Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[O:11][C:10]([C@H:12]([NH:15][C@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][O:18][Si](C)(C)C)[CH2:13][CH3:14])=[CH:9][CH:8]=1.[NH4+].[OH-].[OH-].[Na+]>CC(OC)(C)C.O.C(O)(CC)C>[CH3:6][C:7]1[O:11][C:10]([C@H:12]([NH:15][C@H:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][OH:18])[CH2:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CC[C@@H](N[C@@H](CO[Si](C)(C)C)c1ccccc1)c1ccc(C)o1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCC(C)O
Product: CC[C@@H](N[C@@H](CO)c1ccccc1)c1ccc(C)o1
Temperature: 25 °C

Procedure:
700 ml of 5M H2SO4 are cooled to 5° and 232 g of [(R)-1-(5-Methyl-furan-2-yl)-propyl]-((R)-1-phenyl-2-trimethylsilanyloxy-ethyl)-amine dissolved in 1 l of TBME are added dropwise over a period of 30 minutes at 5-10°. 345 ml of sec-BuOH and 345 ml of H2O are added and the reaction mixture obtained is slowly warmed to rt. The aqueous layer obtained is separated. The organic portion obtained is adjusted to pH 11 with 2.5M NH4OH, the aqueous layer is separated and the organic phases obtained are washed 2× with brine. The aqueous layer obtained are back-extracted with 1 l of EtOAc, the organic portions obtained are combined, dried over Na2SO4, filtered and solvent is evaporated. A residue obtained is dissolved in 500 ml of TBME and 500 ml of H2O and the pH is adjusted to pH 11 with 2.5M NaOH and extracted 2× with 6 l of TBME. The organic portion obtained is dried, filtered and solvent is evaporated. The title compound is obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:38])[C:11]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](OC)=[O:26])=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:38])[C:11]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:2][OH:3])=[O:26])=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: NO
Reactant: COC(=O)CCCCCNC(=O)c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(CCCCCNC(=O)c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Hydroxylamine hydrochloride (0.55 g, 8 mmol) in methanol (3 mL) was mixed with KOH (0.45 g, 8 mmol) in methanol (3 mL) at 0° C., and sonicated for 2 minutes and the white precipitate formed was filtered. The filtrate was added to the methyl 6-(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-enyl)benzamido)hexanoate (0.2 g, 0.4 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature, for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The ethyl acetate layer was washed with water (100 mL), dried over anhydrous Na2SO4 and concentrated to afford the title compound (0.040 g, 20% yield). 1H NMR (DMSO-d6) δ (ppm): 0.52 (2H, m, 0.63-0.64 (2H, m, —CH2), 1.23-1.25 (2H, m, CH2), 1.44-1.50 (4H, m, CH2), 1.90-1.94 (2H, m, CH2), 2.74-2.75 (1H, m, —CH), 3.17-3.19 (2H, m, CH2), 7.04 (2H, d, Ar—H), 7.16-7.22 (4H, m, Ar—H), 7.28 (1H, s, ═C), 7.63 (2H, d, Ar—H), 7.89 (1H, d, NH), 8.36 (1H, t, NH), 8.66 (1H, s, —OH), 10.32 (1H, s, NH), MS m/z: 452.2 (M+−1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1>[Rh]>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]([CH3:13])[CH2:3][CH2:2]2
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Agent: [Rh]
Product: CC1CCc2cc(Cl)ccc2N1

Procedure:
4,6-Dichloroquinaldine was reduced with rhodium on carbon to give 6-chloro-2-methyltetrahydroquinoline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 78.4 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 04 mmol), (prepared as described for the starting material in Example 10), was reacted with 5-hydroxy-2-methylindole (74 mg, 0.5 mol) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (137 mg, 79%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]([CH2:25]S([O-])(=O)=O)C)=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].C([O-])([O-])=O.[K+].[K+].[NH:36]1[CH2:39][CH:38]([OH:40])[CH2:37]1>CC#N>[CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]([N:36]3[CH2:39][CH:38]([OH:40])[CH2:37]3)[CH3:25])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3]
Reactant: OC1CNC1
Reactant: CC(CS(=O)(=O)[O-])c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CC(O)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethylmethanesulfonate (0.19 mmol, 80 mg) in CH3CN (10 mL) was added K2CO3 (0.72 mmol, 106 mg) and azetidin-3-ol (0.38 mmol, 28 mg), the mixture was stirred at 80° C. for 16 h. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 1-(1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethyl)azetidin-3-ol (70 mg, 92% yield). LCMS (ESI) m/z: 395.1 [M+H+]
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[O:15]=[C:16]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][N:17]1[CH2:33][C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:35]=[C:34]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:33][N:17]1[CH2:18][CH2:19][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]1=[O:15]
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1
Reaction time: 60 h

