Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:12][CH2:13][OH:14])[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[C:17]([C:19]1[C:20]([O:32][CH3:33])=[C:21]([C:29](Cl)=[O:30])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)#[N:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:12][CH2:13][OH:14])[CH2:10][NH:11][C:29]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:28]=[C:19]([C:17]#[N:18])[C:20]=2[O:32][CH3:33])=[O:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1c(C#N)cc2ccccc2c1C(=O)NC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]amine in DCM was combined with 1N NaOH solution. The mixture was cooled to 0° C. and a solution of 3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30 min. After stirring overnight at room temperature, the organic phase was concentrated and purified by column chromatography to afford N-[2-(S)-(3,4-dichlorophenyl)4-hydroxybutyl]-3-cyano-2-methoxy-1-naphthamide. 1H NMR (300 MHz, CDCl3) d 8.19 (s, 1H), 7.83-7.80 (d, 1H)), 7.66-7.50 (m, 3H), 7.43-7.38 (m, 2H), 7.17-7.14 (dd, 1H), 6.10 (t, 1H), 4.01 (s, 3H), 3.92-3.68 (m, 3H), 3.60-3.52 (m, 1H), 3.23-3.17 (m, 1H), 2.13-2.02 (m, 1H), 1.93-1.82 (m, 1H); MS APCl, m/z=443 (M+). N-[2-(S)-(3,4-Dichlorophenyl)-3-carboxypropyl]-3-cyano-2-methoxy-1-naphthamide To a solution of Jones Reagent (prepare from 2.734 g of CrO3, 2.3 mL of concentrated H2SO4 and 10 mL of water) (13 mL) in acetone (100 mL) was added a solution of N-[2-(S)-(3,4-Di-chlorophenyl)-4-hydroxybutyl]-3-cyano-2-methoxy-1-napthamide (7.53 g, 17 mmol) in acetone (100 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. Isopropyl alcohol was added until a blue color was persisted. The mixture was stirred 15 min at room temperature and EtOAC/water was added. Combined organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated, following chromatography purification to give product as a yellow solid (6.99 g, 90%yield). 1H NMR (CDCl3) δ 8.19 (s, 1H), 7.84-7.81 (d, 1H), 7.65-7.41 (m, 5H), 7.19-7.15 (dd, 1H), 6.15 (t, 1H), 4.00 (t, 3H), 3.93-2H), 3.54-3.45 (m, 1H), 2.94-2.70 (m, 2H). MS (APCI) m/z 479.2 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[CH:22]=1)=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[CH:22]=1)=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1cn(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1cn(C)c2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with 6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CDCl3) δ 8.43 (1H, d, J=5.5 Hz), 8.05 (1H, d, J=8.7 Hz), 7.67 (1H, s), 7.61 (1H, s), 7.17 (1H, d, J=2.1 Hz), 7.13 (1H, s), 7.08 (1H, dd, J=2.1, 8.7 Hz), 7.02 (1H, s), 6.54 (1H, d, J=5.5 Hz), 3.95 (3H, s), 3.75 (3H, s), 3.01 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 418. found 418. Anal. (C22H19N5O2S.0.25EtOAc) C, H, N.
