Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:4][CH2:5][CH3:6])C.[NH2:7][C@H:8]1[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1>CO>[ClH:1].[C:5]([NH:7][C@H:8]1[CH2:12][NH:11][C@H:10]([C:23]([O:25][CH3:26])=[O:24])[CH2:9]1)(=[O:4])[C:6]1[CH:23]=[CH:10][CH:9]=[CH:8][CH:12]=1
Reactant: CCOCC
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccccc2)CN1
Temperature: 57 °C

Procedure:
To the above methanol concentrate of (2S,4R)-1-benzyl 2-methyl 4-benzamidopyrrolidine-1,2-dicarboxylate, were added a slurry of 10% Pd/C (dry, 4.1 g) in methanol (100 mL) and cyclohexene (80 mL). The mixture was heated at reflux (57° C.) for 7 h. before being cooled to 20-25° C. Palladium catalyst was filtered off through a pad of Celite, and washed with methanol. The filtrate was concentrated, and cyclohexene was removed as a methanol azetrope. To the final methanol solution was added 1 N hydrogen chloride in diethyl ether (110 mL, 0.11 mol) while the temperature was maintained at 20-25° C. The resulting slurry was cooled to 10-15° C. over 20 min. The solid product was filtered and washed with toluene. The wet solid was dried at 60° C. under vacuum to give 22.4 g of (2S,4R)-methyl 4-benzamidopyrrolidine-2-carboxylate hydrochloride as white solid (81.7% overall yield from 1-benzyl 2-methyl (2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate). 1H NMR (CDCl3, δ, ppm): 9.99 (bs, 2H), 8.95 (d, J=6.6 Hz, 1H), 7.97-7.94 (m, 2H), 7.58-7.45 (m, 3H), 4.71 (t, J=8.7 Hz, 1H), 4.68-4.61 (m 1H), 3.78 (s, 3H), 3.58 (dd, J=11.9, 6.6 Hz, 1H), 3.32 (dd, J=11.9, 4.2 Hz, 1H), 2.41 (d, J=8.6 Hz, 1H), 2.39 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1NCCC(C)C)=[O:5])[CH3:2].CS(NC1C=CC2NC(CC(O)=O)=NS(=O)(=O)C=2C=1)(=O)=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1NCCC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-(2-(3-methylbutylamino)-cyclohexanecarboxylic acid ethyl ester (58.7 mg, 0.243 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 162.0 mg, 0.486 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.49 mL, 0.49 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methylbutyl)amino]-cyclohexanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C24H36N4O7S2 556.20, found 557.3 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C>Cl>[NH2:7][C@H:8]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccccc1N1CCN(C(=O)[C@@H](CC2CCCCC2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COc1ccccc1N1CCN(C(=O)[C@H](N)CC2CCCCC2)CC1
Yield: 98 %

Procedure:
2.75 g (6.20 mmol) of the above-described (R)-{1-Cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester was stirred overnight in a mixture of 30 mL of peroxide-free dioxane and 30 mL of 6N aq. HCl. The resulting yellow mixture was concentrated to dryness on a rotary evaporator and the residue was partitioned between dichloromethane and saturated aq. sodium bicarbonate solution The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to yield the desired (R)-2-amino-3-cyclohexyl-1-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-1-one (2.10 g, 98% yield), which was characterized as its dihydrochloride salt by conversion with ethereal HCl to yield the white solid; mp=165-168° C.; MS(+)ESI m/z=346 (M+H)+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[ClH:5].Cl.[CH2:7]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([CH3:28])[CH3:27])[NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.Cl>[ClH:5].[CH2:7]([C:14]1[CH:15]=[C:16]([NH:17][C:2]([NH2:3])=[O:1])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][NH:25][CH:26]([CH3:28])[CH3:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#C[O-]
Reactant: CC(C)NCCCOc1ccc(N)cc1Cc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)NCCCOc1ccc(NC(N)=O)cc1Cc1ccccc1
Reaction time: 2 h
Yield: 283.9 %

