Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@@H:21]([NH:29][C:30]([O:32][C@H:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[NH:4][CH2:5][CH:6]([CH3:8])[CH3:7].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[OH:1][C@@H:2]([C@@H:21]([NH:29][C:30]([O:32][C@H:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:3]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[NH:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CNC([C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCCOC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CNC([C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CCCOC1)S(=O)(=O)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A mixture of 2(S)-hydroxy-3(S)-[3(S)-tetrahydropyranyloxycarbonyl]amino-1-(4-nitrobenzenesulfonyl)-1-isobutylamino-4-phenylbutane (36 mg, 0.067 mmol) and SnCl2.2H2O (77 mg, 0.34 mmol) in 1 mL of EtOAc was heated to 70° C. After 1 h the starting material disappeared and the solution was allowed to cool to room temperature. The mixture was poured into sat aq NaHCO3 solution (3 mL) and extracted with EtOAc (10 mL). The organic extract was dried over anhyd MgSO4 and concentrated under reduced pressure to give 30 mg of 2(S)-hydroxy-3(S)-[3(S)-tetrahydropyranyloxycarbonyl]amino-1-(4-aminobenzenesulfonyl)-1-isobutylamino-4-phenylbutane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH:28]=O>>[CH3:30][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: Cc1ccccc1CC=O
Product: Cc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and o-Tolyl-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 380.126; HRMS: calcd for C23H16F3NO+H+, 380.12567; found (ESI, [M+H]+), 380.126.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9](=[NH:24])[NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[O:7])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:31]1([C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:9](=[NH:24])[NH:8][C:6](=[O:7])[C:5]3[CH:25]=[CH:26][C:2]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)=[C:3]([C:27]([F:30])([F:28])[F:29])[CH:4]=3)=[O:23])=[CH:13][C:14]=2[C:19]([F:20])([F:21])[F:22])[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: c1c[nH]cn1
Reactant: N=C(NC(=O)c1ccc(F)c(C(F)(F)F)c1)NC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N=C(NC(=O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1)NC(=O)c1ccc(-n2ccnc2)c(C(F)(F)F)c1
Yield: 39.4 %

Procedure:
0.25 g of bis(4-fluoro-3-trifluoromethylbenzoyl)guanidine, 0.16 g of imidazole and 0.16 g of potassium carbonate are heated for 16 h in 5 ml of DMF, and after that the solvent is evaporated. Separation of the crude product by column chromatography yielded 0.12 g of bis[4-(1-imi-dazolyl)-3-trifluoromethylbenzoyl]guanidine as a colorless solid, mp 130° C., decomp., Rf (CH2Cl2/MeOH 9:1)=0.4 MS (ES): 536 (M+1) and 0.07 g of N-[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]-N′-(4-fluoro-3-trifluoromethylbenzoyl)guanidine as an oil. Treatment with HClg/ether yielded 0.06 g of N-[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]-N′-(4-fluoro-3-trifluoromethylbenzoyl)guanidine hydrochloride as a colorless solid, mp 217-218, decomp., Rf (CH2Cl2/MeOH 9:1)=0.53; MS (ES): 488 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=1)=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1N
Solvent: c1ccncc1
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.217 mmol) N-[3-amino-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Example 160) in 5 mL pyridine was added at 0° C. to 18 μL (0.239 mmol) of methanesulphonylchloride, the mixture was slowly heated to RT and stirred for 3 h at RT. The reaction mixture was poured onto ice water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate and evaporated down i. vac. The residue was lyophilised.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[NH2:12])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:12][C:11]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:9]([N:4]3[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]3)[CH:10]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(cis-3,5-dimethyl-1-piperazinyl)-4-(methyloxy)aniline (D2) (800 mg, 3.40 mmol) in dichloromethane (50 ml) was treated with morpholinomethyl-polystyrene HL resin (1.70 g, 4.0 mmol/g loading, 6.80 mmol) followed by 4-bromobenzenesulfonyl chloride (1.30 g, 5.09 mmol). The resulting solution was stirred at room temperature overnight and was then filtered, washing with methanol, and the filtrate concentrated in vacuo. The residue was then purified using an SCX ion exchange cartridge (Varian bond-elute) eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and reduced in vacuo to afford a crude product which was purified further by chromatography on silica gel eluting with (0 to 20% methanol in dichloromethane) to afford the title compound (E101). MS (ES+) m/e 454/456 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29]C(=O)OC(C)(C)C)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:29])[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see intermediate 46) (599 mg, 1.131 mmol) in dichloromethane (DCM) (20 mL) was treated with trifluoroacetic acid (TFA) (5.00 mL) and the resulting reaction mixture was stirred for 1 h at room temperature then concentrated in vacuovacuo. Purification of the residue on SP4 using a 50 G silica cartridge (gradient:0 to 12% MeOH in DCM) gave 2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}ethanol (396 mg, 0.885 mmol, 78% yield) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN.S(=O)(=O)(O)O>C(O)C>[CH3:30][N:10]1[CH:11]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[N:9]1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g) in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) and concentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1 h at ambient temperature and solvent evaporated. The reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Preparative HPLC chromatography provided the title compound (major isomer) as a clear oil (0.97 g, 56%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 2 H), 8.17 (d, J=8.7 Hz, 1 H), 8.05 (d, J=8.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1 H), 7.70 (m, 1 H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.53 (m, 1H), 7.37 (d, J=8.7 Hz, 2H) 7.15 (d, J=5.0, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 3.93 (s, 3H); MS: (M+H m/z=393.3).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11](O)[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)([Cl:31])=O)C=CC=CC=1.CCCCCC>C(OCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:31])[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1O
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 100 °C
Yield: 92 %

