HCF3HCF3CF2CF3HCH3OCH(CH3)OCH2CF3
P1305HCF3HCF3CF3HClOCH(CH3)OCH2CF3
P1306HCF3HCF3CF3HCF3OCH(CH3)OCH2CF3
P1307HCF3HCF3CF3HCH3OCH(CH3)OCH2CF3
P1308HCF3HCF3CF3HBrOCH(CH3)SCH2CF3
P1309HCF3HCF3CF3HClOCH(CH3)SCH2CF3
P1310HCF3HCF3CF3HCF3OCH(CH3)SCH2CF3
P1311HCF3HCF3CF3HCH3OCH(CH3)SCH2CF3
P1312HCF3HCF3CF3HBrSCH(CH3)OCH2CF3
P1313HCF3HCF3CF3HClSCH(CH3)OCH2CF3
P1314HCF3HCF3CF3HCF3SCH(CH3)OCH2CF3
P1315HCF3HCF3CF3HCH3SCH(CH3)OCH2CF3
P1316HCF3HCF3CF3HBrOCH(CH3)OCH2CHF2
P1317HCF3HCF3CF3HClOCH(CH3)OCH2CHF2
P1318HCF3HCF3CF3HCF3OCH(CH3)OCH2CHF2
P1319HCF3HCF3CF3HCH3OCH(CH3)OCH2CHF2
P1320HCF3HCF3CF3HBrOCH(CH3)OCH(CH3)CF3
P1321HCF3HCF3CF3HClOCH(CH3)OCH(CH3)CF3
P1322HCF3HCF3CF3HCF3OCH(CH3)OCH(CH3)CF3
P1323HCF3HCF3CF3HCH3OCH(CH3)OCH(CH3)CF3
P1324HCF3HCF3CF3HBrOCH(CH3)OCH2CH2CF3
P1325HCF3HCF3CF3HClOCH(CH3)OCH2CH2CF3
P1326HCF3HCF3CF3HCF3OCH(CH3)OCH2CH2CF3
P1327HCF3HCF3CF3HCH3OCH(CH3)OCH2CH2CF3
P1328HCF3HCF3CF3HBrOCH(CH2CH3)OCH2CF3
P1329HCF3HCF3CF3HClOCH(CH2CH3)OCH2CF3
P1330HCF3HCF3CF3HCF3OCH(CH2CH3)OCH2CF3
P1331HCF3HCF3CF3HCH3OCH(CH2CH3)OCH2CF3
P1332HCF3HCF3CF3HBrOC(CH3)2OCH2CF3
P1333HCF3HCF3CF3HClOC(CH3)2OCH2CF3
P1334HCF3HCF3CF3HCF3OC(CH3)2OCH2CF3
P1335HCF3HCF3CF3HCH3OC(CH3)2OCH2CF3
P1336HCF3HCF3CF3HBrOCH2CH2OCH2CF3
P1337HCF3HCF3CF3HClOCH2CH2OCH2CF3
P1338HCF3HCF3CF3HCF3OCH2CH2OCH2CF3
P1339HCF3HCF3CF3HCH3OCH2CH2OCH2CF3
P1340HFHCF3CF3HBrOCH2OCH2CF3
P1341HFHCF3CF3HClOCH2OCH2CF3
P1342HFHCF3CF3HCF3OCH2OCH2CF3
P1343HFHCF3CF3HCH3OCH2OCH2CF3
P1344HFHCF3CF3HBrOCH2SCH2CF3
P1345HFHCF3CF3HClOCH2SCH2CF3
P1346HFHCF3CF3HCF3OCH2SCH2CF3
P1347HFHCF3CF3HCH3OCH2SCH2CF3
P1348HFHCF3CF3HBrSCH2OCH2CF3
P1349HFHCF3CF3HClSCH2OCH2CF3
P1350HFHCF3CF3HCF3SCH2OCH2CF3
P1351HFHCF3CF3HCH3SCH2OCH2CF3
P1352HFHCF3CF3HBrOCH2OCH2CHF2
P1353HFHCF3CF3HClOCH2OCH2CHF2
P1354HFHCF3CF3HCF3OCH2OCH2CHF2
P1355HFHCF3CF3HCH3OCH2OCH2CHF2
P1356HFHCF3CF3CF3BrOCH2OCH2CF3
P1357HFHCF3CF3CF3ClOCH2OCH2CF3
P1358HFHCF3CF3CF3CF3OCH2OCH2CF3
P1359HFHCF3CF3CF3CH3OCH2OCH2CF3
P1360HFHCF3CF2CF3HBrOCH2OCH2CF3
P1361HFHCF3CF2CF3HClOCH2OCH2CF3
P1362HFHCF3CF2CF3HCF3OCH2OCH2CF3
P1363HFHCF3CF2CF3HCH3OCH2OCH2CF3
P1364HFHCF3CF3HBrOCH2OCH(CH3)CF3
P1365HFHCF3CF3HClOCH2OCH(CH3)CF3
P1366HFHCF3CF3HCF3OCH2OCH(CH3)CF3
P1367HFHCF3CF3HCH3OCH2OCH(CH3)CF3
P1368HFHCF3CF3CF3BrOCH(CH3)OCH2CF3
P1369HFHCF3CF3CF3ClOCH(CH3)OCH2CF3
P1370HFHCF3CF3CF3CF3OCH(CH3)OCH2CF3
P1371HFHCF3CF3CF3CH3OCH(CH3)OCH2CF3
P1372HFHCF3CF2CF3HBrOCH(CH3)OCH2CF3
P1373HFHCF3CF2CF3HClOCH(CH3)OCH2CF3
P1374HFHCF3CF2CF3HCF3OCH(CH3)OCH2CF3
P1375HFHCF3CF2CF3HCH3OCH(CH3)OCH2CF3
P1376HFHCF3CF3HClOCH(CH3)OCH2CF3
P1377HFHCF3CF3HCF3OCH(CH3)OCH2CF3
P1378HFHCF3CF3HCH3OCH(CH3)OCH2CF3
P1379HFHCF3CF3HBrOCH(CH3)SCH2CF3
P1380HFHCF3CF3HClOCH(CH3)SCH2CF3
P1381HFHCF3CF3HCF3OCH(CH3)SCH2CF3
P1382HFHCF3CF3HCH3OCH(CH3)SCH2CF3
P1383HFHCF3CF3HBrSCH(CH3)OCH2CF3
P1384HFHCF3CF3HClSCH(CH3)OCH2CF3
P1385HFHCF3CF3HCF3SCH(CH3)OCH2CF3
P1386HFHCF3CF3HCH3SCH(CH3)OCH2CF3
P1387HFHCF3CF3HBrOCH(CH3)OCH2CHF2
P1388HFHCF3CF3HClOCH(CH3)OCH2CHF2
P1389HFHCF3CF3HCF3OCH(CH3)OCH2CHF2
P1390HFHCF3CF3HCH3OCH(CH3)OCH2CHF2
P1391HFHCF3CF3HBrOCH(CH3)OCH(CH3)CF3
P1392HFHCF3CF3HClOCH(CH3)OCH(CH3)CF3
P1393HFHCF3CF3HCF3OCH(CH3)OCH(CH3)CF3
P1394HFHCF3CF3HCH3OCH(CH3)OCH(CH3)CF3
P1395HFHCF3CF3HBrOCH(CH3)OCH2CH2CF3
P1396HFHCF3CF3HClOCH(CH3)OCH2CH2CF3
P1397HFHCF3CF3HCF3OCH(CH3)OCH2CH2CF3
P1398HFHCF3CF3HCH3OCH(CH3)OCH2CH2CF3
P1399HFHCF3CF3HBrOCH(CH2CH3)OCH2CF3
P1400HFHCF3CF3HClOCH(CH2CH3)OCH2CF3
P1401HFHCF3CF3HCF3OCH(CH2CH3)OCH2CF3
P1402HFHCF3CF3HCH3OCH(CH2CH3)OCH2CF3
P1403HFHCF3CF3HBrOC(CH3)2OCH2CF3
P1404HFHCF3CF3HClOC(CH3)2OCH2CF3
P1405HFHCF3CF3HCF3OC(CH3)2OCH2CF3
P1406HFHCF3CF3HCH3OC(CH3)2OCH2CF3
P1407HFHCF3CF3HBrOCH2CH2OCH2CF3
P1408HFHCF3CF3HClOCH2CH2OCH2CF3
P1409HFHCF3CF3HCF3OCH2CH2OCH2CF3
P1410HFHCF3CF3HCH3OCH2CH2OCH2CF3
P1411HClHCF3CF3HBrOCH2OCH2CF3
P1412HClHCF3CF3HClOCH2OCH2CF3
P1413HClHCF3CF3HCF3OCH2OCH2CF3
P1414HClHCF3CF3HCH3OCH2OCH2CF3
P1415HClHCF3CF3HBrOCH2SCH2CF3
P1416HClHCF3CF3HClOCH2SCH2CF3
P1417HClHCF3CF3HCF3OCH2SCH2CF3
P1418HClHCF3CF3HCH3OCH2SCH2CF3
P1419HClHCF3CF3HBrSCH2OCH2CF3
P1420HClHCF3CF3HClSCH2OCH2CF3
P1421HClHCF3CF3HCF3SCH2OCH2CF3
P1422HClHCF3CF3HCH3SCH2OCH2CF3
P1423HClHCF3CF3HBrOCH2OCH2CHF2
P1424HClHCF3CF3HClOCH2OCH2CHF2
P1425HClHCF3CF3HCF3OCH2OCH2CHF2
P1426HClHCF3CF3HCH3OCH2OCH2CHF2
P1427HClHCF3CF3CF3BrOCH2OCH2CF3
P1428HClHCF3CF3CF3ClOCH2OCH2CF3
P1429HClHCF3CF3CF3CF3OCH2OCH2CF3
