Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:34](C1C=CC(C(O)=O)=CC=1NC(=O)CC(C1C=CC(C(=O)CC)=CC=1OC)CCCCC)(C)(C)[CH3:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:30])[CH2:34][CH3:35])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(=O)CC)cc1OC
Reactant: COC(=O)c1ccc(C(C)(C)C)c(NC(=O)CC(CC(C)C)c2ccc(C=O)cc2OC)c1
Product: CCC(=O)c1ccc(C(CC(=O)Nc2cc(C(=O)O)ccc2C(C)(C)C)CC(C)C)c(OC)c1

Procedure:
Using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)-5-methylhexanamide (prepared as described in Preparation 63B), the procedure described in Preparation 64B was repeated to give the title compound as a foam-like substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.[I-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][N:25]2[CH2:24][CH2:23][N:22]([CH:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[CH2:27][CH2:26]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=CCCl)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(C=CCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of 0.5 gram (0.002 mole) of 3-(4-nitrophenyl)-2-propenyl chloride in 5 mL of dimethyl sulfoxide was added to a solution of 0.7 gram (0.002 mole) of N-[bis(4-fluorophenyl)methyl]piperazine in 10 mL of dimethyl sulfoxide. To this was added 0.1 gram (0.0005 mole) of sodium iodide as a catalyst. Upon completion of the addition 1.2 grams (0.010 mole) of N,N-diisopropylethylamine was added dropwise. To effect solution the reaction mixture was then warmed to 50-80° C., where it stirred for four hours . After this time the reaction mixture was cooled to ambient temperature, where it stirred for about 18 hours. The reaction mixture was then poured into 50 mL of aqueous saturated sodium bicarbonate solution and then extracted with three 50 mL portions of diethyl ether. The combined extracts were washed with 75 mL of aqueous saturated sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding a crude oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 1:1 ethyl acetate:heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.5 gram of of N-[3-(4-nitrophenyl)-2-propenyl]-N′-[bis(4-fluorophenyl)methyl]piperazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=CC=[C:27]([F:31])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:27]([F:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Fc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a light brown solid, MS (ISP): m/e=326.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:14]1=[O:26].CCN(C(C)C)C(C)C.[Cl:36][C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=1.O>CN(C=O)C>[ClH:36].[CH2:43]([C:40]1[CH:39]=[N:38][C:37]([N:23]2[CH2:24][CH2:25][CH:20]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C@H:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:26])[CH2:21][CH2:22]2)=[N:42][CH:41]=1)[CH3:44]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCCCN(C3CCNCC3)C2=O)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N3CCCC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Product: Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
To a solution of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)azepan-2-one (0.10 g, 0.26 mmol) and DIEA (0.14 mL, 0.78 mmol) in DMF (2 mL) was added 2-chloro-5-ethylpyrimidine (0.11 g, 0.78 mmol). This mixture stirred at 100° C. for 4 hours in a sealed tube. The mixture was poured into water (50 mL) and extracted into ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The material was purified by column chromatography using 50% to 100% hexanes/ethyl acetate. The HCl salt was made using HCl in ether to give (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)azepan-2-one hydrochloride (0.055 g, 0.11 mmol, 43%) (APCI POS 490 M+H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Brc1cccs1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Br)s2)cc1
Reaction time: 2 h

