Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([CH:17]=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[NH2:25]/[C:26](/[CH2:33]OC(=O)C)=[CH:27]\[C:28]([O:30][CH2:31][CH3:32])=[O:29].[OH-].[K+].Cl>C(O)C.CO>[CH3:33][C:26]1[NH:25][C:24]2[CH2:23][O:22][C:19](=[O:21])[C:20]=2[CH:17]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:9]3)[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=Cc1cccc2ncc(-c3ccccc3)cc12
Reactant: CCOC(=O)/C=C(\N)COC(C)=O
Reactant: CCOC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1cccc2ncc(-c3ccccc3)cc12
Yield: 18 %

Procedure:
1.4 g (6.0 mmol) of 3-phenylquinoline-5-aldehyde in 20 ml of ethanol are boiled with 0.79 ml (6.2 mmol) of ethyl acetate and 1.16 g (6.2 mmol) of ethyl 3-amino-4-acetoxycrotonate for 2 days. The mixture is cooled and concentrated. The residue is coarsely purified by flash chromatography. The intermediate obtained is boiled in a solution of 970 mg of potassium hydroxide in 50 ml of methanol for 40 minutes. The mixture is cooled, adjusted to pH 5 with 10% strength hydrochloric acid and concentrated, the residue is taken up in ethyl acetate and the solution is washed with water. The organic phase is dried and concentrated. The residue is freed from by-products by column chromatography, and the fractions are concentrated and crystallized from acetonitrile. 460 mg of colorless crystals of melting point 257-260° C. are obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:29][C:12]1[C:10]2[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:7]=[CH:8][C:9]=2[N:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CCCCNc1ncc2c(ccn2-c2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNc1ncc2c(n1)c(Br)cn2-c1ccc(F)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of N-butyl-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (1.03 g, 3.61 mmol) in DMF (10 mL) was added NBS (0.71 g, 3.97 mmol) at room temperature. The resulting solution was stirred for 1 h and diluted with EtOAc. The resulting solution was washed with a sat. aq. solution of NaHCO3, H2O and brine. The EtOAc layer was dried (Na2SO4), concentrated and purified by ISCO to provide the desired product (1.05 g, 80%). 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 7.68 (s, 1H), 7.52-7.42 (m, 2H), 7.32-7.21 (m, 2H), 3.44 (t, J=7.1 Hz, 2H), 1.68-1.54 (m, 2H), 1.49-1.36 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS m/z 363.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:8]=2[CH:26]=1)[CH3:3].[ClH:27]>CO.C(O)C>[ClH:27].[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:8]=2[CH:26]=1)[CH3:1]
Reactant: CC(C)c1ccc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)c1ccc2[nH]c(=O)n(C3CCNCC3)c2c1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl 4-[6-(1-methylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinecarboxylate D34 (0.71 g) in methanol (30 mL) was treated with a saturated solution of hydrogen chloride in ethanol (10 mL). The mixture was stirred for 1 hour when the solvent was removed to give the title compound as a white solid (0.59 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>C(#N)C>[Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13]
Reactant: Cc1ccccn1
Reactant: CCC#CCCCCCCCCBr
Solvent: CC#N
Product: CCC#CCCCCCCCC[n+]1ccccc1C
Product: [Br-]
Yield: 70 %

Procedure:
12-Bromo-dodec-3-yne (1 mmol) was added to a solution of 2-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no 2-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (70%). 1HNMR (300 MHz, CDCl3, ppm), 9.68 (d, 1H), 8.28 (m, 1H), 7.96 (m, 1H), 7.84 (d, 1H), 4.94 (t, 2H), 2.98 (s, 3H), 2.05-2.20 (m, 4H), 1.88-2.00 (m, 2H), 1.20-1.60 (br, 10H), 1.10 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].CO>C(Cl)Cl>[Br:12][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 106.1 %