P1430HClHCF3CF3CF3CH3OCH2OCH2CF3
P1431HClHCF3CF2CF3HBrOCH2OCH2CF3
P1432HClHCF3CF2CF3HClOCH2OCH2CF3
P1433HClHCF3CF2CF3HCF3OCH2OCH2CF3
P1434HClHCF3CF2CF3HCH3OCH2OCH2CF3
P1435HClHCF3CF3HBrOCH2OCH(CH3)CF3
P1436HClHCF3CF3HClOCH2OCH(CH3)CF3
P1437HClHCF3CF3HCF3OCH2OCH(CH3)CF3
P1438HClHCF3CF3HCH3OCH2OCH(CH3)CF3
P1439HClHCF3CF3CF3BrOCH(CH3)OCH2CF3
P1440HClHCF3CF3CF3ClOCH(CH3)OCH2CF3
P1441HClHCF3CF3CF3CF3OCH(CH3)OCH2CF3
P1442HClHCF3CF3CF3CH3OCH(CH3)OCH2CF3
P1443HClHCF3CF2CF3HBrOCH(CH3)OCH2CF3
P1444HClHCF3CF2CF3HClOCH(CH3)OCH2CF3
P1445HClHCF3CF2CF3HCF3OCH(CH3)OCH2CF3
P1446HClHCF3CF2CF3HCH3OCH(CH3)OCH2CF3
P1447HClHCF3CF3HBrOCH(CH3)OCH2CF3
P1448HClHCF3CF3HClOCH(CH3)OCH2CF3
P1449HClHCF3CF3HCF3OCH(CH3)OCH2CF3
P1450HClHCF3CF3HCH3OCH(CH3)OCH2CF3
P1451HClHCF3CF3HBrOCH(CH3)SCH2CF3
P1452HClHCF3CF3HClOCH(CH3)SCH2CF3
P1453HClHCF3CF3HCF3OCH(CH3)SCH2CF3
P1454HClHCF3CF3HCH3OCH(CH3)SCH2CF3
P1455HClHCF3CF3HBrSCH(CH3)OCH2CF3
P1456HClHCF3CF3HClSCH(CH3)OCH2CF3
P1457HClHCF3CF3HCF3SCH(CH3)OCH2CF3
P1458HClHCF3CF3HCH3SCH(CH3)OCH2CF3
P1459HClHCF3CF3HBrOCH(CH3)OCH2CHF2
P1460HClHCF3CF3HClOCH(CH3)OCH2CHF2
P1461HClHCF3CF3HCF3OCH(CH3)OCH2CHF2
P1462HClHCF3CF3HCH3OCH(CH3)OCH2CHF2
P1463HClHCF3CF3HBrOCH(CH3)OCH(CH3)CF3
P1464HClHCF3CF3HClOCH(CH3)OCH(CH3)CF3
P1465HClHCF3CF3HCF3OCH(CH3)OCH(CH3)CF3
P1466HClHCF3CF3HCH3OCH(CH3)OCH(CH3)CF3
P1467HClHCF3CF3HBrOCH(CH3)OCH2CH2CF3
P1468HClHCF3CF3HClOCH(CH3)OCH2CH2CF3
P1469HClHCF3CF3HCF3OCH(CH3)OCH2CH2CF3
P1470HClHCF3CF3HCH3OCH(CH3)OCH2CH2CF3
P1471HClHCF3CF3HBrOCH(CH2CH3)OCH2CF3
P1472HClHCF3CF3HClOCH(CH2CH3)OCH2CF3
P1473HClHCF3CF3HCF3OCH(CH2CH3)OCH2CF3
P1474HClHCF3CF3HCH3OCH(CH2CH3)OCH2CF3
P1475HClHCF3CF3HBrOC(CH3)2OCH2CF3
P1476HClHCF3CF3HClOC(CH3)2OCH2CF3
P1477HClHCF3CF3HCF3OC(CH3)2OCH2CF3
P1478HClHCF3CF3HCH3OC(CH3)2OCH2CF3
P1479HClHCF3CF3HBrOCH2CH2OCH2CF3
P1480HClHCF3CF3HClOCH2CH2OCH2CF3
P1481HClHCF3CF3HCF3OCH2CH2OCH2CF3
P1482HClHCF3CF3HCH3OCH2CH2OCH2CF3
P1483HHFCF3CF3HBrOCH2OCH2CF3
P1484HHFCF3CF3HClOCH2OCH2CF3
P1485HHFCF3CF3HCF3OCH2OCH2CF3
P1486HHFCF3CF3HCH3OCH2OCH2CF3
P1487HHFCF3CF3HBrOCH2SCH2CF3
P1488HHFCF3CF3HClOCH2SCH2CF3
P1489HHFCF3CF3HCF3OCH2SCH2CF3
P1490HHFCF3CF3HCH3OCH2SCH2CF3
P1491HHFCF3CF3HBrSCH2OCH2CF3
P1492HHFCF3CF3HClSCH2OCH2CF3
P1493HHFCF3CF3HCF3SCH2OCH2CF3
P1494HHFCF3CF3HCH3SCH2OCH2CF3
P1495HHFCF3CF3HBrOCH2OCH2CHF2
P1496HHFCF3CF3HClOCH2OCH2CHF2
P1497HHFCF3CF3HCF3OCH2OCH2CHF2
P1498HHFCF3CF3HCH3OCH2OCH2CHF2
P1499HHFCF3CF3CF3BrOCH2OCH2CF3
P1500HHFCF3CF3CF3ClOCH2OCH2CF3
P1501HHFCF3CF3CF3CF3OCH2OCH2CF3
P1502HHFCF3CF3CF3CH3OCH2OCH2CF3
P1503HHFCF3CF2CF3HBrOCH2OCH2CF3
P1504HHFCF3CF2CF3HClOCH2OCH2CF3
P1505HHFCF3CF2CF3HCF3OCH2OCH2CF3
P1506HHFCF3CF2CF3HCH3OCH2OCH2CF3
P1507HHFCF3CF3HBrOCH2OCH(CH3)CF3
P1508HHFCF3CF3HClOCH2OCH(CH3)CF3
P1509HHFCF3CF3HCF3OCH2OCH(CH3)CF3
P1510HHFCF3CF3HCH3OCH2OCH(CH3)CF3
P1511HHFCF3CF3CF3BrOCH(CH3)OCH2CF3
P1512HHFCF3CF3CF3ClOCH(CH3)OCH2CF3
P1513HHFCF3CF3CF3CF3OCH(CH3)OCH2CF3
P1514HHFCF3CF3CF3CH3OCH(CH3)OCH2CF3
P1515HHFCF3CF2CF3HBrOCH(CH3)OCH2CF3
P1516HHFCF3CF2CF3HClOCH(CH3)OCH2CF3
P1517HHFCF3CF2CF3HCF3OCH(CH3)OCH2CF3
P1518HHFCF3CF2CF3HCH3OCH(CH3)OCH2CF3
P1519HHFCF3CF3HBrOCH(CH3)OCH2CF3
P1520HHFCF3CF3HClOCH(CH3)OCH2CF3
P1521HHFCF3CF3HCF3OCH(CH3)OCH2CF3
P1522HHFCF3CF3HCH3OCH(CH3)OCH2CF3
P1523HHFCF3CF3HBrOCH(CH3)SCH2CF3
P1524HHFCF3CF3HClOCH(CH3)SCH2CF3
P1525HHFCF3CF3HCF3OCH(CH3)SCH2CF3
P1526HHFCF3CF3HCH3OCH(CH3)SCH2CF3
P1527HHFCF3CF3HBrSCH(CH3)OCH2CF3
P1528HHFCF3CF3HClSCH(CH3)OCH2CF3
P1529HHFCF3CF3HCF3SCH(CH3)OCH2CF3
P1530HHFCF3CF3HCH3SCH(CH3)OCH2CF3
P1531HHFCF3CF3HBrOCH(CH3)OCH2CHF2
P1532HHFCF3CF3HClOCH(CH3)OCH2CHF2
P1533HHFCF3CF3HCF3OCH(CH3)OCH2CHF2
P1534HHFCF3CF3HCH3OCH(CH3)OCH2CHF2
P1535HHFCF3CF3HBrOCH(CH3)OCH(CH3)CF3
P1536HHFCF3CF3HClOCH(CH3)OCH(CH3)CF3
P1537HHFCF3CF3HCF3OCH(CH3)OCH(CH3)CF3
P1538HHFCF3CF3HCH3OCH(CH3)OCH(CH3)CF3
P1539HHFCF3CF3HBrOCH(CH3)OCH2CH2CF3
P1540HHFCF3CF3HClOCH(CH3)OCH2CH2CF3
P1541HHFCF3CF3HCF3OCH(CH3)OCH2CH2CF3
P1542HHFCF3CF3HCH3OCH(CH3)OCH2CH2CF3
P1543HHFCF3CF3HBrOCH(CH2CH3)OCH2CF3
P1544HHFCF3CF3HClOCH(CH2CH3)OCH2CF3
P1545HHFCF3CF3HCF3OCH(CH2CH3)OCH2CF3
P1546HHFCF3CF3HCH3OCH(CH2CH3)OCH2CF3
P1547HHFCF3CF3HBrOC(CH3)2OCH2CF3
P1548HHFCF3CF3HClOC(CH3)2OCH2CF3
P1549HHFCF3CF3HCF3OC(CH3)2OCH2CF3
P1550HHFCF3CF3HCH3OC(CH3)2OCH2CF3
P1551HHFCF3CF3HBrOCH2CH2OCH2CF3
P1552HHFCF3CF3HClOCH2CH2OCH2CF3
P1553HHFCF3CF3HCF3OCH2CH2OCH2CF3
P1554HHFCF3CF3HCH3OCH2CH2OCH2CF3
