Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([OH:5])([OH:4])([OH:3])[OH:2].[OH-].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9]>>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O[Si](O)(O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: [O-][Si]([O-])([O-])[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
About 1250 ml of 10% aqueous tetramethylammonium hydroxide solution are added to 82.2 g of precipitated silicic acid. After the mixture has been stirred at 25° C. for 16 hours and at 50° C. for 8 hours, a clear solution is obtained. The solution is concentrated to two thirds of its starting volume and the resulting tetramethylammonium silicate is crystallized at 4° C. About 359.5 g of tetramethylammonium silicate which still contains water are obtained. About 160 g of tetramethylammonium silicate are added in portions to a well-stirred mixture containing 400 ml of water, 1000 ml of isopropanol, 1500 ml (1136 g) of 1,1,3,3-tetramethyldisiloxane (obtained under the name "HSi2" from Wacker-Chemie GmbH, D-8000 Munich) and 200 ml of 10% hydrochloric acid and the reaction mixture is then stirred at room temperature for 4 hours. The phases are then separated and the organic phase is washed with water until neutral, dried over sodium sulfate and evaporated completely. The residue is recrystallized from acetone. About 52.0 g of octa(hydrogendimethylsiloxy)octasilsesquioxane are obtained.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:7][CH2:8]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (from Albany Molecular, 1.5 g, 6.5 mmol) in methylene chloride (20 mL) was treated with pyridine (2.14 mL, 26.5 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (1.01 mL, 13.1 mmol) was added dropwise over 5 min. The reaction was stirred at room temperature for 5 h. The resulting mixture was then concentrated and partitioned between EtOAc and water. The organic phases were concentrated and purified on silica gel (eluting with 50% EtOAc in hexanes) to give the desired product (1.48 g, 74%). LCMS calculated for C13H25NO5SNa (M+Na)+: m/z=330.2. Found: 330.0.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:17]2([NH:30][C@H:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:44]I.[NH4+].[Cl-]>C1(C)C=CC=CC=1.O1CCCC1.O>[CH3:44][CH:32]([C:33]([O:35][CH3:36])=[O:34])[C@@H:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:30][C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: CI
Reactant: COC(=O)C[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 26.2 %

Procedure:
Potassium bis(trimethylsilyl)amide in toluene (1.6 mL, 0.5M) was added to tetrahydrofuran (3 mL) and cooled to −78° C. A solution of Example 183B (300 mg, 0.66 mmol) in tetrahydrofuran (2 mL) was added dropwise and stirring was continued at −78° C. for 20 minutes. Methyl iodide (102 uL, 1.64 mmol) was added and the solution was stirred at −78° C. for 3 hours. Potassium bis(trimethylsilyl)amide in toluene (1.6 mL, 0.5M) was added and the solution stirred for another 20 minutes at −78° C. Methyl iodide (102 uL, 1.64 mmol) was added and the solution was warmed to ambient temperature and stirred for 72 hours. To this solution was added 10 mL of saturated NH4Cl and 10 mL of H2O. The resulting solution was extracted with ethyl acetate (3 times 20 mL), the organic extracts were combined, washed with saturated brine solution (20 mL) and dried (Na2SO4). The solution was filtered and the filtrate concentrated to yield a crude residue which was purified by column chromatography on silica gel (3% ethyl acetate/hexane) to give the title compound (79 mg, 25%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:15](Cl)(=[O:17])=[O:16]>O.CC(C)=O>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:15]([N:1]=[N+:2]=[N-:3])(=[O:16])=[O:17]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A solution of sodium azide (3.1 g, 44 mmol) in water (10 ml) was added dropwise at RT to a stirred solution of 2-naphthalenesulfonyl chloride (10 g, 44 mmol) in acetone (60 ml) and stirring was continued for 2 hours. Water (50 ml) was added and the resulting mixture was decanted. The surnatant was discarded, while the brown oily residue was recrystallized from light petroleum producing after drying pure title compound (7.67 g, 32.9 mmol, yield 74.7%) as white needles, m.p.=45°.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[OH-].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:27][CH:26]=3)[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN2CCCC12
Reaction time: 16 h

