Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH2:7][CH2:6]2.[OH-].[Na+].Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27](Cl)=O>ClCCl>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:27][NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(c1ccccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (2.0 g) in thionyl chloride (20 ml) was added toluene (20 ml), the solution was stirred for 30 minutes at 100° C., then the reaction solution was concentrated in vacuo to provide 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (2.0 g). To a solution of 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (253 mg) in dichloromethane (8 ml) were sequentially added an aqueous solution of 1N sodium hydroxide (4 ml) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (400 mg), and the solution was stirred overnight at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting 3-fluoro-N-[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (423 mg) according to an analogous synthetic method to Example 337 described below, the title compound (418 mg) was obtained.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:7]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
Diphenylmethyl bromide (211 mg, 0.877 mmol) was added to a solution of morpholine (23.9 μL, 0.274 mmol), triethylamine (130 μL, 0.932 mmol) and chloroform (1.4 mL) and was allowed to stir at room temperature. After 48 hr, the reaction mixture was concentrated in vacuo and the resulting crude mixture was purified by column chromatography (10% ethyl acetate/hexanes) to provide the title compound in 14% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH2:14][CH3:15])=[CH:6][C:5]=1[NH2:16].[CH3:18]OC(OC)N(C)C.[C:26]([O:30][C:31](=[O:35])[CH2:32][C:33]#[N:34])([CH3:29])([CH3:28])[CH3:27]>C(O)(C)(C)C>[C:26]([O:30][C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:18][NH:16][C:5]1[CH:6]=[C:7]([O:13][CH2:14][CH3:15])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:17])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(OC)N(C)C
Reactant: CCOc1cc(N)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CC(C)(C)O
Product: CCOc1cc(NC=C(C#N)C(=O)OC(C)(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 28.5 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A 3-L round-bottomed flask under N2 equipped with an overhead stirrer, a condenser and a thermocouple is charged with 2-amino-4-ethoxy-5-nitrobenzoic acid methyl ester (100 g, 0.416 mol) and N,N-dimethylformamide dimethyl acetal (59.5 g, 0.499 mol) and t-butanol (800 mL). The reaction mixture is heated to reflux for 1.5 h. The reaction mixture is cooled to 22 to 35° C. and the t-butylcyanoacetate (117 g, 0.832 mol) added. The reaction mixture is stirred at 20 to 30° C. for 2 h. The precipitate is collected by suction filtration, washed with heptane (500 mL), then dried to constant weight under reduced pressure (50 mm Hg)) at 45° C. overnight to provide the title compound as a off-white solid (162.9 g, 95% yield, >95% purity by HPLC). 1H NMR (300 MHz, DMSO-d6): 12.7 (d, J=12.9 Hz, 1H), 8.77 (d, J=12.9 Hz, 1H), 8.50 (s, 1H), 7.47 (s, 1H), 4.37 (q, J=7 Hz, 2H), 3.91 (s, 3H), 1.52 (s, 9H), 1.40 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Cl:27][CH2:28][C:29]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[C:2]([F:1])[CH:7]=2)[CH2:9][CH2:10]1)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Fc1cc(N2CCNCC2)ccc1-c1ncccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Fluoro-4-piperazin-1-yl-phenyl)-pyrimidine (5AB) (889 mg, 3.442 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (5 mL) and triethylamine (697 mg, 959 uL, 6.884 mmol, 2 equiv) was added, followed by slow addition of a solution of chloroacetyl chloride (6AB) (466.5 mg, 330 uL, 4.13 mmol, 1.2 equiv) in tetrahydrofuran at room temperature. The mixture was then stirred for about 1 hour at room temperature.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](ON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (3S)-3-(aminooxy)piperidine-1-carboxylate 16 (0.19 g, 0.86 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.14 g, 1.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.03 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl (3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 17 (0.28 g, 82%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:25]1(O)[CH2:34][CH2:33][C:28]2([O:32][CH2:31][CH2:30][O:29]2)[CH2:27][CH2:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[C:25]1[CH2:34][CH2:33][C:28]2([O:29][CH2:30][CH2:31][O:32]2)[CH2:27][CH:26]=1
Reactant: CCCCCC1CCC(C2CCC(c3ccc(C4(O)CCC5(CC4)OCCO5)c(F)c3)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(C2CCC(c3ccc(C4=CCC5(CC4)OCCO5)c(F)c3)CC2)CC1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
The compound (T-5) (29.4g), p-toluenesulfonic acid monohydrate (1.47 g) and toluene (800 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 120 minutes while water being distilled was removed. After cooling to room temperature, the reaction mixture was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure and the residue was purified by means of column chromatography (silica gel; toluene), giving 8-[2-fluoro-4-(4′-pentyl-1,1′-bicyclohexane-4-yl)phenyl]-1,4-dioxaspiro[4,5]decan-7-ene (T-6) (20.5 g). The yield based on the compound (T-4) was 72%.