P1555HClClClCF3HHOCH2OCH2CF3
P1556HClClClCF3HCF3OCH2OCH2CF3
P1557HClClClCF3HHOCH2SCH2CF3
P1558HClClClCF3HClOCH2SCH2CF3
P1559HClClClCF3HCF3OCH2SCH2CF3
P1560HClClClCF3HCH3OCH2SCH2CF3
P1561HClClClCF3HHSCH2OCH2CF3
P1562HClClClCF3HClSCH2OCH2CF3
P1563HClClClCF3HCF3SCH2OCH2CF3
P1564HClClClCF3HCH3SCH2OCH2CF3
P1565HClClClCF3HHOCH2OCH2CHF2
P1566HClClClCF3HCF3OCH2OCH2CHF2
P1567HClClClCF3HCH3OCH2OCH2CHF2
P1568HClClClCF3HHOCH2OCH2CH2F
P1569HClClClCF3HBrOCH2OCH2CH2F
P1570HClClClCF3HClOCH2OCH2CH2F
P1571HClClClCF3HCF3OCH2OCH2CH2F
P1572HClClClCF3HCH3OCH2OCH2CH2F
P1573HClClClCF3HHOCH2OCH2CH3
P1574HClClClCF3HBrOCH2OCH2CH3
P1575HClClClCF3HClOCH2OCH2CH3
P1576HClClClCF3HCF3OCH2OCH2CH3
P1577HClClClCF3HCH3OCH2OCH2CH3
P1578HClClClCF3CF3HOCH2OCH2CF3
P1579HClClClCF3CF3BrOCH2OCH2CF3
P1580HClClClCF3CF3ClOCH2OCH2CF3
P1581HClClClCF3CF3CF3OCH2OCH2CF3
P1582HClClClCF3CF3CH3OCH2OCH2CF3
P1583HClClClCF2CF3HHOCH2OCH2CF3
P1584HClClClCF2CF3HBrOCH2OCH2CF3
P1585HClClClCF2CF3HClOCH2OCH2CF3
P1586HClClClCF2CF3HCF3OCH2OCH2CF3
P1587HClClClCF2CF3HCH3OCH2OCH2CF3
P1588HClClClCF3HHOCH2OCH(CH3)CF3
P1589HClClClCF3HBrOCH2OCH(CH3)CF3
P1590HClClClCF3HClOCH2OCH(CH3)CF3
P1591HClClClCF3HCF3OCH2OCH(CH3)CF3
P1592HClClClCF3HCH3OCH2OCH(CH3)CF3
P1593HClClClCF3CF3HOCH(CH3)OCH2CF3
P1594HClClClCF3CF3BrOCH(CH3)OCH2CF3
P1595HClClClCF3CF3ClOCH(CH3)OCH2CF3
P1596HClClClCF3CF3CF3OCH(CH3)OCH2CF3
P1597HClClClCF3CF3CH3OCH(CH3)OCH2CF3
P1598HClClClCF2CF3HHOCH(CH3)OCH2CF3
P1599HClClClCF2CF3HBrOCH(CH3)OCH2CF3
P1600HClClClCF2CF3HClOCH(CH3)OCH2CF3
P1601HClClClCF2CF3HCF3OCH(CH3)OCH2CF3
P1602HClClClCF2CF3HCH3OCH(CH3)OCH2CF3
P1603HClClClCF3HHOCH(CH3)OCH2CF3
P1604HClClClCF3HHOCH(CH3)SCH2CF3
P1605HClClClCF3HHSCH(CH3)OCH2CF3
P1606HClClClCF3HBrSCH(CH3)OCH2CF3
P1607HClClClCF3HClSCH(CH3)OCH2CF3
P1608HClClClCF3HCF3SCH(CH3)OCH2CF3
P1609HClClClCF3HCH3SCH(CH3)OCH2CF3
P1610HClClClCF3HHOCH(CH3)OCH2CHF2
P1611HClClClCF3HBrOCH(CH3)OCH2CHF2
P1612HClClClCF3HClOCH(CH3)OCH2CHF2
P1613HClClClCF3HCF3OCH(CH3)OCH2CHF2
P1614HClClClCF3HCH3OCH(CH3)OCH2CHF2
P1615HClClClCF3HHOCH(CH3)OCH2CH2F
P1616HClClClCF3HBrOCH(CH3)OCH2CH2F
P1617HClClClCF3HClOCH(CH3)OCH2CH2F
P1618HClClClCF3HCF3OCH(CH3)OCH2CH2F
P1619HClClClCF3HCH3OCH(CH3)OCH2CH2F
P1620HClClClCF3HHOCH(CH3)OCH2CH3
P1621HClClClCF3HBrOCH(CH3)OCH2CH3
P1622HClClClCF3HClOCH(CH3)OCH2CH3
P1623HClClClCF3HCF3OCH(CH3)OCH2CH3
P1624HClClClCF3HCH3OCH(CH3)OCH2CH3
P1625HClClClCF3HHOCH(CH3)OCH(CH3)CF3
P1626HClClClCF3HBrOCH(CH3)OCH(CH3)CF3
P1627HClClClCF3HClOCH(CH3)OCH(CH3)CF3
P1628HClClClCF3HCF3OCH(CH3)OCH(CH3)CF3
P1629HClClClCF3HCH3OCH(CH3)OCH(CH3)CF3
P1630HClClClCF3HHOCH(CH3)OCH2CH2CF3
P1631HClClClCF3HBrOCH(CH3)OCH2CH2CF3
P1632HClClClCF3HClOCH(CH3)OCH2CH2CF3
P1633HClClClCF3HCF3OCH(CH3)OCH2CH2CF3
P1634HClClClCF3HCH3OCH(CH3)OCH2CH2CF3
P1635HClClClCF3HHOCH(CH2CH3)OCH2CF3
P1636HClClClCF3HHOC(CH3)2OCH2CF3
P1637HClClClCF3HHOCH2CH2OCH2CF3
P1638HClClClCF3HBrOCH2CH2OCH2CF3
P1639HClClClCF3HClOCH2CH2OCH2CF3
P1640HClClClCF3HCF3OCH2CH2OCH2CF3
P1641HClClClCF3HCH3OCH2CH2OCH2CF3
P1642HClHClCF3HHOCH2OCH2CF3
P1643HClHClCF3HBrOCH2OCH2CF3
P1644HClHClCF3HCF3OCH2OCH2CF3
P1645HClHClCF3HHOCH2SCH2CF3
P1646HClHClCF3HBrOCH2SCH2CF3
P1647HClHClCF3HClOCH2SCH2CF3
P1648HClHClCF3HCF3OCH2SCH2CF3
P1649HClHClCF3HCH3OCH2SCH2CF3
P1650HClHClCF3HHSCH2OCH2CF3
P1651HClHClCF3HBrSCH2OCH2CF3
P1652HClHClCF3HClSCH2OCH2CF3
P1653HClHClCF3HCF3SCH2OCH2CF3
P1654HClHClCF3HCH3SCH2OCH2CF3
P1655HClHClCF3HHOCH2OCH2CHF2
P1656HClHClCF3HBrOCH2OCH2CHF2
P1657HClHClCF3HClOCH2OCH2CHF2
P1658HClHClCF3HCF3OCH2OCH2CHF2
P1659HClHClCF3HCH3OCH2OCH2CHF2
P1660HClHClCF3HHOCH2OCH2CH2F
P1661HClHClCF3HBrOCH2OCH2CH2F
P1662HClHClCF3HClOCH2OCH2CH2F
P1663HClHClCF3HCF3OCH2OCH2CH2F
P1664HClHClCF3HCH3OCH2OCH2CH2F
P1665HClHClCF3HHOCH2OCH2CH3
P1666HClHClCF3HBrOCH2OCH2CH3
P1667HClHClCF3HClOCH2OCH2CH3
P1668HClHClCF3HCF3OCH2OCH2CH3
P1669HClHClCF3HCH3OCH2OCH2CH3
P1670HClHClCF3CF3HOCH2OCH2CF3
P1671HClHClCF3CF3BrOCH2OCH2CF3
P1672HClHClCF3CF3ClOCH2OCH2CF3
P1673HClHClCF3CF3CF3OCH2OCH2CF3
P1674HClHClCF3CF3CH3OCH2OCH2CF3
P1675HClHClCF2CF3HHOCH2OCH2CF3
P1676HClHClCF2CF3HBrOCH2OCH2CF3
P1677HClHClCF2CF3HClOCH2OCH2CF3
P1678HClHClCF2CF3HCF3OCH2OCH2CF3
P1679HClHClCF2CF3HCH3OCH2OCH2CF3
P1680HClHClCF3HHOCH2OCH(CH3)CF3
P1681HClHClCF3HBrOCH2OCH(CH3)CF3
P1682HClHClCF3HClOCH2OCH(CH3)CF3
P1683HClHClCF3HCF3OCH2OCH(CH3)CF3
P1684HClHClCF3HCH3OCH2OCH(CH3)CF3
P1685HClHClCF3CF3HOCH(CH3)OCH2CF3
