Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]N.[C:3]1([NH:9][C:10]([NH2:12])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([NH:9][C:10](=[O:11])[NH:12][NH2:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: NN
Product: NNC(=O)Nc1ccccc1

Procedure:
Other known methods for the preparation of 4-aryl-1,2,4-triazol-3-ones involve the use of hydrazine as a raw material. In one such method, phenylurea is reacted with hydrazine to give a 4-phenylsemicarbazide. The semicarbazide is then condensed with ethyl formate to give the 4-phenyltriazolone. The overall yield from this method is about 20%. In another method, a 4-phenylsemicarbazide is reacted with formic acid to form the 1-formyl-4-phenylsemicarbazide intermediate, followed by intramolecular condensation to the 4-phenyltriazolone. The yield obtained by this method is about 40%. In yet another method, a substituted aniline is converted to the phenylcarbamate derivative. The phenylcarbamate is treated with hydrazine to give the phenylsemicarbazide derivative, followed by condensation with formamidine acetate to give the 4-phenyltriazolone. Each of these methods requires the use of the toxic compound hydrazine. In addition, the methods suffer from low overall yield.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:4].Br[CH2:19][C:20]1[O:21][C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1>C1COCC1.[NH4+].[Cl-].CCOCC>[C:25]1([C:23]2[N:24]=[C:20]([CH2:19][N:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]3[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=3)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:21][C:22]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COC(=O)COc1cccc(NC(=O)OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
NaH (0.34 g of a 50% dispersion in mineral oil, 3.5 mmol) was washed twice with hexanes and covered with dry THF (10 mL). A solution of methyl [3-[(methoxycarbonyl)amino]phenoxy]acetate (0.75 g, 3 mmol) in dry THF (10 mL) was added and the mixture stirred at room temperature. After about 30 minutes, a solution of 2-bromomethyl-4,5-diphenyl-oxazole (0.99 g, 3 mmol) in THF (7 mL) was added and the mixture stirred overnight at room temperature. The mixture was diluted with saturated NH4Cl solution and Et2O, the organic phase separated, washed with H2O and saturated NaCl solution and dried over MgSO4. The solvent was evaporated and the residue chromatographed on a column of silica gel using a mixture of hexanes and EtOAc (4:1) as eluent to give methyl [3-[[(4,5-diphenyl-2-oxazolyl)methyl](methoxycarbonyl) amino]phenoxy]acetate (0.71 g, 48%). IR (film) 1760, (CO2CH3), 1715 (NCO2CH3) cm-1 ; 1H NMR (CDCl3) δ3.73 (6H, s, CO2CH3), 4.58 (2H, s, OCH2CO2CH3), 4.99 (2H, s, CH2 -oxazole), 6.79 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 7.02 (2H, m, aromatic H), 7.20 to 7.45 (7H, m, aromatic H), 7.50 to 7.65 (4H, m, aromatic H); MS m/z 473 (MH+).
Reaction SMILES: [OH-].[NH4+:2].[C:3]([P:7](=[O:18])([O:16]C)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(OC)=[O:4]>>[C:3]([P:7](=[O:18])([O-:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])[NH2:2].[NH4+:2]
Reactant: COC(=O)P(=O)(OC)OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)P(=O)([O-])OCc1ccccc1

Procedure:
An aqueous solution of 45 parts ammonium hydroxide is stirred and chilled with an ice bath, while 24.4 parts benzyl methyl carbomethoxyphosphonate is added slowly. Stirring is continued until a clear solution is obtained. Unreacted ammonium hydroxide and water are removed from the mixture under reduced pressure, leaving as a solid residue ammonium monobenzyl carbamoylphosphonate, m.p. 186, after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.ClCCl.[CH3:31][NH:32][C:33]([NH2:35])=[O:34].N1C=CC=CC=1>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:35][C:33]([NH:32][CH3:31])=[O:34])=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(OC2CCCC2)C(=O)O)cc1Cl
Reactant: CNC(N)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Fc1ccccc1
Product: CNC(=O)NC(=O)C(OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A cooled (0° C.) solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetic acid (Example 6; 100 mg, 0.30 mmol) in fluorobenzene (2.5 mL) and N,N-dimethylformamide (1.8 μL). was treated with a 2.0 M solution of oxalyl chloride in dichloromethane (0.18 mL, 0.36 mmol). Immediately a vigorous gas evolution was observed, and the mixture was stirred at 25° C. for 1 h and became light yellow in color. Methyl urea (97 mg, 0.90 mmol) was then added and after the reaction was heated at 70° C. for 10 min, pyridine (0.048 mL, 0.60 mmol) was added and the reaction was maintained at 70° C. for 1 h. The cooled mixture was diluted with ethyl acetate (5 mL) then was filtered through Celite to remove insoluble materials and the filtrate concentrated in vacuo. The concentrate was washed with 3N hydrochloric acid (1×20 mL), saturated sodium bicarbonate (1×15 mL) and brine (1×15 mL), then was dried over sodium sulfate, filtered and evaporated under reduced pressure. The product was purified by chromatography (Biotage Flash 40S column, 50/50 hexanes/ethyl acetate) to provide rac-1-[(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetyl]-3-methyl-urea (78 mg, 67% yield) as a white foam: FAB-HRMS m/e calculated for C16H21N2O5SCl (M+H)+ 389.0938, found 389.0943.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reaction time: 0.5 h