Reaction SMILES: S(Cl)(Cl)=O.BrC1SC(C(O)=O)=CC=1.BrC1SC(C(Cl)=O)=CC=1.[Br:23][C:24]1[S:28][C:27]([C:29]([N:31]=[C:32]=[S:33])=[O:30])=[CH:26][CH:25]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][C:43]1[C:52]2[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=2)[N:46]=[CH:45][CH:44]=1)[NH2:38]>C(O)C.C1(C)C=CC=CC=1>[Br:23][C:24]1[S:28][C:27]([C:29]([NH:31][C:32]([NH:38][C:37]2[CH:39]=[CH:40][C:41]([O:42][C:43]3[C:52]4[C:47](=[CH:48][C:49]([O:55][CH3:56])=[C:50]([O:53][CH3:54])[CH:51]=4)[N:46]=[CH:45][CH:44]=3)=[C:35]([Cl:34])[CH:36]=2)=[S:33])=[O:30])=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(Br)s1
Agent: O=C(Cl)c1ccc(Br)s1
Agent: O=C(O)c1ccc(Br)s1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)s4)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 5-bromo-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 5-bromo-2-thiophene isothiocyanate was prepared using the resultant 5-bromo-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 5-Bromo-2-thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:3]=1.[S:22](Cl)(Cl)(=[O:24])=[O:23].[OH-].[Na+].[C:29](O)(=O)[CH3:30]>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([S:22]([C:30]3[CH:29]=[CH:4][CH:3]=[CH:2][CH:14]=3)(=[O:24])=[O:23])[CH2:20][CH2:21]2)[CH:3]=1
Reactant: CC(=O)O
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)COc1ccc(Cl)cc1CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc(Cl)cc1CN1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
The product of example 11 part b (300 mg) was dissolved in THF (10 ml) and triethylamine (0.28 ml). The sulfonyl chloride (1.1 equivalents) was added and stirred for 3 h. 1M NaOH (3 ml) was added and stirred for 2 hours. Acetic acid (5 ml) was added and then the reaction mixture was concentrated in vacuo. The residue was further purified by RPHPLC to give the sub-title compound (0.19 g).
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:11])[N:5]=[CH:4][CH:3]=1.CC(=CC)C.O.Cl([O-])=[O:19].[Na+]>CC(O)(C)C>[I:1][C:2]1[C:7]([C:8]([OH:19])=[O:9])=[C:6]([O:10][CH3:11])[N:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1nccc(I)c1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1nccc(I)c1C(=O)O
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodo-2-methoxynicotinaldehyde (1 g, 3.58 mmol) in t-BuOH (6 mL), cooled at 25° C., is added 2-methyl-2-butene (6 mL, 2 M solution), Na2HPO4 (1.2 g) and water (3 mL). The reaction mixture is stirred for 5 minutes and sodium chlorite (800 mg, 8.9 mmol) is added slowly. Stirring of the mixture is continued until the aldehyde is completely consumed (3 hours, monitored by LCMS). The reaction is quenched with aq. formic acid. The mixture is partitioned between ethyl acetate (100 mL) and the organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The white powder was used for the next reaction without any further purification. 1H NMR 400 MHz (DMSO-d6) δ 10.06 (s, 1H), 7.89 (d, 1H, J=5.6 Hz), 7.48 (d, 1H, J=5.6 Hz), 3.87 (s, 1H); MS m/z 294.1 (M+1). MS m/z 280.01 (M+1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[S:29][C:22]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Clc1ccnc2cc(I)sc12
Solvent: CN(C)C=O
Product: Clc1ccnc2cc(-c3ccncc3)sc12
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Tereakis(triphenylphosphine)palladium (54 mg, 0.05 mmole) was added to a solution of 4-(tributylstannyl)pyridine (0.432 g, 1.17 mmole) and 7-chloro-2-iodothieno[3,2-b]pyridine (0.347 g, 1.17 mmole) in DMF (5 ml). The reaction mixture was stirred at reflux for 3h, cooled to room temperature. The mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (50 ml) and CH2Cl2 (2×50 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 30–60% EtOAc in hexane to give pale yellow color solid (0.103 g, 36%); 1H NMR (300 MHz, CDCl3) δ 8.61 (1H, d, J=5.1 Hz), 7.95 (1H, s), 7.66 (2H, m), 7.44 (2H, m), 7.31 (1H, d, J=5.1 Hz); ESIMS (MH+): 481.10.
