Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[C:33]=1[Cl:34].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:7]2[C:6]3[C:33]([Cl:34])=[C:2]([C:39]4[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=4)[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1)([CH3:31])([CH3:30])[CH3:32]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)c(Cl)c32)cc1
Product: Cn1cc(-c2ccc3c(c2Cl)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)cn1

Procedure:
The title compound was prepared from 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-7-chloro-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 64) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the procedure of Example 495. Racemic mixture: LC/MS: m/e 576.1 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 8.05 (1H, s), 7.80 (1H, s), 7.58 (1H, d), 7.41 (2H, d), 7.10 (3H, m), 7.05 (1H, d), 7.00-7.10 (2H, d), 5.19 (1H, d), 5.55 (1H, d), 3.96 (3H, s), 1.26 (9H, s). The racemic mixture was separated on a Chiracel OD-H column eluting with 20% EtOH in hexanes at 8.0 mL/min. The faster eluting enantiomer E1 had a retention time of 40 min. The slower eluting enantiomer E2 had a retention time of 50 min.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1cccc(C(F)(F)F)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-iodo-3-(trifluoromethyl)benzene.
Reaction SMILES: FC(F)(F)[S:3]([O-:6])(=[O:5])=[O:4].[C:9]([O:13][C:14](=[O:55])[C:15]([O:18]/[N:19]=[C:20](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[S:45][CH:46]=1)\[C:21]([NH:23][C@@H:24]1[C:27](=[O:28])[NH:26][C@@H:25]1[CH2:29][N:30]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][N+:38]([CH3:41])=[CH:37][CH:36]=2)[N:32]=[N:31]1)=[O:22])([CH3:17])[CH3:16])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14](=[O:55])[C:15]([O:18]/[N:19]=[C:20](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[S:45][CH:46]=1)\[C:21]([NH:23][C@@H:24]1[C:27](=[O:28])[N:26]([S:3]([O-:6])(=[O:5])=[O:4])[C@@H:25]1[CH2:29][N:30]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][N+:38]([CH3:41])=[CH:39][CH:40]=2)[N:32]=[N:31]1)=[O:22])([CH3:16])[CH3:17])([CH3:10])([CH3:11])[CH3:12]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: C[n+]1ccc(-c2cn(C[C@H]3NC(=O)[C@H]3NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)nn2)cc1
Solvent: CN(C)C=O
Product: C[n+]1ccc(-c2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N3S(=O)(=O)[O-])nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
4-(1-(((2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methylpyridin-1-ium trifluoromethanesulfonate (70 mg, 0.10 mmol) in DMF (1 mL) was treated with SO3.DMF (80 mg, 0.52 mmol). The reaction mixture was stirred at rt for 16 h then concentrated in vacuo and purified by HP21 resin (ACN-water, 10-100%), affording the title compound (24 mg, 31%) as a beige solid. LCMS: m/z=748.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(O)(=O)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O.C([BH3-])#N>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COc1ccc(CN)cc1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNCc2ccc(F)c(F)c2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To (4-methoxyphenyl)methanamine (1.77 mL, 13.6 mmol) and acetic acid (2.7 mL, 45 mmol) in dichloromethane (15 mL) was added 3,4-difluorobenzaldehyde (1.0 m, 9.08 mmol). This mixture was heated in the microwave at 100° C. for 15 min. The reaction was cooled to room temperature and macroporous cyanoborohydride resin (9.8 g, 22.7 mmol) was added in portions. This mixture was stirred at room temperature for 16 hours. The resin was filtered off and rinsed with dichloromethane and the organics were washed with saturated sodium bicarbonate until bubbling ceased. The organics were dried over sodium sulfate and concentrated via rotovap. The resulting crude material was purified by silica gel chromatography using methanol dichloromethane gradient as eluent to afford N-(3,4-difluorobenzyl)(4-methoxyphenyl)methanamine as a yellowish oil (1.9 g, 80% yield). MS (M+H, 264); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.63 (br s, 1H), 3.56 (s, 2H), 3.61 (s, 2H), 3.71 (s, 3H), 6.84 (d, J=8.8 Hz, 2H), 7.14 (m, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.34 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][O:13]C(=O)C.N>CO>[CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-:11])=[O:10])[N:4]=[C:3]1[CH2:12][OH:13]
Reactant: CC(=O)OCc1nc([N+](=O)[O-])c(C#N)n1C
Agent: N
Solvent: CO
Product: Cn1c(CO)nc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2.0 G. of 1-methyl-2-acetoxymethyl-4-nitro-5-cyanoimidazole is dissolved in 100 ml. of anhydrous methanol which is saturated with anhydrous gaseous ammonia at 0°C. The reaction mixture is stirred for 15 minutes at 0°C. and the methanol and ammonia removed under high vaccum. The residue is recrystallized from isopropanol affording 1.2 g. of 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole, m.p. 122° to 124°C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11](OCC)C>>[CH3:11][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][O:1]2
Reactant: c1cc2c(cn1)CCCO2
Reactant: CCOCC
Product: Cc1nccc2c1CCCO2

