Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:27]=[CH:28][CH:29]=[CH:30]6)=[O:38])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, white solid (107 mg, 89%), MS (ISP) m/z=484.5 [(M+H)+], mp 238° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:15]([C:18]([C:21]([OH:23])=[O:22])([F:20])[F:19])(F)[F:16])([F:14])[F:13])(F)[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].C(C(C(OC(C(C(C(O)=O)(F)F)F)(F)F)F)(F)F)(F)(F)F.[NH3:45].C(C(C(OC(C(C(C([O-])=O)(F)F)(F)F)(F)F)(F)F)(F)F)(F)(F)F.[NH4+]>>[C:1]([C:5]([CH:8]([O:11][C:12]([CH:15]([C:18]([C:21]([O-:23])=[O:22])([F:19])[F:20])[F:16])([F:13])[F:14])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[NH4+:45]
Reactant: N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(O)C(F)(F)C(F)C(F)(F)OC(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: [NH4+]
Product: O=C([O-])C(F)(F)C(F)C(F)(F)OC(F)C(F)(F)C(F)(F)F

Procedure:
NMR analysis clarified that the fraction 1 was CF3CF2CF2OCF2CF2CF2COOH and the fraction 2 was CF3CF2CHFOCF2CHFCF2COOH. These were neutralized with ammonia so that CF3CF2CF2OCF2CF2CF2COONH4 and CF3CF2CHFOCF2CHFCF2COONH4 were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[Cl:44][C:45]1[S:49][C:48]([NH2:50])=[N:47][CH:46]=1.C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:44][C:45]1[S:49][C:48]([NH:50][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:47][CH:46]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1cc(C(=O)Nc2ncc(Cl)s2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.4 %

Procedure:
A solution of triphenylphosphine (251 mg, 0.82 mmol) in methylene chloride (4 mL) cooled to 0° C. was treated with N-bromosuccinimide (146 mg, 0.82 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 5-chloro-thiazol-2-ylamine (248 mg, 1.45 mmol) and was stirred at 25° C. for 30 min. The reaction was then treated with N,N-diisopropylethylamine (0.22 mL, 1.26 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (30 mL) and ethyl acetate (30 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (10 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-thiazol-2-yl)-amide (30 mg, 13%) as a pink solid: mp 252-253° C.; (ES)+-HRMS m/e calcd for C15H13Cl2N3OS (M+H)+ 354.0229, found 354.0233.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([CH:15]([OH:20])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add sodium borohydride (15.2 g, 423 mmol) to a solution of (S)-3-(3-methylbutanoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (21.6 g, 84.6 mmol) in methanol (500 mL) portion wise and stir at room temperature overnight. Add another equivalent of sodium borohydride (3.04 g, 84.6 mmol). Stir for another 2 hours, evaporate the methanol to half the volume, add brine and extract with EtOAc. Dry the combined organic phases (MgSO4), filter and concentrate under reduced pressure. Separate the diastereoisomers by super critical fluid chromatography (AD-H column) eluting with 10% MeOH/CO2 with 0.2% diethylmethylamine to provide (3S)-3-(1-hydroxy-3-methyl-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, isomer 1 (S-1) as the first eluting isomer (8.2 g, 38%) and (3S)-3-(1-hydroxy-3-methyl-butyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, isomer 2 (S-2) as the second eluting isomer (8.9 g, 41%).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH:7]([O:27][C:28](=[O:44])[C@H:29]([CH:41]([CH3:43])[CH3:42])[NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(C)(C)C>ClCCl>[C:31]([NH:30][C@H:29]([C:28]([O:27][CH:7]([CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:6]([OH:45])=[O:5])=[O:44])[CH:41]([CH3:42])[CH3:43])([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of t-butyl -2,3-bis-(N-CBz-L-valyloxy)-propionate (7.2 g, 11.4 mmole) in dichloromethane (25 ml) was added tifluoroacetic acid (25 ml) and the solution was stirred for five hours at room temperature. The solution was evaporated under reduced pressure and coevaporated two times with toluene. The product was isolated by silica gel column chromatography. Yield: 5.9 g=90%
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.[CH:14]([O:16][CH2:17][CH3:18])=[CH2:15].N1C=CC=CC=1>ClCCl>[CH2:17]([O:16][CH:14]=[CH:15][C:3](=[O:4])[C:2]([F:7])([F:1])[CH3:6])[CH3:18]
Reactant: CC(F)(F)C(=O)O
Reactant: C=COCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC=CC(=O)C(C)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a cooled (0° C.) solution of 2,2-difluoropropionic acid (prepared according to the procedure described in U.S. Pat. No. 5,859,051) (2.20 g, 20.0 mmol) in dichloromethane (15 ml) was added oxalyl chloride (2.79, 22.0 mmol) dropwise over 10 min. The mixture was stirred at 0° C. for 10 min then allowed to warm to ambient temperature overnight. The mixture was cooled to −10° C. and added via a cannula to a cooled (−10° C.) solution of ethyl vinyl ether (1.59 g, 22.0 mmol) and pyridine (1.74 g, 22.0 mmol) in dichloromethane (50 ml). The mixture was stirred at −10° C. for 10 min then at ambient temperature for 5 h. The brown solution was diluted with dichloromethane (30 ml) and washed with ice-cold 1M sulphuric acid (2×50 ml) and ice-cold water (2×50 ml), dried over anhydrous sodium sulfate and evaporated to give crude 1-ethoxy-4,4-difluoropent-1-en-3-one (3.28 g, 100%) as an orange oil: δH (400 MHz, CDCl3) 1.38 (3H, t, J 7), 1.71 (3H, t, J 19), 4.05 (2H, q, J 7), 5.94 (1H, dt, J 12 and 1), 7.81 (1H, d, J 12).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][O:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[CH2:18][CH2:17][O:16][CH2:15][C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](COCCC3CCCCN3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@H]1CC[C@@H](COCCC2CCCCN2)CC1
Reaction time: 8 h

