Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cccnc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and nicotinoyl chloride, there is obtained ethyl N-(nicotinoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 371 (5), 42 (26), 194 (100), 106 (38);
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH:22]([CH3:24])[CH3:23])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]#[N:20])=[CH:8][CH:7]=2.[OH-:25].[Na+]>CS(C)=O>[NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH:22]([CH3:24])[CH3:23])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]([NH2:20])=[O:25])=[CH:8][CH:7]=2
Reactant: CC(C)Cc1nc2ccc(C#N)cc2c(-c2ccccc2)c1CN
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Cc1nc2ccc(C(N)=O)cc2c(-c2ccccc2)c1CN
Temperature: 80 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 3-(aminomethyl)-2-isobutyl-4-phenylquinoline-6-carbonitrile (0.11 g, 0.35 mmol) in dimethyl sulfoxide (4 ml) was added 1N aqueous sodium hydroxide solution (2 ml) and the mixture was stirred at 80° C. for 3 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and 1N aqueous sodium hydroxide solution (50 ml) and the aqueous layer was extracted 4 times with ethyl acetate (50 ml). The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by preparative HPLC. The objective fractions were combined and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (25 ml)-tetrahydrofuran (25 ml) and 1N aqueous sodium hydroxide solution (25 ml). The organic layer was washed with saturated brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from diisopropyl ether-ethyl acetate to give the title compound (0.043 g, yield 37%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:19][C:20]1[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:22][O:23][C:24]=1[CH3:25]>C1COCC1.C(OCC)(=O)C>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[CH2:19][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1CNc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a solution of 2-aminopyridine (109 mg, 1.2 mmol) in THF (2 mL) was added potassium bis(trimethylsilyl)amide (0.9 M in THF, 1.2 mL, 1.1 mmol) at 0° C. under argon. After 10 min, a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (200 mg, 1.0 mmol) in THF (1 mL) was added and the resulting mixture stirred at 0° C. for 1 h. The mixture was then diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous phase was extracted with ethyl acetate and the combined extracts dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1: to 1:1) afforded the title compound (45 mg, 18%) as an off white solid. MS: m/e=266.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH:29]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:29]([N:42]1[CH2:47][CH2:46][N:45]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:44][CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(c5ccccc5)c5ccccc5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
In DMF (3ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150mg), and to the solution were added 1-benzhydrylpiperazine (127mg) and potassium carbonate (268mg). The mixture was stirred at room temperature for 24 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone-diisopropylether to give N-[4-(4-benzhydryl-1-piperazinyl-methyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 43) (140mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CC(C)=O.[Cl:14][CH2:15][C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:14][CH2:15][C:16]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Yield: 85.5 %