Procedure:
A solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (0.037 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring for approximately 60 hours, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.40 (m, 13H), 4.55-4.80 (m, 2H), 4.25 (s, 2H), 3.60-3.85 (m, 2H), 3.45-3.55 (m, 2H), 2.70-2.90 (m, 4H); MS (ESI+) m/z 471 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([C:30]2[CH:43]=[CH:42][C:33]3[N:34]=[C:35]([CH2:37][C:38]([NH:40][NH2:41])=O)[S:36][C:32]=3[CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]([O:18][C:16]([NH:15][C@@H:10]([CH2:11][C:12]1[O:14][C:38]([CH2:37][C:35]2[S:36][C:32]3[CH:31]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:43]=[CH:42][C:33]=3[N:34]=2)=[N:40][N:41]=1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1)C(=O)OCc1ccccc1
Yield: 42 %

Procedure:
Compound 45a was prepared from (S)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid and 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (described in WO 2011/074560) in 42% yield as a yellow solid using the general procedure given for Compound 1b. LCMS=1.13 min using analytical method (M), 571.2 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.19-7.95 (m, 2H), 7.79-7.55 (m, 3H), 7.47 (t, J=7.7 Hz, 2H), 7.42-7.27 (m, 6H), 5.56 (d, J=7.0 Hz, 1H), 5.14 (s, 2H), 4.79 (br. s., 1H), 4.65 (s, 2H), 3.52-3.23 (m, 2H), 1.49-1.32 (m, 9H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[C:17]([CH3:36])=[N:18][C:19]2[C:24]([N:25]=1)=[C:23]([C:26]1[NH:34][C:33]3[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=3[CH:27]=1)[CH:22]=[CH:21][CH:20]=2>CS(C)=O>[CH3:36][C:17]1[C:16]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:25][C:24]2[C:19]([N:18]=1)=[CH:20][CH:21]=[CH:22][C:23]=2[C:26]1[NH:34][C:33]2[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=2[CH:27]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
Prepared according to Example 131, using (R)-3-amino-1-boc-piperidine (180 μL, 0.759 mmol, CNH Technologies, Inc., Woburn, Mass.), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.253 mmol), and DMSO (2.5 mL) and stirring at 100° C. for 2 h. Purification by column chromatography (silica gel: 0.5 to 10% MeOH/DCM) and reverse phase chromatography (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 95%) provided tert-butyl (3R)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (1.2 mg, 1.0%) as the free base after washing with saturated aq. NaHCO3, extracting with 10% MeOH/DCM, drying over Na2SO4, and concentrating under reduced pressure. 1H NMR (CDCl3) δ: 12.37-12.47 (m, 1H), 7.93-7.98 (m, 1H), 7.66-7.71 (m, 1H), 7.37-7.44 (m, 1H), 7.11-7.16 (m, 1H), 5.43-5.49 (m, 1H), 4.10-4.19 (m, 2H), 3.63-3.70 (m, 4H), 2.93-3.00 (m, 3H), 2.57-2.60 (m, 3H), 2.04-2.06 (m, 2H), 1.78-1.91 (m, 3H), 1.59-1.77 (m, 9H). m/z (ESI, +ve) 477.2 (M+H)+.
Reaction SMILES: [B:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:5]1)([OH:3])[OH:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:6](=[O:7])[O:5][CH:4]2[B:1]([OH:2])[OH:3])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C1OC(B(O)O)c2ccccc21
Product: O=C1OC(B(O)O)c2cc([N+](=O)[O-])ccc21
Yield: 71 %