Reaction SMILES: [Cr]([Cl:5])([O-])(=O)=O.[NH+]1C=CC=CC=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[C:14]=1[NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:5][C:18]1[CH:17]=[CH:16][C:15]([CH:19]=[O:20])=[C:14]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(C)(C)C(=O)Nc1c(Cl)cccc1CO
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
Pyridinium chlorochromate (1.19 g, 5.5 mmol) was added to a solution of N-(2-chloro-6-(hydroxymethyl)phenyl) pivalamide (884 mg, 3.67 mmol) in CH2Cl2 (100 mL) at 0° C. 5 min later the mixture was allowed stirring at room temperature for 3 hrs. The reaction mixture was passed through a thin pad layer of silica gel with CH2Cl2 (2×100 mL), concentrated on rotary vacuo, and purified on a flash chromatography column eluting with 20˜50% EtOAc/hexanes (1000 mL) to afford the expected product as a white solid (414 mg, 47% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 9H), 7.30 (t, J=7.81 Hz, 1H), 7.64 (dd, J=7.93, 1.39 Hz, 1H), 7.77 (dd, J=7.55, 1.51 Hz, 1H), 8.25 (s, 1H), 9.84 (s, 1H); Mass spec. 240.08 (MH+), Calc. for C12H14ClNO2 239.07.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH:5]=1
Reactant: CCOc1cc(N)cc(C(=O)OC)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1cc(NS(=O)(=O)CCCCl)cc(C(=O)OC)c1
Reaction time: 16 h
Yield: 97.3 %

Procedure:
A suspension of 3-amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv) in CH2Cl2 (100 ml) was treated with DMAP (400 mg, 3.2 mmol,) and pyridine (1.74 g, 22 mmol, 1.1 equiv) followed by 3-chloropropanesulfonyl chloride (3.89 g, 22 mmol, 1.1 equiv) dropwise. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with 2N aqueous HCl solution (100 ml) followed by saturated aqueous NaHCO3 solution (100 ml), then dried over MgSO4 and concentrated in vacuo to give 3-(3-chloro-propane-1-sulfonylamino)-5-ethoxy-benzoic acid methyl ester (D53) (6.7 g, 98%) as a pale orange solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[OH:7][CH:8]([CH2:16][NH2:17])[CH2:9][CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12].[CH2:18]([O:25][C:26](ON1C(=O)C2C(C3CC2C=C3)C1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(#N)C>[CH2:18]([O:25][C:26]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][CH:8]([OH:7])[CH2:16][NH2:17])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(O)CC[C@H](N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)C2C3C=CC(C3)C2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCC(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
Sodium bicarbonate (4.2 g, 0.050 mol) and 5-hydroxylysine hydrochloride (2.50 g, 0.0126 mol) were dissolved in water (70 ml) with stirring at room temperature. Acetonitrile (40 ml) was added, followed by N-benzyloxycarbonyloxy-5-norbornen-2,3-dicarboximide (3.94 g, 0.0126 mol) in acetonitrile (30 ml) over 15 minutes. After 2 hours, most of the acetonitrile was removed in vacuo and the remaining solution was treated with hydrochloric acid to reduce the pH to 2.0. The solution was extracted with ethyl acetate (50 ml), the pH was increased to 5.5 with sodium hydroxide, and the product was purified over Dowex 50W-2X. The product was eluted with 3% pyridine in water, concentrated to a small volume and freeze dried to give III (1.24 g, 0.0042 mol, 33%); nmr (0.5 M NaOD in D2O)δ 1.4-2.1 (m, 4H, --CH2CH2 --), 3.1-3.5 (m, 2H, --NCH2CH ), 3.5-3.9 (m, 1H, --NCHRCO), 3.9-4.2 (m, 1H, --CH2CHOHCH2 --), 5.10 (s, 2H, --CH2O), 7.39 (s, 5H, --CH2O); mass spectrum (FAB): 297 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:27][C:28](=[CH2:30])[CH3:29].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:28]([CH3:30])([CH3:29])[CH3:27])[N:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)(C)C)n1
Temperature: -50 °C
Yield: 67.8 %

Procedure:
To a stirred suspension of 10 g of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate in 250 mL dry diethyl ether cooled at -50° C. was slowly added 60 mL of liquid isobutylene (previously condensed from gaseous material in a dry ice-alcohol bath). With continued stirring and cooling, 50 mL of concentrated H2SO4 was added slowly and carefully. The mixture was then sealed in a stainless steel Parr container and stirred at -30° C. for 40 hours. After releasing the pressure, the mixture was added slowly and carefully to excess saturated NaHCO3 solution. The aqueous mixture was extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuo to give 7.8 g (67.8%) of the title compound, m.p. 143°-144° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[C:21]([C:25](O)=[O:26])=[N:22][O:23][CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[C:20]([CH3:19])=[CH:24][O:23][N:22]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cc1conc1C(=O)O
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cc1conc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-methyl-isoxazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=369.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13].[OH-].[Na+]>CN(C)C=O>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:11][C:12]1=[O:13]
Reactant: COC(=O)c1sccc1N
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 190 °C
Reaction time: 12 h
Yield: 60.8 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (4.9 g, 31.3 mmol) and urea (19 g, 187 mmol) were dissolved in N,N-dimethylformamide (10 mL), the reaction temperature was raised to 190° C., followed by stirring for 12 hours. After the reaction was complete, the reaction mixture was added to 1N NaOH aqueous solution, cooled to room temperature and filtered under a reduced pressure to remove the insoluble precipitate. The filtrate was acidified (pH 2) with 2N HCl aqueous solution, and the resulting solid was filtered under a reduced pressure with washing using distilled water. The resulting solid was dried under a reduced pressure to obtain the title compound (yield: 3.2 g, 61.5%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]1([C@@H:36]2[CH2:38][C@H:37]2[C:39]([OH:41])=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C@@H:36]2[CH2:38][C@H:37]2[C:39]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:41])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)[C@@H]1C[C@H]1c1ccccc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with trans-2-phenyl-1-cyclopropanecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(trans-2-phenyl-1-cyclopropylcarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 510 (M+H)+.
