Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]([OH:12])=[CH:10][C:9]([CH3:13])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C>O.C(Cl)Cl>[CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[N:8]2[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)n(C2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(=O)n(C2CCCCC2)n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.9 %

Procedure:
A mixture of 2-cyclohexyl-3-hydroxy-5-methylpyrazole (16.5 g) and dimethyl sulfate (10.9 g) was heated with stirring at 150°-160° for 6 hours and then allowed to cool to room temperature. A solution of sodium carbonate (6.5 g) in water (100 ml) was added, and the reaction mixture was heated at reflux temperature for 2 hours, cooled, and extracted with chloroform. The layer was dried and concentrated to give a dark oil, which was dissolved in methylene chloride, treated with charcoal and diatomaceous earth, filtered and concentrated. The concentrate was fractionally distilled, and the portion distilling at 118°/0.020 mm Hg was further purified by column chromatography on silica gel. Elution with chloroform-ethyl acetate (7:3), chloroform-ethyl acetate gradients, ethyl acetate, and ethanol afforded product from the ethyl acetate-rich chloroform-ethyl acetate gradient fractions and the ethyl acetate and ethanol fractions as determined by thin-layer chromatography and nuclear magnetic resonance spectroscopy. Product-rich fractions which were shown by gas chromatography to be highly pure were combined and concentrated to give 2-cyclohexyl-1,5-dimethyl-1,2-dihydro-3H-pyrazol-3-one (3.0 g) as an oil. The assigned structure was confirmed by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH2:20]([N:22](CC)[CH2:23]C)C.Cl.CNC>C(O)(C)C>[CH3:20][N:22]([CH3:23])[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CCN(CC)CC
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Agent: CNC
Agent: Cl
Solvent: CC(C)O
Product: CN(C)c1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of 7-fluoro-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (101 mg, 0.32 mmol), triethylamine (4.4 mL, 32 mmole) and dimethylamine hydrochloride (2.58 g, 32 mmol) in isopropanol (30 mL) contained in a steel bomb is stirred at 100° C. (oil bath) for 4 h. The resulting solution is concentrated under vacuum, basified with aqueous Na2CO3 and diluted with water to give a solid. Filtration and recrystallisation from MeOH/CHCl3 gives 7-dimethylamino-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (102 mg, 94%) as a pale yellow solid. 1H NMR (DMSO) δ 9.93 (1H, brs), 9.42 (1H, s), 8.48 (1H, s), 8.19 (1H, s), 7.85 (1H, d, J=7.7 Hz), 7.35 (1H, t, J=7.9 Hz), 7.30 (1H, brd, J=7.8 Hz), 6.53 (1H, s), 3.16 (6H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:6][CH:7]=3)[CH:28]=2)[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1COc1cccc(OCc2coc(-c3ccccc3)n2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-phenyl-oxazole (100 mg, 0.5 mmol, example 19) in DMF (2 mL) is added methyl 2-methyl-6-[(3-hydroxy-phenoxy)-methyl]-benzoate (136 mg, 0.5 mmol, example 5) followed by K2CO3 (75 mg, 0.54 mmol). The resulting mixture is heated to 60° C. and stirred at this temperature for 8 h. This mixture is then cooled to room temperature, diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ESI) 429 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH3:11])[CH:3]=1.[H-].[Na+].Cl.[CH2:16]([N:18](CCCl)[CH2:19][CH3:20])[CH3:17].C(O)C>CN(C)C=O.C(O)(=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:11][CH2:10][NH:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:17]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(CC)CCNc1cc(C)cc(C)n1
Reaction time: 18 h

Procedure:
To 32.8 g (0.2 m) N-(4,6-dimethyl-2-pyridyl)acetamide dissolved in 300 ml dimethylformamide, sodium hydride (50%) (9.67 g 0.21 m) is added at 30°-40° in three portions with stirring. Ten minutes after this addition diethylaminoethylchloride hydrochloride (37.2 g, 0.216 m) is added and the mixture stirred 20 minutes. Sodium hydride (50%) (10.55 g, 0.229 M) is added in three portions at 40°-45°, the mixture stirred at 50°-55° for 1/2 hour and finally at 90° for 21/2 hours. On cooling ethanol, 50 ml. followed by acetic acid, 25 ml, are added. The mixture is concentrated under vacuum, the residue dissolved in dilute hydrochloric acid, and extracted with hexane. The aqueous is made alkaline with sodium hydroxide, 10 N and extracted with methylene chloride. The organic extracts are washed with water, concentrated and the residue distilled. The fraction distilling at 127°-140°/1.3 mm, weight 35.5 g is collected, hydrolyzed by refluxing in sulfuric acid (85 ml), water (80 ml) and acetic acid (170 ml) for 18 hours. The mixture is cooled in an ice bath and sodium hydroxide solution equivalent to the sulfuric acid is added. Ethanol is added and the salts filtered off. The filtrate is concentrated under vacuum and the residue taken up in dilute sodium hydroxide. The mixture is extracted with methylene chloride, the organic extracts washed with brine, dried over sodium sulfate and concentrated to obtain the 2-(2-diethylaminoethylamino)-4,6-dimethylpyridine as an oil, weight 30 g.
Reaction SMILES: [I-:1].[Na+].CNCCNC.Br[C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([NH2:18])=[CH:12][CH:11]=1.O>O1CCOCC1.[Cu](I)I.C(OCC)(=O)C>[I:1][C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([NH2:18])=[CH:12][CH:11]=1
Reactant: COc1nc(Br)ccc1N
Reactant: [I-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(I)ccc1N
Temperature: 120 °C
Reaction time: 14 h
Yield: 78.1 %

