Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]([CH3:26])[CH:7]=1)=[O:5]
Reactant: COC(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1cn(C)c2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.1 %

Procedure:
A 0° C. suspension of (6-benzyloxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (2.70 g, 8.73 mmol) in dimethylformamide (25 mL) is treated with sodium hydride (437 mg, 10.9 mmol). The mixture is stirred at 0° C. for 20 minutes. Methyl iodide (1.00 mL; 16.1 mmol) is added. The reaction mixture is stirred at 0° C. for 30 minutes and quenched with water (100 mL). The mixture is extracted with EtOAc (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography eluting with 60% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to afford the title compound (0.68 g, 24%). ES.MS m/e 324.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C@@H:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH3:32])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (3R,4R)-4-{[(4-chlorophenyl)carbonyl](methyl)amino}-3-(3,4-dichlorophenyl)piperidine-1-carboxylate (700 mg) obtained in Example 168 in ethyl acetate (5 mL) was added 4N hydrogen chloride/ethyl acetate solution (5 mL), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the precipitate was collected by filtration to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]COC(C)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid(2.07 g, 11.2 mmol) and cH2SO4(0.5 ml) in MeOH(10 ) was refluxed for 8 h. The solvent was evapolated. The residue was dissolved in AcOEt and washed with saturated NaHCO3 aqueous solution, water, brine, dried (Na2SO4) and concentrated to give 2.14 g(96%) of ivory solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].S(Cl)(Cl)=O>CC(O)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:14]([C:13](=[O:18])[CH3:12])[C:15](=[O:17])[CH3:16])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
To a suspension containing 3.0 g (0.02mol) of 4-carboxybenzaldehyde and 3.0 g (0.03mol) of 2,4-pentanedione in 10ml of 2-propanol was gradually added 3.0 g (0.025mol) of thionyl chloride with stirring and cooling (below 20° C). The mixture was stirred over night at 20° C. After filtering the product was washed with 2-propanol, yield 1.8 g, mp 195°-199° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:25][CH:26]([O:32][CH2:33][CH3:34])[C:27]([O:29]CC)=[O:28])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:25][CH:26]([O:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C(C)(C)C)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C(C)(C)C)c1)C(=O)O
Yield: 81.8 %

Procedure:
Ethyl 3-[3-tert-butyl-4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]-2-ethoxypropanoate (0.025 g; 0.050 mmole) was dissolved in THF and water (2:1), 0.1 M lithium hydroxide (2 ml) was added and the reaction mixture was stirred over night. Water was added and the THF evaporated. The remaining water was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.019 g (80% yield) of the product.
Reaction SMILES: [Li]CCCC.[C:6]12([PH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:6]12([PH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: CC(C)(C)Cl
Reactant: PC12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)PC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
nBuLi (20 cm3, 32 mmol 1.6M soln) was added over 1 hour to a cooled solution of 1-adamantyl phosphine (5.0 g, 30 mmol) in THF (100 cm3). The solution was allowed to warm to room temperature and stirred for a further 2 hours. The solution was recooled to 0° C. and tert-butylchloride (2.78 g, 30 mmol) was added and stirring continued for a further 16 hours at room temperature. The reaction mixture was quenched with water and the aqueous phase extracted with dichloromethane (2×50 ml). The organic phase was dried over sodium sulphate and evaporated in-vacuo to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[C:6]([CH3:20])([CH3:19])[CH2:5]2.[CH3:21][O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:28])[C:24]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:7]2[C:6]([CH3:20])([CH3:19])[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[NH:8]2)[CH:13]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(Cl)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 22.2 %

Procedure:
A mixture of 3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1.5 g, 5.25 mmol), 2-bromo-2-methyl-propionic acid methyl ester (2.85 g, 15.7 mmol) and potassium carbonate (3.62 g, 26.25 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 5 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(30% ethyl acetate/hexanes) to afford 2-[3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (450 mg, 22%) as a brown oil: LC/MS m/e calcd for C22H27ClN2O2 (M+H)+: 387.93, observed: 387.1.
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH2:10])=[C:8]([NH2:11])[C:6](=[O:7])[N:5]([CH3:12])[C:3]1=[O:4].[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=O>CO>[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]1[NH:11][C:8]2[C:6](=[O:7])[N:5]([CH3:12])[C:3](=[O:4])[N:2]([CH3:1])[C:9]=2[N:10]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CO
Product: Cn1c(=O)c2[nH]c(-c3ccc(Cl)cc3N)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.5 %

