Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:9].CCN(CC)CC.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([O:1][CH:2]1[CH2:8][CH2:7][CH:6]2[CH:3]1[CH2:4][C:5]2=[O:9])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CC2C(O)CCC12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC1CCC2C(=O)CC12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a stirred solution of compound 1G (1.9 g, 15.1 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen were added Et3N (3.1 mL, 22.2 mmol) and benzoyl chloride (2.33 g, 16.6 mmol). The reaction was stirred at 0° C. for 60 min and RT for 30 min, then quenched with water. The product was extracted with CH2Cl2, the organics were washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (5% EtOAc in hexanes) provide the title compound (3 g).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=[O:32])N(OC)C)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=[O:32])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 2.5 mL, 4.25 mmol) was added at −78° C. to a solution of 4-bromo-1,2-dichlorobenzene (435 mg, 1.93 mmol) in THF (10 mL) under nitrogen atmosphere. The resulting solution was stirred at −78° C. for 15 minutes, and then a solution of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.93 mmol) in THF (2 mL) was slowly added. The reaction mixture was stirred at −78° C. for 20 minutes and then warmed up to room temperature over a period of 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl, then diluted with water and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure to give an oil that was purified by flash chromatography (10% to 30% of EtOAc in hexane) to give 143 mg (22% yield) of 3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:23][CH2:24][CH2:25][CH3:26])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:23][CH2:24][CH2:25][CH3:26])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 1.03 g (2.6 mmol) of Reference Example 43, {butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic acid ethyl ester, and 0.77 g (3.1 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 1.05 g of a light yellow solid; m.p. 94-95° C.; MS (ES) m/z 627.2 (MH+); HRMS (ES) Calcd. for C28H43N4O8S2 (MH+): 627.2517, Found: 627.2505.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20])=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[C:22]([CH3:23])[C:18]([S:17][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)=[C:19]([CH3:20])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (5.0 g), 3-(4-chlorophenylsulfanyl)pentane-2,4-dione (8.4 g), p-toluenesulfonic acid monohydrate (3.20 g) and toluene (150 mL) was heated at reflux for 2 days. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (1:9 by volume) gave title compound as a pale yellow solid, 0.99 g.
Reaction SMILES: [BH4-].[Na+].[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[CH:16][CH:17]=[C:18]2[C:22]([CH:23]=[O:24])=[C:21]([CH3:25])[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:19]=12.O>CO>[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[CH:16][CH:17]=[C:18]2[C:22]([CH2:23][OH:24])=[C:21]([CH3:25])[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:19]=12
Reactant: Cc1c(C=O)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(CO)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Sodium borohydride (4.7 mg, 0.124 mmol) was added to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-carbaldehyde hydrochloride (25 mg) prepared in Example 616 in methanol (2 ml). The reaction mixture was stirred for 1 hour and water was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 8 mg of the titled compound as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:22]O>>[CH2:5]([NH:12][C@@H:13]1[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)[C@H]1CC[C@@H](NCc2ccccc2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](NCc2ccccc2)CC1

Procedure:
Thionyl chloride was added to a solution of compound cis-4-(benzylamino)cyclohexanecarboxylic acid (0.5 g, 2.1 mmol) in MeOH (7 ml) at 0° C. and the reaction mixture was heated at reflux for 18 h. Then volatiles were removed in vacuo and the reaction mixture was basified using saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, water and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 350 mg of cis-methyl 4-(benzylamino)cyclohexanecarboxylate (66%) as brown color solid.