Reaction SMILES: [O:1]([C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=O)=[CH:15][C:14]=1[O:23][CH3:24])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:25].[CH3:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH3:37].C([O-])(=O)C.[NH4+]>C(O)C>[I-:25].[C@@H:2]1([O:1][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=[CH:37][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N+:27]=3[CH3:26])=[CH:15][C:14]=2[O:23][CH3:24])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COc1cc(C=O)cc(OC)c1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: Cc1ccc2ccccc2[n+]1C
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(C=Cc2ccc3ccccc3[n+]2C)cc(OC)c1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 60 °C
Reaction time: 5 h
Yield: 59.5 %

Procedure:
A suspension of 4-formyl-2,6-dimethoxyphenyl β-D-galactopyranoside (0.19 g, 0.55 mmol), 1,2-dimethylquinolinium iodide (0.16 g, 0.55 mmol) in ethanol (20 ml) containing ammonium acetate (0.13 g, 1.7 mmol) was stirred at about 60° C. for 5 h. The dark orange precipitate which formed during the reaction was then filtered off and washed with ethanol followed by acetone to give (22c)(0.2 g, 86%) as an orange powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN1CCCC1=O>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([C:13]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[C:10]([F:11])[CH:9]=[C:8]([F:12])[CH:7]=3)[N:1]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NC(=O)c1cc(F)cc(F)c1N
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2nc3c(F)cc(F)cc3c(=O)[nH]2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-3,5-difluoro-benzamide (86.2 mg, 0.50 mmol), methyl 4-formylbenzoate (82.1 mg, 0.50 mmol) and sodium disulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) is heated to 150° C. and stirred at this temperature for 16 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford 4-(6,8-difluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-benzoic acid methyl ester as brown solid; HPLC/MS 1.88 min (A), [M+H] 316.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:7][C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[C:4][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(C)(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-pentyn-3-ol (75 mg, 0.75 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (25 mg) and CuI (12 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 66 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:43])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCOCC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCOCC4)cc3)cc12
Yield: 31.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) morpholine (100 mg, 0.157 mmol) was hydrolyzed by lithium hydroxide (33 mg, 0.786 mmol), THF/Methanol/water (5/5/3 ml) to afford 24 mg (32% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.36 (s, 1H), 8.56 (s, 1H), 7.87 (s, 1H), 7.75-7.52 (d, 2H), 7.40-7.30 (m, 1H), 7.10-6.95 (m, 3H), 6.90-6.80 (d, 1H), 5.32 (s, 2H), 3.91-3.88 (m, 4H), 3.23-3.20 (m, 4H), 2.26 (s, 3H), 2.15 (s, 3H). MS: m/z=482.3 (M+1), HPLC Purity: 99.13% Method: B.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([C:26](=[O:36])[CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].CO.[OH-].