Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.C([NH:24][CH:25]([C:32](O)=[O:33])[CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(OC(C)(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:32](=[O:33])[CH:25]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)O
Reactant: Nc1ccccc1C(=O)c1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1Nc2ccccc2C(c2ccccc2F)=NC1Cc1cccs1
Reaction time: 72 h

Procedure:
The procedure of Example 1 was carried out using 2-amino-2'-fluorobenzophenone (1.26 gm, 5.86 mmol), N-Boc-β-(2-thienyl)-DL-alanine (1.75 gm, 6.45 mmol), and DCC (6.45 ml of 1.0M solution in CH2Cl2) in CH2Cl2 (25 ml). Filtration, concentration in vacuo and flash chromatography (silica gel, 1% (v/v) Et2O in CH2Cl2) gave a white foam which was deprotected and cyclized by the procedure of Example 2. After stirring 3 days, the mixture was evaporated in vacuo, treated with H2O (50 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, filtered, and evaporated to dryness in vacuo. The resulting foam was crystallized from Et2O to give the title compound as a white solid. The solid was dried in vacuo at 65° C.: (m.p. 189°-91° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[NH4+:47].Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([NH2:47])=[O:27])[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCc1ccc(Cc2ccc(CC(=O)O)cc2OCc2ccccc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(CC(N)=O)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a mixture of [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetonitrile (0.41 g) in ethanol (5 mL) and water (10 mL) was added potassium hydroxide (0.68 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was acidified by adding 2 mol/L aqueous hydrochloric acid solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g). To a solution of the obtained [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g) in tetrahydrofuran (10 mL) were added pyridine (0.19 mL), di-tert-butyl dicarbonate (0.50 g) and ammonium hydrogen carbonate (0.18 g), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 1 mol/L aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetamide (0.38 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([NH2:7])=[CH:5][CH:6]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](Cl)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:6]2[CH:5]=[C:4]([NH2:7])[SH:3]([C:14]3[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=3)[C:2]=2[NH2:1])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(N)s1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=CC(c2ccc([N+](=O)[O-])cc2)=C(N)[SH]1(c1ccc([N+](=O)[O-])cc1)(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 96 h