Procedure:
cis-N,N-Dibenzyl-N-{4-[(2-piperidylethoxy)methyl]cyclohexyl}amine (2.84 g, 6.65 mmol) was dissolved in 20 mL of ethanol. Palladium hydroxide (20% weight) was added (50 mg) and the reaction was stirred overnight under an atmosphere of hydrogen. The catalyst was removed by filtration and washed with small portions of ethanol. The filtrate was concentrated and used without further purification. (quantitative yield): ES-MS (m/z) 241.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH2:1]([CH:5]1[CH2:6][C:7](=[O:12])[CH:8]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[C:9](=[O:11])[CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2C(=O)CC(CC(C)C)CC2=O)cc1

Procedure:
Reaction of equimolar amounts of 5-isobutyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ISOBUTYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 128°-130° C. (corr.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[N+:27]([O-])([OH:29])=[O:28]>>[C:1]([NH:4][C:5]1[C:6]([N+:27]([O-:29])=[O:28])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc2c(cc1Br)C(CCC(=O)O)CC2
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CCC2CCC(=O)O
Reaction time: 2 h

Procedure:
A mixture of 5-acetamido-6-bromo-2-carboxyethylindane (7 g, 20 mmol) and trifluoroacetic acid (150 mL) was cooled in an ice bath and treated with fuming nitric acid (10 mL). After 2 h at 0° C., the solvent was removed and the residue solidified upon addition of water. The solid was collected by filtration, washed with ether and dried. Crystallization from hot toluene gave the pure product (7 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cnco1
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cnco1
Yield: 47.6 %

Procedure:
Racemic compound 5.4 (1.3 g, 5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 20% i-PrOH in hexane as eluant. Eluant containing the peak with greater retention time was concentrated and compound 5.5 (620 mg, 2.38 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 262.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[F:13][C:14]1[CH:27]=[CH:26][C:17]2[S:18][C:19]([S:22](Cl)(=[O:24])=[O:23])=[C:20]([CH3:21])[C:16]=2[CH:15]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:22]([C:19]2[S:18][C:17]3[CH:26]=[CH:27][C:14]([F:13])=[CH:15][C:16]=3[C:20]=2[CH3:21])(=[O:24])=[O:23])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.4 %

