Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)/[C:10](=[N:17]\[NH:18][C:19]([NH2:21])=[O:20])/[C:8]1=[O:9])([CH3:3])[CH3:2].[CH2:25](N)[CH2:26][CH:27]([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:25]([NH:21][C:19](=[O:20])[NH:18]/[N:17]=[C:10]1\[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:22]([CH3:24])[CH3:23])[C:16]2[C:11]\1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CCN
Reactant: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)CCNC(=O)N/N=C1\C(=O)N(CCN(C(C)C)C(C)C)c2ccccc21
Temperature: 120 °C
Reaction time: 23 h
Yield: 84 %

Procedure:
A suspension of 1.10 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone and 0.29 g of isopentylamine in a mixture of 150 ml of dry toluene and 20 ml of dry N,N-dimethylformamide was stirred for 23 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform) to obtain 1.12 g of (Z)-1-(2-diisopropylaminoethyl)isatin 3-(4-isopentylsemicarbazone) in a viscous oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([NH:32][C@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:24]=1.[NH2:44][C:45]1[CH:54]=[C:53]2[C:48]([CH2:49][CH2:50][C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][CH:46]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:44][C:45]2[CH:54]=[C:53]3[C:48]([CH2:49][CH2:50][C:51](=[O:56])[N:52]3[CH3:55])=[CH:47][CH:46]=2)=[O:28])=[C:25]([NH:32][C@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]2[N:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)[CH:24]=1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(Cl)cc1N[C@H]1CCCC[C@@H]1N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3N[C@H]3CCCC[C@@H]3N3CCCC3)cc21

Procedure:
Hydrochloride of 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (174 mg) and dimethylaminopyridine (21 mg) were added to a methylene chloride (5 mL) solution of 4-chloro-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoic acid (220 mg) and 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (100 mg). After stirring the reaction liquid overnight at room temperature, the reaction liquid was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography (hexane:ethyl acetate, 1:0 to 1:1), 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzamide was obtained as a pale yellow amorphous. By treating this with 4 M hydrogen chloride/ethyl acetate solution, 4-chloro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-2-{[(1S*,2S*)-2-pyrrolidin-1-ylcyclohexyl]amino}benzamide hydrochloride (212 mg) was obtained as an amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20](OS(C(F)(F)F)(=O)=O)[C:21]3[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=3)[C:21]3[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1ccc(N)cc1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
An 8-mL vial was charged with 2-(4-aminophenyl)acetonitrile (30 mg, 0.23 mmol, 2 eq.), [2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (50 mg, 0.112 mmol, 1. eq.) and DMF (0.5 ml). The resulting mixture was stirred at 70° C. overnight. After cooling to room temperature, water was added to the mixture (5 ml). The precipitate was collected by filtration and washed with water (10 ml). After drying, the crude product was purified by chromatography on silica gel using dichloromethane as eluent to give the title compound (18 mg, 38% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:12])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[CH2:37]([NH:44][C:7]([C:6]1[S:5][C:4]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:3][C:2]=1[CH3:1])=[O:9])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a mixture of 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid (0.40 g, 1.50 mmol) and 4-methylmorpholine (0.25 mL, 2.20 mmol) in tetrahydrofuran (50 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.32 g, 1.80 mmol). The resulting mixture was stirred at ambient temperature for 4 h, and then benzylamine (0.2 mL, 1.80 mmol) was added. The reaction mixture was stirred at room temperature for 47 h and then concentrated. Purification of the residue by column chromatography afforded the title compound in 45% yield (0.24 g); m.p. 171-172° C.; 1H NMR (DMSO-d6, 300 MHz) δ 13.15 (s, 1H), 8.78-8.63 (m, 3H), 7.94 (dd, J=1.5, 4.5 Hz, 2H), 7.32-7.17 (m, 5H), 4.38 (d, J=6.0 Hz, 2H), 2.51 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.0, 150.9, 140.0, 139.5, 128.7, 127.7, 127.2, 122.2, 114.3, 43.1, 17.1; MS (ES+) m/z 353.3 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][O:8]C(=O)C)(=[O:3])[CH3:2]>CC(C)=O.P([O-])([O-])([O-])=O>[C:1]([O:4][CH2:5][C@@H:6]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][OH:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)OC[C@H](CO)Cc1ccccc1
Temperature: 30 °C
Yield: 38.4 %

