Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[N:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:20]([C:17]3[CH:16]=[N:15][C:14]([CH3:13])=[CH:19][N:18]=3)=[O:21])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1cnc(C(=O)O)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cn1
Yield: 61.5 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (300 mg, 1.30 mmol, Example 1, Step H), 5-methylpyrazine-2-carboxylic acid (378 mg, 2.74 mmol), BOP—Cl (697 mg, 2.74 mmol), and triethylamine (0.909 mL, 6.52 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamide (280 mg, 61% yield).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.[Cl:12]C1C=CC(OC[CH2:19][CH2:20][CH:21]2[CH2:29][CH2:28][C:24]3[NH:25][CH:26]=[N:27][C:23]=3[CH2:22]2)=CC=1.O>CN(C=O)C>[ClH:12].[CH2:1]([O:8][CH2:19][CH2:20][CH:21]1[CH2:29][CH2:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(OCCCC2CCc3[nH]cnc3C2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCCC2CCc3[nH]cnc3C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 31.3 %

Procedure:
A mixture of dry DMF (5 ml), benzylalcohol (216 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) placed under an atmosphere of nitrogen was heated at 50° C. for 30 minutes. The mixture was allowed to cool to ambient temperature and methanesulfonic acid 2-(1(3)-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)ethyl ester (0.5 g, 1.2 mmol, prepared as described in Example 34) dissolved in dry DMF (5 ml) was added and the reaction mixture was stirred for 2 days. The mixture was poured into H2O (100 ml) and extracted with diethyl ether (2×50 ml). The combined organic extracts were washed with H2O (3×50 ml) and the solvent was evaporated. The residue was dissolved in 90% acetic acid (20 ml) and the mixture was heated at reflux for 1-2 hours. The volatiles were evaporated and the residue was stirred with a mixture of H2O (25 ml) and diethyl ether (20 ml). The phases were separated and the aqueous phase was washed with diethyl ether (2×20 ml). The aqueous phase was adjusted to pH 10-11 with 4 N sodium hydroxide and the oily precipitate was extracted with ethyl acetate (2×20 ml). The combined organic extracts were evaporated and the residue was dissolved in 1 N hydrochloric acid and re-evaporated. The residue was re-evaporated with acetone several times and then stirred with acetonitrile (5 ml). The mixture was filtered and the solid was discarded. The filtrate was evaporated to give 110 mg (31%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.C[Si]([N-:17][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[NH2:17][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1
Reactant: Clc1nsnc1-c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nsnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
3-Chloro-4-phenyl-1,2,5-thiadiazole (3.19 g, 16.2 mmol) in THF (32 ml) at 0° C. was treated dropwise with a solution of lithium bis(trimethylsilyl)amide in THF (17.0 ml, 1.0 M, 17.0 mmol). After 10 min the mixture allowed to warm to ambient temperature for 1.5 hr, treated with 1N hydrochloric acid, and extracted three times into ether (total 300 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol (50 ml) and triethylamine (0.5 ml) was heated to reflux for 15 hr and again concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded 3-amino-4-phenyl-1,2,5-thiadiazole (1.96 g, 68%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[NH:29][CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:29]([C:28]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=3[F:26])[CH3:30])=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: CNc1ccc(F)cc1F
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccc(F)cc1F
Yield: 77 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 2,4-difluoro-N-methylaniline, the title compound was isolated as a yellow solid in 77% yield (92% purity by HPLC).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([CH3:43])[C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[NH2:31][S:28]([C:24]1[CH:23]=[C:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([N:39]([CH3:43])[C:40](=[O:42])[CH3:41])=[CH:37][CH:38]=3)[N:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29]
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(S(N)(=O)=O)c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Temperature: 110 °C
Reaction time: 72 h
Yield: 15.7 %