Procedure:
To an ice cooled solution of 4-bromo-2-(trifluoromethyl)benzenamine (CAS 445-02-3, 18 g) in pyridine (25 ml) was added 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (CAS:404964-34-7, 2.0 g). The reaction mixture was stirred at rt for 72 h, concentrated under vacuum, and the residue was chromatographed over silica gel using heptane/chloroform as eluent to obtain 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (2.35 g) as a colorless solid. MS (ISN): 465.9, 468.0 (M−H)−
Reaction SMILES: C(O[C@H:9]1[C@H:14](OCC2C=CC=CC=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])CO)C1C=CC=CC=1.F[C:57](F)(F)[C:58]([OH:60])=O>ClCCl>[CH2:12]([O:11][C@H:9]1[C@H:14]([O:60][CH2:58][C:57]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:54]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH:49]([F:50])[F:51])=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 1 h

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 12k (293 mg, 0.38 mmol) was dissolved in 10 mL dichloromethane, followed by dropwise addition of trifluoroacetic acid (0.1 mL). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 12m (76 mg, white solid), yield: 27.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:30]=[CH:29][C:11]([O:12][CH2:13][O:14][C:15]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][O:14][C:15]([C:21]([F:22])([F:23])[F:24])([C:25]([F:26])([F:27])[F:28])[C:16]([OH:18])=[O:17])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(OCOc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 22 h
Yield: 43.3 %

Procedure:
A mixture of ethyl 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (502 mg.) potassium hydroxide (88 mg.), methanol (4 ml.) and water (1 ml.) is stirred at 20° C. for 22 hours, then evaporated in vacuo. The residue is dissolved in water, and the solution is acidified with 3 N-hydrochloric acid. The solid which separates is filtered off. Crystallisation from a mixture of cyclohexane and light petroleum (b.p. 40°-60° C.) gives prisms (204 mg.) of 2-[4-(4-chlorophenyl)phenoxymethoxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 134°-135° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
(R)-[3-[1-((R)-3-Fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 25a (0.15 g, 0.27 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-((R)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 25 (140 mg, yield 94%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:24]=1>CCCCCC>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)=[CH:21][CH:20]=1
Reactant: O=C(O)CCCc1cccnc1
Reactant: Fc1ccc(C(=CC2CCNCC2)c2ccc(F)cc2)cc1
Solvent: CCCCCC
Product: O=C(CCCc1cccnc1)N1CCC(C=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 64.8 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of example 10 starting with 9.0 g of 4-[2,2-bis(4-fluorophenyl)ethenyl]piperidine, 0.15 molar hexane solvate and the acid chloride prepared from 6.6 g of 3-pyridine butanoic acid. The toluene extracts were evaporated and the residue was crystallized from ether to give 8.7 g (65%) of pure 4-[2,2-bis[4-fluorophenyl)ethenyl]1-[1-oxo-4-(3-pyridinyl)butyl]piperidine, mp 100°-102° C. Analysis Calculated for C28H28F2N2O: C, 75.31; H, 6.32; N, 6.27; F, 8.51. Found: C, 75.36; H, 6.30; N, 6.24; F, 8.30.
Reaction SMILES: C(O)(=O)C.O.[Si]([O:13][CH2:14][C@@H:15]1[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][C@@H:16]1[NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:13][CH2:14][C@@H:15]1[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][C@@H:16]1[NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Reaction time: 48 h
Yield: 99.3 %

