Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(Oc2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mole) with mechanical stirring. When addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-(4-fluorophenoxy)benzene-sulfonylchloride (18.6 grams, 33%) was collected by filtration and dried in the air.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.FC(F)(F)[C:29]1[CH:30]=[C:31]([C:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=1.C1COCC1.C(O)(=O)/C=C/C(O)=O>CN(C=O)C.C(O)C>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:38]1[CH2:37][CH:36]=[C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:29][CH:30]=2)[CH2:40][CH2:39]1)[O:14]3
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2ccccc2)CC1)CO3
Temperature: 25 °C
Yield: 20.1 %

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.40 g, 1.1 mmole) and 4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (0.35 g, 1.54 mmole) were combined in 5 mL of DMF and 5 ml of THF under nitrogen. This solution was refluxed under nitrogen for overnight. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 80 mg of white solid, m.p. 170-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Br)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(Br)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
Ethyl 5-bromosalicylate (299 mg), 4-chloro-6,7-dimethoxyquinoline (270 mg), and 4-dimethylaminopyridine (440 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (40 mg, yield 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].Cl>CCO.[Fe]>[NH2:17][C:16]1[CH:15]=[CH:14][C:4]([CH2:5][P:6](=[O:13])([O:7][CH2:8][CH3:9])[O:10][CH2:11][CH3:12])=[CH:3][C:2]=1[Cl:1]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(N)c(Cl)c1)OCC
Reaction time: 0.17 h

Procedure:
A solution of diethyl (3-chloro-4-nitrobenzyl)phosphonate (Compound 104C, 0.500 g, 1.62 mmol) in EtOH (10 mL) was charged with iron (0.454 g, 8.12 mmol) and heated to reflux. When the reaction mixture reached reflux, it was charged with 0.1 N aq HCl (0.500 mL, 0.0812 mmol) and stirred for 10 min. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The compound was purified on an Isco Combiflash eluting with 40 to 90% EtOAc in heptane to afford the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.19 (t, J=2.40 Hz, 1H), 7.01 (td, J=2.27, 8.08 Hz, 1H), 6.71 (dd, J=0.63, 8.21 Hz, 1H), 3.96-4.08 (m, 4H), 2.96-3.06 (m, 2H), 1.26 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 278.0633 [MH+]. HPLC: tR=1.18 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:27][CH:28]([CH3:30])[CH3:29])[C:5]([CH3:26])=[C:6]([CH:25]=1)[CH2:7][N:8]([CH2:19][CH:20](OC)OC)S(C1C=CC(C)=CC=1)(=O)=O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:27][CH:28]([CH3:30])[CH3:29])[C:5]([CH3:26])=[C:6]2[C:25]=1[CH:20]=[CH:19][N:8]=[CH:7]2
Reactant: COC(CN(Cc1cc(Br)cc(OC(C)C)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(OC(C)C)cc(Br)c2ccncc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