[Na+]>O1CCCC1.O>[N:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:12]2[CH:25]=[CH:24][C:23]3[O:22][C:21]4[C:16](=[CH:17][C:18]([CH:26]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)[OH:36])=[CH:19][CH:20]=4)[CH2:15][C:14]=3[CH:13]=2)[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OC(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(O)CCCN3CCCCC3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled, stirred solution of 25.6 g (0.053 moles) of 2,7-bis(4-piperidinobutyryl)xanthene dissolved in 200 ml of tetrahydrofuran is added a solution of 4.2 g (0.11 moles) of sodium borohydride contained in a solution of 50 ml of methanol and 5 ml of a 10% sodium hydroxide solution. The resulting mixture is allowed to warm gradually to room temperature and stirring continued overnight. The reaction mixture is diluted with water and the solid which forms is filtered, washed with water and air dried. The solid product is dissolved in a 10% hydrochloric acid solution, filtered and the filtrate made alkaline with a 10% sodium hydroxide solution. The alkaline filtrate is extracted with methylene chloride. The organic extract is then washed with water, followed by a wash of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue containing the desired α,α'-bis(3-piperidinopropyl)xanthene-2,7-dimethanol is recrystallized twice from benzene to yield a product having a m.p. of 145°-6° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:18]1[NH:23][CH2:22][CH2:21][N:20]2[CH2:24][CH2:25][CH2:26][CH:19]12.COCCO.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:18]1[N:23]([C:2]2[C:3]3[CH2:13][CH2:12][CH2:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:22][CH2:21][N:20]2[CH2:24][CH2:25][CH2:26][CH:19]12
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Reactant: C1CC2CNCCN2C1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc2c(c(N3CCN4CCCC4C3)n1)CCCc1ccccc1-2
Temperature: 115 °C

Procedure:
The product from Example 68A (40 mg, 0.16 mmol) was treated with octahydro-pyrrolo[1,2-A]pyrazine (31 mg, 0.24 mmol), and to this was added 2-methoxyethanol (0.65 mL) and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol); the reaction was heated at 115° C. for 16 hours, cooled, diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The aqueous layer was extracted with CH2Cl2 (15 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified by chromatography (eluting with 2, 3.5, 5 and 10% (9:1 MeOH:saturated aqueous NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CDCl3) δ 1.43-1.57 (m, 1H), 1.71-1.94 (m, 3H), 2.13-2.29 (m, 4H), 2.30-2.45 (m, 3H), 2.66 (t, J=6.78 Hz, 2H), 2.81 (dd, J=12.21, 10.17 Hz, 1H), 3.06-3.23 (m, 3H), 3.81-3.89 (m, 1H), 3.98 (dt, J=12.29, 2.33 Hz, 1H), 4.76 (s, 2H), 7.20-7.24 (m, 1H), 7.31-7.39 (m, 2H), 7.71-7.76 (m, 1H); MS (M+H)+ m/z 336.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([Cl:20])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c2ccccc2cc2ccccc12
Product: O=C(Cl)c1c2ccccc2cc2ccccc12

Procedure:
The 2-methyl-3,5-dihydro-5,9b-o-benzenobenz[e]isoindol-1-(2H)-one starting material was prepared as follows: a mixture of 25 g of 9-anthroic acid and 75 ml of thionyl chloride is heated under reflux for 1 hour. The excess thionyl chloride is removed under vacuum (30 mm; 90° bath temperature); 50 ml of toluene is added and the mixture is concentrated again. This operation is repeated once more to give 28.3 g of 9-anthroyl chloride as a very moisture-sensitive, yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1.C(O)C>[N:1]1([C:2]2[N:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCCCBr
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCO
Solvent: C1CCOC1
Product: c1ccc2c(c1)[nH]c1cnc(N3CCCCC3)cc12
Yield: 6.6 %

Procedure:
549 mg of 3-amino-β-carboline are refluxed for 4 hours with 1.5 g of 1,5-dibromopentane and 1 g of diazabicycloundecene in 25 ml of tetrahydrofuran and 5 ml of absolute ethanol. After evaporation, the product is chromatographed on silica gel with cyclohexane/ethyl acetate=1:1 as eluant. 50 mg of 3-piperidino-β-carboline are obtained as oil.