Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:7]=[N:8][C:9]=1[CH2:10][O:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:4].C[O:30][C:31](=[O:62])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38]C(C2C(COC3C=CC=CC=3)=NN(C3C(Cl)=CC=CC=3Cl)N=2)=O)[CH:33]=1>>[C:12]12([O:11][CH2:10][C:9]3[N:8]=[N:7][N:6]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:5]=3[C:3]([NH:38][C:34]3[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=3)[C:31]([OH:62])=[O:30])=[O:4])[CH2:19][CH:18]3[CH2:20][CH:14]([CH2:15][CH:16]([CH2:17]3)[CH2:21]1)[CH2:13]2
Reactant: COC(=O)c1c(COC23CC4CC(CC(C4)C2)C3)nnn1C1CCCCCC1
Reactant: COC(=O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Product: O=C(O)c1cccc(NC(=O)c2c(COC34CC5CC(CC(C5)C3)C4)nnn2C2CCCCCC2)c1

Procedure:
5-(Adamantan-1-yloxymethyl)-3-cycloheptyl-3H-[1,2,3]triazole-4-carboxylic acid methyl ester was converted to the corresponding acid (as in Example 28, step c) which was then coupled to methyl 3-aminobenzoate (as in Example 28, step d). Hydrolysis of the methyl ester (as in Example 28, step e) resulted in the preparation of 3-{[5-(adamantan-1-yloxymethyl)-3-cycloheptyl-3H-[1,2,3]triazole-4-carbonyl]-amino}-benzoic acid. 1H NMR (d6-DMSO) 13.02 (1H, s), 10.64 (1H, s), 8.29 (1H, s), 7.89 (1H, d, J=9 Hz), 7.73 (1H, d, J=6 Hz), 7.54-7.49 (1H, m), 4.96-4.92 (1H, m), 4.73 (2H, s), 2.10-2.02 (7H, m), 1.78-1.45 (20H, m). The material was further analysed as its N-methyl D-glucamine salt.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][C:6](=[O:18])[C:5]=1[C:19]([O:21]CC)=[O:20]>CO.C1COCC1>[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][CH:12]=2)[NH:7][C:6](=[O:18])[C:5]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)[nH]c2cc(C(F)(F)F)ccc12
Temperature: 60 °C
Yield: 88.2 %

Procedure:
A 2M aq. LiOH sol. (125 ml) was added to a solution of 15.0 g (50.1 mmol) ethyl 4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylate in a MeOH/THF mixture (175 ml each) and the RS was subsequently heated at 60° C. for 16 h. The mixture was then concentrated in vacuo. The residue was taken up with water and adjusted to pH 2 with a 2M hydrochloric acid, followed by extraction with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. As residue 12.0 g (44.2 mmol, 88%) 4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid was obtained, which was used in the next step without further purification.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1>CS(O)(=O)=O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: CS(=O)(=O)O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h