Procedure:
130 mg of lipase obtained from Pseudomonas fluorescens (Fluka) are added to 0.25 g (1 mmol) of 2-benzyl-1,3-propanediol diacetate (VIII) above dissolved in a mixture of 9.9 ml of acetone and 23.1 ml of phosphate buffer pH=7, and the medium is then heated at 30° C. for 48 hours. The solution is then extracted with ethyl ether (twice 20 ml). The ether phases are combined, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified by chromatography on silica (7/3 ethyl ether/petroleum ether eluent). 80 mg of oil are obtained.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH3:2].C1COCC1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH2:1]([C:3]1[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCc1cc2cc(OC)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2cc(OC)ccc2n1Cc1ccccc1
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
2-Ethyl-5-methoxy-1H-indole (5.6 g, 21.5 mmol) was dissolved in 150 mL of DMF and 20 mL of THF and 1.0 g (25 mmol) of 60% sodium hydride was added. After stirring for 0.17 hours, 3.0 mL (25 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for 10 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, saturated NaCl solution, and dried (Na2SO4). The EtOAc was evaporated and the residue was chromatographed on silica gel eluting with a gradient, 5% EtOAc/hexane→15% EtOAc/hexane to give 4.6 g (82% yield) of 2-ethyl-5-methoxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [P:1]([O:37]CC1C=CC=CC=1)([O:29]CC1C=CC=CC=1)([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]3[C:16]([NH2:27])=[N:17][C:18]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:19]=4[C:20]=3[CH:21]=2)=[C:6]([CH3:28])[CH:5]=1)=[O:2]>CO.[Pd]>[P:1]([OH:29])([OH:37])([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]3[C:16]([NH2:27])=[N:17][C:18]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:19]=4[C:20]=3[CH:21]=2)=[C:6]([CH3:28])[CH:5]=1)=[O:2]
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OP(=O)(OCc4ccccc4)OCc4ccccc4)cc3C)cc12
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OP(=O)(O)O)cc3C)cc12
Reaction time: 18 h

Procedure:
4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dibenzyl phosphate (1.0 equiv.) and 10% Pd/C (20% equiv. by weight) in MeOH (0.66 M) was allowed to stir for 18 hours under a balloon of H2. At this point the reaction mixture was passed through a pad of Celite, washing with a 2:1 mixture of CHCl3:MeOH. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by Reverse Phase-HPLC using a 20-90% 0.5 mM NH4OAc (in MeCN) to 10 mM NH4OAc (in water) gradient to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dihydrogen phosphate (2) as a solid. TFA was added to the 1H NMR sample to solubilize the compound for analysis. 1H NMR (Dimethylsulfoxide-d6): δ 9.69 (br, 1H), 9.33 (s, 1H), 9.03 (s, 1H), 8.87 (s, 1H), 8.54 (d, 1H, J=8.4 Hz), 7.51 (s, 1H), 7.42 (d, 1H, J=9.4 Hz), 7.22 (s, 1H), 7.17 (d, 1H, J=8.3 Hz), 7.10 (s, 1H), 6.97 (s, 1H), 6.92 (d, 1H, J=6.1 Hz), 3.15 (t, 2H, J=6.8 Hz), 3.00 (t, 2H, J=6.8 Hz), 2.50 (s, 3H), 2.29 (s, 3H). LRMS [M+H]=424.1
Reaction SMILES: C[O-].[Na+:3].[CH:4]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:21]=3)[CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5]1>CO>[CH:4]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:21]=3)[CH:13]=2)[CH2:8][C:9]([O-:11])=[O:10])[CH2:5][CH2:6]1.[Na+:3]
Reactant: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)[O-])C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
A 28% solution of sodium methoxide (100 mg) in methanol was added to a solution of 3-cyclopropyl-3-(3-(((2-(2,2-dimethylpropyl)-2′-fluoro-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoic acid (255 mg) in methanol (2.5 mL), and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure to give the title compound (252 mg) as a white amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]Cl)([O-:3])=[O:2].[OH-].[NH4+:13]>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][NH2:13])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: NSc1ccccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
50 grams of o-nitrobenzenesulfenyl chloride was added to carbon tetrachloride with stirring, followed by 50 milliliters of ammonium hydroxide over a one-minute period. The stirring was continued over 5 minutes to obtain an o-nitrobenzenesulfenamide intermediate which precipitated in the reaction mixture. The o-nitrobenzenesulfenamide intermediate was recovered by filtration and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]>C(#N)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:24][CH:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])=[O:21])=[CH:22][CH:23]=3)[CH:14]=2)=[N:2]1
Reactant: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: CN1CCC(N)C1=O
Solvent: CC#N
Product: CN1CCC(NC(=O)c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)C1=O

