Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: COc1ccc2c(Cl)nncc2c1C#CCCCc1ccccc1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCc1ccccc1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution under N2 of 3,5-dichloro-4-methyl-pyridine (1.28 g, 7.9 mmoles) in dry DMF (15 ml) was added under stirring at room temperature with 60% NaH (316 mg, 7.9 mmoles). The mixture was stirred for 1 hour, then dropwise added with 1-chloro6-methoxy-5-(5-phenyl-pent-1-ynyl)-phthalazine (1.33 g, 3.95 mmoles), prepared as described in example 65, in dry DMF (20 ml). After 3 hours the mixture was poured into water, extracted with ethyl acetate, washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 1:1). The separated product was taken up in ethanol (10 ml) and crystallised. The resultant product was filtered and dried under vacuum at 40° C. to give 940 mg of the title compound (yield: 51%). m.p.: 130-132° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Reactant: NN1CCCCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCCCC2)n(C)n1
Yield: 52 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 1-aminopiperidine instead of N,N-dimethylhydrazine, to the title compound (62 mg, 52%) which was obtained as a colorless oil. MS: m/e=414.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].[Br:11][C:12]1[S:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:6][C:17]([C:15]1[S:16][C:12]([Br:11])=[CH:13][CH:14]=1)=[O:18]
Reactant: O=C(Cl)c1ccc(Br)s1
Reactant: NCc1cc(F)cc(F)c1
Solvent: ClCCl
Product: O=C(NCc1cc(F)cc(F)c1)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 90.5 %

Procedure:
Thionyl chloride (35 ml) is added dropwise to 5-bromo-2-thiophenecarboxylic acid (4.92 g, 23.77 mmol) at 0° C., and the mixture is then heated at 90° C. overnight. After the mixture has cooled to room temperature, the solvent is removed in vacuo, and the residue is washed with cold heptane. 5-Bromothiophene-2-carbonyl chloride is obtained as an almost white solid. 3,5-Difluorobenzylamine (209 mg, 1.46 mmol) is added to a mixture of 5-bromothiophene-2-carbonyl chloride (300 mg, 1.33 mmol), piperidinomethylpolystyrene (410 mg, 3.5 mmol/g, 1.44 mmol) in anhydrous dichloromethane (5 mL) and stirred for 2.5 hr. The reaction mixture is diluted with dichloromethane and filtered through silica gel. The filtrate is concentrated to afford 5-bromo-thiophene-2-carboxylic acid 3,5-difluoro-benzylamide as a white solid (400 mg, 90% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])=O)C.[NH3:31].[Cl-].[NH4+]>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])(=[O:3])[NH2:31]
Reactant: N
Reactant: CCOC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Reaction time: 10 h