Procedure:
9α-Hydroxyandrostenedione (.302 g.) is stirred in methanesulfonic acid (3.0 ml.) at 25°. After 80 minutes the reaction is quenched by addition of water (15 ml.). The solids are stirred for 2 hours at 35°, collected, air-dried overnight to give androsta-4,9(11)-diene-3,17-dione, 0.272 g. (95.6% chemical yield).
Reaction SMILES: [O:1]([C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([C:10]3[CH:24]=[CH:23][C:13]([CH2:14]P(=O)(OCC)OCC)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1)[CH3:2].[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([O-:29])=[O:28].C[O-].[Na+].Cl>CO.O>[N+:27]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=[CH:14][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([O:1][CH3:2])[CH:26]=[CH:25][C:6]=3[N:7]=2)=[CH:24][CH:23]=1)([O-:29])=[O:28]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2nc(-c3ccc(C=Cc4ccccc4[N+](=O)[O-])cc3)sc2c1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a stirred solution of diethyl 4-(6-methoxylbenzothiazol-2-yl)benzylphosphonate (0.10 g, 0.25 mmol) and 2-nitrobenzaldehyde (0.39 g, 0.25 mmol) in dry MeOH (10 ml) at 0° C. was added dropwise a solution of 0.5 M sodium methoxide (1.02 ml, 0.51 mmol). The reaction mixture was then allowed to rise to room temperature and heated under reflux for 18 h. The reaction mixture was cooled to room temperature and water (30 ml) was added followed by 1 M HCl until the reaction mixture became acidic. The reaction mixture was then extracted with DCM (3×80 ml) and the combined organic extracts washed with brine (50 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a solid which was purified by flash chromatography (DCM) to give the title compound (0.043 g, 43%) as a yellow solid.
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:1]([N:14]1[CH:19]=[C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccc(C(F)(F)F)cc1
Yield: 43.3 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.33 g, 0.82 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.23 g, 1.22 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.15 g, 45%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 7.27-7.33 (m, 4H), 7.35-7.46 (m, 6H), 7.47 (s, 1H), 7.55-7.63 (m, 2H), 7.65-7.73 (m, 2H), 11.78 (s, 1H). MS (ESI) m/z: 371 [M-H]−. MS (ESI) m/z: 373 [M-H]+, 390 [M-NH4]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6](=[S:10])[CH2:7][CH2:8][CH3:9].[NH3:12]>CO>[C:6]([NH:5][CH2:4][C:3]([NH2:12])=[O:2])(=[S:10])[CH2:7][CH2:8][CH3:9]
Reactant: N
Reactant: CCCC(=S)NCC(=O)OC
Solvent: CO
Product: CCCC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of the product of Example 5B (0.788 g, 4.496 mmol) in methanol (30 mL) was saturated with ammonia gas and the reaction was stirred in a stoppered flask at room temperature for 17 hours. The solvent was concentrated under vacuum giving the title compound and the solid purified by silica gel flash chromatography with 10% methanol/methylene chloride to give the title compound as a white solid (500 mg, 3.12 mmol, 69%).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (140 g), phenol (100 g), sodium bicarbonate (170 g), and water (1000 ml) was heated to 85°C while stirring and kept at this temperature for 16 hours. After cooling to 4°C, the precipitated sodium salt of 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid was filtered off and washed with ice-water. The sodium salt was dissolved in boiling water (3000 ml), and the 3-nitro-4-phenoxy-5-sulphamyl-benzoic acid was precipitated by the addition of 4N hydrochloric acid. After cooling, the acid was isolated by suction and dried. The melting point was 255°-256°C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:17][C:18]1([CH3:27])[CH2:23][CH:22]([CH3:24])[C:21](=[O:25])[CH2:20][C:19]1=[O:26].C(#N)C.CC(C)(O)C#N>Cl.C(N(CC)CC)C>[N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[CH:9][C:5]=1[C:6]([CH:20]1[C:19](=[O:26])[C:18]([CH3:17])([CH3:27])[CH2:23][CH:22]([CH3:24])[C:21]1=[O:25])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(OC(F)F)cc1[N+](=O)[O-]
Reactant: CC1CC(C)(C)C(=O)CC1=O
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1CC(C)(C)C(=O)C(C(=O)c2ccc(OC(F)F)cc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.03 g of 2-nitro-4-difluoromethoxybenzoyl chloride and 2.57 g of 4,4,6-trimethylcyclohexane-1,3-dione are introduced into 20 ml of acetonitrile, and 4.21 g of triethylamine are added dropwise in such a way that the internal temperature does not exceed 40° C. The mixture is subsequently stirred for 15 minutes at room temperature, 1.29 g of acetone cyanohydrin are added, and stirring is continued for 3 hours at room temperature. The reaction mixture is diluted with 100 ml of ethyl acetates and 50 ml of 1N hydrochloric acid are added. After vigorous shaking, the phases are separated, the organic phases are dried over MgSO4, and the solvent is stripped off under reduced pressure. The oil which remains (7.1 g) is chromatographed on silica gel using ethyl acetate/petroleum ether 1:2 as the eluent. This gives 3.28 g (46% of theory) of 2-(2-nitro-4-difluoromethoxy-benzoyl)-4,4,6-trimethylcyclohexane-1,3-dione of melting point 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 19, 200 mg, 0.61 mmol) in methylene chloride (4 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) and stirred at 0° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminoquinoline (131 mg, 0.91 mmol) and pyridine (0.25 mL, 3.03 mmol) in N,N-dimethylformamide (10 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-quinolin-2-yl-propionamide (93 mg, 34%) as an off-white foam: EI-HRMS m/e calcd for C24H21ClN2O3S (M+) 456.1274, found 456.1268.
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2S)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[OH-].[NH4+]>[Ni].C(O)C>[F:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2c(-n3ccnc3S)c(F)ccc2n1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(-n3ccnc3)c(F)ccc2n1

Procedure:
A mixture of 30 g (0.115 mmole) of 6-fluoro-2-methyl-5-(2-mercaptoimidazol-1-yl)quinoline, 60 ml of ammonium hydroxide and 300 ml of 60% aqueous ethanol was heated to 50°-55° C. and 201 g of Raney nickel was added. The mixture was heated to reflux and maintained at reflux for four hours, at which time it was filtered. The residue was washed with hot aqueous ethanol, and the washings and filtrate were combined and evaporated to provide 6-fluoro-5-(imidazol-1-yl)-2-methylquinoline as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
56 mg of pale yellow solid 3-{4-[3-(4-fluoro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-fluoro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[S:39][C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[S:39][C:40]5[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=5[N:42]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1
Product: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzothiazole.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:19][CH:15]([NH:16][C:17]2=[O:18])[CH2:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1.[CH3:20]I>CS(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:19][CH:15]([N:16]([CH3:20])[C:17]2=[O:18])[CH2:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C23CCCC(C2)NC3=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(C23CCCC(C2)N(C)C3=O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
0.36 g of 69% sodium hydride is added to 40 ml of dimethylsulfoxide, The mixture is heated at 70°C for 30 minutes in a nitrogen atmosphere. 2 g of 1-(3-methoxyphenyl)-6-azabicyclo[3,2,1]octane-7-one are added to the mixture at 10° to 15°C. Then, the mixture is stirred at room temperature for 1 hour. 2.1 G of methyl iodide are added to the mixture, and the mixture is further stirred at room temperature for 2 hours. The reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from n-hexane. 2 g of 1-(3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane-7-one are obtained. M.p. 68° - 70°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[Cl:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:5]2[CH:4]=[C:3]([Cl:12])[C:2]([Cl:1])=[CH:7][C:6]=2[N+:8]([O-:10])=[O:9])[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: -5 °C
Yield: 336.3 %