Procedure:
In 600 parts of dimethylformamide, 0.5 mol (60 parts) of 2,5-diaminothiophene, 2.3 mol (360 parts) of p-nitrochlorobenzene, 1.2 mol (170 parts) of anhydrous potassium carbonate and 10 parts of copper powder were refluxed with stirring for 4 days. After the reaction was completed, the reaction mixture was filtered, and the residue was thoroughly washed with dimethylformamide, water and acetone, and then dried. Thus, 105 parts of reddish brown tetrakis(p-nitrophenyl)-2,5-diaminothiophene was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:30][CH2:31][CH3:32])[C:14]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)NCCC3)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCCc2c1c1cc(OC)ccc1n(Cc1ccc(OC)cc1)c2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
The compound of 9-methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one (100 mg, 0.285 mmol) prepared in step 4 of Example 3 was dissolved in N,N-dimethylformamide (5 ml), added with sodium hydride (17 mg, 0.428 mmol) at 0° C. The reaction mixture was stirred for 1 hour at room temperature. After that, 1-bromopropane (0.039 ml, 0.428 mmol) was added and the mixture was stirred for one more hour at room temperature. The mixture was poured into water extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (56 mg, yield: 50%, yellow solid).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.Br[CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1>>[CH3:7][C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=1
Reactant: Cc1cnc(N)s1
Reactant: BrCC1CCCO1
Product: Cc1cn(CC2CCCO2)c(=N)s1
Temperature: 85 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A mixture of 2-amino-5-methylthiazole (1.0 g, 8.7 mmol) and 2-(bromomethyl)tetrahydrofuran (Maybridge, 1.1 mL, 10 mmol) was warmed to 85° C. and allowed to stir for 24 hours. The mixture was then cooled to ambient temperature and purified via column chromatography (SiO2, 9:1:0.1 CH2Cl2:CH3OH:NH4OH) to afford the title compound (1.5 g, 7.5 mmol, 86% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.55-1.70 (m, 1H) 1.89-2.01 (m, 2H) 2.07-2.20 (m, 1H) 2.28 (d, J=1.36 Hz, 3H) 3.72-3.82 (m, 1H) 3.86-4.00 (m, 2H) 4.08-4.24 (m, 2H) 6.98-7.04 (m, 1H); MS (DCI/NH3) m/z 199 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>ClCCl.Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: C1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(CCl)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloromethylbenzoyl chloride (5.0 g) and pyrrolidine (2.2 mL) in dichloromethane (30 mL) at 0° C. was treated with ethyldiisopropylamine (5.2 mL). The resulting mixture was warmed to room temperature over 1 hour and then stirred at this temperature for 2 hours. The mixture was diluted with 1.0 M aqueous hydrochloric acid, extracted with dichloromethane and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound, 6.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([OH:19])=O)[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:27][C:28]([F:42])([F:41])[C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:38]3[CH2:39][CH2:40][N:35]([C:30]4[C:29]([C:28]([F:42])([F:27])[F:41])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:36][CH2:37]3)=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with 1-[3-(trifluoromethyl)pyrid-2-yl]-piperazine to give the title compound as a colorless solid. MS: 589.8 ([M+H]+)
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:33])=[C:22]([O:24]C(=O)C3C=CC=CC=3)[CH:23]=2)[N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:7][CH:6]=1)#[N:4]>O.CO>[F:33][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:11]([N:12]2[CH:13]=[N:14][N:15]=[CH:16]2)[C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=2)=[CH:23][C:22]=1[OH:24]
Reactant: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(N(Cc2ccc(F)c(O)c2)n2cnnc2)cc1

Procedure:
A solution of sodium hydroxide (250 mg, 6.25 mmol) in water (5 mL) was added to a solution of benzoic acid 5-{[(4-cyano-phenyl)-[1,2,4]triazol-4-yl-amino]methyl}-2-fluoro-phenyl ester (CAB02147, 958 mg, 2.32 mmol) in methanol (10 mL). The solution was heated to reflux for 5 minutes and concentrated under reduced pressure. Water (10 mL) was added and the milky suspension was neutralised (pH 7-8) with 2N hydrochloric acid. The white precipitate was filtered off, washed with a small amount of water (5 mL) and dried under high vacuum. Yield: 476 mg (66%). 1H-NMR (400 MHz, d6-DMSO) δ=4.95 (s, 2H), 6.70 (ddd, J=11.4, 8.4, 2.4 Hz, 1H), 6.75 (d, J=9.0 Hz, 2H), 6.84 (dd, J=8.4, 2.4 Hz, 1H), 7.06 (dd, J=11.3, 8.4 Hz, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.75 (s, 2H), 9.90 (s, 1H, —OH). LRMS (FAB+): 310.1 (100, [M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[N:8][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-])=O)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:17][C:10]1[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:7]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Yield: 66.3 %