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)C.ClC(OCC)=O.[C:16]([S:19][CH:20]([CH:25]([C:30]([NH:32][C@H:33]([C:43]([NH:45][CH3:46])=[O:44])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:21][C:22]([OH:24])=O)(=[O:18])[CH3:17].CN>C1COCC1>[C:16]([S:19][CH:20]([CH2:21][C:22]([NH:4][CH3:1])=[O:24])[CH:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:30]([NH:32][C@H:33]([C:43]([NH:45][CH3:46])=[O:44])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:31])(=[O:18])[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)CC(SC(C)=O)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.13 ml, 0.7 mmol) and ethyl chloroformate (0.07 ml, 0.7 mmol) were added to a solution of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid (E5, Isomer A; 300 mg, 0.66 mmol) in dry THF (10 ml), at -20° C. After 15 min a solution of methylamine (20 mg) in THF (0.8 ml) was added dropwise and the mixture was stirred in an ice bath for 3 h. The solvent was evaporated in vacuo, and a solution of the residue in dichloromethane was washed successively with water, 1 M hydrochloric acid, water, saturated sodium hydrogen carbonate and brine. The solution was dried (MgSO4) and evaporated in vacuo. Column chromatography on silica (10 g), eluting with 5% methanol/ethyl acetate gave the title compound, mp 195°-199° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH3:31])[N:24]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH3:31])[N:24]=2)[N:3]=1
Reactant: CCOc1cccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a solution of 3-bromo-4-nitro-1H-indazole (1.5 g, 6.20 mmol) in DMF (0.5M, 12 mL) was added potassium carbonate (1.71 g, 12.4 mmol) at ambient temperature. After 15 minutes, 2-(chloromethyl)-6-ethoxypyridine hydrochloride (1.29 g, 6.20 mmol) was added. The mixture was allowed to stir at ambient temperature for 18 hours. The mixture was concentrated and diluted with ice-water (300 mL). Precipitated solids were collected by filtration, washed with water and dried under high vacuum overnight to provide 3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole (1.21 g, 52% yield).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(Cl)(Cl)[Cl:23].S(Cl)(Cl)=O>CN(C)C=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([Cl:23])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
1.0 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 25 ml. of chloroform, and 1 ml. of thionyl chloride and 0.1 ml. of dimethylformamide are added thereto. The mixture is left for 1 hour then evaporated under high vacuum to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride. In similar manner, substituting the acids prepared in Preparations 3 and 5-9 for the 2-5-oxo-5H-dibenzo[a,d]cyclohepten-2yl)propionic acid used above, the corresponding acid chlorides are prepared.