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12]>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3].C1(C)C=CC=CC=1>[Cl:12][C:1]1[CH:6]=[CH:5][C:4]([C:8](=[O:9])[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])=[CH:3][CH:2]=1
Reactant: C[C@H](C(=O)Cl)c1ccccc1
Reactant: Cl
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: Cc1ccccc1
Product: C[C@H](C(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
Into a 20 L four-necked flask (flask B), 691 g of (S)-2-phenylpropionic chloride and 4.4 L of toluene were put and cooled to −10° C. in an atmosphere of nitrogen, and 1.41 g (4.00 mmol) of iron(III) acetylacetonate was added thereto. While maintaining the reaction temperature to be at most −10° C., the Grignard reagent prepared in the flask A was dropwise added thereto over a period of 4 hours in an atmosphere of nitrogen, and the temperature was raised to room temperature after completion of the dropwise addition, followed by stirring overnight, and then the mixture was cooled to 10° C., and 4 L of diluted hydrochloric acid was added thereto. The organic phase was separated, the aqueous phase was extracted with toluene, the toluene layer and the organic phase were put together, washed with water and saturated salt solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product. The crude product was purified by silica gel column chromatography (developing solvent: hexane/toluene=1/1), and recrystallization from ethanol was carried out to obtain 329 g (1.34 mol) of (S)-1-(4-chlorophenyl)-2-phenylpropane-1-one [H-Ph-CH(CH3)—C(O)-Ph-Cl] as white crystals (yield: 34%).
Reaction SMILES: [CH:1]1([N:7]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]2[C:35]3[S:34][C:33](=[O:36])[NH:32][C:31]=3[C:30]([OH:37])=[CH:29][CH:28]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:39][C:40]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:41]=1[CH2:42][CH2:43][NH2:44].C(N(CC)CC)C>C(O)C>[CH:1]1([N:7]([C:8](=[O:11])[CH2:9][CH2:10][NH:44][CH2:43][CH2:42][C:41]2[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:40]=2[F:39])[CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]2[C:35]3[S:34][C:33](=[O:36])[NH:32][C:31]=3[C:30]([OH:37])=[CH:29][CH:28]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCC1
Reactant: NCCc1cccc(F)c1F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cccc(F)c1F)C1CCCCC1
Temperature: 60 °C

Procedure:
Benzyl 2-(N-cyclohexylacrylamido)ethyl(2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate prepared as in Example 12 step i) (0.33 g), 2,3-difluorophenethylamine hydrochloride (0.244 g) and triethylamine (0.176 mL) were dissolved in ethanol (3 mL) and heated at 60° C. for 48 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the sub-title product (0.420 g) as a light brown gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:33][O:32][CH2:30][CH3:31])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Reactant: CCOCCl
Product: CCOCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 36 above with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and chloromethyl ethyl ether.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](F)=[N:11][CH:12]=1)[CH3:2].CC(C)([O-])C.[K+].[CH3:23][C:24]1[N:25]=[CH:26][C:27]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([OH:41])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[N:28][CH:29]=1>CS(C)=O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:41][C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][N:32]=[C:31]3[NH:30][C:27]2[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][N:28]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: CCOC(COc1ccc(F)nc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4cnc(C)cn4)c3c2)nc1)OCC
Temperature: 130 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
5-(2,2-Diethoxyethoxy)-2-fluoropyridine (680 mg, 3.0 mmol) and potassium tert-butoxide (670 mg, 5.9 mmol) were added to a dimethyl sulfoxide solution (10 ml) of 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol (500 mg, 1.97 mmol), and stirred under a nitrogen atmosphere at 130° C. for 24 hours. The reaction solution was cooled to room temperature, and extracted with a mixed solution of chloroform/methanol (9:1). The organic layer was washed with aqueous saturated ammonium chloride solution and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)quinazoline-4-amine (730 mg, yield: 80%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>O>[CH3:19][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[O:18][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccccc1O