Procedure:
A mixture of 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.21 mmol), N-(4-aminophenyl)-N-methylacetamide (100 mg, 0.61 mmol) and trimethylsilyl chloride (0.050 mL, 0.40 mmol) in nBuOH (2 mL) and dioxane (2 mL) was heated at 110° C. for 4 h. More trimethylsilyl chloride (0.100 mL, 0.79 mmol) was added. The mixture was stirred at 110° C. for another 72 h. It was then purified by HPLC to give N-(4-(4-(3-aminosulfonyl-phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide as a solid (20 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])[CH:6]([CH3:11])[C:7](=[N:9][OH:10])[CH3:8])=[O:4].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C.C(Cl)Cl>[C:20]1([NH:26][C:27]([O:10][N:9]=[C:7]([CH:6]([N:5]([C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:11])[CH3:8])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(=NO)C(C)N(C(=O)CCl)c1c(C)cccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=NOC(=O)Nc1ccccc1)C(C)N(C(=O)CCl)c1c(C)cccc1C

Procedure:
Following the procedure of Example 11, 3 g of 3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone oxime, 3 g phenylisocyanate and 5 drops triethylamine in 100 ml methylene chloride were stirred, refluxed and worked up to yield the title product, m.p. 115°-117° C. This product is tabulated as Compound No. 18 in Table I.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@@H:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>B(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[CH:3]1[C:9]([Cl:15])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CC(C)=C[C@H]1[C@H](C(=O)O)C1(C)C
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
In a 200 ml flask, there were charged (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid (30.0 g) and toluene (70 g), and thionyl chloride (24.0 g) was added thereto from a dropping funnel at 70° to 80° C. over a period of 30 minutes with stirring. After completion of the addition, stirring was continued for an additional 2.5 hours at the same temperature. Thereafter, the reaction mixture was cooled to 0° C., and boron trichloride (0.94 g) was added thereto, followed by stirring for 30 minutes. Then, the catalyst was removed from the reaction mixture, the solvent was recovered by distillation, and the residue was distilled to obtain racemized 2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride (28.6 g) having a boiling point of 55°-62° C./0.3 mmHg. The proportion of the optical isomers in the resulting product was determined by gas chromatography. The result was as follows: (+)-trans, 46.8%; (-)-trans, 46.8%; (+)-cis, 3.2%; (-)-cis, 3.2%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6](N2CCCC2)=[C:5]([C:19]#[N:20])[C:4]1=[O:21])[CH3:2].[OH-:22].[Na+].Cl>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[N:11]=2)[C:6]([OH:22])=[C:5]([C:19]#[N:20])[C:4]1=[O:21])[CH3:2]
Reactant: CCn1c(=O)c(C#N)c(N2CCCC2)c2ccc(C)nc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1c(=O)c(C#N)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 0.5 g. of 1-ethyl-1,2-dihydro-7-methyl-2-oxo-4-(1-pyrrolidinyl)-1,8-naphthyridine-3-carbonitrile in 15 ml. of 20% aqueous sodium hydroxide containing 15 ml. of ethanol was heated under reflux for 3 hours. The solution was cooled and was acidified with concentrated hydrochloric acid. The precipitate which formed was collected, air dried and was recrystallized from ethanol to afford 0.2 g. of the title compound, m.p. 274°-6° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([S:27][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N+:26]=3[O-:39])=[N:19][NH:20]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccccn4)n[nH]c3c1)C(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4cccc[n+]4[O-])n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.8 %

Procedure:
A round bottom flask was charged with (E)-5-methoxy-3-((3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (25 mg, 0.063 mmol), mCPBA (13 mg, 0.076 mmol), and dichloromethane (4 mL). The reaction was stirred at rt for 24 hrs. Solvent was removed in vacuo and the residue was loaded onto a silica gel column. Elution with 90:10 CH2Cl2/MeOH gave 9 mg (35%) of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) δ 8.41 (d, J=6.0 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.19 (d, J=16.3 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.04 (d, J=17.1 Hz, 1H), 7.91 (d, J=16.1 Hz, 2H), 7.67-7.60 (m, 2H), 7.47-7.43 (m, 1H), 7.25 (s, 1H), 6.85 (s, 2H), 3.64 (s, 3H); MS ESI 411.2 [M+H]+, calcd for [C24H18N4O3+H]+ 411.14.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].Br[CH2:19]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[O:17][CH2:19][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[C:10]=2[CH:15]=1
Reactant: Oc1ccc(Cl)cc1-c1nc2ccccc2[nH]1
Reactant: BrCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2c(c1)-c1nc3ccccc3n1CO2
Temperature: 80 °C
Reaction time: 12 h
Yield: 35.4 %

