Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])C.C[C@H]1CCCN1>CS(C)=O>[CH3:25][C@H:23]1[CH2:24][CH2:22][CH2:20][N:19]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: C[C@H]1CCCN1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 35.9 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500.0 mg, crude) in DMSO (6 mL) was added DIEA (543.0 mg, 4.20 mmol), and (S)-2-methylpyrrolidine (268.0 mg, 3.15 mmol). The solution was stirred for 10 h at 100° C. and then quenched by the addition of water (25 mL), extracted with ethyl acetate (3×80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (216.0 mg).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.O>CN1CCCC1=O>[CH2:20]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)[CH:22]1[O:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)c2cc(O)ccc21
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)c2cc(OCC3CO3)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
112.1 g (0.5 mole) of 2-hydroxyanthraquinone are dissolved in 500 ml of N-methylpyrrolidone, and 12 g (0.5 mole) of sodium hydride are added in portions. When the evolution of gas has ended, 46.37 ml (0.5 mole) of epichlorohydrin are added dropwise at 70° C. and stirring is continued at 70° C. for a further 8 hours. 1.5 liters of water are then added, the mixture is filtered and the filter cake is dried in vacuo. After drying, the product is boiled up again in 1 liter of N,N-dimethylformamide with 10 g of active charcoal and filtered hot. The crystals which precipitate on cooling to 0° C. are separated off by filtration and dried under a high vacuum. 69.45 g (50.57% of theory) of 2-anthraquinonyl glycidyl ether are obtained; melting point: 162°-167° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[NH2:16])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:2][C:3]1[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[NH:16][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[C:25]([F:24])([F:35])[F:36])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: NC1CCCCC1c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 34.9 %

Procedure:
0.70 g of 2-[3,5-dichloro-2-pyridinyl]cyclohexanamine hydrochloride (0.00022 mol), 0.07 ml of triethylamine, 49 mg (0.00023 mol) of 2-trifluoromethylbenzoyl chloride are stirred in 3 ml of dichloromethane at room temperature overnight. Dichloromethane is added (5 ml) to the reaction mixture, which is washed twice with water (5 ml). After separation, the organic phase is dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 32 mg of N-{2-[3,5-dichloro-2-pyridinyl]-cyclohexyl}-2-(trifluoromethyl)benzamide (31%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[N:12]=1>C(O)C.Cl.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[O:15][N:14]=[C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:12]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(-c2nc(-c3ccco3)no2)c(Cl)c1
Reaction time: 3 h
Yield: 55 %

Procedure:
To a slurry of 28.8 g of 5-(2-chloro-4-nitrophenyl)-3-(2-furanyl)-1,2,4-oxadiazole in 600 ml of absolute ethanol and 34 ml of hydrochloric acid is added a slurry of 2.0 g of 10% palladium on charcoal in ethanol. The mixture is hydrogenated in a Parr hydrogenator at 45 p.s.i. for 3 hours. The insoluble amine hydrochloride is filtered and washed with ethanol. The filtrate is concentrated to dryness and the residue and precipitate are combined and treated with a solution of 20% potassium carbonate in the presence of chloroform. The phases are separated and the aqueous phases extracted three times with 300 ml of chloroform. The organic phases are dried over magnesium sulfate, filtered and concentrated to dryness yielding 20 g of crude product. Recrystallization from acetone/water yields 14.2 g of the title compound in 2 crops, melting point 175°-176.5°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][CH:36]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH3:43])=[CH:39][CH:40]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][O:34][S:52]([CH3:51])(=[O:54])=[O:53])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCOS(C)(=O)=O)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Reaction time: 0.5 h

