Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:18][C:19]2[S:20][C:21]([CH:24]=O)=[CH:22][N:23]=2)=[O:17])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH2:31]>>[CH3:27][O:28][C:29](=[O:32])[CH2:30][NH:31][CH2:24][C:21]1[S:20][C:19]([NH:18][C:16]([NH:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])=[O:17])=[N:23][CH:22]=1
Reactant: Cc1ccc(NC(=O)Nc2ncc(C=O)s2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNCc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 45 %

Procedure:
({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylmethyl}-amino)-acetic acid methyl ester (38 mg, 45%) was prepared from 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(5-formyl-thiazol-2-yl)-urea (0.072 g, 0.2 mmol) and glycine methyl ester hydrochloride following the general procedure O.
Reaction SMILES: [CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:42])=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN
Reactant: Cc1cc(C(Nc2ccc(C(=O)O)cn2)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Reaction time: 70 h

Procedure:
To a mixture of (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinic acid (731 mg, 1.59 mmol), β-alanine ethyl ester hydrochloride (516 mg, 3.19 mmol), and 1-hydroxy-7-azabenzotriazole (336 mg, 2.39 mmol) in dichloromethane (15.9 mL) was added triethylamine (0.782 mL, 5.58 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (465 mg, 2.39 mmol). After 70 hours, the mixture was diluted with dichloromethane (50 mL) and washed with water (3×50 mL) and sat. aq sodium chloride (50 mL). The organic layer was dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate/heptane) followed by chiral SFC (Cellulose-2 column, 21 mm×250 mm, 35% methanol/carbon dioxide eluent) gave ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 1 (SFC retention time 2.71 min) and ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 2 (SFC retention time 3.43 min). 1H NMR (400 MHz, CDCl3, δ): 8.45 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.81-7.72 (m, 2H), 7.09 (s, 2H), 6.84 (t, J=5.7 Hz, 1H), 6.41-6.27 (m, 1H), 6.26 (d, J=9.0 Hz, 1H), 4.33 (t, J=7.6 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.65 (q, J=6.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 2.33-2.19 (m, 1H), 1.98 (s, 6H), 1.96-1.85 (m, 1H), 1.74-1.37 (m, 6H), 1.34-1.21 (m, 4H). MS (M+1): 558.5.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[F:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[C:16]([NH:24][CH3:25])[CH:15]=1>>[F:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:19])[CH2:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])=[C:16]([NH:24][CH3:25])[CH:15]=1
Reactant: CNc1cc(F)ccc1C(=O)OC
Reactant: CN(C)S(C)(=O)=O
Agent: [Li]CCCC
Product: CNc1cc(F)ccc1C(=O)CS(=O)(=O)N(C)C

Procedure:
In a similar manner to that described in Example 12(a), N,N-dimethylmethanesulphonamide was reacted with n-butyl lithium and the product reacted with methyl 4-fluoro-2-methylaminobenzoate to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(N,N-dimethylsulphamoyl)ethanone, m.p. 120°-124°.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:8][C@@H:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>[Pd].C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:8][C@@H:9]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: COc1ccc(O[C@H](CCN2CC=C(c3ccc([N+](=O)[O-])cc3)CC2)c2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(O[C@H](CCN2CCC(c3ccc(N)cc3)CC2)c2ccccc2)cc1OC

Procedure:
A 25-mL RB flask, equipped with a hydrogen-filled balloon, was charged with 1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (63.0 mg, 0.133 mmol), palladium on carbon (5.0 mol-eq %, 0.00665 mmol, 7.04 mg) and ethanol (2.0 mL) at room temperature. After 1 hr the reaction mixture was filtered through a plug of Celite 545 and concentrated under reduced pressure. The crude product (54.1 mg, 89.4%) was used in next reaction without further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C1(C)C=CC=CC=1.[C:27]1([C@@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([C@@H:33]([NH:35][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][N:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3cnccc32)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cnccc32)n1)c1ccccc1
Temperature: 100 °C

Procedure:
To a flask containing 2-methanesulfonyl-4-[5-azabenzimidazol-1-yl]pyrimidine (33.8 mg) was added toluene (0.25 mL) and (S)-1-phenylethylamine (0.25 mL). The mixture was warmed to 100° C. The 2-methanesulfonyl-4-[5-azabenzimidazol-1-yl]pyrimidine did not dissolve so DMF (0.25 mL) was added and the mixture was maintained at 100° C. overnight. The reaction mixture was cooled and the solvents were removed under reduced pressure. The product was purified by preparative thin layer chromatography (eluted with 7% MeOH in CH2Cl2) to give 28 mg of the title compound. 1H NMR (500 MHz, CD2Cl2): δ 1.63 (3H, d, J=7 Hz), 5.18, (1H, br s), 5.96 (1H, br s), 6.78 (1H, d, J=5.5 Hz), 7.28 (1H, t, J=7 Hz), 7.38 (2H, t, J=7 Hz), 7.46 (2H, m), 7.62 (1H, br), 8.43 (1H, d, J=5 Hz), 8.4-8.6 (2H, m), 9.07 (1H, s).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([O:29]C)[C:22]=2[O:31]C)[C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([O:17]C)[C:10]=2[O:19]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>O>[C:1]1([CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:17])[C:10]=2[OH:19])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:29])[C:22]=2[OH:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=Cc2ccccc2)c2ccc(OC)c(OC)c2OC)c(OC)c1OC
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(C(=Cc2ccccc2)c2ccc(O)c(O)c2O)c(O)c1O