Procedure:
To a cold (0°-5° C.) solution of 2-bromothiophene (32.6 g, 0.2 mol) and p-methoxybenzoyl chloride (34.1 g, 0.2 mol) in methylene chloride was added anhydrous stannic chloride (52 g, 0.2 mol) dropwise over about one hour. When addition was complete, the cooling bath was removed and the solution was stirred for an additional two hours. A solution of water (90 mL) and concentrated hydrochloric acid (10 mL) was added dropwise and the layers were separated. The organic layer was washed with water, saturated sodium chloride solution and dried (MgSO4). Removal of the solvent in vacuo and collection of the slide with the aid of hexane gave 48.5 g, of gray powder, m.p. 97°-99° C. A sample was recrystallized from ligroin for analysis.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:6]2.Br.[OH-].[Na+]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:6]2
Reactant: COc1ccc2ncc(C[C@H](N)C(=O)O)cc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](Cc1cnc2ccc(O)cc2c1)C(=O)O
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A mixture of 0.18 g (0.74 mmol) of 3-(6-methoxy-3-quinolyl)alanine and 5.4 mL of 48% hydrobromic acid was stirred at 85°-90° C. overnight. The reaction mixture was cooled to room temperature and neutralized to pH 7.0 with 1N sodium hydroxide solution, then was concentrated under reduced pressure to give a brown solid. After filtration, the solid product was washed with a small amount of cold water and ethyl ether and then was dried in vacuo to give 57.4 mg (33.4%) of the title compound of the formula: ##STR107## NMR (DMSO-d6, CF3COOH) δ 9.05 (1H, bs), 8.9 (1H, bs), 8.2 (1H, d), 7.7 (1H, dd), 7.5 (1H, d), 4.5 (1H, m), 3.5 (2H, m); IR (KBr) ν 3400, 1630, 1500 cm-1.
Reaction SMILES: [C:1]1([C:7]2[O:11][NH:10][C:9](=[O:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(C)C=CC(S(OC)(=O)=O)=CC=1.[OH-].[Na+].N>O>[CH3:13][C:8]1[C:9](=[O:12])[NH:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(-c2ccccc2)o[nH]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(-c2ccccc2)o[nH]c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To 60 g of 5-phenyl-3-isooxazolone was added 150 ml of methyl p-toluenesulfonate and the mixture obtained wa stirred for 3 hours at 80° C. The reaction mixture was allowed to cool, and after gradually adding thereto 30 ml of an aqueous 10% sodium hydroxide solution and 50 ml of an aqueous 30% ammonia solution under cooling, the resultant mixture was stirred for one hour at room temperature. Then, 500 ml of water was further added thereto and the mixture was stirred for a few hours at room temperature to deposit crystals, which were collected by filtration and dried to provide 30 g of the desired compound. The yield was 46%.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCCc1ccccc1Cl
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCc1ccccc1Cl)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 27 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 2-(2-chlorophenyl)ethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-[2-(2-chlorophenyl)ethyl]-isonicotinamide was obtained as a colorless solid in 27% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.91-10.82 (m, 1H), 8.91-8.85 (m, 1H), 8.56-8.44 (m, 2H), 8.06-7.98 (m, 2H), 7.63-7.17 (m, 8H), 3.55-3.48 (m, 2H), 3.03-2.92 (m, 2H); MS (ES+) m/z 380.5 (M+1), 382.3 (M+2).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O=[C:11]([CH3:20])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCC[C@H]1C(O)=O>CCO>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:20][C:11]=1[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCC(C)=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CCCc1ccc2cccnc2n1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A solution consisting of 2-aminonicotinaldehyde (0.7 g; 5.8 mmol), ethyl 5-oxohexanoate (1.83 g; 11.6 mmol; 1.85 ml), L-proline (0.166 g; 1.45 mmol) and 50 ml of EtOH is heated at 90° C., with stirring, for 6 hours. The reaction mixture is then concentrated and the residue is purified by chromatography on silica gel (eluant: EtOAc) to yield the title product in the form of a beige solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH3:20].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:20][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO

Procedure:
g (3.39 mmol) of 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 7 ml of abs. THF were cooled down to 0° C. and reacted with 7.06 ml of DIBAL-H solution (1.2 M in toluene, 2.5 eq.) for 1 h. Careful quenching with ice/NH4Cl, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=7/3) to deliver 0.875 g of the title compound as off-white solid, mp. 76–78° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[CH:24]=1>>[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]=1[C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:29])[CH:24]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C(=O)NC3CCOCC3)c2)cn1
Yield: 42 %

Procedure:
As described for Example 71, tetrahydro-pyran-4-ylamine was converted, using 3-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (52 mg, 42%) which was obtained as an off-white solid. MS: m/e=413.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 32.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1.03 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.21 g, 1.23 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a pale yellow solid (0.18 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH3:32])[CH:23]=1)=[O:20].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[O:20])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(NC(=O)OC(C)(C)C)CC2)c2ccccc2n1
Temperature: 70 °C
Reaction time: 144 h