Procedure:
To a methylene chloride (2 mL) solution containing tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (0.693 mmol), triethylamine (290 μL, 2.08 mmol) and methanesulfonyl chloride (80 μL, 1.04 mmol) were added with ice-cooling, and the mixture was stirred for 30 min. After the reaction, 1 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2cccc(C)c2)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)c1
Reaction time: 24 h
Yield: 62 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (31 mg, 0.074 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a colourless oil (18 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([C:14]#[N:15])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: CSc1nc(N)nc(-c2occc2C)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccoc1-c1nc(N)nc(OCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-(3-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH2:15]([NH:19][C:20](=[N:23][C:24]#[N:25])SC)[C:16]#[C:17][CH3:18]>>[C:24]([NH:23][C:20]([NH:19][CH2:15][C:16]#[C:17][CH3:18])=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)#[N:25]
Reactant: CC#CCNC(=NC#N)SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CC#CCNC(=NCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamine is reacted in a non-reactive solvent with about an equimolar amount of N-(2-butyn-1-yl)-N'-cyano-S-methylisothiourea [prepared according to the procedure described in U.S. Pat. No. 4,112,234, the complete disclosure of which is incorporated herein by reference] and, after workup and chromatography, the title product is produced.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>Cl>[N+:6]([C:13]1[CH:12]=[CH:11][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:15][CH:14]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
In a 300-ml four-necked flask were placed 206.2 g (2.10 moles) of concentrated sulfuric acid and 19.6 g (0.19 mole) of 60% nitric acid. The mixture was stirred on an ice bath and 25.7 g (0.17 mole) of 4-phenylpyridine was added at 0° C. After the addition, the stirring was continued at 0° C. for three hours. The reaction mixture thus prepared was added in drops to 1250.0 g of ice placed in a 2000-ml four-necked flask. The mixture was stirred on an ice bath and 600.6 g (4.43 moles) of a 29.5% aqueous solution of sodium hydroxide was added in drops. Thereafter, a solid was recovered by filtration at 0° C. The solid was washed with water and recrystallized twice from 200 ml of 5M hydrochloric acid. To the solid thus obtained was added 200 ml of 5M hydrochloric acid in drops. The solid was dissolved by heating and 201.4 g (1.49 moles) of a 29.5% aqueous solution of sodium hydroxide was added in drops. The mixture was cooled to room temperature and a separated solid was recovered by filtration. The solid was washed with water and dried under reduced pressure to give 12.9 g of 4-(4-nitrophenyl)pyridine.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH2:42][CH3:43])[CH:5]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:30]2)=[CH:24][CH:23]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:12]=[CH:13][CH:14]=1)=[O:7]>C1COCC1>[CH3:3][CH:4]([CH2:42][CH3:43])[CH:5]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[N:30]2)=[CH:24][CH:23]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: CCOC(=O)CCc1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)C(C(=O)Nc1cccc(CCC(=O)O)c1)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 ml (1.20 mmol) of 1 N aqueous sodium hydroxide solution were added to a solution of 167 mg (0.30 mmol) of ethyl 3-{3-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}pentanoyl)amino]phenyl}propanoate (Example 146A) in 4 ml of THF, and the mixture was stirred at room temperature overnight. After the reaction had gone to completion, the THF was removed under reduced pressure and the reaction solution was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 155 mg (0.29 mmol, 97% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:19][C:20]1[CH:21]=[C:22]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([O:36][CH3:37])[CH:30]=1)[CH2:16][CH2:17][CH3:18]>C(C(C)=O)C.C(OCC)(=O)C>[CH2:7]([O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:21][C:20]=2[O:19][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:30][C:31]=1[O:36][CH3:37])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(O)c(OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OCc2ccccc2)c(OC)c1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
0.2 g (0.75 mmol) of potassium carbonate and then 0.2 ml (0.75 mmol) of benzyl bromide are added to a solution of 0.25 g (0.62 mmol) of methyl 3-{3-butoxy-4-[3-(4-hydroxy-3-methoxyphenyl)propyl]phenyl}propanoate in 25 ml of methyl ethyl ketone. The reaction mixture is heated at 70° C. for 24 hours and then cooled, diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 276 mg (93%) of methyl 3-{4-[3-(4-benzyloxy-3-methoxyphenyl)propyl]-3-butoxyphenyl}propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]=[C:10]([CH2:14][C:15](O)=[O:16])[C:11]([OH:13])=[O:12]>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:15](=[O:16])[CH2:14][CH:10]([C:11]([OH:13])=[O:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccc(F)cc2)C1
Temperature: 170 °C
Reaction time: 0.25 h

Procedure:
A 250 mL round-bottomed flask was charged with 4-fluoroaniline 50 (12.8 g, 115 mmol) and 2-methylenesuccinic acid 49 (15.0 g, 115 mmol). The flask was fitted with a reflux condenser then heated at 170° C. Once at that temperature, heating was continued for 15 min. After that time, the molten mass was cooled to room temperature and water was added. The resulting precipitate was filtered then dissolved in 2 N NaOH. The solution was filtered again and the filtrate was acidified using concentrated HCl. The resulting precipitate was collected by filtration and dried at 70° C. under vacuum to give 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid 51.
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=3[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:10][N:9]([CH3:28])[C:8]=12.Cl>CO>[CH3:28][N:9]1[C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][C:7]=2[C:11]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:10]1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Nc3ccccn3)cn(C)c12
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2cc([N+](=O)[O-])ccc2Nc2ccccn2)c2cc[nH]c(=O)c21
Temperature: 75 °C
Reaction time: 10 h
Yield: 134.8 %

Procedure:
A mixture of Example 82a (0.1163 g, 0.31 mmol) in methanol (3.1 mL) was treated with hydrogen chloride solution (4 M in 1,4-dioxane) (1.55 mL, 6.2 mmol) and heated at 75° C. overnight and then for another 10 hours at 67° C. The reaction mixture was concentrated to give 0.151 g (>100%) of the title compound as the HCl salt
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]([NH2:18])=O.C(O)(=O)CC.NC1N([C@@H]2O[C@H](COC(=O)CC)[C@@H](OC(=O)CC)[C@H]2OC(=O)CC)C=NC=1C(N)=O.NC1N([C@@H]2O[C@H](COC(=O)CC)[C@@H](OC(=O)CC)[C@H]2OC(=O)CC)C=NC=1C#N>>[NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]#[N:18]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Agent: CCC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N)[C@H](OC(=O)CC)[C@@H]1OC(=O)CC
Agent: CCC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=O)c2N)[C@H](OC(=O)CC)[C@@H]1OC(=O)CC
Solvent: CCC(=O)O
Product: N#Cc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N