Reaction SMILES: [H-].[Na+].CCO.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7]1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OC(=O)C)C>[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([C:8]2[C:9]3[C:14](=[N:13][CH:12]=[CH:11][CH:10]=3)[NH:6][CH:7]=2)([OH:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC1(c2c[nH]c3ncccc23)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.6 %

Procedure:
A 60% dispersion of NaH in mineral oil (9.5 g, 179 mmol) was slowly added to 150 ml EtOH (0° C.). This solution was added to 7-azaindole (5.3 g, 44.9 mmol) and 11.25 g (44.9 mmol) 1-benzyl-piperidin-3-one (as HCl salt). The resulting mixture was stirred for 72 hours at room temperature. Ethylacetate was added to the mixture and the organic layer was washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/ethylacetate gradient (1:1 to pure ethylacetate)) to give compound 3 as an oil (10.3 g, 74.7%). 1H-NMR (400 MHz, CDCl3): δ 10.0 (bs, 1H), 8.27 (dd, J=5 Hz, 2 Hz, 1H), 8.14 (dd, J=8 Hz, 2 Hz, 1H), 7.35-7.24 (m, 6H), 7.03 (dd, J=5 Hz, 8 Hz, 1H), 3.96-3.88 (bs, 1H), 3.60 (dd, J gem=13 Hz, 2H), 3.07-3.01 (m, 1H), 2.95-2.89 (m, 1H), 2.39 (d, J=10 Hz, 1H), 2.16-1.96 (m,2H), 1.92-1.78 (m, 2H), 1.72-1.65 (m, 1H). (TLC EtOAc Rf 0.09).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K30) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (314 mg, 75%).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:19][C:14]=2[CH:13]=[CH:12][CH2:11][N:10]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:24][N:22]([CH3:23])[C:21]([O:20][C:18]1[CH:17]=[CH:16][C:15]2[CH:9]([CH2:8][CH2:7][OH:6])[N:10]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:11][CH:12]=[CH:13][C:14]=2[CH:19]=1)=[O:25]
Reactant: CN(C)C(=O)Oc1ccc2c(c1)C=CCN(C(=O)OC(C)(C)C)C2CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1ccc2c(c1)C=CCN(C(=O)OC(C)(C)C)C2CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of t-butyl 1-[2-(t-butyl-diphenyl-silanyloxy)-ethyl]-7-dimethylcarbamoyloxy-1,3-dihydro-benzo[c]azepine-2-carboxylate (1.82 g, 2.96 mmol) synthesized in step (k) of Example 192 in tetrahydrofuran (10 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (6.0 ml, 6.0 mmol) at room temperature, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (40 ml×2). The organic layer was washed successively with water (40 ml×1) and saturated aqueous sodium chloride solution (40 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1-0:1) as the eluent to afford the title compound (1.07 g, yield: 96%) as a colorless oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.ClCCl.C(Br)(Br)(Br)[Br:14]>C(#N)C>[Br:14][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(O)c1
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Solvent: CC#N
Product: Oc1cccc(CBr)c1
Temperature: 2.5 °C

Procedure:
3-[(Hydroxy)methyl]phenol was dissolved in acetonitrile (300 ml) and dichloromethane (900 ml) and the resulting mixture was poured in the flask kept under argon; magnetic stirring was set on. The solution was then cooled with an ice bath and carbon tetrabromide and triphenilphosphine were added. The latter was added in small portions in order to maintain the temperature at ca. 2-3° C.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21]C(=O)OCC)[NH:6]2.[NH2:27][C@H:28]([CH2:31][CH3:32])[CH2:29][OH:30]>>[NH2:21][C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([NH:27][C@H:28]([CH2:31][CH3:32])[CH2:29][OH:30])[N:10]=[C:9]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20])[N:8]=2
Reactant: CC[C@@H](N)CO
Reactant: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Product: CC[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(N)nc12

Procedure:
The titled compound was prepared from the product of Example 5, step (e) (50 mg) and (2R)-2-amino-1-butanol (66 μl) using the method of example 5, step (f) and purified by preparative HPLC to yield a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][N:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CN(C)c1ccc(CCOCCCCCCBr)cc1
Reactant: NCc1ccccc1
Product: CN(C)c1ccc(CCOCCCCCCNCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 1,6-dibromohexane (73.84 g) 4-(N,N-dimethylamino)benzeneethanol (10 g), 50% w/v sodium hydroxide solution (200 ml) and TAB (3.4 g) was vigorously stirred at room temperature for 72 h, diluted with water (500 ml) and extracted with ER (2×100 ml). The dried extracts were evaporated to give a yellow oil which was purified by FCC eluting with H then H-EA (9:1) to give 4-[2-[(6-bromohexyl)oxy]ethyl]-N,N-dimethylbenzeneamine as a yellow oil. The benzeneamine (15 g) was added to benzylamine (45 ml) with stirring at 140° under nitrogen and stirring continued for 2 h. The benzylamine was removed in vacuo at 90°, the solution was partitioned between sodium bicarbonate (150 ml) and EA (2×100 ml) and the combined organic layers dried and concentrated to give a product which was purified by FCC eluting with ER-H (1:1→ER) to give the title compound as a yellow oil (11.1 g) t.l.c. (T-ET-A 95:4:1) Rf 0.62.