Reactant: O=[N+]([O-])c1cccnc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 10.4 g (48 mmol) of 2-bromomethyl-3-nitropyridine (Example 3.c), 4.8 g (44 mmol) of o-cresol, 10 g (72 mmol) of K2CO3 and 50 ml of dimethylformamide were stirred for 3 days at room temperature (approximately 25° C.). The mixture was subsequently diluted with water and extracted repeatedly using tert-butyl methyl ether. The organic phases were combined, washed and dried, and the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography (cyclohexane/ethyl acetate). This gave 5 g (47%) of the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:10][C:11](OCC)=[O:12])[CH2:9][O:8][CH2:7]1)C.[Cl-].[NH4+]>C1COCC1>[OH:3][CH2:4][CH2:5][C:6]1([CH2:10][CH2:11][OH:12])[CH2:9][O:8][CH2:7]1
Reactant: CCOC(=O)CC1(CC(=O)OCC)COC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCC1(CCO)COC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
(3-Ethoxycarbonylmethyl-oxetan-3-yl)-acetic acid ethyl ester (122) (2.3 g, 10 mmol) was dissolved in 20 ml of THF. This solution was cooled down to 0° C. using an ice bath and AlLiH4 (1.1 g, 30 mmol) was added by portions. The reaction mixture was stirred for 4 h at ambient temperature, and then saturated aqueous solution of ammonium chloride (20 mL) was added. THF was evaporated off under reduced pressure, then the reaction mixture was taken up in ethyl acetate. The organic phase was separated from the aqueous phase. This extraction was repeated one more time and then the organic phases were combined and washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to give the product (123) (1.3 g, 8.9 mmol, yield: 89%). ESI-MS (M+1): 147 calc. for C7H14O3 146.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:6])(=O)C.S(=O)(=O)(O)O.CC(C)=O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=[O:4])[CH3:6]
Reactant: CC(=O)OC(C)c1ccc2ccccc2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1-bromoethyl)naphthalene, prepared as described above, with sodium acetate in acetic acid to afford 2-(1-acetoxyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH:6]1[CH2:11][CH2:10][CH:9]=[CH:8][O:7]1)CCC.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:25]=[C:24]2[CH:38]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39]1>C1(C)C=CC=CC=1>[O:7]1[CH:8]=[CH:9][CH2:10][CH2:11][CH:6]1[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:25]=[C:24]2[CH:38]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39]1
Reactant: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(Br)cc23)C1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CCC=CO1
Solvent: Cc1ccccc1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccc(C4CCC=CO4)cc23)C1
Yield: 566.9 %

Procedure:
To a stirred solution of 2-tributylstannyl-2,3-dihydropyran (Example 6, 0.41 g, 0.11 mmol) in anhydrous toluene (15 mL) was added 5-bromo-3-(N-methylpyrrolidin-3-yl)-1-benzoylindole (Example 5b, 0.280 g, 0.729 mmol) and Pd[PPh3 ]4 (0.09 g, 0.076 mmol). The mixture was heated to reflux for 6.5 hours, cooled, filtered through celite and concentrated by reduced pressure. The crude product was purified by column chromatography [95:5 CH2Cl2 : NH3 (2M in MeOH)] to yield the title compound (0.241 g, 85%) as a yellow oil; HRMS-FAB+ for C25H26N2O2 ; calc. MH+ :387.2072; found MH+ :387.2092.
Reaction SMILES: [C:1](=[O:3])=O.CC(C)=O.[Cl-].[Cl-].[Cl-].[Al+3].C(Cl)(=O)C(Cl)=O.[CH2:18]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>C(=S)=S.C(Cl)(Cl)Cl.O>[F:26][C:22]1[CH:23]=[CH:24][C:25]2[C:1](=[O:3])[C:32]3[CH:31]=[CH:30][C:29]([F:33])=[CH:28][C:27]=3[CH2:18][CH2:19][C:20]=2[CH:21]=1
Reactant: O=C=O
Reactant: Fc1cccc(CCc2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CC(C)=O
Solvent: O
Product: O=C1c2ccc(F)cc2CCc2cc(F)ccc21
Temperature: 35 °C
Yield: 29 %

Procedure:
To a cooled (dry-ice/acetone bath) suspension of anhydrous aluminium trichloride (5 eq, 45.82 g, 0.34 Mol) in carbon disulfide (450 ml) was added oxalyl chloride (4 eq, 23.58 ml) dropwise. The mixture was allowed to reach room temperature before the slow addition of 1,1′-(1,2-ethanediyl)bis[3-fluorobenzene](1 eq, 15.00 g) as a solution in carbon disulfide (20 ml). The mixture was heated overnight at 35° C. and diluted with chloroform (400 ml). The mixture was cooled (ice-bath) and water (400 ml) slowly added. The phases were separated, the aqueous phase extracted with chloroform and the combined organic phases dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (15:1 heptane/ethyl acetate) to afford 2,8-difluoro-10,11-dihydro-dibenzo[a,d]cycloheptene-5-one as a yellow solid (4.98 g, 29%).