Procedure:
A method according to claim 8, wherein 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide is reacted with a reactive derivative of propionic acid, the resulting 5-amino-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)-imidazole-4-carboxamide is dehydrated, the resulting 5-amino-1-(2,3,5-tri-O-propionyl-β-D-ribofuranosyl)imidazole-4-carbonitrile is treated to remove the propionyls to yield 5-amino-1-β-D-ribofuranosylimidazole-4-carbonitrile and the last mentioned compound is reacted with phenylguanidine in the presence of aniline to produce N2 -phenyl-2,6-diaminonebularine.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CC[O:25][CH2:24][CH2:23]1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(O)(=O)C>[C:24]([O:20]/[N:19]=[C:17](/[C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:9])=[O:10])\[NH2:18])(=[O:25])[CH3:23]
Reactant: CN1CCOCC1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O/N=C(\N)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], acetic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-N′2-(acetyloxy)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboximidamide as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:9]1=[O:26].[H][H]>CO.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]2)[C:9]1=[O:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3F)c2=O)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(c3ccccc3F)C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
tert-Butyl 4-(3-(2-fluorophenyl)-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (530 mg, 1.5 mmol) was dissolved in methanol (25 mL). Platinum(IV) oxide (28 mg, 123.3 Emoles) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 60 psi of hydrogen gas. Reaction shook at room temperature for 4 hours. More platinum(IV) oxide (28 mg, 123.3 μmol) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 60 psi of hydrogen gas. Reaction shook at room temperature for 18 hours. Mixture was removed from the apparatus and then filtered over celite. The filtrate was concentrated by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as clear colorless oil in 45% yield. MS (M−C4H10O+H)+=290.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1.Cl[CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:30][CH2:31][CH2:32][S:33]3(=[O:35])=[O:34])=[CH:3][C:4]=2[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:9])[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N3CCCC3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCC3)CC2)c(C)c1

Procedure:
Using [4-amino-2-(pyrrolidin-1-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (268 mg) described in Preparation Example 152 and 3-chloropropane-1-sulfonyl chloride (0.11 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (31 mg) was obtained.
Reaction SMILES: [C:1]([C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:16][CH2:17][CH2:18][CH:19]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:16][CH2:17][CH2:18][CH:19]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1)OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of ethyl 8-acetyl-8-phenyl-12-benzyloxyheptadecanoate (14 g., crude), sodium hydroxide (2.0 g., 0.05 mole) and methanol (150 ml.) is stirred for 48 hours. The methanol is removed in vacuo; and the residual oil is poured into H2 0 (100 ml.), acidified with 6 N HCl (100 ml.), extracted with ether, and the combined ether extracts dried over anhydrous Na2SO4. The ether is removed in vacuo, and the residual oil is chromatographed through a silica gel column (95% CHCH3 -5% MeOH) to obtain 8-acetyl-8-phenyl-12-benzyloxyheptadecanoic acid (1.43 g., slightly impure).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].C1C=C(Cl)C=C(C(OO)=O)C=1.[NH3:38]>O1CCOCC1>[NH2:38][C:13]1[N:14]=[CH:15][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=3)[C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[C:11]=2[N:12]=1
Reactant: N
Reactant: CSc1ncc2cc(-c3ccc(F)c([N+](=O)[O-])c3)c(=O)n(C(C)C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: CC(C)n1c(=O)c(-c2ccc(F)c([N+](=O)[O-])c2)cc2cnc(N)nc21
Yield: 69 %

Procedure:
Using a procedure analogous to Example A1, 6-(4-fluoro-3-nitrophenyl)-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.82 g, 2.2 mmol), MCPBA (0.38 g, 2.2 mmol) and 0.5 M ammonia in dioxane (8 mL) were combined to afford 2-amino-6-(4-fluoro-3-nitrophenyl)-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one as a yellow solid (0.52 g, 69% yield). 1H NMR (400 MHz, MeOH-d4): δ 8.61 (s, 1H), 8.44 (dd, J=7.6 Hz, 2.4 Hz, 1H), 8.03-8.00 (m, 1H), 7.95 (s, 1H), 7.48 (dd, J=10.8 Hz, 7.6 Hz, 1H), 5.96-5.92 (m, 1H), 2.63 (s, 3H), 1.64 (d, J= 6.4 Hz, 6H); MS (ESI) m/z: 344.3 (M+H+).