Procedure:
Boronophthalide (2.86 g, 21.4 mmol) is added to 18.6 mL of chilled, fuming nitric acid (at 45° C.) in portions over 4 minutes with stirring. The reaction is quenched with ice and water (40 g and 60 mL), then the resulting pale yellow solid is collected on a Büchner filter and washed with 75 mL of water. Drying the solid in vacuo over P2O5 gives 2.72 g (15.2 mmol, 71.0%) 5-Nitroboronophthalide as a pale yellow solid (m.p. 178-179° C.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[C:18]([N:34]([CH3:38])[CH2:35][CH2:36][CH3:37])=[N:19][C:20]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[N:21][CH:22]=1.[OH-:39].[Na+].Cl>O1CCCC1>[C:28]([C:27]1[CH:32]=[CH:33][C:24]([NH:23][C:20]2[N:19]=[C:18]([N:34]([CH3:38])[CH2:35][CH2:36][CH3:37])[C:17]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][NH:3][C:2]([C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]([OH:39])=[O:11])=[O:1])=[CH:22][N:21]=2)=[CH:25][CH:26]=1)([OH:30])=[O:29]
Reactant: CCCN(C)c1nc(Nc2ccc(C(=O)OC)cc2)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(C)c1nc(Nc2ccc(C(=O)O)cc2)ncc1C#CCCCNC(=O)c1ccccc1C(=O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-(methyl(propyl)amino)pyrimidin-2-yl)amino)benzoate (H7, 634 mg) in tetrahydrofuran (6.2 mL), 2.0 mol/L aqueous sodium hydroxide (3.1 mL) was added at room temperature, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-((5-(2-((4-carboxyphenyl)amino)-4-(methyl(propyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)carbamoyl)benzoic acid (H8, 526 mg) as white solid.
Reaction SMILES: [Mg].[CH2:2]([C:4]1[C:12]2[N:11]3[C@H:13]([CH3:18])[CH2:14][NH:15][C:16](=[O:17])[C:10]3=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3].[H][H].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[CH2:2]([C:4]1[C:12]2[N:11]3[C@H:13]([CH3:18])[CH2:14][NH:15][C:16](=[O:17])[C@@H:10]3[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCc1cccc2cc3n(c12)[C@H](C)CNC3=O
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Mg]
Solvent: CO
Product: CCc1cccc2c1N1[C@H](C)CNC(=O)[C@@H]1C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Magnesium turnings (87 mg, 3.6 mmol) were added to a solution of (R)-6-Ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (82 mg, 0.36 mmol) in methanol (4 mL). After hydrogen gas started to evolve, the reaction mixture was kept at 10–20° C. and stirred for 2 h to dissolve the magnesium completely. Then the reaction mixture was poured onto 3 mL ice-cold 1 M aq. HCl, neutralized with 1 M aq. potassium phosphate solution (pH 6.85), and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield the title compound (80 mg, 97%). White solid. ISP-MS: m/e=231.2 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([S:34]([O-:37])(=[O:36])=[O:35])[CH:28]=1)([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]>CO.O>[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:15]/[C:9]2[C:10](=[O:14])[O:11][C:12]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=3)=[C:29]([S:34]([O-:37])(=[O:36])=[O:35])[CH:28]=1)([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]
Reactant: Cc1cc[n+](CCCCCC(=O)O)cc1S(=O)(=O)[O-]
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Agent: C[N+](C)(C)CC(=O)O
Solvent: O
Solvent: CO
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)cc3S(=O)(=O)[O-])c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-3-sulfonato-4-methyl-pyridinium betaine are converted according to the general directions above. Column chromatography: SiO2 (RP18), eluent: methanol/water.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:31][C:32]([OH:34])=[O:33])C=1)(=O)C>>[OH:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:31][C:32]([OH:34])=[O:33])[CH:6]=1)=[O:4]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: O=C(CO)c1c[nH]c2ccccc12
Product: O=C(O)Cn1cc(C(=O)CO)c2ccccc21

Procedure:
was prepared from 2-hydroxy-1-(1H-indol-3-yl)-ethanone [2400-51-3] in a similar manner as described in Scheme A13 (step B and C) for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Colored solid. MS: 234.0 [M+H]+, 489.0 [2M+Na]+; tR (HPLC conditions c): 3.11 min.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH:22]4[CH2:23][CH:19]([CH:20]=[CH:21]4)[CH:18]2[CH2:17][N:16]([CH3:24])[CH2:15]3)[CH:11]=[CH:12][CH:13]=1>CN(C)C=O>[CH3:24][N:16]1[CH2:15][C:14]2([C:10]3[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][CH:11]=3)[CH:18]([CH:19]3[CH2:23][CH:22]2[CH:21]=[CH:20]3)[CH2:17]1
Reactant: COc1cccc(C23CN(C)CC2C2C=CC3C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CN1CC2C3C=CC(C3)C2(c2cccc(O)c2)C1

Procedure:
A 733 mg portion of sodium hydride was suspended in 25 ml of dry dimethylformamide and 1.2 ml of ethane thiol in 10 ml of dry dimethylformamide was added dropwise at ice bath temperature. A 1.92 g portion of 2,3,3a,4,7,-7a-hexahydro-3a-(3-methoxyphenyl)-2-methyl-4,7-methano-1H-isoindole was added and the solution was heated at reflux for 6 hours, then cooled and evaporated in vacuo. The residue was taken up in water, extracted with ether, then hexane and neutralized with acetic acid giving a solid which was dissolved in hot methanol and precipitated with ether, then filtered. The filtrate was partially evaporated, then precipitated with ether and hexane. Evaporation of the ether extract gave a foam which was triturated with hexane, giving 240 mg of the desired product as a brown solid, mp 129°-136° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: CN1CCN(CCC(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(CCc2nnc3ccc(F)cn23)CC1
Reaction time: 18 h
Yield: 72.4 %