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C@H:7]1[CH2:12][C@H:11]2[CH2:13][C@H:9]([C:10]2([CH3:15])[CH3:14])[C@@H:8]1[CH3:16])/[CH:3]=[O:4]>[Pd].CCCCCC>[CH3:1][CH:2]([CH2:5][CH2:6][C@H:7]1[CH2:12][C@H:11]2[CH2:13][C@H:9]([C:10]2([CH3:14])[CH3:15])[C@@H:8]1[CH3:16])[CH:3]=[O:4]
Reactant: C/C(C=O)=C\C[C@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C
Agent: [Pd]
Solvent: CCCCCC
Product: CC(C=O)CC[C@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A mixture of 12.0 g (55 mmol) of (E)-2-methyl-4-[(1S,2R,3S,5S)-3-pinanyl]-2-butenal, 100 ml of hexane and 0.36 g of 5% palladium on charcoal is hydrogenated for 3 h. at atmospheric pressure. After filtration of the catalyst and evaporation of the solvent under vacuum there are obtained 12.2 g of (R/S)-2-methyl-4-[(1S,2R,3S,5S)-3-pinanyl]butanal (yield=100%).
Reaction SMILES: Br[CH2:2][C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C[S:24][C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>COCCOCCOC>[CH3:12][N:9]1[C:10](=[O:11])[C:5]2[C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH2:2][N:29]3[C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26][C:25]3=[S:24])[S:18][C:6]=2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]1=[O:13]
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: CSc1nc2ccccc2s1
Solvent: COCCOCCOC
Product: COC(=O)c1c(Cn2c(=S)sc3ccccc32)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
A solution of the product of example 3 step b) (300 mg) and 2-methylthiobenzothiazole (300 mg) in diglyme (3 ml) was heated by microwave irradiation (600 W) to 160° C. After 30 min the solvent was removed by vacuum distillation and the residue purified by gradient chromatography eluting with a gradient of dichloromethane to 5% methanol in dichloromethane to give the sub-title compound as a white solid (150 mg). δ 1HCDCl3 0.93 (6H,d), 2.22 (1H,non), 3.38 (3H,s), 3.71 (2H,d), 4.00 (3H,s), 4.80 (2H,s), 7.33 (1H,dt), 7.45 (1H,dt), 7.77 (1H,dd), 7.92 (1H,d).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([OH:22])(=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].P(Cl)(Cl)Cl>>[C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=2)[OH:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]
Reactant: O=C(O)c1ccccc1O
Reactant: COC(=O)c1cc(N)ccc1N
Solvent: ClP(Cl)Cl
Product: COC(=O)c1cc(NC(=O)c2ccccc2O)ccc1NC(=O)c1ccccc1O
Yield: 54 %

Procedure:
By the procedure similar to that described in Example 15, methyl 2,5-diaminobenzoate was condensed with salicylic acid with the aid of phosphorus trichloride to obtain methyl 2,5-bis(salicylamido)-benzoate (Yield; 54%). The product was confirmed to be identical to that obtained in Example 4.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[CH2:31]([O:33][C:34]([CH2:36][N:37]1[CH2:43][C:42]2[CH:44]=[C:45](/[CH:48]=[CH:49]/[C:50]([OH:52])=O)[CH:46]=[N:47][C:41]=2[NH:40][C:39](=[O:53])[CH2:38]1)=[O:35])[CH3:32].Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH2:31]([O:33][C:34](=[O:35])[CH2:36][N:37]1[CH2:43][C:42]2[CH:44]=[C:45](/[CH:48]=[CH:49]/[C:50](=[O:52])[N:2]([CH3:1])[CH2:3][C:4]3[N:5]([CH3:13])[C:6]4[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:46]=[N:47][C:41]=2[NH:40][C:39](=[O:53])[CH2:38]1)[CH3:32]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cc2C1
Yield: 56 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(4-ethoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.22 g, 56%) was prepared as a yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.53-10.54 (m, 1H), 8.56-8.59 (m, 1H), 8.09-8.16 (m, 1H), 7.28-7.61 (m, 4H), 7.10-7.15 (m, 1H), 6.99-7.04 (m, 1H), 6.19-6.42 (m, 1H), 4.86-5.06 (m, 2H), 4.00-4.14 (m, 5H), 3.62-3.72 (m, 7H), 2.99-3.12 (m, 3H), 1.12-1.20 (m, 3H); MS (ESI) m/e 476 (M+H)+.