P1686HClHClCF3CF3BrOCH(CH3)OCH2CF3
P1687HClHClCF3CF3ClOCH(CH3)OCH2CF3
P1688HClHClCF3CF3CF3OCH(CH3)OCH2CF3
P1689HClHClCF3CF3CH3OCH(CH3)OCH2CF3
P1690HClHClCF2CF3HHOCH(CH3)OCH2CF3
P1691HClHClCF2CF3HBrOCH(CH3)OCH2CF3
P1692HClHClCF2CF3HClOCH(CH3)OCH2CF3
P1693HClHClCF2CF3HCF3OCH(CH3)OCH2CF3
P1694HClHClCF2CF3HCH3OCH(CH3)OCH2CF3
P1695HClHClCF3HHOCH(CH3)OCH2CF3
P1696HClHClCF3HBrOCH(CH3)OCH2CF3
P1697HClHClCF3HClOCH(CH3)OCH2CF3
P1698HClHClCF3HCF3OCH(CH3)OCH2CF3
P1699HClHClCF3HCH3OCH(CH3)OCH2CF3
P1700HClHClCF3HHOCH(CH3)SCH2CF3
P1701HClHClCF3HBrOCH(CH3)SCH2CF3
P1702HClHClCF3HClOCH(CH3)SCH2CF3
P1703HClHClCF3HCF3OCH(CH3)SCH2CF3
P1704HClHClCF3HCH3OCH(CH3)SCH2CF3
P1705HClHClCF3HHSCH(CH3)OCH2CF3
P1706HClHClCF3HBrSCH(CH3)OCH2CF3
P1707HClHClCF3HClSCH(CH3)OCH2CF3
P1708HClHClCF3HCF3SCH(CH3)OCH2CF3
P1709HClHClCF3HCH3SCH(CH3)OCH2CF3
P1710HClHClCF3HHOCH(CH3)OCH2CHF2
P1711HClHClCF3HBrOCH(CH3)OCH2CHF2
P1712HClHClCF3HClOCH(CH3)OCH2CHF2
P1713HClHClCF3HCF3OCH(CH3)OCH2CHF2
P1714HClHClCF3HCH3OCH(CH3)OCH2CHF2
P1715HClHClCF3HHOCH(CH3)OCH2CH2F
P1716HClHClCF3HBrOCH(CH3)OCH2CH2F
P1717HClHClCF3HClOCH(CH3)OCH2CH2F
P1718HClHClCF3HCF3OCH(CH3)OCH2CH2F
P1719HClHClCF3HCH3OCH(CH3)OCH2CH2F
P1720HClHClCF3HHOCH(CH3)OCH2CH3
P1721HClHClCF3HBrOCH(CH3)OCH2CH3
P1722HClHClCF3HClOCH(CH3)OCH2CH3
P1723HClHClCF3HCF3OCH(CH3)OCH2CH3
P1724HClHClCF3HCH3OCH(CH3)OCH2CH3
P1725HClHClCF3HHOCH(CH3)OCH(CH3)CF3
P1726HClHClCF3HBrOCH(CH3)OCH(CH3)CF3
P1727HClHClCF3HClOCH(CH3)OCH(CH3)CF3
P1728HClHClCF3HCF3OCH(CH3)OCH(CH3)CF3
P1729HClHClCF3HCH3OCH(CH3)OCH(CH3)CF3
P1730HClHClCF3HHOCH(CH3)OCH2CH2CF3
P1731HClHClCF3HBrOCH(CH3)OCH2CH2CF3
P1732HClHClCF3HClOCH(CH3)OCH2CH2CF3
P1733HClHClCF3HCF3OCH(CH3)OCH2CH2CF3
P1734HClHClCF3HCH3OCH(CH3)OCH2CH2CF3
P1735HClHClCF3HHOCH(CH2CH3)OCH2CF3
P1736HClHClCF3HBrOCH(CH2CH3)OCH2CF3
P1737HClHClCF3HClOCH(CH2CH3)OCH2CF3
P1738HClHClCF3HCF3OCH(CH2CH3)OCH2CF3
P1739HClHClCF3HCH3OCH(CH2CH3)OCH2CF3
P1740HClHClCF3HHOC(CH3)2OCH2CF3
P1741HClHClCF3HBrOC(CH3)2OCH2CF3
P1742HClHClCF3HClOC(CH3)2OCH2CF3
P1743HClHClCF3HCF3OC(CH3)2OCH2CF3
P1744HClHClCF3HCH3OC(CH3)2OCH2CF3
P1745HClHClCF3HHOCH2CH2OCH2CF3
P1746HClHClCF3HBrOCH2CH2OCH2CF3
P1747HClHClCF3HClOCH2CH2OCH2CF3
P1748HClHClCF3HCF3OCH2CH2OCH2CF3
P1749HClHClCF3HCH3OCH2CH2OCH2CF3
P1750HHClClCF3HHOCH2OCH2CF3
P1751HHClClCF3HBrOCH2OCH2CF3
P1752HHClClCF3HClOCH2OCH2CF3
P1753HHClClCF3HCF3OCH2OCH2CF3
P1754HHClClCF3HCH3OCH2OCH2CF3
P1755HHClClCF3HHOCH2SCH2CF3
P1756HHClClCF3HBrOCH2SCH2CF3
P1757HHClClCF3HClOCH2SCH2CF3
P1758HHClClCF3HCF3OCH2SCH2CF3
P1759HHClClCF3HCH3OCH2SCH2CF3
P1760HHClClCF3HHSCH2OCH2CF3
P1761HHClClCF3HBrSCH2OCH2CF3
P1762HHClClCF3HClSCH2OCH2CF3
P1763HHClClCF3HCF3SCH2OCH2CF3
P1764HHClClCF3HCH3SCH2OCH2CF3
P1765HHClClCF3HHOCH2OCH2CHF2
P1766HHClClCF3HBrOCH2OCH2CHF2
P1767HHClClCF3HClOCH2OCH2CHF2
P1768HHClClCF3HCF3OCH2OCH2CHF2
P1769HHClClCF3HCH3OCH2OCH2CHF2
P1770HHClClCF3HHOCH2OCH2CH2F
P1771HHClClCF3HBrOCH2OCH2CH2F
P1772HHClClCF3HClOCH2OCH2CH2F
P1773HHClClCF3HCF3OCH2OCH2CH2F
P1774HHClClCF3HCH3OCH2OCH2CH2F
P1775HHClClCF3HHOCH2OCH2CH3
P1776HHClClCF3HBrOCH2OCH2CH3
P1777HHClClCF3HClOCH2OCH2CH3
P1778HHClClCF3HCF3OCH2OCH2CH3
P1779HHClClCF3HCH3OCH2OCH2CH3
P1780HHClClCF3CF3HOCH2OCH2CF3
P1781HHClClCF3CF3BrOCH2OCH2CF3
P1782HHClClCF3CF3ClOCH2OCH2CF3
P1783HHClClCF3CF3CF3OCH2OCH2CF3
P1784HHClClCF3CF3CH3OCH2OCH2CF3
P1785HHClClCF2CF3HHOCH2OCH2CF3
P1786HHClClCF2CF3HBrOCH2OCH2CF3
P1787HHClClCF2CF3HClOCH2OCH2CF3
P1788HHClClCF2CF3HCF3OCH2OCH2CF3
P1789HHClClCF2CF3HCH3OCH2OCH2CF3
P1790HHClClCF3HHOCH2OCH(CH3)CF3
P1791HHClClCF3HBrOCH2OCH(CH3)CF3
P1792HHClClCF3HClOCH2OCH(CH3)CF3
P1793HHClClCF3HCF3OCH2OCH(CH3)CF3
P1794HHClClCF3HCH3OCH2OCH(CH3)CF3
P1795HHClClCF3CF3HOCH(CH3)OCH2CF3
P1796HHClClCF3CF3BrOCH(CH3)OCH2CF3
P1797HHClClCF3CF3ClOCH(CH3)OCH2CF3
P1798HHClClCF3CF3CF3OCH(CH3)OCH2CF3
P1799HHClClCF3CF3CH3OCH(CH3)OCH2CF3
P1800HHClClCF2CF3HHOCH(CH3)OCH2CF3
P1801HHClClCF2CF3HBrOCH(CH3)OCH2CF3
P1802HHClClCF2CF3HClOCH(CH3)OCH2CF3
P1803HHClClCF2CF3HCF3OCH(CH3)OCH2CF3
P1804HHClClCF2CF3HCH3OCH(CH3)OCH2CF3
P1805HHClClCF3HHOCH(CH3)OCH2CF3
P1806HHClClCF3HBrOCH(CH3)OCH2CF3
P1807HHClClCF3HClOCH(CH3)OCH2CF3
P1808HHClClCF3HCF3OCH(CH3)OCH2CF3
P1809HHClClCF3HCH3OCH(CH3)OCH2CF3
P1810HHClClCF3HHOCH(CH3)SCH2CF3
P1811HHClClCF3HBrOCH(CH3)SCH2CF3
P1812HHClClCF3HClOCH(CH3)SCH2CF3
P1813HHClClCF3HCF3OCH(CH3)SCH2CF3
P1814HHClClCF3HCH3OCH(CH3)SCH2CF3
P1815HHClClCF3HHSCH(CH3)OCH2CF3