Procedure:
1-[1-(3-Ethoxycarbonylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.5 g), aqueous ammonia (10 ml) and ammonium chloride (the affective amount as a catalyst) are dissolved in ethanol (10 ml) and the mixture is stirred at 110°-130° C. for 10 hours in an autoclave. Ethanol is distilled off under reduced pressure and the residue is extracted with methylene chloride. The organic layer is washed with water and saturated saline solution, dried with sodium sulfate and concentrated. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: methylene chloride:methanol=10:1) to give 1-[1-(3-carbamoylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.15 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:40][CH:41]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42]1)(=O)=O.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH2:40][CH:41]5[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[CH2:42]5)=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1cc(Nc2ncnc3cc(O)ccc23)cn1)Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(Nc4cnn(CC(=O)Nc5cccc(F)c5)c4)ncnc3c2)C1
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A mixture of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.59 g, 1.2 mmol), cesium carbonate (1.95 g, 6.0 mmol) and tert-butyl 3-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (assumed 1.3 mmol) in dimethyl acetamide (10 ml) was heated at 80° C. for 6 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 4 to 7% methanol in dichloromethane to yield tert-butyl 3-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.435 g, 65% yield): MS (+ve ESI): 562 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([CH2:19][O:20][CH2:21][C:22](=[O:27])NCOC)[C@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1>O1CCCC1.[Cl-].[NH4+]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([CH2:19][O:20][CH2:21][C:22]([C:33]1[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=1)=[O:27])[C@H:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCNC(=O)COC[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of {(1R,2R)-2-benzyloxy-1-[(methoxymethylcarbamoyl)methoxymethyl]propyl}carbamic acid t-butyl ester (2.42 g) in tetrahydrofuran (50 mL) was cooled to −40° C. and to the mixture was then dropwise added 4-chlorophenylmagnesium bromide (18.3 mL, 1 M tetrahydrofuran solution). The resultant solution was stirred for 1 hour at −40° C., after which the temperature was slowly raised to 0° C. The solution was then diluted with saturated aqueous ammonium chloride. The resultant solution was extracted using ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/1), to thereby obtain the titled compound (2.61 g). The physical properties of this crude product were as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.CN([CH:18]=[O:19])C.[Na+].[Cl-]>C(OCC)C>[CH:18]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)=[O:19]
Reactant: COc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COc1cncc(C=O)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-Bromo-5-methoxypyridine (2.5 g, 13.3 mmol) in anhydrous diethyl ether cooled to −100° C. was added n-butyllithium (2.5M soln in hexanes: 5.85 mL, 14.6 mmol) dropwise whilst maintaining an internal temperature <−94° C. After subsequent stirring for 30 minutes, anhydrous DMF (1.34 mL, 17.3 mmol) was added and the reaction mixture allowed to warm to −60° C.. The solution was then poured into sat'd. aq. NaCl soln. and extracted with diethyl ether (3×100 mL), the ethereal phase dried (K2CO3), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 30% EtOAc in hexanes to afford the title material as an oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].O.[OH-].[Na+].[Br-].[C:8]([C:11]1[CH:12]=[C:13]([CH2:20][N+](C)(C)C)[CH:14]=[N:15][C:16]=1[C:17]([OH:19])=[O:18])([OH:10])=[O:9]>CO>[CH3:1][O:2][CH2:20][C:13]1[CH:12]=[C:11]([C:8]([OH:10])=[O:9])[C:16]([C:17]([OH:19])=[O:18])=[N:15][CH:14]=1
Reactant: C[O-]
Reactant: C[N+](C)(C)Cc1cnc(C(=O)O)c(C(=O)O)c1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1cnc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of 25% sodium methoxide in methanol (270 g, 1.25 mol) and [(5,6-dicarboxy-3pyridyl)-methyl]trimethylammonium bromide, dimethyl ester (347 g, 1.00 mol) in methanol (650 mL) is heated at reflux for 1 hour under nitrogen. Water (1 L) and sodium hydroxide (80.0 g, 2.0 mol) are added and the reaction mixture is distilled until the pot is 100°-105° C. The reaction mixture is cooled to room temperature, treated with sulfuric acid to adjust the pH to a value from 1.5 to 2 and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to obtain the title product as a white solid (mp 161°-162° C.) which is greater than 99% pure by HPLC analysis.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:2]3=[N:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc3c4c([nH]cc-3c2=O)CCCC4)cc1

Procedure:
A mixture of 5.44 g of ethyl 4-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate and 3.45 g of 4-methoxyphenylhydrazine is refluxed 18 hrs in 100 ml toluene. The resulting mixture is stirred with 50 ml 1N NaOH, the layers separated, and the aqueous phase extracted twice with ether. The aqueous layer is then neutralized with aqueous ammonium chloride and filtered. The product is washed with water, and dried to give 2-(4-methoxyphenyl)-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one m.p. 279°-282°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:15][CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][CH:16]([CH3:18])[CH2:17][N:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]1=[O:1]
Reactant: CC(C)CBr
Reactant: COC(=O)c1ccnc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(CC(C)C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a solution of methyl 2-hydroxy-4-pyridinecarboxylate (D26; 1.02 g, 6.66 mmol) in N,N-dimethylformamide (20 ml) was added sodium hydride (60%; 0.293 g, 7.33 mmol). The resulting solution was stirred at room temperature for 15 mins. 1-Bromo-2-methylpropane (0.87 ml, 7.99 mmol) was then added and the mixture was stirred at 80° C. for 2 hrs. The reaction was quenched with methanol and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water, the organic layer dried over magnesium sulphate and concentrated under vacuum. The crude material was purified by chromatography on silica, eluting with 50-80% ethyl acetate in cyclohexane gave the title compound as a light blue solid (450 mg). MS: m/z 210 [MH+]. O-alkylated material was also isolated.
Reaction SMILES: [C:1]1([O:6][CH:7]([O:10][C:11]2[CH2:15][CH2:14][CH2:13][CH:12]=2)[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:16](OC)(=[O:20])[C:17]([CH3:19])=[CH2:18].O>[OH-].[Li+].COC1C=CC(O)=CC=1.CO>[C:16]([O:9][CH2:8][CH:7]([O:6][C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)[O:10][C:11]1[CH2:15][CH2:14][CH2:13][CH:12]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)OC
Reactant: OCC(OC1=CCCC1)OC1=CCCC1
Agent: COc1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)OCC(OC1=CCCC1)OC1=CCCC1
Yield: 84.7 %