Procedure:
Sodium iodide (40 g), copper iodide (6.0 g) and N,N′-dimethylethylenediamine (7 mL) was added to a solution of 6-bromo-2-methoxypyridin-3-amine (26 g) in 1,4-dioxane (250 mL) in a nitrogen gas stream, and the mixture was stirred at 120° C. for 14 hours. The reaction solution was left to cool, and then water and ethyl acetate were added. Filtration through celite was followed by extraction. The organic layer was washed with a 20% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=85:15→70:30) to give 6-iodo-2-methoxypyridin-3-amine as a colorless powder (25 g, 75%).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45](O)=[O:46]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:45](=[O:46])[CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(Cc1ccccn1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and 2-pyridineacetic acid hydrochloride (20.8 mg) were reacted and treated in the same manner as in the method described in Example.32 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:17]=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C.Cl[C:43]([C:45]1[CH:46]=[C:47]([CH:56]=[CH:57][CH:58]=1)[CH2:48][S:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:44]>ClCCl>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:43]([C:45]3[CH:46]=[C:47]([CH:56]=[CH:57][CH:58]=3)[CH2:48][S:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:44])=[C:3]([C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)[CH:17]=[CH:16][N:15]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccn1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 0 °C
Yield: 109.2 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide (100.0 mg, 0.23 mmol, 1.00 equiv) and N,N-diisopropylethylamine (0.2 mL) in dichloromethane (20 mL). This was followed by dropwise addition of a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate 22d (74.0 mg, 0.27 mmol, 1.20 equiv) in dichloromethane (2.0 mL) with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was combined with the solution of the previous batch and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (100˜100:1˜50:1). The product was obtained as 170 mg (70%) of a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([CH:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][CH2:13][C:14]#[C:15][CH2:16]O)=[O:11])#[N:6]>N1C=CC=CC=1.CCOCC.C(Cl)Cl>[C:5]([CH:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][CH2:13][C:14]#[C:15][CH2:16][Cl:3])=[O:11])#[N:6]
Reactant: N#CC(c1ccccc1)C(CC(=O)OCC#CCO)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(c1ccccc1)C(CC(=O)OCC#CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Thionyl chloride (3.56 g, 30.0 mmol) was added via syringe over a 5 min period to a stirred solution of 8.00 g (24.0 mmol) of 4-hydroxy-2-butynyl 4-cyano-3,4-diphenylbutyrate in 2.4 ml of pyridine at 0°. The reaction mixture was stirred at room temperature for 2 hours in a flask equipped with a Drierite tube. The mixture was diluted with 40 ml of ether and 100 ml of methylene chloride and was washed sequentially with 40 ml of hydrochloric acid, 40 ml of saturated aqueous sodium bicarbonate, three 40-ml portions of water and 40 ml of saturated aqueous sodium chloride. The organic phase was dried (MgSO4), filtered, stripped and purified by column chromatography on silica gel (hexanes/methylene chloride) to yield 2.11 g (25%) of the title compound. The infrared and nmr spectra are in accord with the assigned structure.
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
After boron trichloride (1.0N methylene chloride solution 2.0 ml, 2.0 mmol) was added to a solution of methyl (4′-methoxy-1,1′-biphenyl-4-yl)acetate (210 mg, 0.82 mmol) obtained in Example (6-1) and tetra-n-butyl ammonium iodide (393 mg, 1.1 mmol) in methylene chloride (5 ml) at −78° C., the temperature of the mixture was raised to room temperature and then the mixture was stirred for 1 hour. After ice was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=1/1) to give methyl (4′-hydroxy-1,1′-biphenyl-4-yl)acetate (155 mg, yield: 78%).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=1[CH:24]=O.[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28]1>CO.CCOC(C)=O>[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]1[CH2:24][C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2[C@H](C)CC[C@H]2C)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
Sodium cyanoborohydride (0.071 g, 1.1 mmol) was added to a solution of 66.60C (0.180 g, 0.62 mmol) and (2R,5R)-2,5-dimethylpyrrolidine (available from Aldrich) (0.073 g, 0.74 mmol) in MeOH (3 mL). The reaction was stirred at 110° C. for 30 minutes and then was diluted with EtOAc (100 mL). The mixture was washed with an aqueous Na2CO3 solution and brine, and dried over anhydrous sodium sulfate. After filtration, solvent was removed, and the residue was purified by flash chromatography (silica gel, 1:6 EtOAc/hexane) and gave 66.71A (32 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[C:11]([O:18][CH2:19][O:20][CH3:21])[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[NH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH2:19][O:20][CH3:21]
Reactant: COCOc1cc(OCc2ccccc2)ccc1CCN
Agent: [Pd]
Solvent: CCO
Product: COCOc1cc(O)ccc1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
A mixture of 18.00 g of 2-(4-benzyloxy-2-methoxymethoxy phenyl)ethylamine, 3.6 g of 10% palladium on carbon (Degussa Inc.: E101 NE/W) and 230 mL of ethanol was stirred under a hydrogen atmosphere at room temperature for 1 hour. After the catalyst was filtered off through a diatomaceous earth, the filtrate was concentrated under reduced pressure to give 12.65 g of 4-(2-aminoethyl)-3-methoxymethoxyphenol as a colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.NC1C=C([NH:66][C:67](=[O:69])[CH3:68])C=CC=1>>[OH:31][CH2:30][CH2:29][C:27]1[N:26]=[N:25][N:24]([C:22]2[CH:21]=[CH:20][C:19]([CH3:32])=[C:18]([CH:23]=2)[C:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:3]3[CH:4]=[C:5]([NH:66][C:67](=[O:69])[CH3:68])[CH:6]=[CH:7][CH:2]=3)=[CH:11][C:12]=2[CH3:33])=[O:17])[CH:28]=1
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: CC(=O)Nc1cccc(N)c1
Agent: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: CC(=O)Nc1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(C)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and N-(3-amino-phenyl)-acetamide (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using NH3(aq.)/MeOH/DCM 0:0:100, 1:9:90 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.1, 168.2, 147.9, 145.6, 142.4, 142.0, 141.2, 140.1, 135.1, 135.0, 134.3, 131.9, 129.3, 126.0, 120.6, 120.2, 118.2, 117.6, 114.2, 112.7, 111.1, 110.0, 60.1, 29.1, 24.0, 22.1, 18.7
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:9]([Mg]Br)[CH3:10].B(F)(F)F.CCOCC.O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1([NH2:2])[CH2:10][CH2:9]1
Reactant: N#Cc1ccccn1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NC1(c2ccccn2)CC1
Reaction time: 0.25 h