Procedure:
A solution of 5 g of 1,2-dichloro-4-fluoro-5-nitrobenzene and 4.4 g of methyl 4-chlorophenylacetate in 70 ml of DMF is added, under a stream of nitrogen, to a suspension at −10° C. of 2.85 g of 60% NaH in 45 ml of DMF, and the temperature is maintained at −5° C. The mixture is reacted for 2 hours, while allowing the temperature to return to room temperature. The resulting mixture is poured onto ice, aqueous 10% NH4Cl solution is added and the mixture is extracted with ethyl acetate. The organic phase is dried, filtered and concentrated. 30 g of a brown oil are obtained, and are purified on a column with hexane and then with a 95/5 hexane/EtOAc mixture to give 3.18 g of oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1N.S(=O)(=O)(O)O.O[PH2]=O.N([O-])=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1
Reactant: COc1cc(Br)c(N)c(Br)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96 %

Procedure:
To a solution of 2,6-dibromo-4-methoxyphenylamine (3 g, 10.67 mmol, 1 eq) in 10 ml of toluene cooled at 0° C. are added 6.6 ml of concentrated sulfuric acid and 17.5 ml of H3PO2 50% (15 eq). To the reaction mixture, sodium nitrite (1.47 mg, 21.35 mmol, 2 eq) is added, and all is stirred at 0° C. for 4.5 h. After neutralization with a sodium hydroxide solution, extraction with diethyl ether is performed. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator. Purification of the raw product was not necessary (yield 96%, 2.7 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].O1CCCC1.[CH:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[OH:19][CH:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: O=CCCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
Vinylmagnesium Bromide (120 mmol, 1M) in ether was added to 80 ml of dry tetrahydrofuran and cooled under inert atmosphere to 0° C. Hydrocinnamaldehyde (8.0 ml, 61 mmol) was added dropwise, and the solution was stirred for 10 min, quenched cautiously with saturated aqueous ammonium chloride, extracted with ether, washed with saturated brine, dried over MgSO4, and concentrated to give 9.82 g (98.6%) of the crude desired product.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:32])=[O:22])[CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1cccs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2cccs2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-(2-thienyl)-L-alanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([N:21]2[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:25]1[N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccnn1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccnn1-c1ccccc1
Yield: 62.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0454 g, 0.192 mmol), 1-phenyl-1H-pyrazole-5-carbonyl chloride (0.041 g; 0.192 mmol), and triethylamine (0.068 mL; 0.481 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 4 to 30% of ethyl acetate in dichloromethane gave 0.044 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-phenyl-1H-pyrazole-5-carboxamide as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25](NCC(NC5SC=C(CC(O)=O)N=5)=O)[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].Cl.[CH3:48][O:49][C:50](=[O:56])[C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1>>[CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:52]5[CH2:53][CH2:54][CH2:55][C@H:51]5[C:50]([O:49][CH3:48])=[O:56])[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Agent: Cl
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(N3CCC[C@H]3C(=O)OC)n2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of example 15 step (viii) (0.5 g) and L-proline methyl ester hydrochloride (0.265 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 40% ethyl acetate in isohexane. Yield 0.47 g.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH:21]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([NH2:25])[CH3:24]>ClCCl>[CH2:7]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[N:25][CH2:23][CH3:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CCN
Solvent: ClCCl
Product: CCN=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.5 g (1,4-bis(phenylmethyl)-2-piperazin-carboxaldehyd in 5 ml of dichloromethane was added 0.54 ml ethylamine and 0.5 g molecular sieves. The reaction mixture was stirred for 30 min at rt then filtered. The filtrate was evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][O:17]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:24]([CH3:25])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Clc1cccc(CCCCc2ccccc2OCC2CO2)c1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1cccc(Cl)c1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 1(b), 840 mg of 2-{2-[4-(3-chlorophenyl)butyl]phenoxy methyl]oxirane [prepared as described in step (a) above] dissolved in 20 ml of tetrahydrofuran were treated with 4 ml of 50% by volume aqueous dimethylamine. The crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 789 mg (yield 82%) of the title compound as a colorless oil.