Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([C@@H:50]([NH2:52])[CH3:51])[CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][C@H:50]([CH:47]4[CH2:49][CH2:48]4)[CH3:51])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)C1CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)C2CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-((S)-1-cyclopropyl-ethyl)-amine (Alfa) to give the title compound. LC-MS (ES+) 732 [(M+H)+].
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]([CH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)([CH2:17][CH2:18][CH2:19][CH2:20][B:21]1[O:25]C(C)(C)C(C)(C)[O:22]1)[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.[ClH:39]>O>[ClH:39].[ClH:39].[B:21]([CH2:20][CH2:19][CH2:18][CH2:17][C:9]([NH:8][CH3:6])([CH2:30][CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][CH2:36][CH2:37]1)[C:10]([OH:12])=[O:11])([OH:22])[OH:25]
Reactant: CN(C(=O)OC(C)(C)C)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCN1CCCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Product: CNC(CCCCB(O)O)(CCCN1CCCC1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(3-(pyrrolidin-1-yl)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (183 mg, 0.33 mmol) in 6 N hydrochloric acid (5 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give 6-borono-2-(methylamino)-2-(3-(pyrrolidin-1-yl)propyl)hexanoic acid dihydrochloride, as a colorless foam (81 mg, 80%). 1H NMR (D2O, 300 MHz) δ 3.55-3.45 (m, 2H), 3.14-3.05 (m, 2H), 2.98-2.87 (m, 2H), 2.53 (s, 3H), 2.03-1.92 (m, 2H), 1.92-1.76 (m, 6H), 1.76-1.64 (m, 1H), 1.62-1.48 (m, 1H), 1.36-1.14 (m, 3H), 1.14-0.98 (m, 1H), 0.64 (t, J=7.2 Hz, 2H). ESI MS found for C14H29BN2O4 m/z [301.2 (M+1)].
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[N+:15]([O-])=O)[CH:2]1[O:4][CH2:3]1.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Fe].CCO.O>[OH:4][CH2:3][CH:2]1[NH:15][C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=2[O:5][CH2:1]1
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2c(c1)NC(CO)CO2
Temperature: 25 °C

Procedure:
Iron powder (0.670 g, 12 mmol) was added into EtOH/H2O (v/v=6:1, 100 mL) solution of 2,4-dinitrophenyl glycidyl ether (0.480 g, 2 mmol) and acetic acid (1 mL, 17.5 mmol) at reflux temperature. The reaction mixture was refluxed continuously for 120 minutes, and cooled to room temperature, saturated Na2CO3 solution was used for adjusting pH=8, the solution was leached out with C salt for concentrating ethanol and water in the filtrate, and the solid ethanol was obtained (10 mL×4). Ethanol phase was dried with anhydrous MgSO4 and filtered to obtain crude products; the above crude products were separated with silica gel column chromatography (ethanol as developing agent), and 2,3-dihydro-3-hydroxymethyl-6-amino-[1,4]-benzoxazine (0.149 g, 42%) was prepared.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:28])[CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[Cl:29][C:30]1[N:35]=[C:34]([Cl:36])[C:33]([CH2:37]I)=[CH:32][N:31]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:28])[CH:19]([C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])[CH2:37][C:33]1[C:34]([Cl:36])=[N:35][C:30]([Cl:29])=[N:31][CH:32]=1
Reactant: COC(=O)Cc1c(Cl)cccc1Cl
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 2,6-dichloro-phenylacetic acid methyl ester (2.19 g, 10.0 mmol) (TCI-US) in tetrahydrofliran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To this reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 2-(2,6-dichloro-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester as a colorless oil. (Yield 1.57 g, 82.6%).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:36][C:37]1[N:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:36][C:37]1[N:42]=[CH:41][C:40]([CH2:43][O:18][C:15]2[CH:16]=[CH:17][C:10]3[O:9][C:8]([CH:7]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=4)[CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[C:12]([CH3:13])[C:11]=3[CH:14]=2)=[CH:39][CH:38]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCc4ccc(Cl)nc4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (0.35 g) synthesized in Example A167(1) was dissolved in tetrahydrofuran (5 mL), and 6-chloro-3-pyridinemethanol (0.13 g), tributylphosphine (0.33 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.33 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr then hexane (5 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.31 g, 65%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:19]1(=[O:30])[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Yield: 55 %