Procedure:
4-Benzylamino-3-nitro-6-trifluoromethyl-pyridin-2-ol (61.7 gm 197 mmol) was added to phenylphosphonic dichloride (180 mL) and heated to 100° C. in an oil bath, under N2 overnight. The starting material dissolved on heating to give a light yellow solution. The mixture was then quenched on to ice water (600 gm of ice+100 mL water) to give a pale yellow solid. Filtered off and washed the solid well with water. The solid was dissolved in ethyl acetate (600 mL) and washed with aqueous sodium hydrogen carbonate solution (10% w/v) until there was no further effervescence and the pH of the aqueous washings were basic. The organic layer was dried over sodium sulphate, filtered and evaporated to give a dirty yellow solid. The solid was then dissolved in diethyl ether. To this was then added n-hexane until the solution was cloudy. Within a few minutes a thick flocculent solid had formed, which was then filtered off, washed with n-hexane and dried to give the title compound (60.59 gm 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[S:26][C:27]4[CH2:28][NH:29][CH2:30][CH2:31][C:32]=4[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[CH3:34][N:35]([CH:42]([CH3:44])[CH3:43])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]3[S:26][C:27]4[CH2:28][N:29]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH3:34])[CH:42]([CH3:44])[CH3:43])[CH2:30][CH2:31][C:32]=4[C:19]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1)CCNC3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 90A (80 mg, 0.17 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (47 mg, 0.24 mmol) in DMF (2 mL) was treated with DIPEA (89 mg, 0.69 mmol) and TBTU (83 mg, 0.26 mmol). The mixture was stirred at rt overnight and then directly purified by preparative HPLC to yield 63 mg (61%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:17][CH:16]1[CH2:15][C@H:14]1[C@@H:10]2[CH2:11][N:12](CC2C=CC(OC)=CC=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([NH:8][C@:9]12[CH2:17][CH:16]1[CH2:15][C@H:14]1[C@@H:10]2[CH2:11][NH:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]12CC1C[C@@H]1CNC[C@@H]12
Yield: 95.2 %

Procedure:
To a methanol (20 ml) solution of the (1R,2R,6S)-1-t-butoxycarbonylamino-4-p-methoxybenzyl-4-azatricyclo[6.1.0.02,6]-nonane (453 mg, 1.26 mmol) was added 10% palladium-on-carbon (400 mg), and the mixture was stirred vigorously in a pressurized (5 kg/cm2) hydrogen atmosphere for 30 hours. The insoluble matter was removed by Celite filtration, and the filtrate was concentrated to give 286 mg (1.20 mmol, 95%) of the title compound as a colorless oily substance.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][OH:18].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:4]([Si:1]([O:18][CH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Reaction time: 0.75 h

Procedure:
tert-Butyldimethylsilyl chloride (6.45 g) was added to a stirred solution of 2-(2-fluorophenyl)ethanol (5.00 g) and 1H-imidazole (7.29 g) in dry DMF (30 mL) cooled in an ice bath. After 45 min, the reaction mixture was diluted with ethyl acetate, washed three times with water and evaporated in vacuo. The resulting gum was dissolved in isohexane and applied to a silica gel column eluting with isohexane followed by 1:3 ethyl acetate:isohexane to collect the product as an oil. Yield 9.0 g.
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:36]([BH3-])#N.[Na+]>CO>[CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([C:26]3[CH2:27][CH2:28][N:29]([CH3:36])[CH2:30][CH:31]=3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
3-(Cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.100 g, 0.223 mmol) was dissolved in methanol (5 mL) and cooled to 0° C., formalin (0.067 g, 0.19 mL, 2.23 mmol) was added. Resulting reaction mass was stirred at same temperature for 30 minutes. Sodium cyanoborohydride (0.041 g, 0.66 mmol) was added to above reaction mass and stirred at room temperature for 4 h. After completion, solvent were removed under reduced pressure and water was added to the residue, extraction was carried out using DCM. Combined organic layers were dried, concentrated and purified by column chromatography to provide the desired compound (0.065 g, 63%): LCMS: 463.40 (M+1)+; HPLC: 98.79% (@ 254 nm) (Rt; 3.911; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.43 (s, 1H), 8.04 (t, 1H, J=4.8 Hz), 7.17 (s, 1H), 6.95 (s, 1H), 6.07 (s, 1H), 5.85 (s, 1H), 4.25 (d, 2H, J=4.8 Hz), 3.45 (m, 1H), 2.98 (bs, 2H), 2.53 (m, 2H), 2.42 (bs, 2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.67 (m, 2H), 1.59 (m, 2H), 1.49 (m, 2H), 1.40 (m, 2H).
Reaction SMILES: O.Cl.[CH:3]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:31])[C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25]C(=O)C)=[CH:20][C:19]=3[O:29][CH3:30])[CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[OH-].[Na+]>O>[CH:3]1([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:31])[C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[CH:20][C:19]=3[O:29][CH3:30])[CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Yield: 93.4 %