Procedure:
2-Bromo-5-nitropyridine (0.3 g, 1.48 mmol) was treated with piperazine (0.64 g, 7.89 mmol) in tetrahydrofuran (4 ml) and the reaction mixture was stirred for 30 minutes. Subsequently the reaction mixture was poured onto ice-cold water (25 ml) and extracted with ethyl acetate (25 ml). The organic layer was washed with brine and evaporated to furnish the product.
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:33]([O-])=O)[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5]>CC(C)=O.[Zn]>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:33])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
Ammonium chloride (4.10 g, 76.6 mmol) and water (9.1 mL) were added to a solution of 1-[6-nitro-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (5.92 g, 85% pure, 10.9 mmol) in acetone (46 mL). Zinc dust (5.01 g, 76.6 mmol) was then added in portions with vigorous stirring. Stirring was continued for 45 min, at which point the reaction mixture was filtered through diatomaceous earth. The filter cake was rinsed thoroughly with EtOAc (100 mL). The filtrate was concentrated and the residue was dissolved in EtOAc (75 mL), decanting from the remaining salts. The organic layer was washed with brine (45 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (2-70% EtOAc/hexanes) to yield the titled compound (4.19 g, 89% yield). MS (ESI/Cl): mass calcd. for C20H27N5O4Si, 430.2; m/z found, 429.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (d, J=0.6 Hz, 1H), 8.15 (d, J=0.6 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.6, 2.8 Hz, 1H), 5.78 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 4.09 (s, 2H), 3.57-3.43 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 0.86-0.74 (m, 2H), -0.08 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14]2[S:18][C:17]([C:19]3[N:20]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:21](=[O:25])[CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[C:42](OC(=O)C)(=[O:44])[CH3:43].CO>C(O)(=O)C.[Fe]>[C:42]([NH:1][C:4]1[CH:41]=[CH:40][C:7]([CH2:8][NH:9][S:10]([NH:13][C:14]2[S:18][C:17]([C:19]3[N:20]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:21](=[O:25])[CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(NS(=O)(=O)NCc3ccc([N+](=O)[O-])cc3)s2)nccc1=O)C(=O)C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1ccc(CNS(=O)(=O)Nc2ccc(-c3nccc(=O)n3CC(=O)NC(C(=O)C(F)(F)F)C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[5-(4-nitrobenzylaminosulfonylamino)-6-oxo-2-thienyl-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.431 g) in acetic acid (12 mL) was added acetic anhydride (0.265 mL), followed by iron powder (0.783 g). The reaction was stirred at room temperature overnight. Methanol was added and the reaction mixture filtered through diatomaceous earth to remove excess iron. Ethyl acetate was added and the resultant solution washed (water (twice), brine), dried (MgSO4) and evaporated. The crude material was purified by chromatography, with dichloromethane:methanol (gradient, 99.5:0.5, 98:2) as the eluent, to provide the title compound (0.247 g); TLC: Rf =0.27, dichloromethane:methanol (98:2); NMR: 0.87-0.97 (m,6), 2.17-2.30 (m,1), 3.32 (s,3), 4.02 (d,2), 4.73-4.77 (m,1) 4.77-4.93 (m,2), 7.13-7.20 (m,3), 7.33 (d,1), 7.47 (d,2), 7.80-7.87 (m,1), 7.91 (s,1), 7.97-8.03 (m,1), 9.04 (d,1), 9.09 (s,1), 9.87 (s,1); MS: m/z=629(M+1).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[NH2:2].C([O:13][C:14](=O)[CH2:15][C:16]([CH3:18])=O)C>>[CH3:18][C:16]1[CH2:15][C:14](=[O:13])[N:1]([C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[N:2]=1
Reactant: N#Cc1cccc(NN)c1
Reactant: CCOC(=O)CC(C)=O
Product: CC1=NN(c2cccc(C#N)c2)C(=O)C1