A mixture of N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (108d, 4.7 g, 9.4 mmol) in 6M HCl (75 mL) and 1,4-dioxane (75 mL) was stirred in a sealed tube at 50° C. for 18 hours. Volatiles were removed under vacuum and the aqueous solution was basified to pH 8˜9 with Na2CO3 (s). The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×40 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give 5-bromo-8-methyl-7-(propan-2-yloxy)isoquinoline (108e, 1.6 g, 61%) as a brown oil.
Reaction SMILES: ClC1C(C)=C(S(Cl)(=O)=O)C=CC=1.CC1NC2C=CC=CC=2N=1.[Cl:23][C:24]1[C:25]([CH3:55])=[C:26]([S:30]([NH:33][C:34]2[CH:54]=[CH:53][C:37]3[N:38](S(C4C=CC=C(Cl)C=4C)(=O)=O)[C:39]([CH3:41])=[N:40][C:36]=3[CH:35]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.ClC1C(C)=C(S(NC2C=CC3N=C(C)N(S(C4C=CC=C(Cl)C=4C)(=O)=O)C=3C=2)(=O)=O)C=CC=1.ON1C2C=CC=CC=2N=N1>C1COCC1.O.CO.CO.C(Cl)Cl>[Cl:23][C:24]1[C:25]([CH3:55])=[C:26]([S:30]([NH:33][C:34]2[CH:54]=[CH:53][C:37]3[NH:38][C:39]([CH3:41])=[N:40][C:36]=3[CH:35]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2c(c1)nc(C)n2S(=O)(=O)c1cccc(Cl)c1C
Agent: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2nc(C)n(S(=O)(=O)c3cccc(Cl)c3C)c2c1
Agent: Cc1nc2ccccc2[nH]1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The coupling reaction of 3-chloro-2-methylbenzenesulphonyl chloride (2 eq.) with 2-methylbenzimidazole (1 eq.) under the condition described above yielded a mixture of 3-chloro-N-[1-(3-chloro-2-methylbenzenesulphonyl)-2-methyl-1H-benzoimidazol-5-yl]-2-methyl-benzenesulphonamide and 3-chloro-N-[1-(3-chloro-2-methylbenzenesulphonyl)-2-methyl-1H-benzoimidazol-6-yl]-2-methyl-benzenesulphonamide in 1:1 ratio as judged by 1HNMR. 1H NMR (270 MHz, DMSO): δ 10.7 (2H, s, 2×NH), 7.86-7.96 (3H, m, ArH), 7.65-7.78 (5H, m, ArH), 7.52-7.58 (5H, m, ArH), 7.25-7.40 (3H, m, ArH), 7.07 (2H, t, J=8.2 Hz, ArH), 2.61 (3H, s, CH3), 2.58 (3H, s, CH3), 2.54 (6H, s, 2×CH3), 2.39 (3H, s, CH3), 2.33 (3H, s, CH3). The mixture (200 mg) was dissolved in THF (15 mL), N-hydroxybenzotriazole (200 mg) was added. After stirred at rt for 48 h, the mixture was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulphate and concentrate in vacuo to give a yellow residue, which was purified with flash chromatography (methanol/DCM gradient elution). Off white amorphous powder was obtained. TLC single spot at Rf 10.38 (10% methanol/DCM); HPLC purity 99% (tR 2.0 min in 10% water-methanol); 1H NMR (270 MHz, DMSO): δ 12.1 (1H, s, NH), 10.3 (1H, s, NH), 7.78 (1H, d, J=7.9 Hz, ArH), 7.68 (1H, d, J=7.9 Hz, ArH), 7.29-7.35 (2H, m, ArH), 7.12 (1H, s, ArH), 6.83 (1H, dd, J=8.4, 1.8 Hz, ArH), 2.63 (3H, s, CH3), 2.41 (3H, s, CH3); APCI-MS 334 (M−H+); FAB-HRMS calcd for C15H15ClN3O2S (MH+) 336.0573, found 336.0583.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:21][CH2:22]O>>[Br:1][C:2]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([O:9][CH2:21][CH3:22])=[O:8]
Reactant: CCO
Reactant: O=Cc1cccc(OCCC(=O)O)c1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCOc1cccc(C=O)c1Br