Procedure:
Potassium cyanate (44 mg) was added to a stirred solution of 3-benzyl-4-(3-[N-isopropylamino]propoxy)aniline dihydrochloride (222 mg) in water (5 mls). The reaction mixture was stirred for 2 hours and the resulting precipitate collected by filtration. The solid collected was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 90:10:1 (v/v/v) mixture of dichloromethane/ethanol/ammonia (density=0.88 g/cm3) as eluent to give a residue which was dissolved in saturated methanolic hydrogen chloride solution. The solution was evaporated to give a solid which was crystallised from ethanol to give 3-benzyl-4-(3-[N-isopropylamino]propoxy)phenylurea hydrochloride as a white solid (582 mg), m.p. 204.7° C., microanalysis, found: C, 63.6; H, 7.6; N, 10.9%; C20H23N3O. HCl requires: C, 63.6; H, 7.47; N, 11.1%; NMR:([CD3 ]2SO): 1.2(6H,d), 2.05(2H,m), 2.9(2H,t), 3.25(1H,m), 3.85(2H,s), 4.0(2H,t), 5.7(2H,s), 6.82(1H,d), 7.05-7.3(7H,m), 8.4(1H,s), 7.5(2H,s); m/z 342(M+H).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.C(O)(=O)C.[NH2:13][C:14]1[CH:34]=[C:33]([CH3:35])[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][C:20]=3[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=2[CH:15]=1>C1(C)C=CC=CC=1>[CH3:7][C:6]1[N:13]([C:14]2[CH:34]=[C:33]([CH3:35])[C:17]3[O:18][C:19]4[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][C:20]=4[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=3[CH:15]=2)[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1cc(N)cc2c1Oc1c(C)cc(C(=O)O)cc1S(=O)(=O)C2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(-n2c(C)ccc2C)cc2c1Oc1c(C)cc(C(=O)O)cc1S(=O)(=O)C2
Yield: 51 %