Procedure:
Intermediate 2a (458 mg, 1.63 mmol) was dissolved in THF (15 mL) and cooled in an ice/water bath. Triphenylphosphine (854 mg, 3.26 mmol) was added followed by triethylamine (907 μL, 6.52 mmol) and hexachloroethane (773 mg, 3.26 mmol). The reaction was stirred for 18 h and then loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. Further purification by FCC, using 0-10% [2M NH3 in MeOH] in DCM, afforded the title compound (310 mg, 1.18 mmol, 72%). LCMS (Method 4): Rt 0.28 min, m/z 264 [MH+].
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:21]#[N:22])=[CH:17][NH:18]2)=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:23].[Na+].[OH-].[K+]>CCO>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:21]([NH2:22])=[O:23])=[CH:17][NH:18]2)=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCCC(c1ccccc1)c1ccc2c(C#N)c[nH]c2c1
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CNCCC(c1ccccc1)c1ccc2c(C(N)=O)c[nH]c2c1
Temperature: 25 °C

Procedure:
To a solution of 6-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile CLV (170 mg, 0.59 mmol) in EtOH (5 ml) was added 50% aqueous solution of NaOH (5 ml). The mixture was refluxed for 90 minutes and excess KOH was added. The resulting mixture was refluxed for additional 48 hours, cooled to room temperature, and concentrated. The residue was partitioned between H2O and CHCl3, and the aqueous layer was extracted with CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording 6-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carboxylic acid amide CLVI as a white powder (59 mg, 33% yield). MS (M+H)=308.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]([N:11]1[C:19]2[CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:16]=[C:15]([C:26]([O:28]C)=O)[C:14]=2[CH2:13][CH2:12]1)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][NH2:38]>CCO>[C:1]([O:5][C:6]([C@@H:8]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:9]([N:11]1[C:19]2[CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:16]=[C:15]([C:26]([NH:37][NH2:38])=[O:28])[C:14]=2[CH2:13][CH2:12]1)=[O:10])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2C(=O)[C@H](Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)N1CCc2c(C(=O)NN)cc(-c3ccncc3)cc21
Yield: 75.6 %

Procedure:
To (S)-methyl 1-(2-(tert-butoxycarbonyl)-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxylate 58.A (339 mg, 0.68 mmol, prepared as in example 54.1) was added 4 mL EtOH and hydrazine (0.3 mL, 0.96 mmol). The reaction was refluxed overnight and concentrated. Silica gel purification afforded 250 mg (74%) product 58.B.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)[CH:7]2[CH2:6][C:5]2[CH:32]=[CH:33][C:2](/[CH:36]=[CH:35]/[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[CH:3][CH:4]=2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Yield: 90.4 %

Procedure:
The title compound was prepared as described in Example 135, using 1-(4-bromobenzyl)-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (1.22 g, 2.43 mmol) and ethyl acrylate (0.50 g, 5.0 mmol) to provide the title compound (1.146 g, 90% yield): 1H NMR (CDCl3) 7.65 (d, 1H), 7.33-7.44 (m, 7H), 7.02 (d, 2H), 6.92 (m, 2H), 6.69-6.78 (m, 5H), 6.39 (d, 1H), 5.03 (s, 2H), 4.76 (t, 1H), 4.26 (q, 2H), 3.35 (m, 1H), 3.48 (m, 1H), 3.18 (dd, 1H), 2.95 (m, 2H), 2.67 (dt, 1H), 1.31 (t, 3H); ES-MS m/z 522 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[N:36]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:43][CH2:42][CH2:41][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:33]=3[CH:34]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: NCCN1CCCC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCN4CCCC4)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 2-pyrrolidin-1-yl-ethylamine in an analogous manner to Example 1396. Product isolated as a tan solid (25 mg, 54%). m.p.=172-174° C.; LCMS (m/e) 564 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.19 (s, 1H), 8.68 (d, 1H, J=8.6 Hz), 8.10 (s, 1H), 7.57-7.52 (m, 1H), 7.48-7.41 (m, 1H), 7.38-7.34 (m, 1H), 7.30-7.23 (m, 1H), 7.14-7.08 (m, 1H), 7.07-6.95 (m, 2H), 6.90-6.85 (m, 1H), 3.62-3.53 (m, 4H), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.81-2.69 (m, 8H), 2.65-2.53 (m, 4H), 1.88-1.78 (m, 4H).