Procedure:
To a solution of 3-(2-bromo-3-formylphenoxy)propanoic acid from the previous step (I eq.) in EtOH (0.13 M) was added conc. sulfuric acid (0.8 eq.). The reaction was heated at reflux for 30 min. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and sat. aq. NaHCO3. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11]C(C=O)=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]([O:18][CH3:19])([CH3:17])C>CO.C(Cl)Cl>[CH3:19][O:18][CH:15]([O:14][CH3:13])[C:17]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: COC(C)(C)OC
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1ccc(OCCO)cc1
Reaction time: 5 h
Yield: 69.9 %

Procedure:
To a solution of 4-hydroxyethoxybenzaldehyde (Bernstein et al., J. Am. Chem. Soc., 73: 906-912 (1951); 8.5 g, 51.2 mmol), 2,2-dimethoxypropane (30 mL, 244 mmol) in a mixture of methanol (40 mL) and CH2Cl2 (100 mL) was added anhydrous Amberlyst 15 (Aldrich) (1.0 g). The mixture was stirred for 5 hours, the catalyst was removed by filtration and the filtrate was concentrated to give the crude product contaminated with the starting aldehyde. This material was chromatographed on silica eluting with 1:1 ethyl acetate-hexane. The pure product fractions were pooled and concentrated. Drying under vacuum afforded 7.6 g (70%) of the title compound as a pale yellow, viscous liquid. 1H NMR: d 7.28 (d, J=9 Hz, 2 H), 6.92 (d, J=9 Hz, 2H), 5.31 (s, 1H), 4.86 (t, J=5.5 Hz, 1H), 3.98 (t, J=5 Hz, 2H), 3.71 (q, J=5 Hz, 2H), 3.20 (s, 3H). 13C NMR: d 158.60, 130.19, 127.74, 113.90, 102.46, 69.43, 59.52, 52.27.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH:4]=[CH2:5].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23])[CH:11]=[CH:10]2)[CH:4]=[CH2:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCOc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To a slurry of 0.45 g (9.4 mmol) sodium hydride (50% dispersion in mineral oil) in 40 mL anhydrous THF was added 1.90 g 5-allyloxyindole. The slurry was stirred at room temperature for 15 min upon which time 1.14 mL (9 mmol) benzene sulfonyl chloride was added dropwise. The reaction was stirred at room temperature over three nights and then poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. The product solidified upon concentration and the crude material was triturated with diethyl ether to afford 1.36 g of 5-allyloxy-1-benzenesulfonyl-1H-indole as a light brown solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20]C)=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: CCOC(=O)Cl
Reactant: NCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)NCCCCC(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
5-aminopentanoic acid hydrochloride (1 g, 6.5 mmol), and potassium carbonate (6.5 g, 47 mmol) were dissolved in water (15 ml) and dioxane (5 ml) then cooled to 0° C. Ethyl chloroformate (3 ml, 31.5 mmol) was added over 30 seconds, then the mixture was stirred for 4 hours at 0° C. Conc. HCl was added until acidic then the mixture was diluted with water and extracted with ether. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)amino]pentanoic acid as a white powder (1.07 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: C1=COCCC1
Reactant: Cc1nc(Cl)c2nc[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
6-Chloro-2-methyl-9H-purine (9.45 g, 56 mmol, the material from Step 2) was suspended in DCM (100 mL) and p-toluenesulfonic acid (Acros Organics, Geel, Belgium, 12% in acetic acid, 0.90 mL, 5.6 mmol) and 2,3-dihydropyran (6.6 mL, 73 mmol) were added. The reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (50° C.) and stirred under nitrogen for 30 minutes. Then, the reaction was cooled to room temperature and stirred overnight. After stirring overnight, the reaction was diluted with DCM and treated with saturated sodium bicarbonate (75 mL). The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum at 45° C. (in a water bath) and then at room temperature and then at 60° C. and finally at room temperature again to afford 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (13.73 g, 97% over 3 steps). MS (ESI pos. ion) m/z: 253. Calculated exact mass for C11H13ClN4O: 252. 1H NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 5.78 (d, J=10.56 Hz, 1H), 4.19 (d, J=11.93 Hz, 1H), 3.84-3.76 (m, 1H), 2.80 (s, 3H), 2.20-1.96 (m, 3H), 1.89-1.64 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[CH:11]([O:13]COCCOC)[CH3:12].O>CO>[Br:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:8])=[O:9])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12]
Reactant: COCCOCOC(C)c1cc(S(N)(=O)=O)sc1Br
Solvent: CO
Solvent: O
Product: CC(O)c1cc(S(N)(=O)=O)sc1Br
Temperature: 25 °C
Yield: 48.9 %

Procedure:
5-Bromo-4-[l-(methoxyethoxymethoxy)ethyl]thiophene-2-sulfonamide (5.3 g, 0.014 mol) was dissolved in methanol (25 ml) and water (25 ml) was added. Some oil separated. To this stirred mixture was added sulfuric acid (25 ml) dropwise with cooling over 20 minutes. The resulting solution was stirred at room temperature over night. The methanol was removed in vacuo and the residual suspension was diluted with two volumes of water. The product was extracted into ethyl acetate. The extract was washed with saturated NaHCO3, water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. This gave 4.0 g of a viscous amber oil. The crude oil was chromatographed on silica gel (150 ml) eluting with 5% methanol/chloroform to give 1.96 g of colorless oil which showed a single spot by TLC. Trituration of the oil in n-butyl chloride gave a white solid (1.69 g, 49%), m.p. 126-128.5° C. NMR supported the structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]=[CH:9][CH2:10][OH:11])[CH2:3][CH2:2]1.O[C:13]1[CH:22]=[C:21]2[C:16]([C:17]([S:23][CH3:24])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:24][S:23][C:17]1[C:16]2[C:21](=[CH:22][C:13]([O:11][CH2:10][CH:9]=[CH:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:14][CH:15]=2)[N:20]=[CH:19][N:18]=1
Reactant: CSc1ncnc2cc(O)ccc12
Reactant: OCC=CCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ncnc2cc(OCC=CCN3CCOCC3)ccc12
Yield: 55.5 %

Procedure:
Using a procedure analogous to the one described for the synthesis of the starting material in Example 16, 4-morpholinobut-2-en-1-ol (1.27 g, 8.13 mmol), (J. Med. Chem. 1972, 15, 110-112), was reacted with 7-hydroxy-4-methylsulphanylquinazoline (1.2 g, 6.25 mmol), (prepared as described for the starting material in Example 8), in methylene chloride (30 ml) in the presence of triphenylphosphine (4.09 g, 1.56 mmol) and diethyl azodicarboxylate (2.46 ml, 1.56 mmol) to give 4-methylsulphanyl-7-(4-morpholinobut-2-en-1-yloxy)quinazoline (1.15 g, 55%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([S:15]([NH:18][C:19]2[S:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])[CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH:12]1[C:13]([NH:14][C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:8][CH:9]=[C:10]([S:15]([NH:18][C:19]2[S:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])[CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 67 %