Procedure:
To a stirred suspension of methyl 4-hydroxybenzoate (180 g, 1183 mmol) in DCM (3 L) was added dropwise bromine (64 mL, 1242 mmol) under nitrogen and at 0° C. and the reaction mixture was left to stir at room temperature for 36 hrs. A solution of sodium thiosulfate (500 mL of a 10% solution) was then added while keeping the temperature around 15° C. followed by addition of MeOH (250 mL). The organic layer was washed with water, then brine, dried over magnesium sulfate, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (290 g) as a white solid. Mass Spectrum: [M−H]− 229.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[C@@H:9]([CH2:16]/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:13])[CH3:14])[C:10](=[O:15])[C@@H:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1
Reactant: CC(C)N1C(=O)[C@@H](C/C=C/C(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)[C@@H](CCCC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 0.8 %

Procedure:
In ethyl acetate (20 ml) was dissolved ethyl ester of trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-crotonic acid (0:45 g). To the solution was added 10% palladium carbon (0.1 g), and the mixture was subjected to catalytic reduction at room temperatures under atmospheric pressure. The theoretical amount of hydrogen was allowed to be absorbed, then the catalyst was removed, followed by distilling off ethyl acetate under reduced pressure. The residue was crystallized from a small volume of hexane to give ethyl ester of trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-butyric acid (0.37 g) as prisms, m.p.100°-101° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3].[C:23](=S)=[S:24].C(N(CC)CC)C.[OH-].[Na+]>C(O)C.O>[CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:23]([SH:24])=[N:22][N:21]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CS(=O)c1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Yield: 67 %

Procedure:
A solution of 1-[4-(methylsulfinyl)phenyl]-1H-benzimidazole-6-carbohydrazide (1.26 g, 4.00 mmol), carbon disulfide (0.601 mL, 10.0 mmol) and triethylamine (0.669 mL, 4.80 mmol) in ethanol (20 mL) was heated under reflux for 3 hr. After cooling, the reaction mixture was poured into water, and alkalified with 1 M aqueous sodium hydroxide solution. The obtained aqueous solution was filtered, and the filtrate was neutralized with 1M hydrochloric acid. The precipitate was collected by filtration, and washed with ethanol to give the title compound (0.955 g, yield 67%) as colorless crystals.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[CH:10][C:9]([N:23]2[C:31](=[O:32])[NH:30][C:29]3[C:24]2=[N:25][C:26]([CH2:35][OH:36])=[N:27][C:28]=3[O:33][CH3:34])=[C:8]([Cl:37])[CH:7]=1)([OH:3])=O.CN.Cl.[CH2:41]([N:43]=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:37][C:8]1[C:9]([N:23]2[C:31](=[O:32])[NH:30][C:29]3[C:24]2=[N:25][C:26]([CH2:35][OH:36])=[N:27][C:28]=3[O:33][CH3:34])=[CH:10][C:11]([O:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[C:6]([CH:7]=1)[O:5][CH2:4][C:1]([NH:43][CH3:41])=[O:3]
Reactant: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)c(Cl)cc1OCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)cc1OCc1c(F)cccc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 9-[4-carboxymethoxy-2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-phenyl]-2-hydroxymethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.1 g), 40% aqueous methylamine solution (0.06 mL), 1-hydroxybenzo[r]azole monohydrate (34 mg) and triethylamine (0.1 mL) in N,N-dimethylformamide (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg), and the mixture was stirred at 60° C. overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (54 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[C:4]([C:14]1[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=1)([OH:13])[O:5][C:6]2=[O:7].CO.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C(Cl)Cl>[CH:26]([NH3+:29])([CH3:28])[CH3:27].[Cl:1][C:2]1[C:3]([C:4]([C:14]2[N:15]=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([O:20][CH3:21])[N:19]=2)=[O:13])=[C:8]([C:9]([Cl:12])=[CH:10][CH:11]=1)[C:6]([O-:7])=[O:5]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)ccc(Cl)c32)n1
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CO
Product: CC(C)[NH3+]
Product: COc1cc(OC)nc(C(=O)c2c(Cl)ccc(Cl)c2C(=O)[O-])n1

Procedure:
24.13 g of 4,7-dichloro-3-(4,6-dimethoxy-2-pyrimidinyl)-3-hydroxyphthalide is slurried in 500 ml of methylene dichloride and 200 ml of methanol and 125 ml of freshly distilled isopropylamine added. The mixture is heated to reflux and the solution filtered, cooled and stripped. The solid is dried in vacuum for 4 hrs at 45° C. to give the title product m.p. 194°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[C@@H](O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1
Reactant: COc1cscc1OC
Reactant: C[C@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1COc2cscc2O1
Yield: 69.5 %