Procedure:
1,3-dimethyl-5,6-diaminouracil (0.01 mol) was suspended in 50 ml methanol. 2-amino-4-chlorobenzoic acid (0.01 mol) was added, followed by 0.01 mol of DICD. The reactants were stirred at room temperature for 15 min, then filtered and washed with methanol. The solid was boiled in 40 ml 2.5N NaOH for five min, filtered hot, and the eluate was left to cool for three hours. The material which precipitated on cooling was filtered without washing, redissolved in 40 ml water, and precipitated by neutralization with concentrated HCl. The solid was collected by filtration, washed with H2O, and dried. The product was purified by suspending in 100 ml water, adding NaOH until the compound was dissolved, filtering, precipitating the solid with HCl, filtering, washing with H2O, and drying. The product was identified by chemical ionization mass spectrometry and elemental analysis. Yield 12.5%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]([O:14][CH2:15][CH3:16])=[S:13])[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[O:20]>C(#N)C>[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]([O:14][CH2:15][CH3:16])=[S:13])[N:3]=1)=[O:32])(=[O:28])=[O:29])=[O:20]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CCOC(=S)SCc1cc(OC)nc(N)n1
Solvent: CC#N
Product: CCOC(=S)SCc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)n1

Procedure:
7.0 g of 2-amino-4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidine and 6.5 g of 2-methoxycarbonylphenylsulfonylisocyanate are suspended in 20 ml of abs. acetonitrile, and the suspension is stirred at 20° to 25° C. for 2 hours. A clear solution is firstly formed during this time, and the final product subsequently crystallises out. To isolate the final product, the reaction mixture is cooled to 0° C. and then filtered. The yield is 9.0 g (67% of theory) of N-(2-methoxycarbonylphenyl-sulfonyl)-N'-(4-methoxy-6-ethoxythiocarbonylthiomethyl-pyrimidin-2-yl)-urea, m.p. 160°-162° C. (decomp.).
Reaction SMILES: [CH:1]1([C:5]2[C:10]([O:11][CH2:12][C:13]3[N:17](COCC[Si](C)(C)C)[C:16]4[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=4[N:14]=3)=[N:9][N:8]3[C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])=[N:31][N:32]=[C:7]3[CH:6]=2)[CH2:4][CH2:3][CH2:2]1>Cl.C(O)C>[NH:17]1[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=[C:13]1[CH2:12][O:11][C:10]1[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:6][C:7]2[N:8]([C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])=[N:31][N:32]=2)[N:9]=1
Reactant: C[Si](C)(C)CCOCn1c(COc2nn3c(-c4ccc(F)cc4F)nnc3cc2C2CCC2)nc2ccccc21
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-c2nnc3cc(C4CCC4)c(OCc4nc5ccccc5[nH]4)nn23)c(F)c1
Yield: 41.7 %

Procedure:
A solution of 7-cyclobutyl-3-(2,4-difluorophenyl)-6-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-ylmethoxy]-1,2,4-triazolo[4,3-b]pyridazine (187 mg, 0.333 mmol) in 5M hydrochloric acid (10 ml) and ethanol (4 ml) was heated at 80° C. overnight, then concentrated in vacuo to remove solvents. Saturated potassium carbonate solution was added, then the mixture was diluted with water, filtered and the residual solid washed with water then ether and then dried. The residue was purified by flash chromatography on silica gel using ethyl acetate as eluent to give the title compound (60 mg, 42%). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ10.62 (1H, br s), 7.85 (2H, m), 7.56 (1H, d, J 1.6 Hz), 7.48 (1H, br s), 7.32 (2H, m), 7.00 (2H, m), 5.65 (2H, s), 3.54 (1H, m), 2.24 (2H, m), 2.01 (3H, m). 1.80 (1H, m); MS (ES+) m/e 433 [MH]+.
Reaction SMILES: [Na+].[Br:2][C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[N:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]2[N:8]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]([CH:13]([CH3:15])[CH3:14])[C:10](=[O:12])[O:11]2)=[CH:16][CH:17]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)C(N=Cc1ccc(Br)cc1)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCC(=O)N1C(c2ccc(Br)cc2)OC(=O)C1C(C)C
Temperature: 40 °C
Yield: 34 %

