Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])(=O)[CH2:2][CH2:3][CH3:4].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][NH2:30])=[CH:25][CH:24]=1.CC([O-])=O.[Na+]>CCO>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:6]([C:1](=[N:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH3:4])[CH:11]=1
Reactant: NOc1ccc(Cl)cc1
Reactant: CCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCC(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 62.2 %

Procedure:
A solution of N-(2-butyryl-4-chlorophenyl)trifluoromethanesulfonamide 29A (333 mg, 1.0 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (200 mg, 1.10 mmol) and anhydrous NaOAc (91 mg, 1.10 mmol) in EtOH (30 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:4) and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19 to 3:7) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)butyl]phenyl}trifluoromethanesulfonamide 166 (283 mg, 62%), as a yellow solid. M.p. 62.5-64.5° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.27, br s, 1H; 7.72, d, J=8.8 Hz, 1H; 7.57, d, J=2.4 Hz, 1H; 7.41, dd, J=2.4 and 8.8 Hz, 1H; 7.35, d, J=8.8 Hz, 2H; 7.11, d, J=8.8 Hz, 2H; 2.98, m, 2H; 1.71, sextet, 2H; 1.09, t, J=7.4 Hz, 3H.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1>>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2ccccc2F)ccc1O
Product: COc1cc(C(=O)c2ccccc2F)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
7.8 ml of 65 percent nitric acid are added dropwise at 20° within 20 minutes to 29.4 g of 2'-fluoro-4-hydroxy-3-methoxybenzophenone (dissolved in 450 ml of acetic acid). After stirring for 1.5 hours, the reaction mixture is poured into 2 l of ice-water and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methanol. There is obtained 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone of m.p. 127°-129°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][N:36]=[C:35](S(C)(=O)=O)[N:34]=2)=[CH:31][CH:30]=[CH:29][N:28]=1>O>[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)[N:34]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Cl)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3nccc(-c4cccnc4Cl)n3)cc2)CC1
Temperature: 70 °C

Procedure:
In a 48 mL sealed pressure vessel, was added 4-(4-methylpiperazin-1-yl)benzenamine (0.851 g, 4.45 mmol), potassium carbonate (1.03 g, 7.42 mmol), N,N-dimethylformamide (10 mL) and 4-(2-chloropyridin-3-yl)-2-(methylsulfonyl)pyrimidine (Step 1, 1.0 g). the vessel was heated to 70° C. for 22 hours, cooled to room temperature, diluted with water, extracted into ethyl acetate, washed 1× with water and 1× with NaCl solution. The organics were dried over magnesium sulfate, filtered through fritted Buchner funnel, and concentrated. The crude was chromatographed on silica gel using 15-60% 90:10:1 (CH2Cl2:MeOH:NH4OH/CH2Cl2) as a gradient. Concentrated the product fractions to yield 4-(2-chloropyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine as a brown solid. MS (M+H)+=381. Calc'd 380.87 for C20H21ClN6.
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:24]I>>[CH3:24][O:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: CI
Reactant: OC1(c2ccc(Sc3ccc4ccccc4c3)s2)CCOCC1
Product: COC1(c2ccc(Sc3ccc4ccccc4c3)s2)CCOCC1
Yield: 81 %

Procedure:
Using the procedure described in Example 1, 4-hydroxy-4-[5-(naphth-2-ylthio)thien-2-yl]tetrahydropyran was reacted with methyl iodide to give 4-methoxy-4-[5-(naphth-2-ylthio)thien-2-yl]tetrahydropyran in 81% yield, m.p. 70° C.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:13]([NH:15][C@@H:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:14])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.Cl>C(O)C.[Pd]>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@@H:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H](C)NC(=O)c1cccc2c3c([nH]c12)CCC3
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](C)NC(=O)c1cccc2c1NC1CCCC21
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A solution of ethyl (2S)-2-[(1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (8.4 mmol, 2.5 g) in ethanol (40 mL) was added to a mixture of 5% palladium on carbon (2 g) in ethanol (20 mL). Concentrated hydrochloric acid (10 mL) was added and the resulting mixture was hydrogenated at 45 psi for 4 hours. The reaction mixture was filtered through Celite. The filter bed was washed well with ethanol and the combined filtrates were concentrated. The resulting oil was partitioned between 1 N NaOH and ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated to yield an oil (1.9 g, 6.1 mmol, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14](OCC)[CH2:15][CH3:16])[S:10][C:9]2=[S:20])=[CH:4][CH:3]=1.C(O)C.[S-2:24].[Na+].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([SH:24])[CH2:15][CH3:16])[S:10][C:9]2=[S:20])=[CH:4][CH:3]=1
Reactant: [S-2]
Reactant: CCOC(CC)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(S)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O
Reaction time: 0.25 h