P1816HHClClCF3HBrSCH(CH3)OCH2CF3
P1817HHClClCF3HClSCH(CH3)OCH2CF3
P1818HHClClCF3HCF3SCH(CH3)OCH2CF3
P1819HHClClCF3HCH3SCH(CH3)OCH2CF3
P1820HHClClCF3HHOCH(CH3)OCH2CHF2
P1821HHClClCF3HBrOCH(CH3)OCH2CHF2
P1822HHClClCF3HClOCH(CH3)OCH2CHF2
P1823HHClClCF3HCF3OCH(CH3)OCH2CHF2
P1824HHClClCF3HCH3OCH(CH3)OCH2CHF2
P1825HHClClCF3HHOCH(CH3)OCH2CH2F
P1826HHClClCF3HBrOCH(CH3)OCH2CH2F
P1827HHClClCF3HClOCH(CH3)OCH2CH2F
P1828HHClClCF3HCF3OCH(CH3)OCH2CH2F
P1829HHClClCF3HCH3OCH(CH3)OCH2CH2F
P1830HHClClCF3HHOCH(CH3)OCH2CH3
P1831HHClClCF3HBrOCH(CH3)OCH2CH3
P1832HHClClCF3HClOCH(CH3)OCH2CH3
P1833HHClClCF3HCF3OCH(CH3)OCH2CH3
P1834HHClClCF3HCH3OCH(CH3)OCH2CH3
P1835HHClClCF3HHOCH(CH3)OCH(CH3)CF3
P1836HHClClCF3HBrOCH(CH3)OCH(CH3)CF3
P1837HHClClCF3HClOCH(CH3)OCH(CH3)CF3
P1838HHClClCF3HCF3OCH(CH3)OCH(CH3)CF3
P1839HHClClCF3HCH3OCH(CH3)OCH(CH3)CF3
P1840HHClClCF3HHOCH(CH3)OCH2CH2CF3
P1841HHClClCF3HBrOCH(CH3)OCH2CH2CF3
P1842HHClClCF3HClOCH(CH3)OCH2CH2CF3
P1843HHClClCF3HCF3OCH(CH3)OCH2CH2CF3
P1844HHClClCF3HCH3OCH(CH3)OCH2CH2CF3
P1845HHClClCF3HHOCH(CH2CH3)OCH2CF3
P1846HHClClCF3HBrOCH(CH2CH3)OCH2CF3
P1847HHClClCF3HClOCH(CH2CH3)OCH2CF3
P1848HHClClCF3HCF3OCH(CH2CH3)OCH2CF3
P1849HHClClCF3HCH3OCH(CH2CH3)OCH2CF3
P1850vHClClCF3HHOC(CH3)2OCH2CF3
P1851HHClClCF3HBrOC(CH3)2OCH2CF3
P1852HHClClCF3HClOC(CH3)2OCH2CF3
P1853HHClClCF3HCF3OC(CH3)2OCH2CF3
P1854HHClClCF3HCH3OC(CH3)2OCH2CF3
P1855HHClClCF3HHOCH2CH2OCH2CF3
P1856HHClClCF3HBrOCH2CH2OCH2CF3
P1857HHClClCF3HClOCH2CH2OCH2CF3
P1858HHClClCF3HCF3OCH2CH2OCH2CF3
P1859HHClClCF3HCH3OCH2CH2OCH2CF3
P1860HClFClCF3HHOCH2OCH2CF3
P1861HClFClCF3HClOCH2OCH2CF3
P1862HClFClCF3HCF3OCH2OCH2CF3
P1863HClFClCF3HHOCH2SCH2CF3
P1864HClFClCF3HBrOCH2SCH2CF3
P1865HClFClCF3HClOCH2SCH2CF3
P1866HClFClCF3HCF3OCH2SCH2CF3
P1867HClFClCF3HCH3OCH2SCH2CF3
P1868HClFClCF3HHSCH2OCH2CF3
P1869HClFClCF3HBrSCH2OCH2CF3
P1870HClFClCF3HClSCH2OCH2CF3
P1871HClFClCF3HCF3SCH2OCH2CF3
P1872HClFClCF3HCH3SCH2OCH2CF3
P1873HClFClCF3HHOCH2OCH2CHF2
P1874HClFClCF3HBrOCH2OCH2CHF2
P1875HClFClCF3HClOCH2OCH2CHF2
P1876HClFClCF3HCF3OCH2OCH2CHF2
P1877HClFClCF3HCH3OCH2OCH2CHF2
P1878HClFClCF3HHOCH2OCH2CH2F
P1879HClFClCF3HBrOCH2OCH2CH2F
P1880HClFClCF3HClOCH2OCH2CH2F
P1881HClFClCF3HCF3OCH2OCH2CH2F
P1882HClFClCF3HCH3OCH2OCH2CH2F
P1883HClFClCF3HHOCH2OCH2CH3
P1884HClFClCF3HBrOCH2OCH2CH3
P1885HClFClCF3HClOCH2OCH2CH3
P1886HClFClCF3HCF3OCH2OCH2CH3
P1887HClFClCF3HCH3OCH2OCH2CH3
P1888HClFClCF3CF3HOCH2OCH2CF3
P1889HClFClCF3CF3BrOCH2OCH2CF3
P1890HClFClCF3CF3ClOCH2OCH2CF3
P1891HClFClCF3CF3CF3OCH2OCH2CF3
P1892HClFClCF3CF3CH3OCH2OCH2CF3
P1893HClFClCF2CF3HHOCH2OCH2CF3
P1894HClFClCF2CF3HBrOCH2OCH2CF3
P1895HClFClCF2CF3HClOCH2OCH2CF3
P1896HClFClCF2CF3HCF3OCH2OCH2CF3
P1897HClFClCF2CF3HCH3OCH2OCH2CF3
P1898HClFClCF3HHOCH2OCH(CH3)CF3
P1899HClFClCF3HBrOCH2OCH(CH3)CF3
P1900HClFClCF3HClOCH2OCH(CH3)CF3
P1901HClFClCF3HCF3OCH2OCH(CH3)CF3
P1902HClFClCF3HCH3OCH2OCH(CH3)CF3
P1903HClFClCF3CF3HOCH(CH3)OCH2CF3
P1904HClFClCF3CF3BrOCH(CH3)OCH2CF3
P1905HClFClCF3CF3ClOCH(CH3)OCH2CF3
P1906HClFClCF3CF3CF3OCH(CH3)OCH2CF3
P1907HClFClCF3CF3CH3OCH(CH3)OCH2CF3
P1908HClFClCF2CF3HHOCH(CH3)OCH2CF3
P1909HClFClCF2CF3HBrOCH(CH3)OCH2CF3
P1910HClFClCF2CF3HClOCH(CH3)OCH2CF3
P1911HClFClCF2CF3HCF3OCH(CH3)OCH2CF3
P1912HClFClCF2CF3HCH3OCH(CH3)OCH2CF3
P1913HClFClCF3HHOCH(CH3)OCH2CF3
P1914HClFClCF3HBrOCH(CH3)OCH2CF3
P1915HClFClCF3HClOCH(CH3)OCH2CF3
P1916HClFClCF3HCF3OCH(CH3)OCH2CF3
P1917HClFClCF3HCH3OCH(CH3)OCH2CF3
P1918HClFClCF3HHOCH(CH3)SCH2CF3
P1919HClFClCF3HBrOCH(CH3)SCH2CF3
P1920HClFClCF3HClOCH(CH3)SCH2CF3
P1921HClFClCF3HCF3OCH(CH3)SCH2CF3
P1922HClFClCF3HCH3OCH(CH3)SCH2CF3
P1923HClFClCF3HHSCH(CH3)OCH2CF3
P1924HClFClCF3HBrSCH(CH3)OCH2CF3
P1925HClFClCF3HClSCH(CH3)OCH2CF3
P1926HClFClCF3HCF3SCH(CH3)OCH2CF3
P1927HClFClCF3HCH3SCH(CH3)OCH2CF3
P1928HClFClCF3HHOCH(CH3)OCH2CHF2
P1929HClFClCF3HBrOCH(CH3)OCH2CHF2
P1930HClFClCF3HClOCH(CH3)OCH2CHF2
P1931HClFClCF3HCF3OCH(CH3)OCH2CHF2
P1932HClFClCF3HCH3OCH(CH3)OCH2CHF2
P1933HClFClCF3HHOCH(CH3)OCH2CH2F
P1934HClFClCF3HBrOCH(CH3)OCH2CH2F
P1935HClFClCF3HClOCH(CH3)OCH2CH2F
P1936HClFClCF3HCF3OCH(CH3)OCH2CH2F
P1937HClFClCF3HCH3OCH(CH3)OCH2CH2F
P1938HClFClCF3HHOCH(CH3)OCH2CH3
P1939HClFClCF3HBrOCH(CH3)OCH2CH3
P1940HClFClCF3HClOCH(CH3)OCH2CH3
P1941HClFClCF3HCF3OCH(CH3)OCH2CH3
P1942HClFClCF3HCH3OCH(CH3)OCH2CH3
P1943HClFClCF3HHOCH(CH3)OCH(CH3)CF3
P1944HClFClCF3HBrOCH(CH3)OCH(CH3)CF3
P1945HClFClCF3HClOCH(CH3)OCH(CH3)CF3