Procedure:
A solution of 1.28 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.81 g of homophthalic anhydride, 50 ml of toluene and 25 ml of tetrahydrofuran was heated to reflux for 0.5 hr. The solvents were removed by rotary evaporation and the residual materials were triturated with ethyl ether to yield 1.15 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid. Recrystallization from acetonitrile yielded 0.81 g of material; m.p. 204°-206° C. Anal. Calcd for C24H22N2O3S: C, 68.88; H, 5.30; N, 6.69. Found: C, 68.15; H, 5.21; N, 6.54.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH:23][C:24]3[C:25](=O)[C:26](=[O:30])[C:27]=3[O:28]C)[C:17]=2[NH:16][N:15]=1>CO>[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([NH:23][C:24]3[C:27](=[O:28])[C:26](=[O:30])[C:25]=3[NH:13][CH:7]([C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:8]3([CH3:12])[CH2:9][O:10][CH2:11]3)[C:17]=2[NH:16][N:15]=1
Reactant: COc1c(Nc2cccc3nn[nH]c23)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc4nn[nH]c34)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 43.1 %

Procedure:
A mixture of 263 mg (1.45 mmol, 1.2 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine and 1.02 g (1.21 mmol, 1 eq) of 3-(3H-benzotriazol-4-ylamino)-4-methoxycyclobut-3-ene-1,2-dione at 29% in 25 ml of methanol was heated at 50° C. for 24 hours. The insoluble material (dimer) was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel (column puriFlash PF-30SIHP/40G, Spot II) eluted with dichloromethane/methanol (gradient). The solid was taken up with ethyl acetate and this organic phase was washed several times with a 1 N sodium dihydrogen phosphate solution, dried over magnesium sulfate, filtered and evaporated. 205 mg of 3-(3H-benzotriazol-4-ylamino)-4-{[(5-methyl furan-2-yl)-(3-methyloxetan-3-yl)methyl]amino}cyclobut-3-ene-1,2-dione were obtained in the form of a yellow solid. (Mp=178-180° C.). Yield=43%, LC/MS: 95.97% [393].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]([CH3:14])[CH3:13].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:11]([NH:15][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:18]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)CNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (4.0 g), N-isobutylthiourea (2.60 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 2:1 by volume ratio) to give the title compound (3.30 g, 71%) as a yellow oil.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C.CCOC(C)=O>[C:1]([N:9]1[CH2:13][CH2:12][C@H:11]([N:14]([CH3:24])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of compound 4b (0.15 g, 0.517 mmol) in DMF (2 mL) was added NaH (60% in mineral, 31 mg, 0.775 mmol) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 30 min and then MeI (0.065 mL, 1.034 mmol) was added. The reaction was allowed to warm to room temperature with continuous stirring for 2 h. To the reaction mixture was added water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 35% EtOAc/hexanes) gave compound 4c (0.12 g). MS m/z (M-Boc+) 204.2.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([C:4](=[O:22])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3].[CH:24]([Mg]Cl)=[CH2:25].O>O1CCCC1>[CH3:3][C:2]([CH3:23])([C:4]([CH:24]=[CH2:25])([OH:22])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)C(CCCCOc1ccccc1)n1cncn1
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)(C(CCCCOc1ccccc1)n1cncn1)C(C)(C)C

Procedure:
A solution of 12.6 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-8-phenoxyoctan-3-one was added dropwise to a solution of 8.7 g of vinyl magnesium chloride in 70 ml of tetrahydrofuran, while stirring. After the weakly exothermic reaction was complete, the mixture was refluxed for a further 5 hours and then cooled. Thereafter, a mixture of 5 ml of water and 5 ml of tetrahydrofuran was added dropwise, while cooling with ice, the reaction mixture was stirred for a further 2 hours at room temperature, the precipitated magnesium salts were then filtered off, and the filtrate was concentrated under reduced pressure. The residue from the filtrate was taken up in 100 ml of dichloromethane, the solution was washed with 100 ml of water and then with 100 ml of saturated ammonium chloride solution, and the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. 8.0 g of pale yellowish crystals of melting point 66°-69° C. (diastereomer mixture 2:1) crystallized from the residual oil on trituration with diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[O:23][C:16]3=[C:17]([NH2:22])[N:18]=[CH:19][C:20](Br)=[C:15]3[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)[CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][C:17]1[N:18]=[CH:19][C:20]([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)[CH:38]=2)=[C:15]2[CH:14]=[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)[O:23][C:16]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(Br)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-4-bromo-furo[2,3-c]pyridin-7-ylamine (0.449 g, 1.06 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.419 g, 1.11 mmol) in 1,4-dioxane (60 mL) and water (12 mL) was stirred for 10 min and degassed with nitrogen for 15 min. To this stirred mixture was added Pd(PPh3)2Cl2 (100 mg, 0.14 mmol) and the solution was degassed with nitrogen for an additional 5 min. Na2CO3 (168 mg, 1.59 mmol) was added and resulting mixture was stirred at 95° C. for 4 h. The reaction mixture was cooled to RT and the solvent was removed on a rotary evaporator to give the crude compound, which was purified by flash chromatography (2% MeOH:DCM) to afford 229 mg (36%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.45 (s, 9H), 2.10 (m, 2H), 2.22 (m, 2H), 2.97 (t, J=13.2 Hz, 2H), 4.35 (m, 3H), 5.59 (br, 2H), 7.34 (s, 1H), 7.71 (s, 1H), 7.81 (s, 1H), 7.92 (d, J=5.1 Hz, 2H), 8.32 (s, 2H). MS (ESI): 596 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH:3](=[CH:1][NH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: CN
Solvent: Cc1ccccc1
Product: NC=Cc1ccccc1
Temperature: 0 °C
Yield: 88 %

