Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22](=[O:34])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:22]([C:19]2[CH:20]=[CH:21][C:15]3[N:14]=[C:13]([C:9]4[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][C:10]=4[CH3:12])[NH:17][C:16]=3[CH:18]=2)=[O:34])=[CH:25][CH:26]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCC(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1

Procedure:
A mixture of 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester (310 mg, 640 mmols) and 3.2 mL of 1N sodium hydroxide in MeOH (1.6 mL) was stirred until the reaction was complete. The solution was neutralized to pH 4-5 with 1N hydrochloric acid and the resulting precipitate was filtered, washed with water, and dried under reduced pressure to afford 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid. 1H-NMR (DMSO-d6, 400 MHz): δ 12.17 (s, broad, 1H), 10.22 (s, 1H), 8.29 (s, broad, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 7.72 (m, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.10 (s, 2H), 2.85 (t, J=7.3 Hz, 2H,), 2.59 (t, =7.3 Hz, 2H), 2.10 (s, 6H). MS (ESI) m/z 470.2 (M+H). High resolution MS (M+H): theory 470.2444, measured 470.2434.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:3]1=2.Cl>CO.CCOCC>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)=[CH:13][C:12]3=[O:29])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:30][NH:31][CH2:32][CH2:33][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.43 g, 0.77 mmol) was treated with 1.25 M HCl in MeOH (15 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with Et2O (50 mL). The resulting solids were collected by filtration, dissolved in 10:3 CH2Cl2/MeOH (50 mL), and washed with saturated NaHCO3 solution (50 mL). The aqueous layer was extracted with CH2Cl2 (8×25 mL), and the organic extracts were combined. The remaining solids in the aqueous solution were separated by filtration and washed with MeOH (100 mL). The resulting filtrate was extracted with CH2Cl2 (3×50 mL). All the organic extracts were combined and concentrated to dryness under reduced pressure. The resulting residue was diluted in CH2Cl2, washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to provide the title compound (0.27 g, 76%) as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=1.5 Hz, 1H), 8.19 (dd, J=8.0, 1.5 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.19 (dd, J=7.5, 2.5 Hz, 1H), 6.03 (s, J=3.0 Hz, 1H), 5.36 (s, 2H), 3.87 (s, 2H), 3.65 (s, 3H), 3.08 (t, J=5.5 Hz, 2H), 2.74 (t, J=5.5 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]([CH3:48])[CH2:36][CH2:37][O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[NH2:42].Cl>C(O)(C)C>[CH3:48][N:35]([CH3:34])[CH2:36][CH2:37][O:38][C:39]1[CH:40]=[C:41]([NH:42][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(N)cc1OCCN(C)C
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1OCCN(C)C

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (prepared according to a procedure similar to that described in Example 27, Step C) and 3-{[2-(dimethylamino)ethyl]oxy}-4-(methyloxy)aniline were heated in isopropanol with catalytic conc. aq. HCl using conditions similar to those described in Example 27, Step D. HRMS C35H32N7O3F2 (M+H)+ calcd 636.2535, found 636.2527.
Reaction SMILES: O[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1.S(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[Cl:31][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)c1
Yield: 76.3 %

Procedure:
To a mixture of methyl 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (1.50 g) and toluene (100 mL) was added thionyl chloride (0.51 g), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (1.20 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH3:12])[C:7]=1[C:13](=[O:15])[NH2:14])=[O:4].[OH:16]O>OO.C(O)(=O)C>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH3:12])=[O:16])[C:7]=1[C:13](=[O:15])[NH2:14])=[O:4]
Reactant: OO
Reactant: CNC(=O)Nc1snc(SC)c1C(N)=O
Solvent: CC(=O)O
Product: CNC(=O)Nc1snc(S(C)=O)c1C(N)=O