Procedure:
A solution of 3,4-dimethoxythiophene (5.18 g), (S)-1,2-propanediol (3.0 g) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (50 ml) was heated at 95° C. during which a continuous stream of nitrogen was passed over the solution. After 30 h the reaction mixture was poured into ethyl acetate, washed with NaHCO3 and the organic phase was concentrated. Subsequent filtration over SiO2 using n-hexane as eluant resulted in pure product (3.90 g). GC-MS: 156 (purity>99%); 1H-NMR (CDCl3): δ 6.30 (2×d, 2H), 4.26 (m, 1H), 4.15 (dd, 1H), 3.82 (dd, 1H), 1.35 (d, 3H) ppm; specific rotation [α]=−46° at 25° C. and 436 nm in hexane (c=0.066).
Reaction SMILES: O.[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10].[H][H]>[C].[Pd].C1(C)C=CC=CC=1>[F:2][C:3]([F:15])([F:16])[C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCc1cccc(C(F)(F)F)c1
Yield: 97.8 %

Procedure:
Palladium carbon (10%, 6 gm) was added to water (20 ml) and then added 3-(trifluoromethyl)cinnamic acid (100 gm) and toluene (1000 ml). The resulting contents were hydrogenated with hydrogen gas at a pressure of 4 kg at 45 to 50° C. for 2 hour 30 minutes. The reaction mass was then filtered through celite bed and the layers were separated. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 98.7 gm of 3-[3-(trifluoromethyl)phenyl]propionic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH2:21])=[NH:20])=[CH:14][CH:13]=2)=[O:6])[CH2:3][CH2:2]1.CN(C)/[CH:24]=[C:25](\[F:37])/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>COCCO>[CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[N:21]=[C:26]([C:28]4[N:32]([CH:33]([CH3:34])[CH3:35])[C:31]([CH3:36])=[N:30][CH:29]=4)[C:25]([F:37])=[CH:24][N:20]=3)=[CH:16][CH:17]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Reactant: N=C(N)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Solvent: COCCO
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCC[C@@H]4C(=O)NC4CC4)cc3)ncc2F)n1C(C)C
Temperature: 200 °C
Yield: 61.6 %

Procedure:
(R)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid cyclopropylamide (Method 63) (0.36 g, 1.25 mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 0.15 g, 0.63 mmol) were added to 2-methoxyethanol (4 ml) and heated at 200° C. for 2 hours in the microwave. The solvent was removed in vacuo and the gum was carefully chromatographed eluting with DCM, 1% MeOH/DCM, 2% MeOH/DCM and finally 3% MeOH/DCM to yield a yellow solid (180 mg, 62%). NMR (400.132 MHz, CDCl3) 8.21 (d, 1H), 7.56 (d, 1H), 7.34 (d, 2H), 6.80 (s, 1H), 6.59 (m, 3H), 5.55 (septet, 1H), 3.62 (t, 1H), 3.21-3.15 (m, 1H), 2.74-2.68 (m, 1H), 2.58 (s, 3H), 2.28-2.22 (m, 2H), 2.05-1.98 (m, 1H), 1.96-1.86 (m, 1H), 1.45 (d, 6H), 0.79-0.72 (m, 2H), 0.44-0.37 (m, 2H); m/z 464.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(#N)C>[N:19]1([S:2]([C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)N3CCC3)ccc12
Reaction time: 72 h