Procedure:
81 g (0.5 mol) of 3,4-dichloroaniline are dissolved 500 ml of acetone. 85 g (0.75 mol) of chloroacetyl chloride are poured in, over a period of 17 minutes, with stirring. The mixture is heated under reflux for 15 minutes, cooled and 350 ml of a 30% strength potassium carbonate solution in water (pH=8) are poured in. This solution is poured into a 2,000 ml Erlenmeyer flask and 500 ml of H2O+ice are added. The precipitate which appears is filtered off, washed with water, dried and recrystallised from benzene. 102 g (yield 85%) of N-chloroacetyl-3,4-dichloroaniline are thus obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:19][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]([C:14]([OH:16])=[O:15])=[C:5]2[C:3]([OH:2])=[O:4])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Reactant: BrCc1cccc2ccccc12
Product: O=C(O)c1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 1H-indole-2,3-dicarboxylic acid dimethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 344.3 ([M−H]−).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([Br:16])[CH3:15])=[CH:12][CH:13]=1)=[O:7]
Reactant: CCc1ccc(C(=O)c2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Br)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 23.5 parts of p-ethylphenyl 2-thienyl ketone, 19.5 parts of N-bromosuccinimide, 220 parts of carbon tetrachloride, 1.1 parts of benzoyl peroxide and one drop of toluene is stirred and refluxed for 2 hours. The precipitated succinimide is filtered off and the carbon tetrachloride filtrate is dried and evaporated. The oily residue solidifies on cooling. The solid product is dissolved in 2-propanol and the product is allowed to crystallize. It is filtered off and dried in vacuo, yielding α-bromo-α-methyl-p-tolyl 2-thienyl ketone; m.p. 71.1° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (Aldrich; 3 g, 16.21 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 2.03 g, 17.83 mmol), HATU (6.77 g, 17.83 mmol), DIPEA (8.5 mL, 48.63 mmol) and DMF (30 mL) were combined and stirred at ambient temperature for 18 hrs. Solvents evaporated and partitioned between DCM (200 ml) and water (100 ml). The aqueous phase was re-extracted with DCM (100 ml). The combined organic phases were dried (MgSO4) and evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM then 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid (2.67 g, 59%)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:11]1[CH2:10][CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cnccn2)CC1
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 2-chloropyrazine (2.13 g, 18.7 mmol), tert-butyl piperazine-1-carboxylate (3.16 g, 17 mmol) and caesium carbonate (7.7 g, 23.7 mmol) in DMF (35 ml) was heated at 100° C. for 16 hours. Cooled to RT and diluted with ether. Ether layer was washed with water and brine, dried over sodium sulphate and distilled off the solvent to afford 2 g (40.7% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 40% ethyl acetate in hexane as eluent.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].O>ClCCl>[N+:1]([C:4]1[C:14]2[CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1CNCCN2
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCNc2cccc([N+](=O)[O-])c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
6-Nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (140 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL) and the mixture was treated with acetic anhydride (0.16 mL, 1.68 mmol). The reaction was then allowed to stir overnight at room temperature. The reaction mixture was then poured over water (10 mL) and organics were extracted with dichloromethane (3×10 mL). Combined organics were dried over Na2SO4, filtered and reduced. The crude product was then isolated and purified by flash column chromatography (0% MeOH/DCM-10% MeOH/DCM) to afford 120 mg of 1-(6-Nitro-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-ethanone as a yellow oil. LC/MS (ESI)=236.30 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.07 (d, 1H, J=8.08 Hz), 6.86 (d, 1H, J=8.34 Hz), 5.95 (s, 1H), 4.64 (s, 2H), 3.55 (q, 2H, J=5.56 Hz), 3.33 (t, 2H, J=5.56 Hz), 1.97 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(OC)nc1
Temperature: 90 °C

Procedure:
A solution of the 5-bromo-2-methoxypyridine 7-2 (74.3 g, 0.4 mol), ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08 mol), palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20 g, 0.066 mol) in 100 mL acetonitrile was degassed with argon for 10 minutes. The mixture is heated at 90° C. for 12 hr, then the volatiles were removed m vacuo. Toluene (300 mL) was added and the mixture concentrated again. Diethyl ether (300 mL) was added and the mixture filtered through a pad of silica gel eluting with 800 mL of diethyl ether. After removal of the diethyl ether, the residue was chromatographed on silica gel eluting with EtOAc/hexane 1:19 then 1:14 then 1:9 to give 7-3 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.34 (3H, t), 3.97 (3H, s), 4.26 (2H, q), 6.34 (1H, d),6.76 (1H, d), 7.63 (1H, d), 7.77 (1H, dd),8.27 (1H, d).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27]([OH:29])=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30](OC(=N)C(Cl)(Cl)Cl)([CH3:33])([CH3:32])[CH3:31].B(F)(F)F.CCOCC>C1COCC1>[C:30]([O:28][C:27]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[OH:26])=[O:15])[CH2:12][N:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Temperature: 0 °C
Yield: 34 %

Procedure:
A mixture of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid (50 mg, 0.13 mmol) and 2,2,2-trichloro-acetimidic acid tert-butyl ester (70 mg, 0.33 mmol) in THF (1 mL) was stirred at 0° C. for several minutes. Then BF3.OEt2 (20 mg, 0.13 mmol) was added dropwise at 0° C. and the reaction mixture was warmed to room temp. and stirred for 2 h. The reaction mixture was then quenched with brine solution, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (using 5% EtOAc in hexane as eluent) to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid tert-butyl ester (20 mg, 35.0% yield) as a bluish sticky liquid. MS calcd. for C27H37N2O4 [(M+H)+] 453.0, obsd. 453.2.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: COc1ccccc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 2-methoxyphenylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Cl:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([O:16][C:7]2[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:14]([Cl:15])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH:19]=1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1C=CCCC1
Temperature: 110 °C