Procedure:
To a suspension of 3 g. (0.091 m.) of 3-(4'-chlorophenyl)-5-(1'-ethoxypropylidene)-rhodanine in 15 ml. of ethanol is added a solution of sodium sulfide in 10 ml. of water and the mixture is stirred at room temperature until solution is complete (15-20 minutes). This solution is added to 100 ml. of water, allowed to stand for 15 minutes, filtered and the filtrate is acidified with 2N hydrochloric acid to give 3-(4'-chlorophenyl)-5-(1'-mercaptopropylidene)-rhodanine, m.p. 163°-165°C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C>>[C:18]([O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)(=[O:20])[CH3:19]
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@H](c2ccc(CN(C)C)cc2)CC1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and acetylchloride/triethylamine. Colourless syrup.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:25]1([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=4[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I8) (0.131 g, 0.224 mmol) was dissolved in DCM (7 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.857 mL, 11.2 mmol) was added to the solution and the reaction was stirred at room temperature for 24 hours. Volatiles were removed in vacuo, EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the oil and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL), the combined organics were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was taken up in DCM (˜5 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice to give the title compound (1) (0.104 g, 96% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.96 (s, 1H), 8.60 (s, 1H), 7.61-7.53 (m, 2H), 7.43 (br s, 1H), 7.25-7.13 (m, 4H), 6.98-6.86 (m, 3H), 3.50 (s, 2H), 3.12-3.05 (m, 2H), 3.04-2.94 (m, 6H), 2.86-2.78 (m, 4H). LCMS Method C: rt 4.774 min; m/z 485.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[C:8]([CH3:18])[C:7]=2[N:6]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1Br
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1n[nH]c2c1nc(-c1ccccc1Br)c1ccccc12
Reaction time: 4 h

Procedure:
The preparation took place in analogy to example 34 (D) using 196 mg of 2-bromo-N-(3-methyl-5-phenyl-1H-pyrazole-4-yl)-benzamide, except 6 ml of phosphorous oxychloride was used and the reaction was stirred for 4 hrs. The residue was triturated with dichloromethane to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35]Br)[CH:32]=[CH:31][N:30]=1)=[O:28])[CH3:25]>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:32]=[CH:31][N:30]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1cc(CBr)ccn1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)ccn1
Temperature: 80 °C
Yield: 63 %

Procedure:
3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (100 mg, obtained in Example 93, step 6) and ethyl-4-(bromomethyl)-pyridine-2-carboxylate (85 mg, [CAS Reg. No. 153994-03-7]) were dissolved in DMF (5 mL) followed by addition of silver carbonate (80 mg). The mixture was heated to 80° C. for 3 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow foam (98 mg, 63%). MS (m/e)=509.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[C:34]1[CH:44]=[CH:43][C:37]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][O:22][C:34]2[N:35]=[CH:36][C:37]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])=[CH:43][CH:44]=2)=[N:6][CH:7]=1
Reactant: CCNC(=O)c1ccc(Br)nc1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)nc1
Reaction time: 0.17 h