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g) was added to azetidine (0.7 ml) and diisopropylethylamine (0.4 ml) in tetrahydrofuran (5 ml) and acetonitrile (5 ml) and the mixture was stirred for 72 h then evaporated. The solid was crystallised from methanol then hydrochloric acid was added to acidify the mixture, which was filtered to yield 7-(azetidin-1-ylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[NH:31]1[CH:35]=[N:34][C:33]([CH:36]=O)=[N:32]1.[C:38]([BH3-])#[N:39].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:39]([CH2:38][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:36][C:33]3[N:34]=[CH:35][NH:31][N:32]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: O=Cc1nc[nH]n1
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nc[nH]n3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (100.0 mg) obtained in Example 47-3 was dissolved in methanol (3.0 ml). Then, the solution was added with 1H-[1,2,4]-triazol-3-carboxaldehyde (51.0 mg) synthesized by the method described in Heterocycles (vol. 15, No. 1, page 1981) and sodium cyanoborohydride (30.0 mg). Subsequently, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 17 hours. After completion of the reaction, the reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to separation/extraction with a mixture solution of chloroform/methanol. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (37.4 mg) of the subject compound as a white solid.
Reaction SMILES: C(OC([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=O)C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:40][CH2:41][CH2:42][OH:43]>ClCCl.O>[NH2:11][C:12]([CH3:16])([CH3:17])[C:13]([NH:40][CH2:41][CH2:42][OH:43])=[O:15]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(N)C(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (0.5 g) in dichloromethane (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g), 1-hydroxybenzotriazole (0.43 g) and 2-aminoethanol (1.16 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (0.10 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 2-(2-amino-2-methylpropionylamino)ethanol (0.11 g). To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (70 mg) in N,N-dimethylformamide (0.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg), 1-hydroxybenzotriazole (23 mg) and 2-(2-amino-2-methylpropionylamino)ethanol (0.11 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, 5 mol/L aqueous sodium hydroxide solution (0.25 mL) was added to the filtrate, and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added acetic acid (0.09 mL), and the mixture was diluted with water (1 mL). The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) to give 3-(β-D-glucopyranosyloxy)-4-(4-{(1E)-3-[1-(2-hydroxyethylcarbamoyl)-1-methylethylcarbamoyl]prop-1-enyl}phenyl)methyl)-5-isopropyl-1H-pyrazole (14 mg). This material was dissolved in methanol (0.5 mL). To the solution was added 10% palladium-carbon powder (7 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (11 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:15]([CH3:16])[N:22]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:4]2=[O:6]
Reactant: c1c[nH]cn1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc2ccc(Cl)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a stirred mixture of 2-amino-5-chlorobenzoic acid (2.0 g, 12 mmol) and imidazole (1.0 g, 14 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.0 mL, 14 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.9 g, 12 mmol), imidazole (1.8 g, 26 mmol) and triphenyl phosphite (3.7 mL, 26 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give 3-(6-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (2.9 g, 80% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 6.65 min (98.5%); mp: 276-278° C.; 1H NMR (DMSO-d6) δ 2.15-2.24 (m, 1H, CHH), 2.58-2.71 (m, 5H, CH3, 2CH—), 2.78-2.92 (m, 1H, CHH), 5.30 (dd, J=6, 11 Hz, 1H, NCH), 7.66 (d, J=9 Hz, 2H, Ar), 7.85 (dd, J=3, 9 Hz, 1H, Ar), 7.98 (d, J=2 Hz, 1H, Ar), 11.06 (s, 1H, NH; 13C NMR (DMSO-d6) δ20.79, 23.45, 30.57, 56.71, 121.47, 124.89, 128.89, 130.77, 134.87, 145.57, 155.67, 159.53, 169.31, 172.56; LCMS: MH=306, 308; Anal Calcd for C14H12N3O3Cl+2H2O: C, 49.20; H, 4.72; N, 12.30; Cl, 10.37. Found: C, 49.34; H, 4.57; N, 12.20; Cl, 10.39.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1(N)CCCCC[CH2:24]1>>[CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2][CH2:24][CH2:23]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCCCCC1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1-cycloheptylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26-1.32 (m, 2H), 1.38-1.50 (m, 8H), 1.68 (bs, 2H), 1.81 (s, 3H), 2.07 (s, 3H), 3.80-3.88 (m, 1H), 4.49 (d, J=9.91, 2H), 5.70 (d, J=7.25, H), 6.63 (brs, 1H), 7.15-7.20 (m, 1H), 7.21-7.28 (m, 1H), 7.68 (t, J=7.25, 1H), 8.46 (bs, 1H); MS (ESI) m/z 326.9 (M+1)+.