Procedure:
12.6 g of 2-[(4-bromobenzylidene)amino]-3-methylbutyric acid sodium salt (41.1 mmoles) are suspended in 80 ml of dry dichloromethane. The mixture is refluxed (40° C.), under slight nitrogen stream. 7.9 g of valeryl chloride (65.5 mmoles) are added. After 2 hours under reflux, the mixture is cooled to 25° C. The organic phase is washed three times with 50 ml of water and concentrated under reduced pressure, at 25-30° C., to obtain an oily residue. 50 ml of ethyl acetate are added and the organic phase is washed with a weakly basic NaOH solution and/or with water to neutrality. The organic phase is washed with a sodium bisulfite solution. The organic phase is washed with water and dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue is taken up with ethanol from which the product crystallizes as a white solid. 2-(4-Bromophenyl)-4-isopropyl-3-pentanoyl-oxazolidin-5-one is obtained (5.2 g; 14.1 mmoles; molar yield: 34%).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[N+:37]([O-:39])=[O:38].O>CN(C)C=O>[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([O:23][C:32]4[CH:33]=[CH:28][C:29]([N+:37]([O-:39])=[O:38])=[CH:30][C:31]=4[N+:34]([O-:36])=[O:35])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 270 mg, 6.75 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (2.0 g, 6.16 mmol) in N,N-dimethylformamide (30 mL) at 0° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 1-chloro-2,4-dinitrobenzene (1.37 g, 6.78 mmol) and the mixture was stirred for 20 minutes at room temperature. The reaction mixture was poured into water (50 mL), and extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (1.5 g, yield 50%).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH:19]=O>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH2:19][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[C:3]([OH:2])=[O:11]
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccccc1N
Product: O=C(O)c1ccccc1NCc1c(Cl)cncc1Cl

Procedure:
Prepared by a similar procedure as described for preparation 1J, starting from anthranilic acid methyl ester and 3,5-dichloro-4-pyridinecarboxaldehyde (Aldrich). 13C-NMR (DMSO-d6) δ 170.1, 149.7, 147.9, 142.6, 133.5, 132.2, 131.7, 115.1, 113.2, 110.9, 41.4.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14]>C(OCC)(=O)C.P(Cl)(Cl)(Cl)=O>[CH2:13]([O:15][CH2:16][CH2:17][O:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5])[CH3:14]
Reactant: C=COCC
Reactant: COC(=O)C(=NO)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOCCON=C(C(=O)OC)c1cccs1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred mixture of methyl 2-hydroxyimino-2-(thien-2-yl)acetate syn-isomer (3.98 g.) and ethyl vinyl ether (2.5 mls) in ethyl acetate (25 mls) was added phosphorous oxychloride (2 drops). After 20 mins. at 50° the ethyl acetate was washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to an oil, giving methyl 2-(1-ethoxy)ethoxyimino-2-(thien-2-yl)acetate (syn-isomer) (5.7 g; 100%) λmax. (EtOH) 289 nm (ε 11,700), τ (CDCl3 ; 60 MHz) 2.61 (multiplet; thienyl H5), 2.82 to 2.97 (multiplet; thienyl H3 and H4), 4.64 (quartet, J5 Hz; ##STR57## 6.06 (singlet, --COOCH3), 6.24 (quartet, J 7 Hz, OCH2), 8.56 (doublet J 5 Hz; CH--CH3), 8.79 (triplet, J 7 Hz; O.CH2CH3).
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[N:9]=[C:8](F)[C:7]=1[F:16])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>C(O)CC>[C:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[N:9]=[C:8]([NH:18][NH2:19])[C:7]=1[F:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COc1c(F)nc(F)c(F)c1OC(C)(C)C
Solvent: CCCO
Solvent: O
Product: COc1c(F)nc(NN)c(F)c1OC(C)(C)C
Yield: 88.5 %