Procedure:
A solution of acetic acid, water, and THF (30 mL, 3:1:1) was added to benzyl (1S,2R)-2-((tert-butyldimethylsilyloxy)methyl)-4-oxocyclohexylcarbamate (2.56 g) in one portion. After 48 h, the reaction solvent was removed in vacuo and replaced with ethyl acetate (100 mL). The mixture was washed with water (1×25 mL), sat'd NaHCO3 (2×25 mL), and brine (1×25 mL). The resulting organic layer was dried over MgSO4, filtered, and then evaporated to dryness in vacuo to give benzyl (1S,2R)-2-(hydroxymethyl)-4-oxocyclohexylcarbamate (1.80 g) as a clear viscous oil after drying under vacuum overnight: 1H NMR (300 MHz, CDCl3) δ 7.37 (s, 5H), 5.57 (d, J=6.9 Hz, 1H), 5.13 (s, 2H), 4.25 (br s, 1H), 3.69 (m, H), 3.45 (m, 2H), 2.38-2.02 (m, 7H).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)=[N:5][CH:4]=1)[CH3:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([C:3]1[O:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:22][C@H:23]4[O:25][CH2:24]4)[C:10]=3[CH:9]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(-c2cc3c(O)cccc3o2)o1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 99.7 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(5-ethyloxazol-2-yl)-4-hydroxybenzo(b)furan (1.10 g), (S)-glycidyl nosylate (1.24 g) and potassium carbonate (1.99 g), a crude product of the title compound (1.36 g) was obtained as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:8])[CH:5]([Cl:7])[CH3:6].C(N(CC)CC)C.[CH3:16][N:17]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:18](Cl)=[O:19]>C1C=CC=CC=1>[Cl:7][CH:5]([CH3:6])[C:4]([O:8][C:18](=[O:19])[N:17]([CH3:16])[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:3][O:2][CH3:1]
Reactant: CN(C(=O)Cl)C1CCCCC1
Reactant: CONC(=O)C(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CON=C(OC(=O)N(C)C1CCCCC1)C(C)Cl
Temperature: 25 °C

Procedure:
N-Methoxy-α-chloropropionamide (13.8 grams; 0.1 mole), benzene (70 ml) and triethylamine (12 grams; 0.12 mole) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. N-Methyl-N-cyclohexylcarbamoyl chloride (17.9 grams; 0.1 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-1-methyl-2-(N-methyl-N-cyclohexylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1)[C:9]([O:11]CC)=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:6][N:7]=[C:8]([C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCON=C(C(=O)O)c1csc(N)n1
Yield: 86.9 %

Procedure:
Ethyl 2-pentyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (28.6 g.) and 2 N sodium hydroxide aqueous solution (100.2 ml.) were reacted in a mixture of methanol (100 ml.) and tetrahydrofuran (100 ml.) according to similar manners to those of Preparation (9-1) and (9-2) to give 2-pentyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (22.4 g.), mp 176° C. (dec.).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]([O:6][C:7]([C:9]1[C:10]([CH3:24])=[N:11][S:12][C:13]=1[NH:14][C:15](OC1C=CC=CC=1)=[O:16])=[O:8])[CH3:5].O>C(O)C>[CH2:1]([NH:3][C:15](=[O:16])[NH:14][C:13]1[S:12][N:11]=[C:10]([CH3:24])[C:9]=1[C:7]([O:6][CH2:4][CH3:5])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Reactant: CCN
Solvent: O
Solvent: CCO
Product: CCNC(=O)Nc1snc(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 50% w/v solution of ethylamine in ethanol (30 ml.) was added to a solution of 4-ethoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole (prepared according to the method of Goerdeler and Horn, Chemische Berichte, 1963, 96, 1551; 30.6 g.) in warm ethanol (120 ml.). The mixture was then heated under reflux for 1 minute, and allowed to cool to ambient temperature and stand for 2 days. The mixture was then heated under reflux for 5 minutes, allowed to cool to ambient temperature and stand for 1 day and poured into cold water (1 liter). The precipitated solid was filtered off, dried and recrystallised from benzene (300 ml.) to give 3-ethyl-1-(4-ethoxycarbonyl-3-methylisothiazol-5-yl)urea (24.8 g.), m.p. 141° C.