Procedure:
In a 3000-liter reactor equipped with a stirrer, a thermometer, an air introducing pipe, a distillation column and a reflux condenser, 776 kg (4 kmoles) of dicyclopentenyloxyethyl alcohol, and 1200 kg (12 kmoles) of methyl methacrylate were placed and mixed well with stirring. The water content of the resulting mixture was 800 ppm. The water content was measured by using a Karl Fischer type digital microamount water content measuring device (mfd. by Mitsubishi Chemical Industries Ltd.). Subsequently, 3 kg of anhydrous lithium hydroxide as a catalyst and 390 g of hydroquinone monomethyl ether as a polymerization inhibitor were added to the reactor, and the reaction was carried out while introducing dried air at a rate of 4 m3/ hr and refluxing the methyl methacrylate through the distillation column. While removing methanol by-produced by the reaction from the distillation column, the reaction was continued until almost no methanol was distilled (about 8 hours), followed by removal of unreacted methyl methacrylate under reduced pressure. After cooling, the reaction solution was filtered under pressure (5 kg/cm2) using a filter paper (pore size 0.1 mm, area 5 m2) placing thereon 10 kg of diatomaceous earth to yield 943 kg of dicyclopentenyloxyethyl methacrylate. The filtering time was 2.5 hours.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:13]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:18]([O-])=O)([CH3:3])[CH3:2].N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:18][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:14](=[O:17])(=[O:16])[NH2:15])[C:5]=1[NH:4][CH:1]([CH3:2])[CH3:3])[C:9]([OH:11])=[O:10]
Reactant: CC(C)Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: CC(C)Nc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
By substituting 4-isopropylamino-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 226° C (decomp.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:5][C:4]=1[N+:19]([O-])=O.[CH3:22][O:23][C:24]([NH:26][C:27](=NC(OC)=O)SC)=[O:25]>CO.[Pd]>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)=[CH:5][C:4]=2[N:19]=[C:27]1[NH:26][C:24](=[O:25])[O:23][CH3:22]
Reactant: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: [Pd]
Solvent: CO
Product: COC(=O)Nc1nc2cc(Oc3ccc(N)cc3)ccc2n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 12.3 %

Procedure:
To a mixture of N-methyl-4-(4-nitrophenoxy)-2-nitroaniline (Intermediate 8B -2.10 g, 2.27 mmol) in MeOH (100 mL) was added 5% Pd—C (catalytic amount) and stirred at room temperature under H2 atmosphere. After 7 hrs, the catalyst was removed by filtration then the solvent was evaporated off. The residual mixture was dissolved into MeOH (50 mL) and added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (3.0 g, 14.5 mmol). The mixture was refluxed overnight. The solvent was removed by evaporation and sequence purification on SiO2 column chromatography gave title compound (87.3 mg, 4%): MS m/e 313 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[O:26].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:25](=[O:26])[NH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1=C(O)N(C)S(=O)(=O)c2sccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.82 g (4.6 mmol) of 2-methyl-4-nitrophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethyl sulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 80 ml methanol. There is obtained 3-hydroxy-2-methyl-4-(2-methyl-4-nitrophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 189°-191° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSc1nnc(N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a mixture of 3.9 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 4.2 g of potassium carbonate and 50 ml of ethanol was gradually added 5 g of ethyl bromoacetate under ice cooling. Then, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 200 ml of water followed by extraction with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The solid obtained was washed with toluene and dried to obtain 2.7 g of ethyl [(5-amino-1,3,4-thiadiazol-2-yl)thio]acetate.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9](F)[CH:8]=2)=[CH:4][CH:3]=1.Br.[CH:17]1([CH2:20][S:21]C(=N)N)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([S:21][CH2:20][CH:17]3[CH2:19][CH2:18]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)s2)cc1F
Reactant: N=C(N)SCC1CC1
Agent: Br
Product: N#Cc1ccc(-c2ccc(Cl)s2)cc1SCC1CC1
Yield: 89.9 %