Procedure:
Acetonylacetone (0.040 g, 0.35 mmol)) and acetic acid (0.1 mL, 1.7 mmol) were added to a solution of the methylester of Example 36j in toluene (10 mL). The reaction mixture was refluxed for 6 h, concentrated and triturated with PE60-80° C. The organic extract was concentrated and the crude obtained was purified using flash chromatography (silica gel, EtOAc/PE60-80° C.). It was then subjected to hydrolysis as described in Example 11 to obtain the title compound (J. Chem. Soc., Chem. commun, 800-801, (1982)). Yield: 51%; 1H NMR (DMSO-d6): δ 2.0 (s, 6H, 2CH3), 2.40 (s, 3H, CH3), 2.65 (s, 3H, CH3), 5.20 (s, 2H, CH2), 5.70 (s, 2H, pyrrolyl), 7.30 (s, 1H, Ar), 7.35 (s, 1H, Ar), 8.20 (s, 1H, Ar), 8.35 (s, 1H, Ar); MS: m/e (ES+) 411 (M+).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.[C:30]([O:34][CH3:35])(=[O:33])[C:31]#[CH:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:32][C:31]([C:30]([O:34][CH3:35])=[O:33])=[C:16]2[CH:17]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc[n+](N)cc1
Reactant: C#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnn2ccc(CO[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-amino-4-((tert-butyldimethylsilyloxy)methyl)pyridinium 2,4-dinitrophenolate Y-4 (13.4 g, 31.6 mmol) in DMF (60 mL) were added methyl propiolate (2.7 g, 31.6 mmol) and K2CO3 (6.5 g, 47.4 mmol). The reaction was stirred at room temperature for 24 h, then treated with water. The resulting mixture was extracted with ethyl acetate (100 ml×3), the combined organic layers were washed with water, brine and dried over Na2SO4, then concentrated in vacuo, the residue was purified by silica gel chromatography to afford the title compound (2.9 g). MS (m/z): 321 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>CN(C=O)C>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([O-:19])=[O:18]
Reactant: Nc1ncccn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Nc1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 2-aminopyrimidine (10 g, 105 mmol) in DMF (100 mL) cooled to 5° C. was added 60% sodium hydride in mineral oil (5.47 g, 137 mmol) and the resulting mixture was stirred one hour with cooling. 1-fluoro-2-nitrobenzene (14.83 g, 105 mmol) in DMF (30 mL) was added dropwise over a 20 minute period to the cooled, stirring solution. The solution was allowed to warm slowly to ambient temperature and stirred 3 h. The product was precipitated with the addition of water (300 mL), separated by filtration, and dried to give the title compound (13.39 g, 61.9 mmol) as an orange solid: 1H NMR (Acetone-d6, 400 MHz): 10.34 (br s, 1H), 9.00 (d, 1H, J=8.6 Hz), 8.60 (d, 2H, J=4.8 Hz), 8.23 (d, 1H, J=8.4 Hz), 7.74 (t, 1H), 7.17 (t, 1H), 7.06 (t, 1H); TLC (EtOAc/Hexanes (3:17)): Rf =0.27.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:20]([Zn]CC)[CH3:21].CCCCCC>O1CCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(Br)c1
Reactant: CC[Zn]CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(C(=O)O)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
3-Bromo-4-(3,4-dichlorophenoxy)benzoic acid (Preparation 8, 240 mg, 0.663 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and cooled to 0° C. Bis(tributylphosphine)palladium (0) (33.7 mg, 0.07 mmol) was added followed by the slow addition of a 1M solution of diethyl zinc in hexane (3.32 mL, 3.32 mmol). The reaction mixture was stirred overnight under an atmosphere of nitrogen. The reaction mixture was then quenched with a 1M aqueous solution of hydrogen chloride and extracted with ethyl acetate. The combined organic phase was concentrated in vacuo and the resulting residue then purified by reverse phase column chromatography (Trilution method) to afford the title compound as a white solid (75 mg, 36%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:18](=[O:21])[NH:19][CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:18]([NH:19][CH3:20])=[O:21])=[CH:16][CH:15]=1
Reactant: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
((1R)-2-(4Fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamic acid tert-butylester (1.0 g; 3.22 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred for 30 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid), were added to the reaction mixture, until pH 9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.62 g of (2R)-3-(4-fluorophenyl)-N-methyl-2-methylaminopropionamide.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26]2[CH:27]=[CH:28][NH:29][C:30]=2[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: FC(F)(F)c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.60 g, 2.2 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.65 g, 2.2 mmol) and potassium carbonate (0.46 g, 3.4 mmol). The product was isolated as a white foam. Yield 165 mg(17%). mp 92-97° C. FDMS m/e=442 (M+ of free base).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH2:15]O)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:15][C:12]1[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:9]2[CH:8]=[N:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:14]=2[CH:13]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(C)c(CNC(=O)c2cc(CO)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(CBr)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 0 °C
Yield: 51.8 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(hydroxymethyl)-1H-indazole-4-carboxamide (0.75 g, 1.90 mmol) in DCM (10 mL), triphenyl phosphine (0.998 g, 3.807 mmol) was added at room temperature. The mixture was cooled to 0° C. after 5 minutes then carbon tetrabromide (1.26 g, 3.80 mmol) was added. On completion, reaction mixture was evaporated under reduced pressure and the crude residue purified by column chromatography over silica gel to afford desired 6-(bromomethyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydro pyridine-3-yl)methyl)-1H-indazole-4-carboxamide (0.45 g, 51.84%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:20]([NH2:21])=[C:19]([CH3:25])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OCC)(=O)C>C1COCC1>[Br:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:20]([NH:21][C:2]2[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=2)=[C:19]([CH3:25])[CH:18]=1
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Reactant: Cc1cc(Br)cc(C)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(COC)n1cc(Cl)nc(Nc2c(C)cc(Br)cc2C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
To (+/−)-3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (300 mg) and 4-bromo-2,6-dimethylaniline (238 mg) in THF (anhydrous, 9.4 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.0 M/THF, 2.6 mL). The mixture was stirred at 0° C. for 10 minutes. Ethyl acetate (100 mL) was added and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4 and concentrated and the crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. The product was then crystallized from ethyl acetate/hexane to afford the title compound (419 mg). Elemental analysis calcd. for C17H21N3O2BrCl: C, 49.23; H, 5.10; N, 10.13. Found: C, 49.33; H, 5.05; N, 10.09.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[NH:5][C:4]1=[O:15].[Cl:16]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:16][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[NH:5][C:4]1=[O:15]
Reactant: CSC1C(=O)Nc2cccc([N+](=O)[O-])c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CSC1(Cl)C(=O)Nc2cccc([N+](=O)[O-])c21