Procedure:
To 2.45 g (18.15 mmol) of 6-azachroman (prepared as described in Sliwa, et al., J. Het. Chem. 12:809 (1975)) in 25 ml of ethyl ether is added 61 ml of 1.5 M methyllithium-lithium bromide complex. The mixture is heated at reflux for 17 hours and worked up as described above to yield 0.800 g of the titled compound. High resolution mass spectrum: Calcd. for C9H11NO: 149.0841; Found: 149.0834.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][C:9]([OH:11])=O)=[C:6]([CH3:12])[NH:5][N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:9](=[O:11])[CH2:8][C:7]1[C:3]([CH3:2])=[N:4][NH:5][C:6]=1[CH3:12])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1n[nH]c(C)c1CC(=O)O
Agent: Cl
Product: Cc1n[nH]c(C)c1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 42 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 152, (S)-3-(benzyloxy)-2-(2-(3,5-dimethyl-1H-pyrazol-4-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (28 mg, 42%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 11.96 (br s, 1H) 10.20 (br s, 1H), 8.12-8.10 (d, 1H), 7.63-7.59 (d, 2H), 7.33-7.27 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.96 (m, 4H), 4.71-4.66 (m, 1H), 4.51 (s, 2H), 3.68-3.61 (d, 2H), 3.22 (s, 2H), 2.07 (s, 6H). MS (EI) for C29H29FN4O4. found 517.0 (MH+).
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (0.55 g, 1.09 mmol) in DCM (4 mL) is treated with TFA (2 mL) and stirred at room temperature. After 2 hours, the solvent is removed in vacuo to yield the title compound which is used in the next step without further purification. MS (ES+) m/e 304 (MH+).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C:13](=[O:23])[CH:12]=2)C(=O)O1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:17]1([CH:15]2[CH2:16][C:11]3[NH:10][CH:9]=[CH:5][C:6](=[O:8])[C:12]=3[C:13](=[O:23])[CH2:14]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OC(=O)C(=CNC2=CC(=O)CC(c3ccccc3)C2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C1CC(c2ccccc2)Cc2[nH]ccc(=O)c21
Yield: 72.8 %

Procedure:
A solution of 2,2-dimethyl-5-[(3-oxo-5-phenyl-1-cyclohexenylamino)methylene]-[1,3]dioxane-4,6-dione (1.0 g) in diphenylether (15 ml) was stirred at 260-280° C. for 30 minutes. Under reduced pressure, the solvent was evaporated, and the resulting crystals were washed with petroleum ether. The crystals were recrystallized from ethanol to give crystals of 7-phenyl-1,4,5,6,7,8-hexahydroquinoline-4,5-dione (0.51 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:24][CH:25]1[CH2:30][CH2:29][CH:28]([C:31](OCC)=[O:32])[CH2:27][CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Si:7]([O:24][CH:25]1[CH2:26][CH2:27][CH:28]([CH2:31][OH:32])[CH2:29][CH2:30]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OC1CCC(CO)CC1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a suspension of lithium aluminum hydride (1.13 g) in THF (100 mL) was slowly added a solution of ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate (12.2 g) in THF (100 mL) under ice-cooling. The reaction mixture was stirred at 0° C. for 1 hr, and water (1.2 mL) and 1M aqueous sodium hydroxide solution (1.2 mL) were successively added thereto. The mixture was stirred at room temperature for 30 min, and water (3.6 mL) was further added thereto. The mixture was stirred at room temperature for 1 hr, and the insoluble material was filtered off through celite under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (9.38 g).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[O:17])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)O)ccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)OC)cc3)ccc12
Yield: 91.4 %

Procedure:
This compound was prepared according to the method of Example 11, using 300 mg (1.16 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid and 193 mg (1.28 mmol, 1.1 equiv) methyl-4-amino-benzoate as starting materials to give 415 mg (91%) of white crystals: mp 129-132° C.; Anal. calcd for C23H25N3O3: C, 70.56; H, 6.44; N, 10.73. Found: C, 70.36; H, 6.43; N, 10.61.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[C:31](CO)=[C:30]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[Cl:41])[CH:29]=[C:28]([Cl:42])[N:27]=1>C(#N)C>[Br:24][CH2:20][C:31]1[C:26]([Cl:25])=[N:27][C:28]([Cl:42])=[CH:29][C:30]=1[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[Cl:41]
Reactant: OCc1c(-c2ccc(F)cc2Cl)cc(Cl)nc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1ccc(-c2cc(Cl)nc(Cl)c2CBr)c(Cl)c1
Reaction time: 8 h