Procedure:
In 25 ml of ethyl acetate was dissolved 0.35 g of 3,4-diethoxycarbonyl-5-nitro-6-phenyl-2-(1,2,4-triazol-1-yl)pyridine, whereto 0.2 g of 10% Pd-C (50% wet) was added. The mixture was stirred in a stream of hydrogen at room temperature for 2.5 hours. After the catalyst was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluent:chloroform/ethyl acetate 4:1), to give 0.215 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:28]([O:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
In dry methylene chloride (10 ml) was dissolved 220 mg (0.700 mmol) of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-8), followed by addition of 201 mg (2.00 mmol) of triethylamine. Then, 78.0 mg (1.00 mmol) of acetyl chloride was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added for neutralization, and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1) to give 170 mg of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methyl acetate (Compound I-40) (yield 69%). mp 92-93° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].O>C(O)(=O)C>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([CH3:1])[C:11]=2[C:10]=1[OH:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)O
Reactant: CC1(C)CCCc2cccc(O)c21
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(c1O)C(C)(C)CCC2
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a solution of 8,8-dimethyl-5,6,7,8-tetrahydro-1-naphthol (10.1 g, 57.3 mmole) and tert-butanol (4.25 g, 57.3 mmole) in glacial acetic acid (30 ml) 90% aqueous sulphuric acid (3.0 ml) was added. The mixture was stirred at 40° for 3 hours, poured into water (100 ml) and extracted with diethylether (2×200 ml). The ethereal extract was washed with water and with aqueous saturated sodium chloride, dried and evaporated. The residue was chromatographed on silica gel using a n-pentane: dichloromethane (1:1) mixture to give 2-tert-butyl-8,8-dimethyl-5,6,7,8-tetrahydro-1-naphthol as a colourless oil (9.5 g, 71%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5].I[CH2:23][CH2:24][CH3:25].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20]#[N:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH2:23][CH2:24][CH3:25]
Reactant: CCCI
Reactant: CNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 140 °C

Procedure:
A suspension of 10-[(2RS)-1-methylamino-2-propyl]-2-phenothiazinecarbonitrile (4.7 g), 1-iodopropane (1.55 cc) and sodium hydrogen carbonate (2 g) in dimethylformamide (47 cc) is heated for 6 hours to a temperature of 140° C. After cooling, the reaction mixture is diluted with ethyl acetate (200 cc), washed with distilled water (4×30 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual oil (5.2 g) is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (70:30 by volume) (1 liter) of cyclohexane and ethyl acetate and collecting 60-cc fractions. The combined fractions 6 to 14 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-(N-Methyl-N-propylamino)-2-propyl]-2-phenothiazinecarbonitrile (4.4 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:12]3[N:11]=[C:10]([CH3:23])[C:9]=2[CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1.[C:31](OC(=O)C)([CH3:34])([CH3:33])[CH3:32].C(Cl)Cl.Cl(O)(=O)(=O)=O>CCOC(C)=O>[C:31]([O:29][CH:24]([C:9]1[C:10]([CH3:23])=[N:11][C:12]2[N:13]([N:14]=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)[C:8]=1[N:5]1[CH2:4][CH2:3][C:2]([CH3:30])([CH3:1])[CH2:7][CH2:6]1)[C:25]([O:27][CH3:28])=[O:26])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)C(O)c1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of methyl 2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (56 mg, 0.137 mmol) in t-butylacetate (2 ml, 0.137 mmol) was added anhydrous DCM (Volume: 2 ml) followed by perchloric acid (0.012 ml, 0.205 mmol). The resulting mixture was stirred at r.t for 1 h. Diluted with EtOAc, washed with sat'd NaHCO3. The organic phase was dried and evaporated to an oil, which was purified by Pre-HPLC to afford methyl 2-tert-butoxy-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (25 mg, 0.053 mmol, 38.5% yield). 1H-NMR (400 MHz, CDCl3) δ 1.16 (6H, s), 1.26 (9H, s), 1.58-1.60 (2H, m), 1.69-1.73 (2H, m), 2.69 (3H, s), 3.77 (3 H, s), 5.87 (1 H, s), 7.49-7.53 (3 H, m), 8.35-8.37 (2 H, m).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[O:25][C:24](=[O:26])[NH:23][N:22]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>CN(C=O)C>[CH3:1][N:23]1[N:22]=[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:25][C:24]1=[O:26]
Reactant: O=c1[nH]nc(-c2ccccc2SCc2ccccc2)o1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(-c2ccccc2SCc2ccccc2)oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a suspension of 2.9 g of potassium t-butoxide in 60 ml of DMF under a N2 atmosphere was added portionwise 7 g of the product of Example 1 while maintaining the reaction temperature at 25°-30° C. with an ice-water bath. After stirring at 25° C. for 1 hour, 7 g of methyl iodide was added dropwise to cause an exotherm to 37° C. The suspension was heated at 40°-60° C. for 5 hours, then cooled to 25° and poured onto excess ice-water to yield a precipitate. The suspension was filtered, and the isolated solid was dissolved in tetrahydrofuran and dried over MgSO4. The isolated solid was passed through a silica gel column with methylene chloride and, after evaporation of the first eluant, 5 g of the subject compound was obtained; m.p. 137°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([Cl:1])[CH:8]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Yield: 81 %

