Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[N:23]([CH3:48])[C:24]2[C:29]([N:30]=1)=[C:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:27]=[C:26]([N:37]1[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=[C:38]1[CH2:46][CH3:47])[N:25]=2>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]2[N:23]([CH3:48])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:26]([N:37]2[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=[C:38]2[CH2:46][CH3:47])[N:25]=3)[C:10](=[O:14])[CH:9]1[CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C(C)C)C3=O)n(C)c2n1
Reaction time: 19 h
Yield: 76.5 %

Procedure:
To a solution of 2-isopropyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.24 mmol) in DMF (1.5 mL) at 0° C. was added NaH (11 mg, 0.29 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred at r.t. for 30 min before the addition of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in DMF (1.5 mL). The resulting mixture was allowed to stir for 19 h then partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a yellow oil (104 mg, 77%), LCMS (method H): RT 3.03 min [M+H]+ 618.4
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:7]([S:8][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cc(C(F)(F)F)ccn1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccnc(SCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of phenylmethanethiol (356 μl, 3.03 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (369 μl, 3.03 mmol) in dimethylformamide (5 mL) was added potassium carbonate (628 mg, 4.54 mmol). The reaction mixture was stirred at 60° C. for 2 hours, then cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-20% ethyl acetate in isohexane) to afford 2-(benzylthio)-4-(trifluoromethyl)pyridine (510 mg) as a colourless oil. LCMS (Method F, ES-API): RT 3.04 min, m+H=270.1.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:41][C:42]([F:53])([F:52])[O:43][C:44]1[CH:51]=[CH:50][C:47](C=O)=[CH:46][CH:45]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:47]4[CH:46]=[CH:45][C:44]([O:43][C:42]([F:41])([F:52])[F:53])=[CH:51][CH:50]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(COc2ccc(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.1 %

Procedure:
Tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 148 (4.22 g, 9.60 mmol) was dissolved in methylene chloride (10 ml). To the solution, trifluoroacetic acid (30 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (10 ml) and triethylamine (10 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in dichloroethane. To the solution, 4-trifluoromethoxybenzaldehyde (1.64 ml, 11.5 mmol) and sodium triacetoxyborohydride (3.05 g, 14.4 mmol) were added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was stirred and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from methylene chloride-ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (3.23 g, yield 63%) as a light yellow powder.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:10]([CH3:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:8]=1[CH:7]=[CH:6][CH:5]=[C:4]2[S:1]([NH:21][CH2:20][CH2:18][OH:19])(=[O:3])=[O:2]
Reactant: NCCO
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)NCCO)cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, dansyl chloride (5.05 g, 18.72 mmol) was placed in a dry 250 mL round bottom flask equipped with a stir bar. Dry methylene chloride (50 mL) was added via syringe, the flask attached to an addition funnel and the system cooled to 0° C. Ethanolamine (1.25 g, 1.24 mL, 20.59 mmol), triethylamine (2.27 g, 3.13 mL, 22.46 mmol), and 75 mL of dry methylene chloride were loaded into the addition funnel, and the solution was added dropwise with stirring over 30 min. The solution was stirred for an additional 30 min before the ice bath was removed, the solution allowed to reach ambient temperature and left to stir for an additional 14 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C1(C)C=CC=CC=1.ClS([N:22]=[C:23]=[O:24])(=O)=O.Cl>O>[N:1]1([C:23]([NH2:22])=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 53.7 %