Procedure:
The title compound was obtained following procedure described for example 26, but starting from 4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid (100 mg; 0.33 mmol; 1.0 eq.) and 3-amino-1-methylpyrrolidin-2-one (Chem Bridge Corp., 56 mg, 0.49 mmol, 1.5 eq.). The crude obtained was suspended in acetonitrile, filtered and dried to afford the title compound as a beige powder. 1H NMR (300 Mz, DMSO-d6) δ 13.38 (s, 1H), 9.43 (s, 1H), 8.94 (d, J=8.4 Hz, 1H), 8.36 (d, J=8.1 Hz, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.50-7.38 (m, 1H), 7.31-7.15 (m, 1H), 4.74-4.52 (m, 1H), 3.42-3.32 (m, 2H), 2.77 (s, J=7.8 Hz, 3H), 2.44-2.27 (m, 1H), 2.13-1.85 (m, 1H). HPLC (Condition A): Rt 2.69 min (purity 92.2%). MS (ESI+): 402.3, MS (ESI−): 400.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].I[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCCI
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Yield: 71.9 %

Procedure:
A solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (1.78 g, 7.51 mmol), 1-iodopropane (1.92 g, 11.3 mmol), and potassium carbonate (4.15 g, 30.0 mmol) in acetonitrile (50 mL) was heated in a pressure vessel at 80° C. for 24 hours. The reaction was cooled and the acetonitrile was removed under reduced pressure. The solids were dissolved in methylene chloride/water. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The resultant residue was purified by chromatography on SiO2 (10% MeOH/CH2CL2 with 0.2% NH3) to give 1-[3-(methyloxy)-4-nitrophenyl]-4-propylpiperazine as a pale yellow solid (1.5 g, 5.4 mmol, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (t, J=7.32 Hz, 3H), 1.51-1.61 (m, 2 H), 2.34-2.42 (m, 2 H), 2.59 (s, 4 H), 3.38-3.45 (m, 4 H), 3.95 (s, 3 H), 6.31 (d, J=2.20 Hz, 1 H), 6.42 (dd, J=9.34, 2.38 Hz, 1 H), 8.00 (d, J=9.52 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[C:12]#[C:13][CH2:14][O:15][CH3:16]>CO.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCC#Cc1nn(C)c2ccc(Br)cc12
Agent: [Pd]
Solvent: CO
Product: COCCCc1nn(C)c2ccc(Br)cc12
Reaction time: 1.5 h