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.03 g, 0.09 mmol) in 0.6 ml of THF was added 1M NaHMDS in THF (0.11 ml, 0.11 mmol). After 10 min at rt, 6-bromo-N-ethylnicotinamide (0.02 g, 0.08 mmol) was added. After 3 h, a drop of water was added to the reaction and purified by reverse phase HPLC to give 6-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)-N-ethylpyridine-3-carboxamide. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.4 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H), 8.08 (m, 2H), 7.96 (dd, J=8.6, 2.6 Hz, 1H), 7.48 (dd, J=8.4, 2.6 Hz, 1H), 7.13 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.8 (d, J=8.8 Hz, 1H), 5.94 (s, 1H), 5.48 (s, 2H), 3.46 (m, 2H), 1.24 (t, J=7.3 Hz, 3H); HRMS exact mass calc for C23H18ClFN4O3S [M+H]+: 485.0845; observed: 485.0854.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14](C(OC(C)(C)C)=O)[S:15]([N:18]1[C:23]2([CH2:25][CH2:24]2)[CH2:22][N:21]([C:26]2[C:27]3[CH:34]=[CH:33][N:32](C(OC(C)(C)C)=O)[C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][S:15]([N:18]1[C:23]2([CH2:24][CH2:25]2)[CH2:22][N:21]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCCN1Cc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NC[C@@H]1CCCN1Cc1ccccc1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-butyl 4-[8-[[(2S)-1-benzylpyrrolidin-2-yl]methyl-tert-butoxycarbonyl-sulfamoyl]-5,8-diazaspiro[2.5]octan-5-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (Intermediate 48) (0.57 mmol) was dissolved in DCM (10 mL) and added TFA (1 mL). The reaction mixture was stirred at rt for 16 h, then added NaHCO3 (15 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc and MeOH in heptane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:30])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (678 mg), ethyl 2-bromopropionate (362 mg), and potassium carbonate (207 mg) in dry N,N-dimethyl formamide (2 ml) was stirred overnight at ambient temperature. The mixture was poured into water and extracted twice with ethyl acetate. The organic layers were washed with water, dried, and evaporated under reduced pressure. The residue was crystallized from n-hexane to yield 2-(4-chlorophenyl)-6-[1-(ethoxycarbonyl)ethoxy]-4-methyl-2H-1,2,4-benzothiadiazine -3(4H)-one 1,1-dioxide (816 mg). (R,S mixture)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:5](=[CH:7][C:8]3[N:9]=[C:10]([NH2:14])[S:11][C:12]=3[CH:13]=2)[N:6]=1.[Cl:15][CH2:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O>O1CCOCC1>[Cl:15][CH2:16][C:17]([NH:14][C:10]1[S:11][C:12]2[C:8](=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:17](=[O:19])[CH2:16][Cl:15])[S:3][C:4]=3[CH:13]=2)[N:9]=1)=[O:19]
Reactant: Nc1nc2cc3nc(N)sc3cc2s1
Reactant: O=C(CCl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: O=C(CCl)Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1
Yield: 93 %

Procedure:
A mixture consisting of 222 mgm of 2,6-diamino-benzo[1,2-d:5,4-d']bisthiazole, 500 mgm of p-nitro-phenyl chloroacetate and 5 ml of dioxane were refluxed for 15 minutes. The reaction mixture was allowed to cool, and the crystalline substance which had separated out was filtered off, washed and dried. 350 mgm (93% of theory) of 2,6-bis-(chloroacetyl-amino)-benzo[1,2-d:5,4-d']bisthiazole, M.P. 330° C., were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[NH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=O)[C:6]=2[S:5][CH:4]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:22])=O>>[CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([Cl:22])=[C:6]2[S:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2c(OC)csc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnc2c(OC)csc2c1Cl
Reaction time: 0.5 h

Procedure:
3-Methoxy-6-ethoxycarbonylthieno[3,2-b]pyridin-7-(4H)-one (3 g, 0.0118 mol) and phosphorus oxychloride (10 ml) was heated under reflux for one hour. The reaction mixture was poured onto ice (200 g) and stirred for 30 minutes. The mixture was then basified with 40% sodium hydroxide solution and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound as a buff-colour solid, 3.2 g, m.p. 135°-137°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][NH2:13])=O)=[CH:5][CH:4]=1.[N:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[C:17]=[S:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[S:30]1[CH:31]=[CH:32][N:33]=[C:29]1[NH:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:16][C:17]2[S:18][C:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=3)=[N:12][N:13]=2)=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: NNC(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(N=C=S)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nnc(Cc3ccc(C(F)(F)F)cc3)s2)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 15.1 %