Procedure:
A mixture of 2-(1H-benzo[d]imidazol-2-yl)-4-chlorophenol (80 mg, 0.33 mmol), dibromo-methane (341 mg, 1.96 mmol), K2CO3 (137 mg, 0.99 mmol) in DMF (6 mL) was allowed to stir at 80° C. for 12 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide 2-chloro-6H-benzo[e]benzo[4,5]imidazo[1,2-c][1,3]oxazine (30 mg, yield: 36%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.07 (d, J=2.1 Hz, 1H), 7.83˜7.81 (m, 1H), 7.78˜7.75 (m, 1H), 7.63 (dd, J=8.8, 2.2 Hz, 1H), 7.54˜7.52 (m, 2H), 7.30 (d, J=8.8 Hz, 1H), 6.33 (s, 2H). MS (M+H)+: 257.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:10])=[O:7].O.[C:25]1([CH:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:5]=1[C:6]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:17]=1)=[O:10])=[O:7]
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(O)cc1
Reactant: CCCCCCC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(Oc1ccc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
0.24 g of 55% sodium hydride dispersion in mineral oil were added to a solution of 1.63 g of N-(2,6-dichlorobenzoyl)-N'-(4-hydroxyphenyl)urea in 15 ml of dimethylformamide; the reaction mixture was stirred for 20 minutes with external cooling with water until a bright solution was obtained. 1.6 ml of 77% 1-phenylheptylbromide were added to this solution after which the reaction mixture was left to stand at room temperature for approximately 2 days. After pouring the reaction mixture on a mixture of ice water and petroleum ether a crystalline product was obtained which was sucked off, washed with successively water and little isopropanol and dried in air. The desired product was obtained in a yield of 0.87 g; melting point 146°-149° C. The product was identified by means of its NMR spectrum. The following compounds were prepared in a corresponding manner:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:37](CC)CC.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl.CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32]([NH2:37])=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCN(CC)CC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.25 h

Procedure:
To a solution of the title acid of Example 2 (200 mg) in CH2Cl2 (3 mL) and CH3CN (1 mL) at 0° C. was added Et3N (120 μL) followed by 2-chloro-methylpyridinium iodide (220 mg). After stirring for 75 mins. at 0° C., an excess of NH3 was slowly bubbled into the mixture and the reaction was allowed to stir at RT for 12 h. It was then diluted with ethyl acetate and washed successively with aq. NH4OAc (×2) and brine. After drying, the organic solution was concentrated and the residue was purified on a column of silica to afford the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]=1[CH3:15]>O1CCCC1.C(=O)([O-])O.[Na+]>[N:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]=1[CH3:15])=[C:1]=[S:2]
Reactant: Cc1cc(C(N)=O)ccc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1N=C=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
Thiophosgene (2.57 mL, 34.6 mmol) was added dropwise to a stirred mixture of 4-amino-3-methylbenzamide (2.60 g, 17.3 mmol) in tetrahydrofuran (43 mL) and saturated aqueous sodium hydrogen carbonate (43 mL) at 0° C. The mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropylether to give the title compound as a brown solid (3.02 g, 15.7 mmol, 91%).
Reaction SMILES: [CH3:1][N:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N+:12]([O-])=O)[CH:3]=O.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][N:2]1[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=2[N:12]=[CH:3]1
Reactant: Cc1ccc(N(C)C=O)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)ncn2C
Temperature: 80 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
N-Methyl-N-(4-methyl-2-nitrophenyl)formamide, 20 g (103 mmols), was added to 400 ml of ethanol and a solution of sodium hydrosulfite, 54g (310 mmols) in 300ml of water was added dropwise to the mixture at 80° C. After stirring at 80° C. for 7 hours, the mixture was stirred at room temperature for further 16 hours. The solvent was distilled off under reduced pressure and 200 ml of 1N sodium hydroxide aqueous solution was added to the residue followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were washed with ether to give 10.0 g (67,3%) of 1,5-dimethylbenzimidazole.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](/[CH:36]=[CH:37]/[O:38][CH3:39])[C:22]([O:34][CH3:35])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([C:23]3[CH:24]=[C:19]([F:18])[CH:20]=[C:21](/[CH:36]=[CH:37]/[O:38][CH3:39])[C:22]=3[O:34][CH3:35])=[CH:3][N:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CO/C=C/c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C/c1cc(F)cc(-c2cnc(-c3ccc(OC(C)C)c(Cl)c3)s2)c1OC
Temperature: 120 °C
Yield: 47.7 %