Procedure:
From the reaction of 3-hydrazinobenzonitrile and ethylacetoacetate, 3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzonitrile is obtained. Subsequent reaction with 2-ethylaniline yields 3-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzonitrile, Mp 210.8° C.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:19][OH:20])[C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1F)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([C@@H:8]1[C@@H:9]([OH:10])[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H](Cc1ccccc1)[C@@H](O)c1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (prepared from 33.5 kg (54.8 moles) of [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, 1-methyl-2-pyrrolidinone solvate without isolation) in 185 L of tetrahydrofuran was added 12.9 kg (115 mol) of potassium tert-butoxide. The reaction mixture was heated at reflux for 4 hours at which point the reaction was found to be complete by thin layer chromatography (hexanes/ethyl acetate, 3:1). The reaction mixture was cooled to ambient temperature, quenched with 170 L of water, diluted with 83 L of ethyl acetate, and acidified to pH 5.3 (aqueous layer) with 7.5 L of concentrated hydrochloric acid. The organic layer was concentrated under vacuum to approximately 38 L of a slurry, diluted with 76 L of isopropyl ether, warmed to dissolve the solids, slowly cooled to 0° C., and granulated at 0° C. for 12 hours. (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol, 5.1 kg of white solid, was isolated by filtration. The mother liquor was washed with 4 L of saturated aqueous sodium chloride, concentrated to a final volume of 57 L, and granulated at 0° C. for 12 hours affording a 4.3 kg second crop of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1.CCN(CC)CC.O>C1COCC1>[C:1]([NH:5][C:6]1[N:15]=[CH:14][C:13]2[C:12]([S:16][CH3:17])=[N:11][CH:10]=[N:9][C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ncnc2cc(NC(C)=O)ncc12
Temperature: 20 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Acetyl chloride (0.70 mL, 9.84 mmol) is added to a solution of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.20 g, 1.04 mmol) (described in a previous experimental) and Et3N (1.51 mL, 10.8 mmol) in THF at 0° C., and then the mixture is stirred at 20° C. for 4 h. Water (50 mL) was added, then the solution was extracted with EtOAc (3×50 mL). Evaporation and chromatography on alumina (1% EtOH/CHCl3) yields 7-acetylamino-4-methylthiopyrido[4,3-d]pyrimidine (0.12 g, 49%) as a yellow solid, . 1H NMR (DMSO) δ 11.05 (1H, s), 9.30 (1H, s), 9.02 (1H, s), 8.38 (1H, s), 2.71 (3H, s), 2.18 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:23][C:24]([OH:26])=[O:25]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:23][C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Product: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccc(Cl)cc1

Procedure:
A mixture of 2 parts of (p-chlorophenyl)diphenyl carbinol and 8 parts of malonic acid are heated at 170° for 31 hours. This mixture is cooled and then dissolved in hot ethanol, affording 3-p-chlorophenyl-3,3-diphenylpropionic acid. 1 Part of 3-(p-chlorophenyl)3,3-triphenylpropionic acid is then refluxed with 5 parts of thionyl chloride for 4 hours and the excess thionyl chloride is removed in vacuum to provide the crude 3-(p-chlorophenyl)3,3-diphenylpropionyl chloride. 9 Parts of this 3-(p-chlorophenyl)-3,3-triphenylpropionyl chloride are then reacted with 27.0 parts of 4-benzyl-4-hydroxypiperidine in the presence of 4 parts of triethylamine in benzene. The resulting amide is reduced with 5 parts of lithium aluminum hydride in ether at reflux for 2.5 hours. The reaction mixture is cooled and treated with 15% aqueous sodium hydroxide solution to decompose any unreacted lithium aluminum hydride. The reaction mixture is then filtered and washed with ether. The ether solution is evaporated to give an oil. This oil is then slurried in 10% HCl and extracted with ether. The aqueous phase which contains an insoluble oil is extracted with methylene chloride, and the methylene chloride extract dried over anhydrous sodium sulfate. Evaporation of this methylene chloride solution gives a solid which is taken up in acetone and precipitated with ether which affords 1-[3-p-chlorophenyl)-3,3-diphenylpropyl]-4-benzyl-4-hydroxypiperidine hydrochloride having the following structural formula ##STR20##
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3](OCC)=[O:4].C[O-].[Na+].CO.[CH3:17][NH:18][CH3:19].P(=O)(O)(O)O>>[OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([N:18]([CH3:19])[CH3:17])=[O:4]
Reactant: CNC
Reactant: CCCCC(O)C(=O)OCC
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCC(O)C(=O)N(C)C
Yield: 81 %