Procedure:
A mixture of 4.9 g of 1-methyl-3-(4-carbamoyl-3-(methylthio)-5-isothiazolyl)urea and 20 ml of acetic acid was heated to 95° and to the hot mixture was added dropwise 2.2 ml of 30% hydrogen peroxide. The mixture became homogeneous, but solid began to appear again after a few minutes. The mixture was maintained at 95° for two hours and then 9 drops of 30% hydrogen peroxide were added. After heating was continued an additional hour, thin-layer chromatographic analysis indicated that the reaction was completed. The mixture was cooled to -5°; the solid was isolated, washed with cold water and dried to give 4.7 g of 1-methyl-3-(4-carbamoyl-3-(methylsulfinyl)-5-isothiazolyl)urea; m.p. above 355°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.C[C:14]1(C)[C:18]2(CS(O)(=O)=O)[C:19](C[CH:15]1[CH2:16]C2)=[O:20]>C1COCC1.O1C=CCCC1>[O:20]1[CH2:19][CH2:18][CH2:14][CH2:15][CH:16]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C1=COCCC1
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 1414.9 %

Procedure:
To a solution of 1H-benzo[d]imidazole-5-carboxylic acid (1.62 g, 10 mmol) in THF (20 mL), 3,4-dihydro-2H-pyran (2 mL) and CSA (100 mg) were added. The mixture was heated at reflux for 24 h under argon. Removal of solvent followed by SiO2 chromatography afforded 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid as a light red solid (1.5 g, 60% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH:40]([C:42](OC(C)(C)C)=O)[NH2:41].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.C(OCC)(=O)C.CN(C=O)C>[O:37]1[CH:42]=[N:40][N:41]=[C:36]1[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCc3nnco3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetic acid (0.45 g), tert-butyl hydrazinecarboxylate (0.13 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g), 1-hydroxybenzotriazole (0.13 g) and N,N-dimethylformaldehyde (5 mL) was stirred at room temperature for 13 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 1 hr. 1 M Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was mixed with ethyl orthoformate (0.37 g), methanesulfonic acid (0.016 g) and tetrahydrofuran (7 mL), and the mixture was heated under reflux for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 37%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](OCC3CCN(CCS(C)(=O)=O)CC3)=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][N:3]=1.OC1C=C2C(=CC=1)NC(C)=C2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Agent: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2ncncc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 164.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (115 mg, 0.28 mmol), (prepared as described for the starting material in Example 12), 5-hydroxy-2-methylindole (50 mg, 0.33 mmol) and potassium carbonate (60 mg, 0.42 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5 and 1/0/9) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-41-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (60 mg, 41%).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([O:5][C:6]1[CH:11]([OH:12])[NH:10][CH:9]=[N:8][C:7]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].[CH2:19](Br)[CH:20]=[CH2:21].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:21]([N:10]1[C:11](=[O:12])[C:6]([O:5][C:3](=[O:4])[C:2]([CH3:18])([CH3:17])[CH3:1])=[C:7]([C:13]([O:15][CH3:16])=[O:14])[N:8]=[CH:9]1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: COC(=O)C1=C(OC(=O)C(C)(C)C)C(O)NC=N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCn1cnc(C(=O)OC)c(OC(=O)C(C)(C)C)c1=O

Procedure:
Methyl 5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-1,6-dihydropyrimidine-4-carboxylate (see Example 4, Step 3) was dissolved in THF, then allyl bromide (2 eq.) and Cs2CO3 (2 eq.) were added. The reaction mixture was refluxed for 2 h, then evaporated. The residue was diluted with EtOAc, washed with 1N HCl, dried (Na2SO4) and the solvent evaporated. The product was-purified by flash chromatography on silica gel eluting with a gradient of petroleum ether/EtOAc.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16]
Reactant: [N-]=[N+]=NCCCn1cnc2c(N)ncnc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCCCn1cnc2c(N)ncnc21
Yield: 76 %