Procedure:
Triphenyl phosphine (0.67 g, 2.55 mol) and carbon tetrabromide (0.85 g, 2.56 mmol) were added to a solution of [2,6-dichloro-4-(2-chloro-4-fluorophenyl)pyridin-3-yl]methanol (2.14 mmol theoretical) in 15 mL acetonitrile at rt. After stirring overnight, the solution was concentrated and the residue partitioned between water and dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl ether/hexanes as the eluent to give 3-(bromomethyl)-2,6-dichloro-4-(2-chloro-4-fluorophenyl)pyridine. Mass spectrum (ESI) 368 (M+1). 1H NMR (500 MHz, CDCl3): δ 4.10(d, 1H, J=10.8 Hz); 4.53(d, 1H, J=10.6 Hz); 7.17(s, 1H); 7.15-7.21(m, 1H); 7.30-7.34(m, 1H); 7.36-7.41(m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:13][CH3:14])[CH3:11])=[CH:5][CH:4]=1.[CH3:22][N:23]=[C:24]=[O:25]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:24]([NH:23][CH3:22])=[O:25])[CH2:18][CH2:17]2)[CH2:13][CH3:14])[CH3:11])=[CH:7][CH:8]=1
Reactant: CCN(CC1CCNCC1)C(C)Cc1ccc(OC)cc1
Reactant: CN=C=O
Solvent: CCOCC
Product: CCN(CC1CCN(C(=O)NC)CC1)C(C)Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine (0.23 grams, 0.79 mmole) in ethyl ether (10 ml) was added methyl isocyanate (0.2 ml, 3.4 mmole). After 1.0 hour at 22° C., the solution was concentrated under reduced pressure and the residue was recrystallized from ethyl ether/hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-[1-(methylaminocarbonyl)piperidin-4-ylmethyl]amine (0.249 grams, 91%) m.p. 97-98° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].II>C(Cl)Cl>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH2:19][C:10]=1[CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCC1=Cc2ccccc2CC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCN(CC2=Cc3ccccc3CC2)CC1

Procedure:
A mixture of 4-piperidone (2.2 g), 3,4-dihydro-2-chloromethylnaphthalene (4.0 g), and powdered sodium carbonate (3.5 g) in tolune (200 ml) containing several crystals of iodine is refluxed for 14 hours with vigorous stirring under nitrogen. The reaction mixture is then cooled, diluted with methylene chloride (100 ml), and filtered. The filtrate is concentrated and the crude product triturated with 1:1 hexane/ether (100 ml) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[S:6].S(=O)(=O)(O)O.[CH3:22]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH3:22])=[S:6]
Reactant: Cc1cc(C(O)=S)ccc1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=S)c1ccc(-c2ccccc2)c(C)c1
Reaction time: 4 h

Procedure:
A mixture of 3-methyl-4-phenylthiobenzoic acid (85 g), conc. sulfuric acid (20 ml) and methanol (1.2 liter) is refluxed with stirring for 4 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure. To the residue is added ethyl acetate (1.5 liter), and the mixture is washed with saturated aqueous sodium chloride solution (400 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 3-methyl-4-phenylthiobenzoate (80.33 g).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:12])[CH:6]=[CH:7][C:8](=[N:10]O)[CH:9]=1)([CH3:3])[CH3:2]>CO>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([OH:12])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)C1=CC(=NO)C=CC1=O
Solvent: CO
Product: CC(C)c1cc(N)ccc1O
Reaction time: 5 h
Yield: 75.2 %

Procedure:
To a solution of 2-isopropyl-[1,4]benzoquinone 4-oxime (1.1 g, 6.7 mmol) in methanol was added catalytic amount of Ra/Ni complex. The reaction was stirred under 50 psi H2 atmosphere for 5 hrs and filtered through celite. The filtrate was concentrated to give 4-amino-2-isopropyl-phenol (762 mg, 76%)
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][NH:5][C@@H:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:7].CN1CCCC1=O.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][CH:32]=1.Cl>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].C1(C)C=CC=CC=1.O>[ClH:1].[C:8]1([C@H:6]([NH:5][CH2:4][CH:3]=[CH:2][C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:36])([F:35])[F:25])[CH:32]=2)[CH3:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Reactant: C[C@@H](NCC=CCl)c1cccc2ccccc12
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NCC=Cc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 2.5 °C
Reaction time: 0.29 h
Yield: 70.23 %