Procedure:
A mixture of 2.5 g methyl 4-acetylamino-5chlorosalicylate, 2 g of 3-bromocyclohexene, 2 g K2CO3 and 30 ml DMF are combined and heated at 110° C. overnight. The reaction mixture is then poured into water, filtered, dried and then extracted into ether. The ether solution is treated with charcoal, filtered and evaporated to dryness to obtain methyl 2-(cyclohexen -3-yloxy)-4-acetylamino-5-chlorobenzoate. This is then purified by recrystallization from ether/hexane. (M.P. 100°-102° C.)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[C:7]([O:16]C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[C:7]([OH:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(C)(C)C)ccc1CCN(C)C
Agent: Br
Product: CN(C)CCc1ccc(C(C)(C)C)cc1O
Temperature: 25 °C

Procedure:
A mixture of 0.092 g (0.39 mmol) of the product from step D and 3.0 mL of 48% aqueous hydrobromic acid was refluxed for 1 h. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous NaHCO3 and ether. The aqueous layer was separated and re extracted with ether. The organic layers were combined, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:17])[CH2:10][C:11](N(OC)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][Mg]Br.C(OCC)C.Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]([CH3:17])[CH2:10][C:11](=[O:12])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C[C@H](C)OCc1ccccc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C[C@H](C)OCc1ccccc1
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of the above (3S)-3-(benzyloxy)-N-methoxy-N-methylbutanamide (196 g) in THF (1.5 L), a 3M methyl magnesium bromide/diethyl ether solution (0.38 mL, 1.1 mol) was gradually added under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. After the reaction, the reaction mixture was poured to 2N hydrochloric acid, and after THF was distilled off under reduced pressure, it was extracted with diethyl ether. After it was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure to give a crude product. This was purified by reduced pressure distillation to give a title compound (44 g) as an oil.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)=[CH:10][C:9]=1[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)O>O1CCOCC1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)=[CH:10][C:9]=1[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(O)c2cccc(Cl)c2)c1
Reactant: O=C(O)CCS
Solvent: C1COCCO1
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(SCCC(=O)O)c2cccc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3-mercapto-propanoic acid (0.00433 mol) was added slowly to a mixture of intermediate (17) (0.00456 mol) in dioxane (20 ml) and D (20 ml). The mixture was stirred at 80° C. for 5 hours. The solvent was evaporated till dryness. The product was used without further purification, yielding 3-[[[2-amino-5-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methyl]thio]-propanoic acid (intermediate 22).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 87.2 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (4.8 g, 8.03 mmol), NaOH (1.6 g, 40 mmol), H2O (30 mL) and methanol (50 mL) was heated at 80° C. for 1 h. Then methanol was removed under reduced pressure and the aqueous solution was acidified by concentrated hydrochloride to “pH” 1-2. The white precipitate was collected by filtration and dried to give the title compound as a white solid (4 g).
Reaction SMILES: [C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:26]([O:28]CC3C=CC=CC=3)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)O
Yield: 61.3 %

Procedure:
58 mg (10% by mass) of 10% palladium-on-charcoal are introduced into a solution containing 580 mg of benzyl 3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-tert-butoxycarbonylaminopropionate in 8 ml of ethyl acetate. After bubbling hydrogen into the solution for 16 h at ambient temperature and 2 h at 50° C., the reaction medium is filtered through Celite and the solvents are evaporated off. The residue obtained is purified by chromatography on a column of silica and eluted with a 3/7 heptane/ethyl acetate mixture. 300 mg of 3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-tert-butoxycarbonylaminopropionic acid are obtained with a 61% yield. Melting point: 80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH:10][CH3:11])=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([NH:10][CH3:11])=[CH:8][CH:9]=1
Reactant: CNc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CNc1ccc(N)cn1

Procedure:
To 40 ml of an ethanol solution of the methylamino compound (4 g) obtained in (a) described above was added, 400 mg of platinum oxide, followed by reaction in an atmosphere of hydrogen at room temperature for 15 hours. The solvent was thereafter removed by distillation, and the residue was purified by silica gel column chromatography (eluent: chloroform, and subsequently chloroform: methanol=20:1 (v/v)) to obtain 320 mg of the intended product as brown crystals.