P1946HClFClCF3HCF3OCH(CH3)OCH(CH3)CF3
P1947HClFClCF3HCH3OCH(CH3)OCH(CH3)CF3
P1948HClFClCF3HHOCH(CH3)OCH2CH2CF3
P1949HClFClCF3HBrOCH(CH3)OCH2CH2CF3
P1950HClFClCF3HClOCH(CH3)OCH2CH2CF3
P1951HClFClCF3HCF3OCH(CH3)OCH2CH2CF3
P1952HClFClCF3HCH3OCH(CH3)OCH2CH2CF3
P1953HClFClCF3HHOCH(CH2CH3)OCH2CF3
P1954HClFClCF3HBrOCH(CH2CH3)OCH2CF3
P1955HClFClCF3HClOCH(CH2CH3)OCH2CF3
P1956HClFClCF3HCF3OCH(CH2CH3)OCH2CF3
P1957HClFClCF3HCH3OCH(CH2CH3)OCH2CF3
P1958HClFClCF3HHOC(CH3)2OCH2CF3
P1959HClFClCF3HBrOC(CH3)2OCH2CF3
P1960HClFClCF3HClOC(CH3)2OCH2CF3
P1961HClFClCF3HCF3OC(CH3)2OCH2CF3
P1962HClFClCF3HCH3OC(CH3)2OCH2CF3
P1963HClFClCF3HHOCH2CH2OCH2CF3
P1964HClFClCF3HBrOCH2CH2OCH2CF3
P1965HClFClCF3HClOCH2CH2OCH2CF3
P1966HClFClCF3HCF3OCH2CH2OCH2CF3
P1967HClFClCF3HCH3OCH2CH2OCH2CF3
P1968HBrHBrCF3HHOCH2OCH2CF3
P1969HBrHBrCF3HBrOCH2OCH2CF3
P1970HBrHBrCF3HClOCH2OCH2CF3
P1971HBrHBrCF3HCF3OCH2OCH2CF3
P1972HBrHBrCF3HCH3OCH2OCH2CF3
P1973HBrHBrCF3HHOCH2SCH2CF3
P1974HBrHBrCF3HBrOCH2SCH2CF3
P1975HBrHBrCF3HClOCH2SCH2CF3
P1976HBrHBrCF3HCF3OCH2SCH2CF3
P1977HBrHBrCF3HCH3OCH2SCH2CF3
P1978HBrHBrCF3HHSCH2OCH2CF3
P1979HBrHBrCF3HBrSCH2OCH2CF3
P1980HBrHBrCF3HClSCH2OCH2CF3
P1981HBrHBrCF3HCF3SCH2OCH2CF3
P1982HBrHBrCF3HCH3SCH2OCH2CF3
P1983HBrHBrCF3HHOCH2OCH2CHF2
P1984HBrHBrCF3HBrOCH2OCH2CHF2
P1985HBrHBrCF3HClOCH2OCH2CHF2
P1986HBrHBrCF3HCF3OCH2OCH2CHF2
P1987HBrHBrCF3HCH3OCH2OCH2CHF2
P1988HBrHBrCF3HHOCH2OCH2CH2F
P1989HBrHBrCF3HBrOCH2OCH2CH2F
P1990HBrHBrCF3HClOCH2OCH2CH2F
P1991HBrHBrCF3HCF3OCH2OCH2CH2F
P1992HBrHBrCF3HCH3OCH2OCH2CH2F
P1993HBrHBrCF3HHOCH2OCH2CH3
P1994HBrHBrCF3HBrOCH2OCH2CH3
P1995HBrHBrCF3HClOCH2OCH2CH3
P1996HBrHBrCF3HCF3OCH2OCH2CH3
P1997HBrHBrCF3HCH3OCH2OCH2CH3
P1998HBrHBrCF3CF3HOCH2OCH2CF3
P1999HBrHBrCF3CF3BrOCH2OCH2CF3
P2000HBrHBrCF3CF3ClOCH2OCH2CF3
P2001HBrHBrCF3CF3CF3OCH2OCH2CF3
P2002HBrHBrCF3CF3CH3OCH2OCH2CF3
P2003HBrHBrCF2CF3HHOCH2OCH2CF3
P2004HBrHBrCF2CF3HBrOCH2OCH2CF3
P2005HBrHBrCF2CF3HClOCH2OCH2CF3
P2006HBrHBrCF2CF3HCF3OCH2OCH2CF3
P2007HBrHBrCF2CF3HCH3OCH2OCH2CF3
P2008HBrHBrCF3HHOCH2OCH(CH3)CF3
P2009HBrHBrCF3HBrOCH2OCH(CH3)CF3
P2010HBrHBrCF3HClOCH2OCH(CH3)CF3
P2011HBrHBrCF3HCF3OCH2OCH(CH3)CF3
P2012HBrHBrCF3HCH3OCH2OCH(CH3)CF3
P2013HBrHBrCF3CF3HOCH(CH3)OCH2CF3
P2014HBrHBrCF3CF3BrOCH(CH3)OCH2CF3
P2015HBrHBrCF3CF3ClOCH(CH3)OCH2CF3
P2016HBrHBrCF3CF3CF3OCH(CH3)OCH2CF3
P2017HBrHBrCF3CF3CH3OCH(CH3)OCH2CF3
P2018HBrHBrCF2CF3HHOCH(CH3)OCH2CF3
P2019HBrHBrCF2CF3HBrOCH(CH3)OCH2CF3
P2020HBrHBrCF2CF3HClOCH(CH3)OCH2CF3
P2021HBrHBrCF2CF3HCF3OCH(CH3)OCH2CF3
P2022HBrHBrCF2CF3HCH3OCH(CH3)OCH2CF3
P2023HBrHBrCF3HHOCH(CH3)OCH2CF3
P2024HBrHBrCF3HClOCH(CH3)OCH2CF3
P2025HBrHBrCF3HHOCH(CH3)SCH2CF3
P2026HBrHBrCF3HBrOCH(CH3)SCH2CF3
P2027HBrHBrCF3HClOCH(CH3)SCH2CF3
P2028HBrHBrCF3HCF3OCH(CH3)SCH2CF3
P2029HBrHBrCF3HCH3OCH(CH3)SCH2CF3
P2030HBrHBrCF3HHSCH(CH3)OCH2CF3
P2031HBrHBrCF3HBrSCH(CH3)OCH2CF3
P2032HBrHBrCF3HClSCH(CH3)OCH2CF3
P2033HBrHBrCF3HCF3SCH(CH3)OCH2CF3
P2034HBrHBrCF3HCH3SCH(CH3)OCH2CF3
P2035HBrHBrCF3HHOCH(CH3)OCH2CHF2
P2036HBrHBrCF3HBrOCH(CH3)OCH2CHF2
P2037HBrHBrCF3HClOCH(CH3)OCH2CHF2
P2038HBrHBrCF3HCF3OCH(CH3)OCH2CHF2
P2039HBrHBrCF3HCH3OCH(CH3)OCH2CHF2
P2040HBrHBrCF3HHOCH(CH3)OCH2CH2F
P2041HBrHBrCF3HBrOCH(CH3)OCH2CH2F
P2042HBrHBrCF3HClOCH(CH3)OCH2CH2F
P2043HBrHBrCF3HCF3OCH(CH3)OCH2CH2F
P2044HBrHBrCF3HCH3OCH(CH3)OCH2CH2F
P2045HBrHBrCF3HHOCH(CH3)OCH2CH3
P2046HBrHBrCF3HBrOCH(CH3)OCH2CH3
P2047HBrHBrCF3HClOCH(CH3)OCH2CH3
P2048HBrHBrCF3HCF3OCH(CH3)OCH2CH3
P2049HBrHBrCF3HCH3OCH(CH3)OCH2CH3
P2050HBrHBrCF3HHOCH(CH3)OCH(CH3)CF3
P2051HBrHBrCF3HBrOCH(CH3)OCH(CH3)CF3
P2052HBrHBrCF3HClOCH(CH3)OCH(CH3)CF3
P2053HBrHBrCF3HCF3OCH(CH3)OCH(CH3)CF3
P2054HBrHBrCF3HCH3OCH(CH3)OCH(CH3)CF3
P2055HBrHBrCF3HHOCH(CH3)OCH2CH2CF3
P2056HBrHBrCF3HBrOCH(CH3)OCH2CH2CF3
P2057HBrHBrCF3HClOCH(CH3)OCH2CH2CF3
P2058HBrHBrCF3HCF3OCH(CH3)OCH2CH2CF3
P2059HBrHBrCF3HCH3OCH(CH3)OCH2CH2CF3
P2060HBrHBrCF3HHOCH(CH2CH3)OCH2CF3
P2061HBrHBrCF3HBrOCH(CH2CH3)OCH2CF3
P2062HBrHBrCF3HClOCH(CH2CH3)OCH2CF3
P2063HBrHBrCF3HCF3OCH(CH2CH3)OCH2CF3
P2064HBrHBrCF3HCH3OCH(CH2CH3)OCH2CF3
P2065HBrHBrCF3HHOC(CH3)2OCH2CF3
P2066HBrHBrCF3HBrOC(CH3)2OCH2CF3
P2067HBrHBrCF3HClOC(CH3)2OCH2CF3
P2068HBrHBrCF3HCF3OC(CH3)2OCH2CF3
P2069HBrHBrCF3HCH3OC(CH3)2OCH2CF3
P2070HBrHBrCF3HHOCH2CH2OCH2CF3
P2071HBrHBrCF3HBrOCH2CH2OCH2CF3
P2072HBrHBrCF3HClOCH2CH2OCH2CF3
P2073HBrHBrCF3HCF3OCH2CH2OCH2CF3
P2074HBrHBrCF3HCH3OCH2CH2OCH2CF3