Procedure:
In a three-neck flask, at 20° C. and under an inert atmosphere, are mixed ethyl 2-hydroxycaproate (24.24 g; 150 mmol) and sodium methylate in solution in methanol (25% w/w) (1.6 g; 7 mmol). To this mixture, is added dimethylamine in solution in methanol (50% w/w) (26.75 g; 297 mmol) within 30 minutes. The temperature of this mixture is brought to 40° C. and maintained for 3 hours. After the return of the temperature of this reaction mixture to 20° C., orthophosphoric acid is added until a pH of 5 is obtained. The salts formed are removed by filtration and the solvents are removed under reduced pressure. 2-hydroxy-N,N-dimethylhexanamide is then obtained with a purity of 98%, i.e. a yield of 81%.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: CCn1ccnc(Br)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1ccnc(-c2ccc(Cl)cc2)c1=O
Yield: 47.6 %

Procedure:
To 200 mg (0.98 mM) of 3-bromo-1-ethylpyrazin-2(1H)-one and 57 mg (0.05 mM) of palladium tetrakis triphenylphosphine in 4 ml of toluene were added, under nitrogen, 231.0 mg (1.48 mM) of 4-chlorophenylboronic acid and 2.9 ml of 2M sodium carbonate aqueous solution The mixture was stirred for 3 h at reflux under nitrogen atmosphere, and then at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, over anhydrous sodium sulfate, and concentrated. The compound was purified through a silica plug, eluting with dichloromethane, which afforded 110 mg of 3-(4-chlorophenyl)-1-ethylpyrazin-2(1H)-one as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[F:6][C:7]1[CH:8]=[C:9]([CH:15]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[S:13][CH3:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:6][C:7]1[CH:8]=[C:9]([CH:15]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:16]([N:4]([O:3][CH3:2])[CH3:5])=[O:18])[CH:10]=[CH:11][C:12]=1[S:13][CH3:14]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)O)cc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (467 mg) in acetonitrile (16 mL) was neutralized with triethylamine (1.82 mL), and 2-[3-fluoro-4-(methylsulfanyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (1.30 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (918 mg) and 1-hydroxybenzotriazole (73.4 mg) were added under ice-cooling. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.33 g, yield 89%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12]
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 0.754 ml of tert.-butanol were reacted to obtain 0.235 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclo-propane-1-carboxylate with a specific rotation of [α]D20 =-23°±1.5°(c=0.9% in chloroform).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8]C=1C.OS(O)(=O)=O>O>[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:2]=1[C:1]([OH:4])=[O:3]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C

Procedure:
To a stirred glacial acetic acid solution of Na2Cr2 07 (80.46 g, 0.26 mol) in a 2 1 beaker was added 2-fluoro-4-nitrotoluene (31.03 g, 0.2 mol) followed during 10 minutes by concentrated H2SO4 (200 g). The initially bright orange solution became viscous and black and then boiled at just over 100° C. The resulting green slurry was heated for a further 1 hour at 90° C. Water (236 ml) was added and the resulting solution was cooled to 0° C. to give pale green crystals which were recovered by filtration and washed sparingly with cold water. The product (22.14 g) was recrystallised from water (200 ml) as pale green microneedles (21.16 g, 57.2%). M.P. 175°-178° C., Lit. F. C. Schmelkes and M. Rubin, J. Am. Chem. Soc. 66, 1631, (1944), 176°-177° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(C(=O)O)cs1
Temperature: 25 °C
Yield: 119.5 %

Procedure:
To a solution of ethyl 2-amino-1,3-thiazole-4-carboxylate (150 mg) (for example available, from Maybridge Chemical Company) in 1,4-dioxane (3 ml) was added 2M hydrochloric acid (2 ml) and the mixture heated at reflux under nitrogen for 70 h. The mixture was cooled to room temperature and the solvent removed in vacuo. Toluene (15 ml) was added and the solvent removed in vacuo to give a solid that was dried in an vacuum oven overnight to give the title compound (150 mg) as a brown solid.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(C3OC(C#N)=CC=3)=O)=[C:29]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:28]=2)[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:17]([C:6]3[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=3)=[O:19])=[C:29]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:28]=2)[CH2:25][CH2:26]1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCCCC3)c2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(N3CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
A flask was charged with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (0.043 g, 0.14 mmol) (as prepared in Example 3, step (d)), 4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (0.028 g, 0.10 mmol) (as prepared in Example 5, step (b)), EDCI (0.030 g, 0.16 mmol), DMAP (0.012 g, 0.010 mmol), and DMF (0.5 mL) and was stirred for 12 h at RT and then 1 h at 60° C. The reaction mixture was loaded on a 10-g SPE cartridge (silica) and eluted with 10% MeOH/DCM to give 0.030 g (57%) of title compound. Mass spectrum (ESI, m/z): Calcd. for C27H41N7O2Si, 524.3 (M+H), found 524.1.