Procedure:
A solution of 54.00 g of 5-bromo-3-(3-methoxyprop-1-ynyl)-1-methyl-1H-indazole in 1700 ml of methanol is admixed at room temperature with 20.58 g of 10% Pd/C. The mixture is hydrogenated over 1.5 hours and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.56 (1:1 EtOAc-heptane). Rt=4.37 (gradient I).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][S:5][CH2:4][CH2:3][S:2]1.Cl.[CH2:9]([O:19][C:20](=[O:25])[C@H:21]([CH2:23][SH:24])[NH2:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[SH:2][CH2:3][CH2:4][S:5][CH2:6][C:1]([NH:22][CH:21]([C:20]([O:19][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:25])[CH2:23][SH:24])=[O:7]
Reactant: O=C1CSCCS1
Reactant: CCCCCCCCCCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)C(CS)NC(=O)CSCCS
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.42 g (0.1 mol) of 2,5-dithia cyclohexanone dissolved in 250 ml of anhydrous dichloromethane are added by dropping, and in an argon atmosphere, to a solution of 29.79 g (0.1 mol) of cysteine decyl ester hydrochloride and 10.12 g (0.1 mol) of triethyl amine in 500 ml of anhydrous dichloromethane. The reaction mixture is kept agitated overnight at room temperature and then washed three times with 2% aqueous citric acid, saturated sodium hydrogencarbonate solution and with water. After drying above sodium sulfate, the solvent is evaporated under reduced pressure. The oily residue is crystallized by trituration with diethyl ether.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:49])[CH2:43][C@@H:44]1[CH2:48][CH2:47][CH2:46][O:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:49])[CH2:43][C@@H:44]2[CH2:48][CH2:47][CH2:46][O:45]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 79.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N—[(S)-tetrahydrofuran-2-ylmethyl]acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Product: O=C(Cc1cccnc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Example 1, but substituting 2-(pyridin-3-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 247, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(pyridin-3-yl)acetamido)propanamide (3 mg, 50%). MS (EI) for C29H26FN3O4. found 500.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11](B(O)O)=[CH:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COC>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:24]2[C:19]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2ccccc2-c2ccccc2)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
Under an argon atmosphere, 18.7 g of 3-bromoanisole, 23.8 g of 2-biphenylboronic acid and 2.31 g of tetraxis(triphenylphosphine)palladium(0) were placed in a flask. 340 mL of dimethyl ether (DME) and 170 mL of a 2M aqueous sodium carbonate solution were added to this flask, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 23.4 g (yield: 90%) of intended 3-methoxy[1,1′:2′,1″]terphenyl was obtained.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:16][C:15]2[NH:14][C:13](=[O:17])[CH2:12][CH2:11][C:10]=2[C:9](=[O:18])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C1C2C(CCCC2)CCC1.[Pd]>[CH2:1]([C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13](=[O:17])[NH:14]2)=[C:9]([OH:18])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1CC(=O)C2=C(C1)NC(=O)CC2
Agent: [Pd]
Solvent: C1CCC2CCCCC2C1
Product: CCCCCCc1cc(O)c2ccc(=O)[nH]c2c1
Temperature: 200 °C
Reaction time: 17 h
Yield: 88.3 %

Procedure:
The obtained 7-n-hexyl-1,2,3,4,5,6,7,8-octahydroquinoline-2,5-dione (11.0 g) was suspended in decalin (150 ml). To the suspension, 10% palladium-on-carbon (3.7 g) was added, followed by stirring at 200° C. for 17 hours. After completion of the reaction, the insoluble matter was collected by filtration, washed with ether, then extracted with a solvent mixture of chloroform-methanol (2:1). The extract was dried to solidity under reduced pressure. Recrystallization from methanol yielded 9.56 g of 7-n-hexyl-5-hydroxycarbostyril as colorless needles having a melting point of 252°-255° C. (dec.) (87.9%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:5]=3[C:4]=2[CH:3]=1.I[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[C:6]3[CH2:20][CH2:21][N:22]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:31]=4[CH3:32])[C:23](=[O:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NCCc2c1c1cc(F)ccc1n2S(=O)(=O)c1ccccc1
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c(c3cc(F)ccc3n2S(=O)(=O)c2ccccc2)C1=O
Yield: 10.5 %

Procedure:
Using analogous reaction conditions and work up as described for the preparation of Example 1A, 8-fluoro-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (I-60a: 450 mg, 1.308 mmol) was reacted with 3-iodo-4-methylpyridine (286 mg, 1.308 mmol), 1,4-dioxane (25 mL), copper iodide (25 mg, 0.13 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (58.46 mg, 0.392 mmol) and potassium phosphate (693 mg, 3.27 mmol) at 120° C. overnight to afford the crude product. Purification by column chromatography on silica gel (5% methanol in DCM) afforded 60 mg of the product (15% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25][CH2:26][O:27][CH3:28])[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:38][CH2:39][O:40][CH3:41].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:38][CH2:39][O:40][CH3:41])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:25][CH2:26][O:27][CH3:28])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCCOC)c2)cc1OCOC
Temperature: 70 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a solution of 4-[4-(2-hydroxyphenyl)-3-cyanopyrrole-1-yl]-2-methoxymethoxy benzoic acid ethyl ester (0.12 g) and potassium carbonate (0.10 g) in N,N-dimethylformamide (1 mL) was added 1-bromo-3-methoxy-propane (0.092 g), and this mixture was stirred at 70° C. for 18 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.12 g).