Example A: Bioassays on Beet Armyworm (“BAW”) and Corn Earworm (“CEW”) and Cabbage Looper (“CL”)

BAW has few effective parasites, diseases, or predators to lower its population. BAW infests many weeds, trees, grasses, legumes, and field crops. In various places, it is of economic concern upon asparagus, cotton, corn, soybeans, tobacco, alfalfa, sugar beets, peppers, tomatoes, potatoes, onions, peas, sunflowers, and citrus, among other plants. CEW is known to attack corn and tomatoes, but it also attacks artichoke, asparagus, cabbage, cantaloupe, collards, cowpeas, cucumbers, eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes, pumpkin, snap beans, spinach, squash, sweet potatoes, and watermelon, among other plants. CEW is also known to be resistant to certain insecticides. CL is also known to be resistant to certain insecticides. Consequently, because of the above factors control of these pests is important. Furthermore, molecules that control these pests are useful in controlling other pests.

Certain molecules disclosed in this document were tested against BAW, CEW and CL using procedures described in the following examples. In the reporting of the results, the “BAW & CEW & CL Rating Table” was used (See Table Section).

Bioassays on BAW (Spodoptera exigua)

Bioassays on BAW were conducted using a 128-well diet tray assay. One to five second instar BAW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg/cm2 of the test compound (dissolved in 50 μL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25° C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the tables entitled “Table 3: Assay Results Part 1” and “Table 4: Assay Results Part 2” (See Table Section).