Procedure:
an Indo-Sulfathiazole Analog: Compound 27j was synthesized by the method outlined in FIG. 1. Briefly, Compound 27j was synthesized by first complexing succinic anhydride with sulfathiazole by reacting these compounds at room temperature for 6 hours in tetrahydrofuran (THF) in the presence of triethylamine (TEA) to produce succinylsulfathiazole as a white solid (67% yield). The succinylsulfathiazole was then reacted for 2 hours at room temperature with O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) in dichloromethane in the presence of TEA to produce the corresponding succinimidyl ester, which was reacted with 1-(4-aminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide in dichloromethane in the presence of TEA at room temperature for 16 hours to produce Compound 27j as a yellow gummy mass (45% yield). Compound 27j was characterized by NMR, two-dimensional NMR, and mass spectroscopy.
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[CH2:5](O)[CH3:6]>>[S:1]([CH2:6][CH2:5][S:1]([OH:4])(=[O:3])=[O:2])([OH:4])(=[O:3])=[O:2]
Reactant: CCO
Reactant: O=S(=O)=O
Product: O=S(=O)(O)CCS(=O)(=O)O

Procedure:
The second method relates to a process for the direct sulfonation of ethanol with gaseous sulfur trioxide. A two stage process is described by Breslow et al (J. Am. Chem. Soc., 1954, Vol 76, pp 5361-5363). First, ethanol is reacted with the first mole of sulfur trioxide at a lower temperature of 0-5° C., then with the second mole of sulfur trioxide at a higher temperature of 50-70° C. Ethionic acid is obtained as a viscous, pale amber liquid. This two stage process is difficult to implement on an industrial scale, since the reaction heat from the exothermic sulfonation is inherently difficult to remove in the first stage at a temperature of 0-5° C.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[Cl:8][C:9]1[C:10]([NH:27][NH2:28])=[N:11][CH:12]=[C:13]([C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])[C:14]([OH:16])=[O:15].C(N(CC)CC)C.O=P(Cl)(Cl)Cl>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:8][C:9]1[C:10]2[N:11]([C:1]([CH3:2])=[N:28][N:27]=2)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26]
Reactant: NNc1ncc(C(=O)O)c(Nc2ccc(I)cc2F)c1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nnc2c(Cl)c(Nc3ccc(I)cc3F)c(C(=O)O)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (0.95 mmol) is added to a solution of 5-chloro-4-(2-fluoro-4-iodophenylamino)-6-hydrazinylnicotinic acid (0.4 g, 0.95 mmol) and triethylamine (1.9 mmol) in DCM (10 ml) at 0° C. The reaction mixture is warmed to room temperature, stirred for an additional 10 min and POCl3 (0.95 mmol) is added. After stirring overnight at room temperature the mixture is refluxed for 3 days. It was diluted with EtOAc and NaHCO3 and stirred for 20 min. The organic layer is washed with H2O, brine, dried with Na2SO4 and concentrated under reduced pressure. The crude product is purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH2:23][OH:24])[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH:23]=[O:24])[CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(CO)nn1-c1cccnc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1cc(S(=O)(=O)c2ccc(F)cc2)n(-c2cccnc2F)n1
Temperature: 100 °C
Reaction time: 42 h
Yield: 80.5 %

Procedure:
{5-[(4-Fluorophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methanol (135 mg) was dissolved in toluene (2 mL), manganese dioxide (167 mg) was added, and the mixture was stirred at 100° C. for 42 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1) to give the title compound as a colorless oil (yield 108 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[I:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[I:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(I)c4)cc23)CC1
Yield: 78.7 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32.0 mg (0.131 mMol) 3-iodobenzoic acid, 15.9 mg (80%) of the title compound were recovered.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15](Cl)=[O:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[N:23]([C:15]([CH:12]3[CH2:13][CH2:14][N:9]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:10][CH2:11]3)=[O:16])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(C1CCN(Cc2ccccc2)CC1)N1c2ccccc2CCc2ccccc21
Reaction time: 14 h
Yield: 36.4 %

Procedure:
A mixture of 1-benzyl-4-piperidinecarbonylchloride hydrochloride (25.0 g, 91 mmol), 10,11-dihydro-5H-dibenzo[b,f]azepine (17.6 g, 90 mmol), N,N-dimethylaniline (25 ml) and toluene (150 ml) was heated at reflux temperature under stirring for 14 h. The mixture was decanted and to the remaining solid 10% ammonia (100 ml) and chloroform (150 ml) were added. The phases were separated and the combined toluene and chloroform phases were dried (K2CO3) and evaporated in vacuo. The residue was purified by chromatography on silica gel (300 g) using benzene and ethyl acetate as eluents. The crude base was crystallised from cyclohexane, yielding 13.0 g (36%) of 4-((10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)carbonyl)-1-benzylpiperidine.