Procedure:
The product of Example 9 was heated under reflux with pyridine chlorhydrate for 10 minutes then the reaction mixture was added to water. On recrystallisation of the resulting precipitate from a mixture of water and alcohol, crystals of 1-phenyl-2,2-di-(2,3,4-trihydroxyphenyl) ethylene having a melting point of 142° - 143° C were obtained. ##STR10##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[OH-].[K+]>O1CCCC1>[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(4-aminophenyl)quinazoline-4-carboxylic acid (25.3 mg, 0.95 mmol, 1.00 equiv), acetyl acetate (18.36 mg, 0.18 mmol, 2.00 equiv), potassium hydroxide (5.07 mg, 1.00 equiv) and tetrahydrofuran (10 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 20 mg (68%) of 2-(4-acetamidophenyl)quinazoline-4-carboxylic acid as a yellow solid. MS (ESI) m/z 308 ([M+H]+).
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.N#N.C([N-]C(C)C)(C)C.[Li+].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([I:33])[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:6]2([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH:3]([CH:2]([F:13])[F:1])[CH2:8][CH2:7]2)=[C:27]([I:33])[CH:26]=1
Reactant: BrCc1ccc(Br)cc1I
Reactant: COC(=O)C1CCC(C(F)F)CC1
Agent: CC(C)[N-]C(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)F)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Methyl 4-(difluoromethyl)cyclohexanecarboxylate (Intermediate 89, 2.46 g, 12.8 mmol) was dissolved in THF (25 mL). The atmosphere was exchanged to N2 (g), and the solution was cooled to −78° C. Lithium diisopropylamide (1.8M in THF/heptane/ethylbenzene) (8.51 mL, 15.3 mmol) was added, while the temperature was kept at −78° C. The solution was stirred for 60 min at −78° C. A solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239., 4.8 g, 12.8 mmol) in THF (5.0 mL) was added via syringe. The reaction was removed from the cooling bath, and allowed to reach r.t., while stirred for 2.5 h. Water (30 mL) was added, followed by DCM (30 mL). The organic layer was collected and dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography, (0-100% EtOAc in heptanes, 220 g SiO2) to give the title compound (3.29 g, 53% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.11-1.20 (m, 2H), 1.39 (td, 2H), 1.67-1.80 (m, 3H), 2.30 (d, 2H), 3.01 (s, 2H), 3.70 (s, 3H), 5.49 (d, 1H), 6.89 (d, 1H), 7.38 (dd, 1H), 7.99 (d, 1H), MS (CI) m/z 487 [M+H]+.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)[CH:12]=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35](=[O:36])[CH2:34][NH:33][C:32]2=[S:37])=[CH:27][CH:26]=1>C(O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)/[CH:12]=[C:34]1/[C:35](=[O:36])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32](=[S:37])[NH:33]/1
Reactant: COc1ccc(N2C(=O)CNC2=S)cc1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(N2C(=O)/C(=C/c3ccc(-n4cnc(C)c4)c(OC)c3)NC2=S)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
Piperidine (0.019 mL) was added to an ethanol (2 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (20 mg) obtained in Example 1 and 3-(4-methoxyphenyl)-2-thioxoimidazolidine-4-one (21 mg), and heat-refluxing of the reaction solution was carried out for 12 hours. The reaction solution was allowed to be cooled to room temperature and the solid deposited was separated by filtering, and 18 mg (47%) of the title compound was obtained by washing with ethanol and ether. The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[O:27][N:26]=[C:25]([C:28]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:29])[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)C)on1
Yield: 53.6 %