Procedure:
A mixture of 9-(3-azidopropyl)adenine (0.5 g, 2.3 mM) and 5% palladium on carbon (0.5 g) in methanol was reacted with hydrogen gas at room temperature for 22 hours. The catalyst was removed by filtration, the solvent removed to give 9-(3-aminopropyl)adenine as a white solid in 76% yield. 1H NMR (DMSO-d6): δ=1.80 (m, 2H, CH2), 2.45 (m, 2H, CH2), 3.35 (S, 2H, NH2), 4.20 (m, 2H, CH2), 7.20 (s, 2H, NH2), 8.10 (s, 2H, CH). MS (ED+): 193.0.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:11]=[C:10]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Product: COc1ccc(Nc2nc(Cl)nc3cc(OC)c(OC)cc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol) and 4-methoxyaniline (49 mg, 0.386 mmol) by a procedure similar to Example 1b and was isolated as white powder (10 mg, 10%). 1H NMR (CDCl3): 8.10 (s, 1H), 7.70-7.68 (m, 2H), 7.23 (s, 1H), 6.96-6.94 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:38]([N:39]([CH3:45])[CH:40]3[CH2:44][CH2:43][S:42][CH2:41]3)=[CH:37][C:15]3[N:16]([CH3:36])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=4[Cl:35])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:56])C=1.C(Cl)Cl.C(O)(=O)C>C([O-])(O)=O.[Na+]>[F:47][C:2]([F:1])([F:46])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:38]([N:39]([CH3:45])[CH:40]3[CH2:44][CH2:43][S:42](=[O:56])[CH2:41]3)=[CH:37][C:15]3[N:16]([CH3:36])[C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[C:21]=4[Cl:35])=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: CN(c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C)C1CCSC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C)C1CCS(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[N-methyl-N-(tetrahydro-thiophen-3-yl)-amino]-1-methyl-1H-benzimidazole-5-carboxylic acid amide (compound 117, 70 mg, 0.098 mmol), mCPBA (23 mg, ˜0.10 mmol), DCM (5 mL) and glacial acetic acid (0.5 mL) is stirred for 2.5 h at rt. The mixture is diluted with sat aq NaHCO3, extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)#[N:8].Br[CH2:19][CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][CH2:19][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]#[N:8])[CH:17]=2)[CH:13]=[CH:14]1
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: OCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1ccc2ccn(CCCO)c2c1
Reaction time: 0.25 h

Procedure:
0.776 mol (87 g) of potassium tert-butylate is added to a solution of 0.703 mol (100 g) of 6-cyanoindole in 2500 ml of tetrahydrofliran at 20° C. After 15 minutes' stirring, 1.41 mol (196 g) of 3-bromo-1-propanol are added and the reaction mixture is stirred for 24 hours at room temperature. After concentration, the residue is taken up in 1000 ml of dichioromethane, and the organic phase is washed with 500 ml of water an d then with 500 ml of a saturated sodium chloride solution. The organic phase is then dried and concentrated to yield the expected compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:28]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][NH:29]1>>[CH:25]1([C:21]2[CH:22]=[C:23]([CH3:24])[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:30][CH2:31][CH2:32][S:28]5(=[O:34])=[O:33])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C#N)CC1
Yield: 83 %

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 189 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (386 mg) was obtained.
Reaction SMILES: [K].S1N=C(C(O)=[O:8])C(C(O)=O)=N1.[C:13]([C:15]1[C:19]([C:20]#[N:21])=[N:18][S:17][N:16]=1)#[N:14].[OH-].[K+]>>[C:13]([C:15]1[C:19]([C:20](=[O:8])[NH2:21])=[N:18][S:17][N:16]=1)#[N:14]
Reactant: O=C(O)c1nsnc1C(=O)O
Reactant: N#Cc1nsnc1C#N
Agent: [K+]
Agent: [K]
Agent: [OH-]
Product: N#Cc1nsnc1C(N)=O