Procedure:
A solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (80 mg, 0.352 mmol) and powdered KOH (138 mg, 2.46 mmol) in NMP (2 mL) was stirred at RT for 5 min. 2-(Trifluoromethyl)-5-vinylpyridine (122 mg, 0.704 mmol) was added into the reaction mixture and stirring continued for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 10-methyl-7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [Na].[Cl-].[C:3]([CH2:6][O:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH3+:14])([OH:5])=[O:4].[C:15]1([N:21]=[C:22]=[S:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([NH:21][C:22](=[S:23])[NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]2[O:7][CH2:6][C:3]([OH:5])=[O:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Reactant: S=C=Nc1ccccc1
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: O=C(O)CO[C@@H]1CCCC[C@H]1NC(=S)Nc1ccccc1
Yield: 30 %

Procedure:
To a solution of sodium ethoxyde prepared from Na (0.046 g, 2 mmoles) and ethanol (10 ml), there were added trans-2-carboxymethoxy-cyclohexyl ammonium chloride (0.419 g, 2 mmoles) and phenylisothiocyanate (0.270 g, 2 mmoles). The mixture was refluxed for 1 hour, evaporated and the residue was dissolved in 1N NaOH (25 ml). The solution was extracted with diethyl ether (2×20 ml), the aqueous phase was acidified with HCl 18% to pH 2 and reextracted with diethyl ether (3×20 ml). The organic phase was dried with MgSO4, the drying agent was filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol/ether. Thus, there were obtained 0.185 g (30%) of the title compound in the form of white crystals, melting point 147°-149° C.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35](ON1C(=O)CCC1=O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][C:35]([NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Nc1cnn2c1NCCC2
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.2 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (4.44 g) and N-ethyldiisopropylamine (3.88 g) in methylene chloride (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.29 g). The mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 3-[3-(tert-butoxycarbonylamino)propionyl]amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (3.67 g) as an oil.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:17])[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[CH3:2][C:3]1([CH3:17])[CH2:8][N:7]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=3)[CH:26]=2)[CH2:6][CH2:5][N:4]1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC1(C)CNCCN1c1ccc(C#N)cn1
Agent: Cl
Product: CC1(C)CN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CCN1c1ccc(C#N)cn1
Yield: 33 %

Procedure:
This compound was synthesized from 6-(2,2-dimethylpiperazin-1-yl)nicotinonitrile hydrochloride and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (50 mg, yield 33%). 1H NMR (400 MHz, MeOD) δ 8.43 (d, J=1.8 Hz, 1H), 8.29-8.22 (m, 2H), 7.75-7.72 (m, 3H), 6.88 (d, J=9.0 Hz, 1H), 4.05-3.85 (m, 4H), 3.67 (m, 2H), 1.67-1.47 (m, 6H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.2 (M+H)+
Reaction SMILES: C([O:5][C:6](=[O:35])[C@@H:7]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH2:8][NH:9][C:10](=[O:24])[CH2:11][NH:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:19]1[S:20][CH:21]=[C:17]([CH2:16][CH2:15][CH2:14][C:13]([NH:12][CH2:11][C:10]([NH:9][CH2:8][C@H:7]([NH:25][S:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:6]([OH:35])=[O:5])=[O:24])=[O:23])[N:18]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)CNC(=O)CCCc1csc(N)n1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(CCCC(=O)NCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cs1