Procedure:
In glacial acetic acid, 51.8 g (300 mmoles) of 4-chloro-2-nitroaniline was reacted with 57.5 g (360 mmoles) of bromine to give 61.6 g (243 mmoles) of 6-bromo-4-chloro-2-nitroaniline.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH3:7])[NH:5][C:4](=O)[CH2:3]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>>[OH:1][C@H:2]1[CH2:3][CH2:4][N:5]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C@H:6]1[CH3:7]
Reactant: C[C@@H]1NC(=O)C[C@@H]1O
Reactant: N#Cc1ccc(F)cc1
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)cc1

Procedure:
Using (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one and 4-fluorobenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 2 (reaction time 1 hr).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:10][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:13](=[O:14])[CH2:12][O:8][C:7]=2[C:6]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(ccc(F)c2F)N1

Procedure:
6-Amino-2,3-diflourophenol (81KK30a) (0.113 g, 0.78 mmol), 2-chloroacetyl chloride (0.10 g, 0.89 mmol) and K2CO3 (0.226 g, 1.6 mmol) were mixed according to GP1 to give the title compound as a crude (81MF2082A) (0.12 g)
Reaction SMILES: [N:1]([C@H:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[NH:16][C:15]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:13]=2[N:12]([CH3:29])[C:10]1=[O:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C@H:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[NH:16][C:15]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[N:14][C:13]=2[N:12]([CH3:29])[C:10]1=[O:11]
Reactant: [H][H]
Reactant: C[C@H](CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Yield: 79.2 %

Procedure:
To a solution of (R)-1-(5-azidohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.7 g, 1.6 mmol) in ethanol (40 ml) was added 10% palladium on carbon catalyst (0.3 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. Removal of the catalyst by filtration and evaporation of the solvent under reduced pressure provided (R)-1-(5-aminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.5 g, 77% yield) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:14])[C:11](Cl)=[O:12])=[N:8][N:9]=1)(=[O:4])=[O:3].[O:15]1[CH2:20][CH2:19][CH2:18][O:17][CH:16]1[CH2:21][NH2:22].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:14])[C:11]([NH:22][CH2:21][CH:16]2[O:17][CH2:18][CH2:19][CH2:20][O:15]2)=[O:12])=[N:8][N:9]=1)(=[O:4])=[O:3]
Reactant: NCC1OCCCO1
Reactant: CN(C(=O)Cl)c1nnc(S(C)(=O)=O)s1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C(=O)NCC1OCCCO1)c1nnc(S(C)(=O)=O)s1
Temperature: 25 °C

Procedure:
N-(2-Methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride (0.05 mole), N-(1,3-dioxan-2-ylmethyl)amine (0.05 mole), triethylamine (0.07 mole) and benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 4 hours. After this time the mixture is cooled to room temperature and is filtered. The filtrate is washed with water and is dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure to yield the desired product N-(2-methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methyl-N'-(1,3-dioxan-2-ylmethyl)urea.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([NH2:14])=O>O>[CH3:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][NH:14][C:7]2=[O:8]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: NC=O
Solvent: O
Product: Cc1ccc2nc[nH]c(=O)c2c1

Procedure:
8 g of 5-methyl 2-aminobenzoic acid and 15 ml formamide was heated at 170° C. 1.5 hour. Water was added and the solid filtered to give 7.3 g of 6-methyl 4-quinazolinone as a light brown-white solid, mp-268° C.