Procedure:
To a stirred mixture of 2-oxindole (5.86 g, 44.0 mmole) and dry toluene (160 ml) was added chlorosulfonyl isocyanate (7.47 g, 52.8 mmole). Hydrogen chloride was immediately evolved. The mixture was stirred under reflux for 15 minutes and then it was cooled to room temperature. Water (50 ml) was added to the cooled mixture (some HCl was initially evolved) and then the mixture was stirred for 1.5 hours. The solid which formed was collected by filtration and dried (4.10 g). The filtrate was extracted with ethyl acetate (100 ml), and the resulting extract was washed with brine (2×100 ml) and dried (MgSO4). Evaporation of the extract under reduced pressure gave 4.16 g of solid. The combined solids were recrystallized by dissolution in acetonitrile (200 ml) followed by concentration of the solution under reduced pressure to about 75 ml. The small amount of amorphous material which separated was filtered off, the filtrate was decolorized and concentrated under reduced pressure to about 50 ml volume, then seeded. This gave the title compound as dark red crystals which were filtered off and dried (3.0 g; 38%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>ClCCl>[CH3:62][S:63]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH3:12])[CH:6]=[C:7]([CH2:9][O:10][S:63]([CH3:62])(=[O:65])=[O:64])[CH:8]=1)(=[O:65])=[O:64]
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(CO)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2-(3,5-bis(hydroxymethyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (265d) (71 mg, 0.091 mmol) in anhydrous dichloromethane (1.4 mL) was added triethylamine (0.038 mL, 0.272 mmol). The mixture was cooled to −5° C. and methanesulfonyl chloride (0.018 mL, 0.227 mmol) was added slowly. After stirring for one hour at −5° C. the reaction was quenched with cold water and extracted with cold ethyl acetate. The organic extracts were washed with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate. MS (m/z). found 960.2 (M+Na)+. To a mixture of methyl 2-(3,5-bis((methylsulfonyloxy)methyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (69 mg, 0.074 mmol) and compound 8 (54.1 mg, 0.184 mmol) in anhydrous DMF (0.8 mL) was added potassium carbonate (50.8 mg, 0.368 mmol). The reaction was allowed to stir for 18 hours at room temperature. The reaction was quenched with water and extracted twice with dichloromethane. The remaining aqueous layer was extracted twice with 50% MeOH/CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash silica gel chromatography (5% MeOH/CH2Cl2) followed by preparative reverse phase HPLC (C18 column, eluted with CH3CN/H2O) gave compound 265e (23 mg, 23%). MS (m/z). found 1375.4 (M+Na+H2O)+, 1393.4 (M+Na+2H2O)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:14])[NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:5].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>C(O)(=O)C.C(O)C>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[NH:1][CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=1)[N:6]([CH2:7][C:8]([NH:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:14])[C:4]2=[O:5]
Reactant: CC(C)(C)NC(=O)CNC(=O)c1cc(Br)ccc1N
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)NC(=O)CN1C(=O)c2cc(Br)ccc2NC1c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
In a capped 20 mL scintillation vial, a solution of 2-amino-5-bromo-N-(tert-butylcarbamoylmethyl)benzamide (0.65 g, 2.0 mmol), 3-chlorobenzaldehyde (0.27 mL, 2.4 mmol) and catalytic glacial acetic acid (2 drops) in anhydrous ethanol (10 mL) was heated with stirring at 85° C. for 16 h. The resulting white suspension was cooled to room temperature, the white solid collected by suction filtration and washed with cold EtOH to give 2-[6-bromo-2-(3-chlorophenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-N-tert-butylacetamide (0.53 g, 1.21 mmol, 58%).
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[CH3:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([CH3:13])[CH:12]=1.O>ClCCl>[CH3:15][O:14][C:9]1[CH:10]=[C:11]([CH3:13])[C:12]([S:1]([Cl:5])(=[O:3])=[O:2])=[C:7]([CH3:6])[CH:8]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Chlorosulfuric acid (2.3 eq) in dichloromethane (0.5 ml/mmol) was slowly added dropwise over 10 min to a solution of 3,5-dimethylanisol (1 eq) in dichloromethane (1 ml/mmol) cooled to 0° C. The reaction mixture was stirred for a further 10 min and then slowly dropped into iced water (5 eq relative to chlorosulfuric acid). The phases were separated and the aqueous phase extracted with dichloromethane (repeatedly, UV analysis). The combined organic phases were dried (Na2SO4) and concentrated to small volume under vacuum. Yield: 82%
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:21].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:21])[CH:12]=1
Reactant: C=CC1(CCC(C)C)C(OC)=CCc2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CC1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Yield: 34 %

Procedure:
To a solution of Example 181B (0.13 g, 0.5 mmol) in benzene (5 mL) was added celite (0.13 g), pyridinium dichromate (0.38 g, 1.0 mmol), and a solution of 70% t-butyl peroxide in water (0.13 mL, 1.0 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (10 mL), washed with 5% Na2S2O5 (10 mL), dried (Na2SO4), and concentrated in vacuo. Column Chromatography on silica (20% dichloromethane/hexane -15% ethyl acetate/hexane) afforded product as a light yellow oil (46 mg, 35%). 1H NMR (300 MHz, CDCl3) δ ppm 0.51 (m, 1H), 0.76 (m, 7H), 1.37 (m, 1 H), 2.01 (m, 1H), 2.33 (m, 1H), 3.81 (s, 3H), 5.12 (m, 2H), 5.94 (m, 2H), 7.37 (m, 2H), 7.54 (m, 1H), 8.18 (d, J=8.09 Hz, 1H); MS m/z 270.9 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:10]([CH:2]1[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)C1Cc2ccccc2O1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1Cc2ccccc2O1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 2,3-dihydro-1-benzofuran-2-carboxylic acid (500 mg, 3.1 mmol) in anhydrous dichloromethane (20 ml), under nitrogen, was added 1,1′-carbonyldiimidazole (543 mg, 3.4 mmol). After stirring for 1 h, N,O-dimethylhydroxylamine hydrochloride (327 mg, 3.4 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The mixture was washed with hydrochloric acid (1N), followed by 10% aqueous potassium carbonate solution, and the organic phase was separated, dried (MgSO4) and concentrated in vacuo to give the title compound (352 mg).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:40])[F:41])=[CH:35][CH:34]=3)(=[O:37])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling of 1a and 4-(trifluoromethyl)benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (18%); 1H NMR (d6-DMSO) δ 12.46 (br s, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 7.40-7.07 (m, 13H), 6.84 (d, J=8.1 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+)
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].[OH-].[Na+]>O.O1CCCC1>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH2:20][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Reaction time: 1 h