Procedure:
Ester 1-8 (365 mg, 0.69 mmol) was dissolved in CH2Cl2 (3.5 mL), then TFA (3.5 mL) was added. After 5 h the reaction mixture was concentrated, azeotroped with toluene, then purified by sequential flash chromatography (silica, 22:20:1:1 EtOAc/EtOH/H2O/NH4OH, then silica, 4:1:1 CH2Cl2/MeOH/HOAc, then 7:1:1 CH2Cl2/MeOH/HOAc), providing 1-9 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([O:12][C:11]([F:10])([F:20])[F:21])[CH:14]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1cccc(OC(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-trifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.12 (d, 1H, J=3 Hz), 7.68 (bs, 1H), 7.53 (dd, 1H, J=1.2 and 8.4 Hz), 7.41 9 t, 1H, J=8.1 Hz), 7.04 (bdt, 2H); 19F NMR (CDCl3): −16430 and −44463; LCMS: purity: 89%; MS (m/e): 308 (MH+).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[I:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([I:12])[C:5]2=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2ccnc-2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(Cl)c2c(I)cnc-2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.66 mmol) was dissolved in anhydrous DMF (20 mL) and N-iodo succinimide (718 mg, 3.19 mmol) was added. After stirring for 45 minutes at rt, reaction mixture was poured into water (400 mL) and extracted with EtOAc (2×500 mL) Organics were combined and washed with brine (500 mL) and dried over sodium sulfate. Solvents were removed under reduced pressure and purified via column chromatography to afford 2,4-dichloro-5-iodo-1H-pyrrolo[2,3-d]pyrimidine (660 mg, 2.103 mmol) as a yellow solid. ESIMS (M+H)+=315
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CC1(C)CCCC(C)(C)N1[Li].Cl([F:27])(=O)(=O)=O>C1COCC1>[F:27][C:9]1[S:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: COc1cccc2ccsc12
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: COc1cccc2cc(F)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 1-benzothien-7-yl methyl ether (230 mg, 1.40 mmol) in dry THF (5 mL) was added dropwise to a freshly prepared solution of 2,2,6,6 tetramethyl-lithio-piperidine (1.68 mmol) in THF (10 mL) at −78° C. The resulting solution was stirred at this temperature for 30 mins before perchloryl fluoride gas was condensed into the reaction. After the strong exotherm had stopped the mixture was allowed to stir at −78° C. for a further 30 mins. After this time the reaction was quenched with NH4Cl (sat, 20 mL) and diluted with diethyl ether. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane to yield a colourless oil (128 mg, 50%); δH (300 MHz, CDCl3) 7.32–7.20 (2H, m, Ar), 6.80–6.62 (2H, m, Ar), 3.95 (3H, s, OCH3).
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].[Na].CS.Cl[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[CH:3]=[S:4]
Reactant: O=Cc1ccccc1Cl
Reactant: CS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1C=S
Temperature: 25 °C
Yield: 106.1 %

Procedure:
A four-necked flask of 200 ml capacity, equipped with a stirrer, thermometer and reflux condensor, was charged with 11.2 g (0.28 mol) of sodium hydroxide and 80 g of water under a nitrogen atmosphere and 13.5 g (0.28 mol) of methanethiol was bubbled through the charge at room temperature for about 1 hour to prepare an aqueous solution of methanethiol sodium salt. To this aqueous solution was added 28.1 g (0.2 mol) of 2-chlorobenzaldehyde and the reaction was conducted in the presence of 1.1 g of tetra-n-butylammonium bromide (phase transfer catalyst) at 80° C. for 4 hours. The reaction mixture was then cooled to room temperature and extracted with methylene chloride. The methylene chloride layer was separated, concentrated and distilled under reduced pressure to give 28.9 g of 2-methylthiobenzaldehyde (b.p. 116°-118° C./5 mmHg). The yield based on 2-chlorobenzaldehyde was 95%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][N:23]=1>CS(C)=O.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][N:23]=2)[CH:12]=1)=[O:10]
Reactant: Clc1nccc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccc(C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2nccc3ccccc23)c2ccc(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
1.65 g (11.9 mmol) of potassium carbonate are added at 25° C. under an argon atmosphere to 0.900 g (4.75 mmol) of 3-methoxycarbonyl-5-methyl-1H-indole in 10 cm3 of dimethyl sulphoxide. After stirring at 25° C. for 0.5 hour, 0.677 cm3 (4.75 mmol) of 1-chloroisoquinoline is added. After stirring at 100° C. for 48 hours, the reaction mixture is cooled and diluted with 100 cm3 of ethyl acetate and then washed with 3 times 50 cm3 of water and 25 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.50 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), 1.4 g of 3-methoxycarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole are obtained in the form of a white solid melting at 142° C.
Reaction SMILES: [H-].[Na+].[NH:3]([C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([Cl:19])[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.C(Cl)(Cl)Cl>C(#N)C>[NH:3]([C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:20][CH:22]2[O:24][CH2:23]2)=[C:12]([Cl:19])[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCC1CO1
Reactant: Clc1nc(Nc2ccccc2)nc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Clc1nc(Nc2ccccc2)nc2c1ncn2CC1CO1
Reaction time: 48 h
Yield: 34.6 %