Procedure:
To a solution of 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (500 mg), 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (510 mg) and tripotassium phosphate (702 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (191 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazole (D79) (311 mg) as a brown oil. MS (ES): C22H21ClFNO3S requires 433. found 434.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:17]([O-])([O-])OCC>C(OCC)C>[F:10][C:8]([F:9])([F:11])[C:6]1[C:5]([F:12])=[CH:4][C:3]2[S:13](=[O:14])(=[O:15])[NH:16][CH:17]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1cc(C(F)(F)F)c(F)cc1S(N)(=O)=O
Solvent: CCOCC
Product: O=S1(=O)NC=Nc2cc(C(F)(F)F)c(F)cc21
Yield: 91.5 %

Procedure:
A mixture of 6 g 2-amino-4-trifluoromethyl-5-fluoro-benzenesulfonamide, m.p.= 152° C. (formula V: R2 = F) and 18 g ethyl orthoformate is heated at 120°-125° C., during 30 minutes to one hour, in an open vessel. After cooling, the reaction mixture is diluted with 150 ml dry diethyl ether. The resulting precipitate is collected and recrystallized from aqueous ethanol, to give 5.7 g of 6-trifluoromethyl-7-fluoro-2H-1,2,4-benzothiadiazine-1,1-dioxide, M.p.= 234° C. B. Action of formic acid
Reaction SMILES: [N+:1]([C:4]1[CH2:5][N:6]([NH:14][CH2:15][C:16]([CH3:19])([NH2:18])[CH3:17])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>ClCCl>[CH3:17][C:16]([NH:18][C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])([CH3:19])[CH2:15][NH:14][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH2:5]1
Reactant: CC(C)(N)CNN1CC([N+](=O)[O-])=Cc2ccccc21
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)NC(C)(C)CNN1CC([N+](=O)[O-])=Cc2ccccc21
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Under a nitrogen atmosphere, a suspension of N1-(3-nitroquinolin-1-yl)-2-methylpropane-1,2-diamine (60.0 g, 231 mmol) in dichloromethane (1.0 L) was chilled in an ice bath. Isopropyl isocyanate (23.8 mL, 242 mmol) was added dropwise over a period of 10 minutes. The reaction was allowed to slowly warm to room temperature. After 17 hours additional isopropyl isocyanate (about 2 mL) was added. After an additional 3 hours more isopropyl isocyanate (1 mL) was added. After 2 more hours the reaction mixture was concentrated under reduced pressure to provide 79.8 g of 1-{1,1-dimethyl-2-[(3-nitroquinolin-1-yl)amino]ethyl}-3-(1-methylethyl)urea as a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:16][O:17][CH2:18][CH2:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCNc1ccc(C2=NNC(=O)NC2C)cc1
Temperature: 80 °C
Yield: 16 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2 g), 2-methoxyethyl-p-toluenesulfonate (3.8 g), potassium iodide (0.5 g) and potassium carbonate (1.3 g) in DMF (18 ml) was heated at 80° C. for 16 hours and evaporated in vacuo. The residue was extracted with ethyl acetate after an addition of water and the extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was triturated with ethyl acetate, collected by filtration, and recrystallized from aqueous ethanol to give 6-[4-(2-methoxyethylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.41 g).