Procedure:
0.9 g (4.0 mmol) of 4-(5-chlorothiophen-2-yl)-2-fluorobenzonitrile and 0.9 g (4.3 mmol) of S-cyclopropylmethylisothiourea hydrobromide were allowed to react in the same manner as described above in Example 8 (4), and purification of the crude product by silica gel icolumn chromatography afforded 1.1 g of 4-(5-chlorothiophen-2-yl)-2-cyclopropylmethylthiobenzonitrile (yield 91%) as yellow feathery crystals (m.p. 123-124° C.).
Reaction SMILES: CCN(CCN[C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])CC.CCN(C(C)C)C(C)C.CN(C([O:46][N:47]1[N:55]=[N:54][C:49]2[CH:50]=[CH:51][CH:52]=[N:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:25][C:26](=[O:27])/[C:18]/2=[CH:17]\[C:13]1[NH:14][C:15]([CH3:16])=[C:11]([C:9]([O:46][N:47]2[C:48]3=[N:53][CH:52]=[CH:51][CH:50]=[C:49]3[N:54]=[N:55]2)=[O:10])[C:12]=1[CH3:29]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reaction time: 0.08 h
Yield: 86.1 %

Procedure:
15 (10 g, 33.3 mmol) was suspended in DMF (50 ml, 5 P.) and stirred for 5 minutes. DIPEA (9.0 mL, 54.5 mmol) was then added and the mixture was stirred for 10 minutes. HATU (13.95 g, 36.7 mmol) was added and the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight. The intermediate (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (15b) (12 g, 86.5 percent yield) with 86.8% HPLC purity as a yellow powder was got. 1H NMR (300 MHz, DMSO-d6): δ 2.61 (s, 3H, H-31), 2.68 (s, 3H, H-16), 6.87 (m, 1H, H-2), 7.01 (m, 1H, H-6), 7.64 (m, 1H, H-10), 7.85 (m, 1H, H-3), 8.73 (dd, J=1.5, 1.2 Hz, 1H, H-28), 8.83 (dd, J=1.2, 1.5 Hz, 1H, H-27), 13.11 (s, 1H, NH). To a 15b (10.0 g, 23.9 mmol) DMF solution was added N,N-diethylethane-1,2-diamine (7; 3.33 g, 28.7 mmol), the reaction mixture was stirred at 25° C. for completion. HPLC was applied to detect the completion of the reaction. Most of the DMF was removed by rotary evaporating and the residue was suspended in MeCN (100 mL, 10 P.) and stirred for another 1 hour. The solid was collected by filtration, washed with MeCN, and dried under vacuum at 40° C. overnight to give Sunitinib (8.38 g, 88% yield) with 77.6% HPLC purity.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[N+:7]([C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=1[CH3:19])([O-])=O>>[CH3:5][O:4][C:1]([NH:7][C:10]1[CH:15]=[C:14]([NH:16][C:1]([O:4][CH3:5])=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:19])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)OC
Product: COC(=O)Nc1ccc(C)c(NC(=O)OC)c1
Reaction time: 23 h
Yield: 63 %

Procedure:
In a 5 ml reinforced glass flask capable of pressure sealing dimethyl carbonate (2 ml), 2,4-dinitrotoluene (150 mg), the Au/CeO2 catalyst (100 mg, 1 wt % gold relative to cerium) are placed, and the reactor is closed. After purging with N2 for 5 minutes, the reactor is loaded with hydrogen gas at a pressure of 15 bars. The reactor is immersed in a silicone bath preheated at 150° C. and the mixture is magnetically stirred for 23 hrs. After this time, the reactor is brought to atmospheric pressure and opened. The catalyst is filtered and the liquid phase is analyzed by gas chromatography. The disappearance of 2,4-dinitrotoluene and the formation of 2,4-bis(methoxycarbonylamino) toluene in a 63% yield is observed. Smaller amounts (20%) of ortho and para mixtures of the mono carbamoylate 2,4-diaminotoluene derivative are detected.