Procedure:
A mixture of ethyl 8-acetyl-12,13-epoxytridecanoate (14.9 g., 0.05 mole), 4-tert-butylphenol (11.2 g., 0.075 mole), sodium hydroxide (7.0 g., 0.175 mole), water (30 ml.) and tetrahydrofuran (200 ml.) is stirred 4 hours at 40°-45°, 17 hours at 25° and one hour on the steam bath letting the tetrahydrofuran slowly boil away. The residue is treated with water and extracted with ether. The aqueous solution is acidified with hydrochloric acid. The oily product is taken up in ether. The ether is evaporated and the residue treated with a solution of 16.8 g. sodium bicarbonate in 275 ml. of water. The resulting solution is extracted twice with ether to remove the excess weakly acidic phenol. The aqueous solution is acidified, the product taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated leaving 10.2 g. of the crude title compound as a yellow viscous oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[C:5]=1[Cl:10].C[O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20](Cl)(=[O:22])=[O:21])=[O:14]>O1CCCC1>[Cl:10][C:5]1[C:6]([CH3:9])=[N:7][O:8][C:4]=1[NH:3][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([OH:14])=[O:12])(=[O:21])=[O:22]
Reactant: Cc1noc(N)c1Cl
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
At about 0° C., sodium hydride (60% dispersion in mineral oil, 458 mg, 19 mmol) was added to a solution of 5-amino-4-chloro-3-methylisoxazole (1.1 g, 8.3 mmol) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was stirred for about 10 minutes and 2-(methoxycarbonyl)thiophene-3-sulfonyl chloride (1.95 g, 8.11 mmol) was slowly added. Under continuous stirring, the mixture was maintained at ambient temperature for about 4 hours. The mixture was then diluted with hexanes (30 mL) and the resulting precipitate was filtered and washed with hexanes. The precipitate was then dissolved in 1 N sodium hydroxide and stirred at ambient temperature for about 1 hour. After acidifying to pH ˜2 with 2 N hydrochloric acid, the resulting precipitate was filtered, washed with water, and dried in vacuo to give the desired product 3-[(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxylic acid (1.2 g, 45%) as a yellow powder. 1H NMR (300 MHz, CD3OD) δ 7.82 (d, J=5.4 Hz, 1H), 7.53 (d, J=5.4 Hz, 1H), 2.24 (s, 3H); LC-MS: m/z=323 (MH)+.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(O)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(Oc2ccc(Br)cc2)c(C)cc1N
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCO
Product: COc1ccc(-c2ccc(Oc3cc(C)c(N)cc3C)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
Under argon, 0.50 g (1.7 mmol) of 4-(4-bromophenoxy)-2,5-dimethylaniline and 0.34 g (2.2 mmol) of 4-methoxyphenylboronic acid are dissolved in 10 ml of 1-butanol and the solution is admixed with 2.23 g (6.8 mmol) of cesium carbonate, 39.5 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2.5 ml of water. The reaction mixture is stirred at 80° C. for 16 h, poured into water and extracted repeatedly with ethyl acetate. The combined organic phases are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (0.44 g, purity 99.0%, yield 79.7%, log P (pH 2.3)=3.06).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([O:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
0.725 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione was dissolved in 4 ml of benzene; 400 mg of dry pyridine were added; 0.2 g of acetic anhydride was added dropwise under a nitrogen stream at 5°-10° C.; and the mixture was reacted for 2 days at room temperature. The resulting white crystals were separated by filtration, washed with benzene and vacuum-dried for 30 minutes at 90° C., giving 0.74 g of the benzene mono adduct of 5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione. This substance was liquefied at 98°-100° C., solidified and again liquefied at 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)=[O:6].[Na].[CH3:23][OH:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:24][CH3:23])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)=[O:6]
Reactant: CO
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)c(Cl)c1
Agent: [Na]
Product: COc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]

Procedure:
Prepared according to the procedure described for Example 10, Step A from 3,4-dichloro-N-3-nitro-4-fluorophenyl)-benzamide from Example 22, Step A (5.2 g, 20 mmol) and sodium (1.3 g, 57 mmol) using methanol in place of ethanol to afford the product (5.8 g). m.p. 215-218° C. after chromatography on silica gel in dichloromethane/methanol 99:1.