Procedure:
A mixture of (4-trifluoromethyl-phenyl)-acetic acid hydrazide (55 mg, 0.25 mmol, 1.5 equiv), 4-isothiocyanato-N-thiazol-2-yl-benzenesulfonamide (50 mg, 0.2 mmol, 1.0 equiv) and sodium carbonate (20 mg, 0.18 mmol, 1.1 equiv) in 1.0 mL of ethanol was heated at 85° C. After 16 h, the heterogeneous reaction mixture was concentrated in vacuo, diluted with 500 μL of acetonitrile, filtered, and purified via reverse phase HPLC. The fraction containing product was lyophilized to afford the product as an off-white solid (15 mg, 20%).
Reaction SMILES: [C:1]([S:5][C:6]([F:14])([F:13])[C:7]([F:12])([F:11])[C:8]([O-:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Na+].S(OC)(O[CH3:20])(=O)=O>>[C:1]([S:5][C:6]([F:14])([F:13])[C:7]([F:11])([F:12])[C:8]([O:10][CH3:20])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)SC(F)(F)C(F)(F)C(=O)[O-]
Agent: [Na+]
Product: COC(=O)C(F)(F)C(F)(F)SC(C)(C)C
Reaction time: 8 h
Yield: 42 %

Procedure:
The resulting dark solution, which contained sodium 3-t-butylthiotetrafluoropropionate, was stirred with 69.3 g (0.55 mole) of dimethyl sulfate while the temperature was maintained at 30°. After an initial exothermic reaction subsided, the mixture was stirred overnight and then distilled to give a crude product with bp about 45° (2 mm, 2.6×10-1 kPa). The distillate was washed with 1 liter of water, dried and fractionated to give 52.1 g (42%) of methyl 3-t-butylthiotetrafluoropropionate, bp 55° (2 mm, 2.6×10-1 kPa). IR (neat): 2970 (sat'd CH), 1775 (C=O), 1100-1250 cm-1 (CF). NMR (CCl4): 1H 3.87 (s, 3H, OCH3) and 1.52 ppm (s, 9H, C(CH3)3 ; 19F -86.3 (t, JFF 7.1 Hz, 2F, CF2S) and -117.6 ppm (t, JFF 7.1 Hz, 2F, CF2C=O).
Reaction SMILES: [CH2:1]([C:3]([CH2:13][NH:14][CH2:15][CH:16]([OH:18])[CH3:17])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)O)[CH3:2].S(=O)(=O)(O)O.O.N>CCOCC>[CH2:1]([C:3]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[O:18][CH:16]([CH3:17])[CH2:15][NH:14][CH2:13]1)[CH3:2]
Reactant: CCC(O)(CNCC(C)O)c1cccc(OC)c1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CCC1(c2cccc(OC)c2)CNCC(C)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
METHOD A The product from Example 15 (1.77 g, 0.007 mole) was treated dropwise at 0° C. with concentrated sulphuric acid (2.3 ml). The resulting green gum was allowed to stand overnight at room temperature and was then treated with 25 ml of crushed ice and after thorough mixing, 50 ml of water. The solution was neutralised with excess ammonia and the solution shaken with ether (2×50 ml). The ether layers were washed, and dried (MgSO4) and evaporated to give 360 mg of the title compound as a 50:50 mixture of diastereoisomers.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:18][C:16]1[N:17]=[C:13]([C:9]2[C:8]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][CH:23]=3)=[CH:7][C:6]([CH3:5])=[C:11]([CH3:12])[N:10]=2)[S:14][C:15]=1[CH3:19]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2nc(C)c(C)s2)nc1C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6-dimethyl-2-(4,5-dimethylthiazol-2-yl)-pyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (143 mg), cesium carbonate (209 mg), and 4-(N,N-dimethylamino)-pyridine (78 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the cooled solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (7.7 mg, yield 9%).
Reaction SMILES: [OH2:1].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[OH:27])([CH3:17])([CH3:16])[CH3:15]>S(=O)(=O)(O)O.O.C(OCC)C>[C:14]([C:18]1[C:19](=[O:27])[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][C:22](=[O:1])[CH:23]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O
Reactant: CC(C)c1cccc(C(C)(C)C)c1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reaction time: 2.5 h

Procedure:
A 160 g quantity of sodium dichromate dihydrate was dissolved in a mixture of 100 ml of 97% sulfuric acid and 230 ml of water, and the solution was added to a solution of 45.0 g of 2-tert-butyl-6-isopropylphenol in 350 ml of diethyl ether with stirring at a temperature of 5°-10° C. over a period of 2.5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed serially with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:10), giving 12.7 g of the title compound as a pale yellow oil.