Procedure:
A solution of 3-chloro-N-[(1R)-1-(naphthalen-1-yl)ethyl]prop-2-en-1-amine (Example 1; 50 g), iron acetylacetonate (3.6 g) and N-methyl-2-pyrrolidone (1.0 g) in tetrahydrofuran (200 mL) at 0 to −5° C. was added to a solution of 3-(trifluoromethyl)phenyl magnesium bromide (Example 3) in tetrahydrofuran (150 mL) at −25° C. to −30° C. under inert atmosphere. The reaction mixture was stirred at 0 to 5° C. for 15 to 20 minutes. After the completion of the reaction, de-ionized water (75 mL) was added at 0 to 10° C. Toluene (250 mL) was added to the reaction mixture and the pH of mixture was adjusted to 0 to 1 using hydrochloric acid (6 Normal; 250 mL) at 10° C. to 35° C. and stirred at the same temperature for about 15 minutes. Layers were separated, and the organic layer was washed with de-ionized water (2×250 mL) and concentrated under vacuum at 55° C. to 60° C. Isopropyl alcohol (125 mL) was added to the residue obtained and heated to 40° C. to 45° C. to get a clear solution. The solution was cooled to 20° C. to 30° C. and stirred for about 2 hours to give solid. The solid was filtered, washed with isopropyl alcohol (2×50 mL) and dried under vacuum at 45° C. to 50° C. to give N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine hydrochloride.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][N+:13]([O-:21])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2ccncc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Part B. A solution of 4-(4-isopropyl-phenyl)-pyridine (1.01 g, 5.1 mmol) in dichloromethane (20 mL) is cooled to 0° C., and a solution of m-chloroperoxybenzoic acid (1.33 g, 7.6 mmol) in dichloromethane (20 mL) is added dropwise. The mixture is allowed to warm to ambient temperature over 12 h. with stirring, then heated to reflux for 2 h. An excess of m-chloroperoxybenzoic acid (0.5 g) is added, and reflux continued for 2 h. The solution is cooled and washed successively with 10% aq. sodium sulfite, 10% aq. sodium carbonate and saturated brine. The organic phase is dried over anhydrous magnesium sulfate and evaporated. The residue is separated by flash chromatography to afford 4-(4-isopropyl-phenyl)-pyridine-N-oxide (0.85 g, 78%).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH3:17])=[CH:9][CH:8]=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C1CCCCC1.C(OCC)C>[CH3:22][O:21][C:19]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][CH3:17])=[CH:9][CH:8]=1)=[O:20]
Reactant: CCn1ccc2ccc(Br)cc21
Reactant: COC(=O)Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C

Procedure:
Sec-butyl lithium (9.4 ml of a 1.3M solution in cyclohexane) was added to a stirred solution of 6-bromo-1-ethylindole [the compound of step (a), 2.5 g] in diethylether (20 ml) at −78° C. under a nitrogen atmosphere. After 30 minutes this solution was transferred by cannula to a stirred solution of methyl chloroformate (1.29 ml, 16.74 mmol) in diethyl ether (8 ml) at −78° C. under a nitrogen atmosphere. After 1 hour the cooling bath was removed and the mixture was allowed to warm to room temperature. After a further 1 hour the mixture was poured into brine and extracted with ethyl acetate. The organic layers were dried (MgSO4) and concentrated in vacuo to give a yellow oil. Flash column chromatography (elution with 90% hexane, 10% ethyl acetate) gave 1.76 g of the subtitle compound as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[F:29][C:30]1[CH:37]=[CH:36][C:33](CBr)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:12])=[O:13])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:32][CH:31]=1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: Fc1ccc(CBr)cc1
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21
Yield: 79 %

Procedure:
(S)-1-(4-Fluorobenzyl)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (11c) was prepared according to the same procedure for compound 11a, except using 4-fluorobenzyl bromide, and purified with hexanes-ether (1:2) to afford 196 mg (79%) of 11c as an orange solid, mp 74.5-75.4° C. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.95 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.34-7.19 (m, 4H), 7.06 (t, J=8.7 Hz, 2H), 6.92 (t, J=7.2 Hz, 1H), 6.87-6.79 (m, 3H), 4.89 (s, 2H), 4.13 (m, 1H), 3.93 (m, 2H), 3.47 (m, 1H), 3.23 (m, 1H), 2.01 (m, 2H), 1.78 (m, 2H). Anal. Calcd for C26H23FN2O5S: C, 63.15, H, 4.69; N, 5.66. Found: C, 63.05, H, 4.69; N, 5.60.