Procedure:
A solution of 3-methylthio-4-nitrooxindole (1.58 g, 7 mmol) and N-chlorosuccinimide (1.20 g, 9 mmol) in 100 ml of methylene chloride was stirred at room temperature for 48 hours. The solvent was removed in vacuo, yielding crude 3-chloro-3-methylthio-4-nitrooxindole. The residue was dissolved in 25 ml of tetrahydrofuran and added rapidly in a vigorously stirred slurry of red mercuric oxide (1.52 g, 7 mmol) and boron trifluoride etherate (1.00 g, 7 mmol) in 100 ml of 50 percent aqueous tetrahydrofuran. After stirring for 3 hours, the solution was filtered through a Celite pad which was then washed with copious amounts of chloroform. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel. Elution with chloroform-ethanol (9:1) gave 4-nitroisatin (535 mg, 40%), mp 248°-250° (dec) (recrystallized from ethanol); ir (KBr) 3200 (NH), 1750 (C=O), 1710 (C=O), 1520 (NO2) and 1350 cm-1 (NO2); nmr (DMSO-d6)τ-1.30 (1H, b s, NH), 2.20-2.80 (m, 3H, aryl H).
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2]>C(OP(O)(O)=O)[C@H]1O[C@H](OP(OP(O)(O)=O)(O)=O)[C@H](O)[C@@H]1O>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([O:7][P:1]([OH:4])([OH:3])=[O:2])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)OP(=O)(O)O)[C@H](O)[C@@H]1O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 0.47 h

Procedure:
The following additions were made to each reaction: 2 μl PRPP, 2 μl PRPP Synthetase, and 20 μl PRPP Synthetase buffer. The reactions proceeded at 37° C. for 28 min at which time the reactions were transferred to 100 μl LAR containing 2 μl ADP and 2 μl NDPK. This second reaction was allowed to proceed at room temperature for 20 min. The amount of ATP produced was measured by the addition of 10 ng of luciferase followed by measuring light output with a luminometer. The data is presented in Table 30.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(C2CCCCC2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
A mixture of 2-cyclohexyl-pyrimidine-5-carboxylic acid (100 mg, 0.48 mmol), 1-hydroxybenzotriazole (74.2 mg, 0.55 mmol), and PS-DCC (505 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 minutes, and aniline (30 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours, PS-trisamine (388 mg, 3.75 mmol/g, 1.45 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated in vacuo to afford 2-cyclohexyl-pyrimidine-5-carboxylic acid phenylamide (45.6 mg, 51%) as a solid. MS: 282 (M+H); IC50=4960 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[CH:25]12[O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]2.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[OH:31])[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Reactant: C1CCC2OC2C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN([C@@H]2CCCC[C@H]2O)C3)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 500 mg, 1.33 mmol), cyclohexene oxide (1.34 mL, 13.3 mmol), and trietylamine (0.55 mL, 3.99 mmol) in ethanol (14 mL) was heated at reflux for 20 h. The solution was cooled to rt, and evaporated. The residue was purified by silica gel column, eluting with 3:1 to 2:1 hexanes:ethyl acetate. The product, racemic trans-2-[1-(2-chlorophenyl)-2-(4-methoxyphenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]cyclohexanol, was isolated as a pale yellow solid (398 mg, 63%). LC-MS m/z (MH+) 437.1, retention time 2.45 min (method 1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:2]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 39 h
Yield: 89.6 %

Procedure:
About 7.23 g of ethyl 3-aminopropionate hydrochloride, 15.71 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 23.00 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 39 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 3-[bis(trimethylsilyl)amino]propionate (3-BTMSAEP) as a colorless oil (11.03 g, 90% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.91 (quartet, 2H, OCH2 protons), 3.21 (multiplet, 2H, NCH2CH2 protons), 2.36 (multiplet, 2H, NCH2CH2 protons), 0.91 (triplet, 3H, CH3 protons), 0.07 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][NH2:17].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)CCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)CCNc1nc(N)nc(O)c1[N+](=O)[O-]

Procedure:
2-Amino-4-chloro-6-hydroxy-5-nitropyrimidine (4 g), 3-methylbutylamine (1.8 g) and triethylamine (6 ml) were heated at reflux for 5 h then left stirring overnight at room temperature in ethanol. The precipitate was filtered and washed with water and air dried to yield the title compound as a yellow solid.