Procedure:
A mixture of 4-tert-butoxy-2,3,6-trifluoro-5-methoxypyridine (1.5 g. 6.4 mmol) and hydrazine monohydrate (1.7 mL, 34 mmol [Qun Li et al. J. Med. Chem. 1996, 39(16), 3070-3088]) in n-propanol (10 mL) was heated to reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichlromethane, washed with water and concentrated to afford crude (4-tert-butoxy-3,6-difluoro-5-methoxypyridin-2-yl)hydrazine (1.4 g, 90%). 1.2 g of the material was redissolved in methanol (12 mL) and 20% aqueous sodium hydroxide (2.5 mL). Oxygen was passed through the solution with vigorous stirring for 20 hours. The deep blue solution was diluted with water (12 mL) and extracted with hexane (2×30 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexane (1:16) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 1H), 3.93 (m, 3H), 1.41 (s, 9H). MSCI: m/z=218 (MH+).
Reaction SMILES: Cl.[C:2]([CH:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[NH:7]1)([O:4][CH3:5])=[O:3].[C:13]([CH2:18][CH2:19][C:20](Cl)=[O:21])([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>CC(C)=O>[C:13]([CH2:18][CH2:19][C:20]([N:7]1[CH:6]([C:2]([O:4][CH3:5])=[O:3])[CH:11]2[CH2:12][CH:8]1[CH2:9][CH2:10]2)=[O:21])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: COC(=O)C1NC2CCC1C2
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(=O)N1C2CCC(C2)C1C(=O)OC

Procedure:
Using the method of Example 1, 4.45 g (0.0232 m) of 3-carbomethoxy-2-azabicyclo[2.2.1]heptane hydrochloride and 3-carbethoxypropanoyl chloride were reacted using triethylamine and acetone to give 4.59 g of syrupy 2-(3-carbethoxypropanoyl)-3-carbomethoxy-2-azabicyclo[2.2.1]heptane.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([Cl:5])=[C:7]([S:14]([N:17]2[CH2:18][CH2:19][S:20](=[O:23])[CH2:21][CH2:22]2)(=[O:16])=[O:15])[C:8]=1[OH:13])=[O:33]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Yield: 46 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (88 mg, 0.27 mmol) and 2-bromophenylisocyanate (65 mg, 0.33 mmol) were coupled to form the desired urea (65 mg, 46%). LC-MS (m/z) 524.2 (M+).
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[C:6]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Agent: O=S(=O)(O)O
Product: CCC(=O)Nc1n[nH]c(C(C)(C)C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2 g (0.01 mole) of 5-t-butyl-3-propionylaminopyrazole as prepared in Example 5 was dissolved in 20 ml of concentrated sulfuric acid, and the solution was cooled to 0° C. 0.6 ml of fuming nitric acid was added dropwise thereto, and the mixture was allowed to react for one hour at 0° C. After completion of the reaction, the reaction solution was poured into a large amount of ice, whereby crystals were precipitated. The crystals were collected by filtration and washed with water to obtain 1 g of 5-t-butyl-4-nitro-3-propionylaminopyrazole.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][N+:13]([O-:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc[n+]([O-])cc1

Procedure:
A solution of 40.6 g of 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine and 40 g of m-chloroperbenzoic acid in 500 ml methylene chloride is stirred 16 hours at room temperature. Solution is washed with 2N sodium hydroxide and water, dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyldimethylsilyloxymethyl)-pyridine-N-oxide.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[H-].[Na+].Cl[C:7]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:23])[CH:13]=2)[N:8]=1.O>CN(C=O)C>[Cl:23][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:3][CH:1]=[O:2])[N:16]=[C:15]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC=O
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a solution of 54 mg of dry formamide in DMF (5 ml) was added 48 mg of sodium hydride (60%), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3), followed by warming to 85° C. and further stirring for 3 hours. The resulting reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The extract was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 64 mg of the titled compound. Mp.252.1° C. 1H NMR: 7.59-7.66 (3H, m), 7.72-7.81 (3H, m), 7.88 (1H, d, J=8.8 Hz), 8.02 (1H, d, J=2.0 Hz), 8.37 (1H, br. d, J=10.4 Hz), 9.71 (1H, d, J=10.4 Hz).