Procedure:
2-Cyano pyridine (5 g, 48.0 mmol, 1 eq) was taken in dry THF under Argon atmosphere. To this mixture was added slowly Titanium isopropoxide (17 ml, 57.6 mmol, 1.2 eq) at ambient temperature. The reaction mass was stirred for 15 mins. Ethyl Magnesium Bromide (1 M solution) in THF (107 ml, 809 mmol, 2.5 eq) was added via syringe slowly at room temperature, (During the addition of EtMgBr reaction mass becomes black). Then the reaction mass stirred for an hour and BF3.Et2O (16.7 ml, 120.0 mmol, 2.5 eq) was added slowly at 0° C. After the completion of addition process, reaction mass was allowed to attain ambient temperature and the stirring continued for one more hour. Finally, 50 ml of water was added and the reaction mass was filtered through the Celite. The bed was further washed with water and Ethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9) then extracted with DCM and washed with brine solution, the required product was purified by silica gel (60-120) column chromatography using DCM/methanol as the eluent. Yield: 1.3 g (23%). 1H NMR (400 MHz, CDCl3): δ 1.12-1.14 (m, 2H), 1.27-1.29 (m, 2H), 2.12 (broad s, 2H), 7.03-7.07 (t, 1H), 7.33-7.35 (d, 1H), 7.60-7.62 (t, 1H), 8.48-8.49 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC(=Cc2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(F)cc2)C1
Reaction time: 16 h

