Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][C:19]=2[N:20]=1.Cl.Cl.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH:35]=[CH:34][C:33]=1[NH2:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)[CH:35]=[CH:34][C:33]=1[NH:45][C:25]([C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([C:3]3[CH:4]=[C:5]([C:8]4[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:6]=[CH:7][C:2]=3[OH:1])[NH:17][C:18]=2[CH:24]=1)=[O:26]
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), 2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamine di HCl salt (29.4 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.2 mL) was added DIEA (45 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 3 h, and then evaporated under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (26.4 mg, 39%). ESI-MS m/z 565.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:34][C:35]1[CH:43]=[CH:42][C:38]([CH3:39])=[CH:37][CH:36]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-methylbenzoyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a colorless powder. APCI-Mass m/Z 419 (M+NH4). 1H-NMR (DMSO-d6) δ 2.24 (3, 3H), 3.21-3.25 (m, 2H), 3.37-3.46 (m, 2H), 3.63-3.67 (m, 2H), 4.04 (s, 2H), 4.53 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.1 Hz, 1H), 5.37 (d, J=9.0 Hz, 1H), 6.74 (dd, J=11.1, 7.9 Hz, 1H), 7.05-7.07 (m, 3H), 7.13-7.15 (m, 2H), 7.20 (s, 1H), 7.35 (d, J=8.3 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][C:5]=1[Cl:14].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28][OH:29])[CH3:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23](/[C:26](=[N:28]/[O:29][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[C:5]([Cl:14])[CH:6]=2)/[CH3:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(=NO)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)c1ccc(OCCBr)cc1Cl
Product: C/C(=N\OCCOc1ccc(C(=O)O)c(Cl)c1)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared as white solid (0.334 g, 53%) from 4-(2-bromo-ethoxy)-2-chloro-benzoic acid methyl ester and 1-(4-tert-butyl-phenyl)-ethanone oxime using a procedure similar to that of step 1 of example 6. mp=142.7-143.9° C.; mass spectrum (−ESI, M−H) m/z 388. 1H NMR (400 MHz, DMSO-d6); δ 12.97 (bs, 1H), 7.81 (d, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 7.14 (d, 1H), 7.02 (dd, 1H), 4.42 (t, 2H), 4.38 (t, 2H), 2.13 (s, 3H), 1.28 (s, 9H). Elemental analysis: Calcd. for C21H24ClNO4: C, 64.69; H, 6.20; N, 3.59, Found: C, 64.43; H, 6.20; N, 3.42.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[C:6](=[CH:7][C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=2)[N:5]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:4](=[O:27])[CH2:3]1.C(N(CC)CC)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[C:11]2[C:6](=[CH:7][C:8]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:9][CH:10]=2)[N:5]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:4](=[O:27])[CH2:3]1
Reactant: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc32)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(C#C[Si](C)(C)C)cc32)cc1
Temperature: 85 °C

Procedure:
To a solution of 0.20 g (0.57 mmol) of 4,4-dimethyl-3,4-dihydro-N-(4-methylphenyl)-7-[(trifluoromethanesulfonyl)oxy]-2(1H)-quinolinone (Compound 18) in 1.45 g (2.0 mL, 14 mmol) of triethylamine were added 0.70 g (1.0 mL, 7.1 mmol) of (trimethylsilyl)acetylene and 94 mg (0.13 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting mixture was heated at 85° C. for 16 h. The reaction mixture was cooled, methylene chloride was added and the mixture adsorbed onto silica gel. The mixture was purified by flash chromatography (25% ethyl acetate in hexanes) to give the title compound as a foam. PNMR (300 MHz, CDCl3) d 0.19 (9 H, s), 1.40 (6 H, s), 2.44 (3 H, s), 2.66 (2 H, s), 6.53 (1 H, d, J=1.4 Hz), 7.09 (2 H, d, J=8.4 Hz), 7.15 (1 H, dd, J=7.9, 1.4 Hz), 7.25 (1 H, d, J=7.9 Hz), 7.33 (2 H, d, J=8.4 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:26]([O-])([N+]([O-])=O)=[O:27]>>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(Cc1ccccc1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(Cc1ccccc1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 68.4 %

Procedure:
3.8 g of 1-(2-chloroethyl)-3-benzyl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-benzyl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:8]2=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)=O.O.[NH2:27][NH2:28]>C(O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]2[C:8]3=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=[C:7]3[CH:6]=[C:5]2[C:3]2[O:2][CH:1]=[N:27][N:28]=2)=[CH:24][CH:23]=1
Reactant: NN
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1nnco1)n2Cc1ccc(F)cc1
Yield: 71.4 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester obtained in Example 33 (5) (0.3 g) in ethanol (9 ml), hydrazine monohydrate (0.22 g) was added at 15 to 30° C. and the mixture was heated under reflux for 6 hours, followed by further addition of hydrazine monohydrate (0.11 g), and the mixture was heated under reflux for 4 hours. Furthermore, hydrazine monohydrate (0.11 g) was added to the mixture, followed by heating under reflux for 16 hours. The reaction solution was concentrated under reduced pressure. To the resulting crude product was added orthoformic acid triethyl ester (25 ml) and the mixture was heated under reflux for 18 hours. The reaction solution was separated using silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 220 mg of the desired product.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH:11]2[CH2:16][CH2:15][C:14]([C:18]([O:20][CH3:21])=[O:19])([CH3:17])[CH2:13][CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:10][CH:11]1[CH2:12][CH2:13][C:14]([CH3:17])([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16]1