Procedure:
(S)-5-tert-butyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.69 mmol) and 5-tert-butylisoxazole-3-carboxylic acid (132 mg, 0.782 mmol). The product was purified by Flash-chromatography (reverse phase). Yield 53.6%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 1.35 (s, 9H), 4.26-4.45 (m, 2H), 4.51-4.63 (m, 1H), 6.34 (s, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.77 (dd, 1H), 7.87 (dd, 1H), 8.09 (dd, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([C:15]([NH:17][NH2:18])=O)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C(O[C:24](=[NH:26])[CH3:25])C.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([C:15]2[NH:26][C:24]([CH3:25])=[N:18][N:17]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(C)=N
Reactant: NNC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nnc(C2(NC(=O)OCc3ccccc3)CC2)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a vial was added (1-hydrazinocarbonyl-cyclopropyl)-carbamic acid benzyl ester HCl salt (300 mg, 1.05 mmol), acetimidic acid ethyl ester HCl salt (195 mg, 1.58 mmol) and triethylamine (320 mg, 3.16 mmol) in toluene (8 ml). The reaction mixture was stirred at 120° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc/sat. NaHCO3. The organic phase was separated, washed with brine, dried under anhy. Na2SO4, filtered and concentrated. The residue was purified by prepHPLC to afford 57 mg of [1-(5-methyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester, m/z 273.6 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>C1COCC1>[S:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(C#N)cc32)cc1
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 1H-indole-6-carbonitrile (70 mg, 0.5 mmol, CASRN 15861-36-6) in THF (5 mL) cooled to 0° C. was added with vigorous stirring NaH (25 mg, 60% in oil, 0.65 mmol). After stirring for 30 min, TsCl (140 mg, 0.75 mmol) was added to the mixture. The reaction mixture was stirred at RT for 18 h then partitioned between DCM (300 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (5 to 10% EtOAc) to afford 100 mg (67%) of 1-tosyl-1H-indole-6-carbonitrile (34) as a white solid: MS (ESI) m/z=297.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH3:24])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(=O)CCl
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Product: CC(CCl)=NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 7-bromo-2-[(2-chloro-1-methylethylidene)hydrazino]-5-(2-pyridyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36](O)=[O:37])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([NH:46][CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:47])=[O:37])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CN
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CCC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
A mixture of 350 mg of the crude 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid obtained in Example 9 (1), 101 mg of glycine ethyl ester hydrochloride, 45 mg of HOBt, 73 mg of triethylamine and 5 ml of dichloromethane was mixed with 190 mg of WSC hydrochloride and stirred at room temperature for 2 days. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 315 mg of ethyl ({4-[(3R,4S)-3-({(tert-butoxycarbonyl) [(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoyl}amino)acetate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:14]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:31]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[O:32])[CH2:14]3)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Clc1ccc(C2(CN3CCCC(CNc4ccccc4)C3)CCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CCC1)N(CC1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
A solution of 203 (0.276 mmol, 102 mg) in CH2Cl2 (2 mL) at 0° C. was treated with cyclobutanecarbonyl chloride (1.5 equiv, 0.414 mmol, 50 μL) and diisopropylethylamine (1.5 equiv, 0.414 mmol, 72 μL) under Ar. After warming to 25° C. and stirring for 12 h, the reaction mixture was purified directly by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, 8:1 hexane-acetone) which provided 204 (100 mg, 124 mg theoretical, 81%) as a yellow oil: Rf 0.27 (SiO2, 8:1 hexane-acetone); LRMS m/z 451 (M+, C28H35ClN2O, requires 451).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42](=[O:52])(=[O:51])[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:38][CH:37]=3)[N:30]=2)=[CH:27][N:26]=[C:25]1[CH3:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:23][N:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[CH:38][C:39]([S:42](=[O:52])(=[O:51])[N:43]([C:44]([O:46][C:47]([CH3:49])([CH3:50])[CH3:48])=[O:45])[CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:40][CH:41]=3)[N:30]=2)=[CH:27][N:26]=[C:25]1[CH3:53]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc3)n2)n1C
Reactant: COCCOCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCCN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
2-(2-Methoxyethoxy)ethanol (50 μl, 0.4 mmol) followed by diisopropyl azodicarboxylate (0.1 ml, 0.4 mmol) was added to a stirred solution of 4-(1,2-dimethylimidazol-5-yl)-2-{4-[N-(t-butoxycarbonyl)sulphamoyl]anilino}pyrimidine (Example 36; 90 mg, 0.2 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in anhydrous THF (4 ml) under nitrogen at 0° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was poured directly on to an Isolute SCX-2 column, eluted first with MeOH (8×15 ml) and then the product was eluted with 2% methanolic ammonia (6×15 ml). The solvent was evaporated and the residue dissolved in EtOAc (25 ml), washed with saturated aqueous sodium hydrogen carbonate solution (2×25 ml), dried and the solvent evaporated to give the title compound (77 mg, 71%) as a yellow oil. NMR 1.38 (s, 9H), 2.49 (s, 3H), 3.38 (s, 3H), 3.56 (m, 2H), 3.68 (m, 2H), 3.76 (t, 2H), 3.96 (s, 3H), 4.06 (t, 2H), 7.03 (d, 1H), 7.49 (s, 1H), 7.58 (s, 1H), 7.78 (d, 2H), 7.93 (d, 2H), 8.40 (d, 1H); m/z 547.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=O)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[S:24])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1
Reactant: CC1(C)CC(=O)Nc2ccccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(=S)Nc2ccccc2N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 144.4 %

Procedure:
A disposable tube was charged with 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (697 mg, 3.66 mmol) in THF (20 mL). Lawesson's Reagent (815 mg, 2.015 mmol) was added, and the solution was stirred at 80° C. for 3 h. The solution was concentrated, partitioned between water and ethyl acetate, separated, dried with sodium sulfate, concentrated with celite, and purified by silica gel chromatography to yield 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a yellow oily solid (0.60 g, 2.91 mmol, 79%).