Procedure:
A mixture of N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide hydrochloride monohydrate (10 g; 0.02 moles), concentrated hydrochloric acid (6 ml) and water (20 ml) was boiled under reflux for 1.5 hours. The solution was then made alkaline with sodium hydroxide solution and extracted with chloroform. The organic solution was dried (Na2SO4) and the solvent removed in vacuo to give N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (7.1 g), m.p. 213°-215° C. after recrystallization from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].C(O[C:17]1(OCC)[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH:13]=[C:17]1[CH2:21][CH2:20][CH2:19][N:18]1[CH3:22])([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC1(OCC)CCCN1C
Solvent: c1ccccc1
Product: CN1CCCC1=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 34.6 %

Procedure:
Stir 7.0 g of 2,4-dinitrotoluene and 9.65 g of 2,2-diethoxy-1-methylpyrrolidine for 5 hours at 40° in 50 ml of benzene. Allow the resulting reaction mixture to cool to ambient temperature. Filter off the precipitate and wash it with a little benzene and hexane to obtain 3.5 g of the title compound (m.p. 188° to 190°) in the form of black-violet crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CN.O.[N:16]1(O)[C:20]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:20][NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
In 5 mL of N,N-dimethylformamide, 500 mg (3.1 mmol) of 1H-indole-5-carboxylic acid, 750 mg (9.3 mmol) of 40% methylamine, 477 mg (3.1 mmol) of benzotriazole-1-ol hydrate and 713 mg (3.8 mmol) of (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride were dissolved and the solution was stirred at room temperature for three hours, and then the solvent was distilled under reduced pressure. The obtained residue was dissolved in ethyl acetate and washed with a saturated sodium hydrogencarbonate solution (50 mL, twice) and a saturated saline (50 mL) in the order named. The organic layer was dried and then concentrated to obtain 397 mg (73%) of a crude product of 1H-indole-5-carboxylic acid methylamide. The product was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:31])[CH2:4][O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Temperature: 100 °C
Yield: 118.4 %

Procedure:
To a solution of 5-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-2-carbonitrile (0.4 g, 1.4 mmol) in a mixture of toluene (20 mL) and THF (10mL, help to dissolve the starting material) was added at rt under nitrogen the Lawesson's reagent (0.29 g, 0.71 mmol). The mixture was heated at 100° C. for 10 minutes, cooled to rt, and concentrated. The residue was purified by a flash chromatography on silica gel column (hexane:THF/4:1) to give the title compound as a yellowish solid (0.25 g, 60%). 1H-NMR (DMSO-d6) δ 12.66 (s, 1H), 11.96 (s, 1H), 7.69 (d, J=1.49 Hz, 1H), 7.64 (dd, J=1.48, 8.44 Hz, 1H), 7.35 (d, J=8.51 Hz, 1H), 7.01 (m, 1H), 6.79 (m, 1H), 4.49 (s, 2H), 1.60 (s, 6H); MS (FI) m/z 296 ([M−H]−, 100%)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH:19]([CH3:21])[CH3:20])[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:24][N:25]1[C:29]([CH3:30])=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]([CH3:40])=[N:26]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([N:17]([CH3:18])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:28]2[C:27]([CH3:40])=[N:26][N:25]([CH3:24])[C:29]=2[CH3:30])[CH2:12]1)([CH3:21])[CH3:20]
Reactant: CC(C)N(C)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)C(C)C)C2
Reaction time: 4 h
Yield: 55.8 %

Procedure:
(S)-6-(Isopropyl(methyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (184 mg, 0.524 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (142 mg, 0.602 mmol) and Pd(PPh3)4 (60 g, 0.0524 mmol) were added to a solution of K2CO3 (145 mg, 1.047 mmol) in a mixture of 1,2-dimethoxyethane (7 mL) and H2O (1 mL). The reaction mixture was purged with Ar (g) for 10 min, and warmed up to reflux. The reaction was completed in 4 h. It was allowed to reach room temperature, diluted with CH2Cl2 (20 mL) and acidified with HCl aqueous solution (10%, 30 mL). The organic layer was discarded, and the aqueous layer was taken to pH=9-10 with NaOH aqueous solution (10%). It was extracted with CH2Cl2 (3×20 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude was purified by flash chromatography on silica gel (5% Et3N/AcOEt), to afford 91 mg of the desired product (yellow oil, 56% yield).