Procedure:
A method for preparing the monopotassium salt of 1,2,5-thiadiazol-3,4-dicarboxylic acid by double stage saponification of 3,4-dicyano-1,2,5-thiadiazole, this method comprising adding aqueous KOH to an aqueous suspension of 3,4-dicyano-1,2,5-thiadiazole in such amount that the molar ratio of 3,4-dicyano-1,2,5-thiadiazole to KOH is from about 1:1.01 to 1:0.8, and maintaining the temperature at from about 20° to 50° C. to thereby catalytically hydrogenate and form 3-cyano-4-carbamoyl-1,2,5-thiadiazole, effecting further hydrolysis by adding additional aqueous KOH in such amount as to result in an overall molar ratio of 3,4-dicyano-1,2,5-thiadiazole to KOH of from about 1:2.0 to 1:2.35 and an overall molar ratio of 3,4-dicyano-1,2,5-thiadiazole to H2O of from about 1:20 to 1:23, at a temperature of from about 85° to 100° C., to thereby form a solution of the dipotassium salt of 1,2,5-thiadaizole-3,4-dicarboxylic acid, and separating the monopotassium salt by acidifying, to a pH of from about 2 to 3, said solution of dipotassium salt of 1,2,5-thiadiazole-3,4-dicarboxylic acid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.C([O-])(O)=O.[Na+].[C:18](Cl)([Cl:20])=[O:19]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:18]([Cl:20])=[O:19])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: NC1CCC2(CC1)OCCO2
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Cl)NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1,4-dioxaspiro[4.5]decan-8-amine (785 mg, 0.005 mol; see Liebigs (1990) Ann. Chem. 8:781-7) in CH2Cl2 and then add H2O (20 mL) followed by saturated NaHCO3 solution (50 mL). Add a toluene solution of phosgene (20% solution, 5 mL) to the reaction mixture and stir at room temperature for 1 hour. Dry the CH2Cl2 layer (Na2SO4) and concentrate under reduced pressure. Dissolve the resulting oil in dry toluene to produce a stock solution (˜0.2 M) of (1,4-dioxa-spiro[4.5]dec-8-yl)-carbamoyl chloride.
Reaction SMILES: [CH:1]([S:14]([CH2:16][C:17]([OH:19])=[O:18])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]([S:14]([CH2:16][C:17]([O-:19])=[O:18])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:20][CH:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CS(=O)C(c1ccccc1)c1ccccc1
Agent: CC(N)c1ccccc1
Product: O=C([O-])CS(=O)C(c1ccccc1)c1ccccc1

Procedure:
(1°) reacting (±)-benzhydrylsulfinylacetic acid with (-)-α-methylbenzylamine to give the (-)-benzhydrylsulfinylacetate of (-)-α-methylbenzylamine (the reaction advantageously being carried out in the presence of a small excess of amine relative to the stoichiometric conditions, and more particularly with a molar ratio amine/acid of between 1.02/1 and 1/15/1 and preferably of between 1.05/1 and 1.10/1),
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:21])[S:12][CH2:13][C:14](=O)[CH2:15][O:16]C(=O)C.Cl.S(=O)(=O)(O)O>C(O)C>[OH:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:21])[S:12][CH:13]=1
Reactant: CC(=O)OCC(=O)CSC(=S)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: OCc1csc(=S)n1-c1ccc(F)c(F)c1F

Procedure:
That is, first the compound (VI) is obtained from the compound (V) in the same manner as in the process (a). The compound (VI) is then reacted with 1-acetoxy-3-halogenoacetone in an organic solvent such as chloroform, methylene chloride or a lower alcohol to give 3-acetoxy-2-oxopropyl N-(2,3,4-trifluorophenyl)dithiocarbamate (XVI). The compound (XVI) is then heated with an inorganic acid such as hydrochloric acid or sulfuric acid in a lower alcohol such as ethanol to give 4-hydroxymethyl-3-(2,3,4-trifluorophenyl)-2(3H)-1,3-thiazolethione (XVII). The compound (XVII) is then reacted with an inorganic base such as sodium hydride, potassium carbonate or sodium carbonate in an aprotic organic solvent such as N,N-dimethylformamide, acetonitrile or dioxane to give 6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (XVIII). The compound (XVIII) is then reacted with a lower alkyl halide such as methyl iodide or ethyl iodide in a polar organic solvent such as N,N-dimethylformamide, acetonitrile or ethanol to give 6,7-difluoro-1-alkylthio-4H-[1,4]benzoxazino[4,3-c]thiazolium halide (XIX). The compound (XIX) is then reacted with di(lower alkyl) malonate sodium salt, which is prepared from di(lower alkyl) malonate and sodium hydride, in an organic solvent such as tetrahydrofuran or dioxane to give di(lower alkyl) (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (XI), which is treated in the same manner as in the process (a) to give the compound (II).