Procedure:
Anhydrous monomethylamine (about 1-1.5 eq.) was introduced below the surface of a stirred solution of benzaldehyde (1062 g, 10.0 mol) in toluene (2000 ml) cooled to 0° C. The rate of addition of monomethylamine was adjusted so as to maintain the reaction temperature between 25°-30° C.; after 45 minutes the addition of monomethylamine was terminated. The organic phase was separated and concentrated in vacuo. Distillation of the residual oil afforded N-benzylidenemethylamine (1047 g, 8.79 mol) in 88% yield. The product had a boiling point of 79° C. at 20 mm. [This N-benzylidinemethylamine starting material is reported by R. B. Moffett et al, Org. Syn. Coll. Vol. IV, 605-608 (1963)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1.C[O:27]C1C=CC(N2[C@@H](C)[C@@H](COC3C=CC(C#N)=CC=3)OC2=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Reactant: COc1ccc(N2C[C@@](C)(COc3ccc(C#N)cc3)OC2=O)cc1
Product: COc1ccc(N2C[C@@](C)(COc3ccc(C=O)cc3)OC2=O)cc1
Yield: 85 %

Procedure:
The same procedure of Example 16 was repeated except that 4-[(S)-(+)-3-(4-methoxyphenyl)-5-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile obtained in Reference Example 16 was used in lieu of 4-[(4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile to give the title compound (compound 49) as an oil (yield 85%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:3][C:2]([NH:17][C:18]3[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.599 g, 2.42 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.451 g, 2.42 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)phenyl)methane sulfonamide 33 (0.393 g, 41% yield) as a solid. MS (ES) m/z 398 (M+H+).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]2([C:36]([F:39])([F:38])[F:37])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:34])[CH:27]([S:31][CH2:32][CH3:33])[S:28][CH2:29][CH3:30])=[C:20]([Cl:35])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:50])C=1.S([O-])(O)=O.[Na+]>ClCCl>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:36]([F:38])([F:37])[F:39])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:34])[CH:27]([S:28]([CH2:29][CH3:30])=[O:50])[S:31][CH2:32][CH3:33])=[C:20]([Cl:35])[CH:19]=3)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:8]=1
Reactant: CCSC(SCC)C(=O)NCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCSC(C(=O)NCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Cl)S(=O)CC
Temperature: 25 °C

Procedure:
To a solution of 0.37 g of N-[4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-chlorophenyl]methyl-2,2-bis(ethylthio) acetamide (compound of the present invention No. 1-215) in 5 mL of dichloromethane, 0.098 g of 3-chloroperbenzoic acid (75%) was added while stirring the solution at room temperature and the resultant reaction mixture was stirred at the same temperature for 1 hour. After the completion of the reaction, 5 mL of a saturated sodium hydrogen sulfite aqueous solution was added to the reaction mixture and the resultant mixture was extracted with dichloromethane (5 mL×2). The organic phase was washed with water and then dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative medium pressure liquid chromatography eluting with ethyl acetate-hexane (a gradient from 1:1 to 1:5) using a medium pressure preparative apparatus (trade name: YFLC-Wprep; manufactured by Yamazen Corporation) to obtain 0.282 g of the objective substance as a colorless resinoid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])C.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1>[F:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[CH:12]=1
Reactant: CCOC(=O)CCc1cc(F)ccc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(F)cc1CCC=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of ethyl-3-(5′-fluoro-2′-methoxyphenyl)propionate (5.8 g, 25.7 mmol) in dry toluene (40 mL) under Ar was added DIBAL solution (1 M in toluene, 30 mL, 30 mmol) at −78° C. The reaction was stirred at this temperature for 2 h. Methanol (2 mL) was added to the reaction mixture and the reaction was allowed to warm to 0° C. The reaction mixture was then poured into a separatory funnel containing HCl solution (1 N, 150 mL). The organic function was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine (80 mL) and dried over sodium sulfate. The crude product that was obtained after removal of the solvent in vacuo was purified by flash column chromatography (20% EtOAc in hexane, Rf=0.20) to give the product (3.1 g, 66%).