Reactant: COC(=O)C1(C)CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C1(C)CCC(O)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Into a 250-mL round-bottom flask containing a solution of 4-(methoxycarbonyl)-4-methylcyclohexyl 4-nitrobenzoate (4.5 g, 14.00 mmol, 1.00 equiv) in methanol/water (30 mL/6 mL) was added potassium carbonate (5.8 g, 41.97 mmol, 3.00 equiv) and the resulting solution was stirred overnight at 50° C. The reaction was quenched by the addition of NH4Cl (aq.) and extracted with 3×100 mL of ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2) to afford the desired methyl 4-hydroxy-1-methylcyclohexane-1-carboxylate (2.2 g, 91%) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]([CH3:27])[CH3:26])=[O:18])C)(C)(C)C>ClCCl>[CH3:26][N:25]([CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17](=[O:18])[C@H:16]([NH:14][CH3:13])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:27]
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.9 %

Procedure:
At 0° C., trifluoroacetic acid (8 ml) was added to a solution of N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester (2.26 g, 5.80 mmol) in dichloromethane (8 ml). The reaction mixture was stirred for 20 min at 0° C. The solvent was removed in vacuo. Dichloromethane (70 ml) was added, and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.24 g of (2R)-1-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-methylamino-3-phenylpropan-1-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.ClC(OCC(C)C)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[NH2:18][C:19]1[N:20]=[C:21]([NH:25][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(N)n1
Reactant: COCCOCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOCC(=O)Nc1cccc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.9 ml of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml of tetrahydrofuran. 9.7 ml of triethylamine and 5.6 ml of isobutyl chloroformate are added at 0° C., and it is stirred for 30 minutes at 0° C. 3.96 g of 2,6-diaminopyridine is added, and it is stirred for another 4 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation, and after purification by chromatography on silica gel, 5.04 g of the title compound is obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:41][C:42]1[C:43]([C:52]([F:54])([F:53])[F:55])=[N:44][N:45]([CH2:48][C:49]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:39])[F:40])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)=[O:50])[C:46]=1[CH3:47]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Trifluromethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.50 (d, 2H), 7.07 (d,2H), 5.38 (s, 2H), 3.60 (m, 4H), 3.41 (m, 2H), 3.31 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=455.1, found=455.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[C:22]([C:34]1[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=1)[N:23]2[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@H:12]([O:15][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[C:22]([C:34]2[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=2)[N:23]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](O)C1
Reactant: Clc1ncnc2c1nc(-c1cccc3ccccc13)n2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](Oc2ncnc3c2nc(-c2cccc4ccccc24)n3C2CCCCO2)C1
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of (1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanol (111.0 mg, 0.0004817 mol) (azeotroped with toluene) in DMF (3.6 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (24.1 mg, 0.000602 mol). The mixture was stirred for 15 min. To this cold solution was added a solution of 6-chloro-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (163 mg, 0.000401 mol) in DMF (1.8 mL). The flask was rinsed with DMF (1.0 mL)) and this was added to the reaction as well. The resulting mixture was stirred for 20 h. The reaction mixture was quenched with water and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and collected in vacuo. The residue was purified by flash chromatography (10 to 40% EtOAc/hexanes) to obtain 156.9 mg (70%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:12]2=[C:13]([CH2:20][CH2:21][OH:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1(O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([N:8]1[CH2:24][CH2:23][C:12]2=[C:13]([CH2:20][CH2:21][O:22][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: OCCc1c2n(c3ccccc13)CCN(Cc1ccccc1)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3c(CCOc4ccccc4)c4ccccc4n3CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