Procedure:
Sodium hydride (161 mg, 4 mmol; 60% suspension in mineral oil) was added to a suspension of 2-anilino-6-chloropurine (1 g, 4 mmol; Focher et al. (1988) J. Med. Chem. 31:1496-1500) in anhydrous acetonitrile (240 ml) at room temperature. After stirring for 1 hr epibromohydrin (0.35 ml, 4 mmol) was added, and the suspension was stirred for 48 hr. An equal volume of chloroform was added, and, after filtration through Celite, the filtrate was evaporated to dryness. The residue was chromatographed on silica gel, and the major product was eluted with chloroform to give 417 mg (34% yield) of 2-anilino-6-chloro-9-(2,3-epoxypropyl)purine. 1H NMR δ9.97 (s, 2-NH), 8.24 (s, 8-H), 7.40 (m, C6H5), 4.38 (m, 1'-CH2), 3.45 (m, 2'-CH), 2.72 (m, 3'-CH2). Further elution gave 46 mg (3.8% yield) of the minor 7-isomer.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH3:8][O:9][N:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1>>[CH3:8][O:9][N:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:2]3[O:3][CH:4]=[CH:5][C:6]=3[Br:7])=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: Brc1ccoc1Br
Reactant: CON=C1CCc2cc(B(O)O)ccc21
Product: CON=C1CCc2cc(-c3occc3Br)ccc21
Yield: 30 %

Procedure:
The title compound (1.6 g, 30%) was prepared from 2,3-dibromofuran and the product of Example 5 Step 6 using the method of Example 15 Step 1; 1H NMR (CDCl3) 7.88 (2H, m), 7.72 (1H, d, J 8.3 Hz), 7.42 (2H, d, J 3.1 Hz), 4.01 (3H, s), 3.17 (2H, m), 2.92 (2H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[S:18](=[O:20])(=[O:19])[N:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16](=[O:25])[CH:15]=2)[CH:9]=1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[S:18](=[O:20])(=[O:19])[N:17]([C:21]([CH3:23])([CH3:22])[CH3:24])[C:16](=[O:25])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)N1C(=O)C=C(c2cccc(N)c2)S1(=O)=O

Procedure:
[3-(2-tert-Butyl-1,1,3-trioxo-2,3-dihydro-1H-isothiazol-5-yl)-phenyl]-carbamic acid tert-butylester (77 mg, 0.20 mmol) was treated with 1,4-dioxane-HCl following general procedure V to give 5-(3-Amino-phenyl)-2-tert-butyl-isothiazol-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]\[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:11][CH:10]=1)([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+:33].CO>>[CH3:6][C:2]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]\[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:11][CH:10]=1)([CH3:1])[C:3]([O-:5])=[O:4].[Na+:33]
Reactant: Cc1ccc(C(=O)c2cccn2C/C=C\c2ccc(COC(C)(C)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)c2cccn2C/C=C\c2ccc(COC(C)(C)C(=O)[O-])cc2)cc1

Procedure:
To the compound of Example 1-2 (384 mg, 0.92 mmol) was added sodium hydroxide in methanol (0.1 mol/l, 9.2 ml, 0.92 mmol) and the solvent was removed in vacuo. The residue was subjected to azeotropic distillation with diethyl ether to give the subject compound (quant.).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([O-])(=[O:17])=[O:16])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].S(Cl)([Cl:24])=O>>[N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([Cl:24])(=[O:17])=[O:16])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCCS(=O)(=O)[O-])OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (20 mL) was added to sodium 2-(4-nitrobenzyloxycarbonylamino)-ethanesulfonate (A, 1.25 g). After stirring at room temperature for 10 min, the mixture was refluxed for 3 hr and concentrated in vacuo. The residue was suspended in benzene and the mixture was filtered over diatomaceous earth. The filtrate was concentrated in vacuo to afford the title compound (0.1 g) as a white powder: 1H NMR (400 MHz, CDCl3) δ 3.82-3.97 (m, 4H), 5.23 (s, 2H), 5.43 (br s, 1H), 7.51 (d, J=8.8 Hz, 2H), and 8.23 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:37]([CH3:39])[CH3:38]>>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]1[N:31]=[CH:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(C)Br
Product: COc1ccc(N2CCN(C(=O)Cc3cn(C(C)C)cn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 20 %

Procedure:
Prepared using the same procedure described in Example 336 using 1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-(1H-imidazol-4-yl)-ethanone and 2-bromopropane to afford the title compound as an orange solid (67 mg, 20% overall). LC/MS (Method B) 2.88 min, [M+1]+ 517.