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10 mmol), 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (10 mmol), NaHCO3 (20 mmol), Nal (0.5 mmol), and THF (70 mL) is stirred in a sealed vessel at 70° C. for 6 d. The reaction mixture is filtered, evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:11]([CH3:12])=[CH:10][C:9]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH3:27])[CH:19]=2)=[N:6]1)=[O:4].O.NN>CO.ClCCl.[Ni]>[CH3:1][NH:2][C:3]([N:5]1[C:11]([CH3:12])=[CH:10][C:9]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:8]=2[C:7]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH3:27])[CH:19]=2)=[N:6]1)=[O:4]
Reactant: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C=C1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)ccc2C=C1C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
10.89 g (28 mmoles) 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine 3-carboxylic acid methyl amide are dissolved in the mixture of 190 ml of methanol and 95 ml of dichloromethane, and about 5.0 g of wet Raney nickel catalyst and 3.5 ml (70 mmoles) of 98% hydrazine hydrate are subsequently added to it under vigorous stirring. The mixture is stirred for further 1 hour, the catalyst is filtered off, washed with dichloro-methane, the filtrate is evaporated and the residue is solidified by rubbing with 100 ml of water. The crude product is recrystallized from ethanol. Thus 7.73 g (78%) of the desired compound melting at 210-212° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[C:7]=1[CH3:14])[CH3:2].[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[C:20]#[N:21].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][C:28]=1[Cl:37]>C(OC(=O)C)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[C:7]=1[CH3:14])[CH3:2].[Cl:37][C:28]1[CH:29]=[C:30]([S:33](=[O:34])(=[O:35])[NH2:36])[CH:31]=[CH:32][C:27]=1[NH:26][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[CH3:16])=[C:8]([CH3:13])[C:7]=1[CH3:14]
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Reactant: Cc1cc(C#N)ccc1F
Agent: CCOC(=O)Cc1ccc(O)c(C)c1C
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1Oc1ccc(CC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c(C)c1C

Procedure:
(4-Hydroxy-2,3-dimethyl-phenyl)-acetic acid ethyl ester (45c) was prepared as described in Example 13. N-(2-Chloro-4-sulfamoyl-phenyl)-2-[4-(4-cyano-2-methyl-phenoxy)-2,3-dimethyl-phenyl]-acetamide (I-25) was prepared starting with 45c utilizing the procedure from example 1 except in step 1, 45c was used in place of 3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and 3-methyl-4-fluoro-benzonitrile was used in place of 3-chloro-5-fluoro-benzonitrile and in step 4, 4-amino-3-chloro-benzenesulfonamide was used in place of 4-amino-benzenesulfonamide.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@H:12]2[O:22][CH3:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(O)C>[CH3:23][O:22][C@H:12]1[C@@H:11]([N:10]([CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: CCOC(=O)N1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@@H]1CNCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Yield: 55 %

Procedure:
To a stirred mixture of 230 parts of potassium hydroxide and 1600 parts of 2-propanol were added 155 parts of ethyl cis-4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinecarboxylate. The whole was stirred and refluxed for 7 hours. The reaction mixture was evaporated. Water was added and the mixture was evaporated till all traces of 2-propanol were removed. The product was extracted with dichloromethane. The extract was washed twice with a sodium chloride solution in water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in dichloromethane. The solution was washed with a sodium hydroxide solution 5%, dried, filtered and evaporated, yielding 70 parts (55%) of cis-3-methoxy-N,N-bis(phenylmethyl)-4-piperidinamine as a residue (int. 47).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:40])[C@@H:10]([NH:22][C:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:48]1([C:54](Cl)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)(Cl)Cl>[C:28]([O:27][C:25]([N:24]=[C:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:22][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:54]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:40])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-5-oxopentylcarbamate and triethylamine (170 mg) in chloroform (30 ml) was added triphenylmethyl chloride (470 mg), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (4S)-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (850 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[CH2:13]([O:11][C:10](=[O:12])[CH2:9][C:3]1[CH2:4][CH2:5][C:6]([CH3:7])([CH3:8])[C:2]=1[CH3:1])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=C(CC(=O)O)CCC1(C)C
Solvent: CCO
Product: CCOC(=O)CC1=C(C)C(C)(C)CC1
Temperature: 78 °C
Yield: 745.7 %

Procedure:
A solution of β-campholenic acid (10 g) and p-toluenesulfonic acid (1 g) in ethanol (500 ml) was kept at reflux (78° C.) for 5 hours, while the condensate was perculated through a layer of molecular sieves (3 Å) (40 g). The alcohol was then removed, the residue taken up in CH2Cl2 (500 ml) and the solution extracted with ice cold 5% aqueous sodium hydroxide (500 ml) and water (2×500 ml). Concentration of the dried CH2CL2 solution gave a crude oil (12 g) which was distilled through a 3" Vigreux column to give 8.5 g of a colorless liquid; bp 58° C. @ 0.8 mm Hg; analysis: (CW 20M fused silica column, 120°-190° C.; 5° C./min.) 96% ethyl β-campholenate; odor: fruity, berry, resinous; flavor: fruity, woody, winey, berry.