(Chart D, Step 3): A dry round bottom flask is charged with 2-(3-benzyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indol-11-yl)-1-ethanol (420 mg, 1.31 mmol), phenol (185.2 mg, 1.97 mmol), triphenylphosphine (413 mg, 1.57 mmol), and THF (12 mL, freshly distilled). After cooling the reaction to 0° C., diethylazodicarboxylate (DEAD) (0.248 mL, 1.57 mmol) is added dropwise via syringe. The ice bath is allowed to expire, and the reaction is stirred at ambient temperature for 18 hours. The reaction is quenched with 30% H2O2 (0.20 mL), diluted with ethyl ether and washed twice with 10% aq. NaHSO3. The organics are washed twice with aq. 1N NaOH, once with brine, dried with Na2SO4, filtered and concentrated to 1.08 g of a crude yellow solid. Purification of the crude using silica gel and 10% ethyl acetate in heptane as the eluent gives 392 mg (76%) of 3-benzyl-11-(2-phenoxyethyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a pale yellow oil. HRMS (FAB) calculated for C27H28N2O+H1 397.2280, found 397.2271.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]=[O:11])=[CH:4][C:3]=1[O:2][CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
15.2 g (0.1 mol) of vanilline, 20.5 g (0.12 mol) of benzyl bromide, 17.9 g (0.13 mol) of potassium carbonate and 150 ml of N,N-dimethylformamide were mixed and stirred at 50° C. for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and then saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 23.1 g of 4-benzyloxy-3-methoxybenzaldehyde.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>ClCCl>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:34][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
Triethylamine (38.6 mL, 0.277 mol) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (72.9 g, 0.232 mol) in dichloromethane (1200 mL). Isobutylamine (25.24 mL, 0.2540 mol) was then added, and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with dichloromethane, washed sequentially with water (2×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 67.4 g of (7-benzyloxy-3-nitroquinolin-4-yl)(2-methylpropyl)amine as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][CH2:14][C:15]([OH:17])=[O:16].[Li]CCCC.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:7]2[CH3:12])=[CH:26][CH:25]=1
Reactant: COc1ccc2[nH]c(C)c(CCC(=O)O)c2c1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a cold (-78° C.) solution of the indole from Step 1 (877 mg, 4.04 mmol) in 40 mL of THF and 2.5 mL of HMPA was added n-BuLi (1.45M solution in hexanes, 5.6 mL, 8.12 mmol), giving a thick slurry. The mixture was warmed to 0° C., then cooled to -78° C. A solution of p-bromobenzyl bromide (1.18 g, 4.72 mmol) in 8 mL of THF was then added, and the mixture was warmed to room temperature. After 30 min, the reaction was poured into 1M HCl and extracted with ether. The organic layer was washed thrice with water, then with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to give 529 mg of the title compound as a crystaline solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([NH2:36])[CH3:35]>>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([NH:36][C:24]([C:21]1[O:22][C:23]2[C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=[CH:18][C:19]=2[CH:20]=1)=[O:26])[CH3:35]
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: CC(N)c1ccccn1
Agent: [Li+]
Product: CC(NC(=O)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1)c1ccccn1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 1-(pyridin-2-yl)ethanamine (23 mg, 0.19 mmol). Yield: 20 mg (25%).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:3]1=2.C(O)C.[OH-].[Na+].Cl>O>[CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2
Reactant: C=C1c2ccccc2COc2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C1c2ccccc2COc2ccc(C(=O)O)cc21
Reaction time: 2 h

Procedure:
Dissolve the residue of Step A above in 40 ml. of ethanol with warming. Cool and add 40 ml. of 20% aqueous sodium hydroxide solution. Allow to stand for 2 hour and strip away the alcohol. Dilute with water and acidify with 5 N hydrochloric acid. Separate the solids by filtration and dry to obtain the title product (yield 850 mg). Purify by recrystallization from ethanol (m.p. 255°-257° C.).
Reaction SMILES: C[CH:2]([CH:6]1[C:11]2=[CH:12][C:13]3[C:18]([N:10]2[CH2:9][CH2:8][CH2:7]1)=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH:20]([CH3:22])[CH3:21])[C:3]([O-:5])=[O:4].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([C:12]2[C:13]3[C:18](=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH:20]([CH3:22])[CH3:21])[N:10]3[CH2:9][CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:11]=23)=[O:29])=[CH:26][CH:25]=1
Reactant: CC(C)c1cc(F)cc2c1cc1n2CCCC1C(C)C(=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc(Cl)cc1)c1n2CCCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl(3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (Example 122, Step 4) and 4-chlorobenzoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[CH:8]=[N:11][C:12]1[N:16]2[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: Cc1cc(N)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc2ncc3c(Cl)ncnc3n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
The product from Example 1a (1.24 g, 7.01 mmol) in 30 mL of THF was reacted with 5-amino-3-methylpyrazole (0.68 g, 7.01 mmol) in 10 mL of THF under an argon atmosphere by dropwise addition. Stirred at room temperature for 1 hour than added diisopropylethylamine (1.22 mL, 7.01 mmol) dropwise with stirring. Heated overnight at 60° C. Quenched with water and extracted with EtOAc washed with brine and dried over Na2SO4. Filtered and the solvent was removed under vacuum. The product was purified by silica gel chromatography eluting with EtOAc/hexane to give the title compound as a pale yellow solid (405 mg, 29%).