Bioassays on CEW (Helicoverpa zea)

Bioassays on CEW were conducted using a 128-well diet tray assay. One to five second instar CEW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg/cm2 of the test compound (dissolved in 50 μL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25° C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled “Table 3: Assay Results Part 1” (See Table Section).

Bioassays on CL (Trichoplusia ni)

Bioassays on CL were conducted using a 128-well diet tray assay. One to five second instar CL larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 μg/cm2 of the test compound (dissolved in 50 μL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover, and held at 25° C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled “Table 4: Assay Results Part 2” (See Table Section).

Example B: Bioassays on Green Peach Aphid (“GPA”) (Myzus persicae)

GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of the leaves, and the death of various tissues. It is also hazardous because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other plants. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has developed resistance to many pesticides.

Certain molecules disclosed in this document were tested against GPA using procedures described in the following example. In the reporting of the results, the “GPA Rating Table” was used (See Table Section).

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) true leaves, were used as test substrate. The seedlings were infested with 20-50 GPA (wingless adult and nymph stages) one day prior to chemical application. Four pots with individual seedlings were used for each treatment. Test compounds (2 mg) were dissolved in 2 mL of acetone/MeOH (1:1) solvent, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5× with 0.025% Tween 20 in water to obtain the solution at 200 ppm test compound. A hand-held aspirator-type sprayer was used for spraying a solution to both sides of cabbage leaves until runoff. Reference plants (solvent check) were sprayed with the diluent only containing 20% by volume of acetone/MeOH (1:1) solvent. Treated plants were held in a holding room for three days at approximately 25° C. and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope. Percent Control was measured by using Abbott's correction formula (W. S. Abbott, “A Method of Computing the Effectiveness of an Insecticide” J. Econ. Entomol. 18 (1925), pp. 265-267) as follows.


Corrected % Control=100*(X−Y)/X

    • where
    • X=No. of live aphids on solvent check plants and
    • Y=No. of live aphids on treated plants

The results are indicated in the tables entitled “Table 3: Assay Results Part 1” and “Table 4: Assay Results Part 2” (See Table Section).

Pesticidally Acceptable Acid Addition Salts, Salt Derivatives, Solvates, Ester Derivatives, Polymorphs, Isotopes and Radionuclides

Molecules of Formula One may be formulated into pesticidally acceptable acid addition salts. By way of a non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Additionally, by way of a non-limiting example, an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium, and magnesium.

Molecules of Formula One may be formulated into salt derivatives. By way of a non-limiting example, a salt derivative can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt. A free base may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide, such as 2,4-D, is made more water-soluble by converting it to its dimethylamine salt.

Molecules of Formula One may be formulated into stable complexes with a solvent, such that the complex remains intact after the non-complexed solvent is removed. These complexes are often referred to as “solvates.” However, it is particularly desirable to form stable hydrates with water as the solvent.

Molecules of Formula One may be made into ester derivatives. These ester derivatives can then be applied in the same manner as the invention disclosed in this document is applied.

Molecules of Formula One may be made as various crystal polymorphs. Polymorphism is important in the development of agrochemicals since different crystal polymorphs or structures of the same molecule can have vastly different physical properties and biological performances.

Molecules of Formula One may be made with different isotopes. Of particular importance are molecules having 2H (also known as deuterium) in place of 1H.

Molecules of Formula One may be made with different radionuclides. Of particular importance are molecules having 14C.

Stereoisomers

Molecules of Formula One may exist as one or more stereoisomers. Thus, certain molecules can be produced as racemic mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers may be obtained by known selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. Certain molecules disclosed in this document can exist as two or more isomers. The various isomers include geometric isomers, diastereomers, and enantiomers. Thus, the molecules disclosed in this document include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.

Combinations

Molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties. Additionally, the molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists. Examples of such compounds in the above groups that may be used with the Molecules of Formula One are -(3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdepallthrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl α-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, j aponilure, j apothrins, j asmolin I, j asmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, me