Procedure:
To a stirring solution of the t-Butyl 3-(4-fluorobenzylidene)-1-piperidinecarboxylate (3.82 g, 13.1 mmol) and 10% palladium on carbon (0.76 g) in degassed methanol (200 mL) was added hydrogen gas to 55 psi. The reaction was stirred for 16 h and then filtered through a pad of celite. The celite was washed with methanol (200 mL). The filtrates were combined and concentration in vacuo to yield 2.76 g as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.12-7.07 (m, 2H), 6.98-6.93 (m, 2H), 3.89 (dt, J=13, J′=4, 1H), 3.84-3.74 (m, 1H), 2.57-2.43 (m, 4H), 1.75-1.60 (m, 4H), 1.42 (s, 9H), 1.15-1.09 (m, 1H).
Reaction SMILES: [C@H:1]1([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][C:12]([NH2:19])=[N:13][C:14]=3N)[S:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:22]>O>[C@H:1]1([N:9]2[CH:17]=[N:16][C:15]3[C:14](=[O:22])[NH:13][C:12]([NH2:19])=[N:11][C:10]2=3)[S:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Nc1nc(N)c2ncn([C@@H]3C[C@H](O)[C@@H](CO)S3)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2C[C@H](O)[C@@H](CO)S2)c(=O)[nH]1
Yield: 93 %

Procedure:
To a solution of 9-(2-deoxy-4-thio-α-D-ribofuranosyl)-2,6-diaminopurine (formula 8) (30 mg, 0.11 mmol) in distilled H2O (10 mL) was added a suspension of adenosine deaminase in 3.2M (NH4)2SO4 (0.1 mL) and reaction mixture was kept at room temperature. A 12-day TLC aliquot showed complete reaction. The solution was evaporated to dryness, the residue was crystallized from EtOH to give 9-(2-deoxy-4-thio-α-D-ribofuranosyl)-2-amino-1,6-dihydro-6-oxopurine (28 mg, 93%); mp 257°-260° C.; TLC 3: 1 CHCl3, MeOH, Rf 0.55; MS z/e 284 (M+1)+, UV λmax pH 1 254 (11.15), pH 7 254 (12.51), pH 13 267 (11.09); 1H NMR (Me2SO-d6, 300 MHz) δ2.30-2.40 (m, 1, H-2'), 2.52-2.62 (m, 1, H-2'), 3.30-3.40 (m, 1, H-5'), 3.46-3.58 (m, 1, H-5'), 3.60-3.66 (m, 1, H-4'), 4.46 (br t, 1, H-3'), 5.04 (br t, 1, 5'-OH), 5.50 (d, 1, 3'-OH, J=4 Hz), 5.94 (dd, 1, H-1', J=4 and 8 Hz), 6.50 (s, 2,NH2), 8.08 (s, 1, H-8); 13C NMR (Me2SO-d6, 300 MHz) δ42.57 (C-2'), 57.32 (C-1'), 59.63 (C-4'), 63.58 (C-5'), 74.34 (C-3'), 116.09 (C-5), 136.53 (C-8), 150.63 (C-4), 153.41 (C-2), 156.54 (C-6). Anal. (C10H13N5O3S) C, H, N, S.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].[F:12][B-:13]([F:16])([F:15])[F:14].[H+].[N:18](OCCC(C)C)=O.C(OCC)C>C(#N)C>[F:12][B-:13]([F:16])([F:15])[F:14].[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]([Cl:10])[C:2]=1[N+:1]#[N:18]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: CC(C)CCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1cc(Cl)c([N+]#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To a solution of 4-amino-3,5-dichlorobenzonitrile (2.00 g, 10.63 mmol) in acetonitrile (12 ml) was added dropwise tetrafluoroboric acid (2.80 ml, 21.27 mmol). After stirring for 10 min, isoamyl nitrite (1.50 ml, 10.63 mmol) was added and the reaction mixture was cooled to 0° C. After a further 10 min, diethyl ether (50 ml) was added and the resulting precipitate was collected by filtration and dried to give the titled compound (1.9 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:29]([Cu])#[N:30]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OC)cc3)cc2c1O

Procedure:
The title compound was synthesized from 1-Bromo-4-hydroxy-6-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=392.9.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:23]=[C:24]([CH3:26])[CH3:25])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:6]>C(O)(=O)C.[Pd]>[CH2:23]([C:3]1[C:2]([CH3:1])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([NH:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16]1)=[O:6])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1CC(C)C
Yield: 54.4 %

Procedure:
To a solution of 2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid (135) (120 mg, 0.34 mmol) in acetic acid (15 mL) is added the catalyst, Pd—C (5 wt. % Pd, 72 mg, 3.4% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, 95° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed by EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (136) as white solid (65 mg, 54%).