1-(1-isocyanoethylsulfonyl)-4-methylbenzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl acrylate (0.523 mL, 5.81 mmol) and 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.215 g, 5.81 mmol) in diethyl ether (16.5 mL) and DMSO (8.5 mL) were added dropwise to a stirred suspension of sodium hydride (60% dispersion) (0.372 g, 9.29 mmol) in diethyl ether (25 mL) under nitrogen. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was poured into 2% sodium chloride solution (200 mL), layers separated and the aqueous extracted with Et2O (4×50 mL), the organic layers were combined washed with water (50 mL), dried over Na2SO4, filtered and evaporated to afford beige solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired compound as a white solid (0.527 g, 65.2% yield); 1H NMR (400.132 MHz, CDCl3) δ 2.19 (3H, s), 3.72 (3H, s), 6.23 (1H, m), 7.21 (1H, m), 8.09 (1H, s); m/z (LC-MS, ESI+), RT=1.30 min (no mass ion detected). separated the aqueous extracted with Et2O (4×50 mL) the organic layers were combined washed with water (50 mL) dried over Na2SO4 filtered evaporated to afford beige solid The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane Pure fractions were evaporated to dryness

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl acrylate (0.523 mL, 5.81 mmol) and 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.215 g, 5.81 mmol) in diethyl ether (16.5 mL) and DMSO (8.5 mL) were added dropwise to a stirred suspension of sodium hydride (60% dispersion) (0.372 g, 9.29 mmol) in diethyl ether (25 mL) under nitrogen. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was poured into 2% sodium chloride solution (200 mL), layers separated and the aqueous extracted with Et2O (4×50 mL), the organic layers were combined washed with water (50 mL), dried over Na2SO4, filtered and evaporated to afford beige solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired compound as a white solid (0.527 g, 65.2% yield); 1H NMR (400.132 MHz, CDCl3) δ 2.19 (3H, s), 3.72 (3H, s), 6.23 (1H, m), 7.21 (1H, m), 8.09 (1H, s); m/z (LC-MS, ESI+), RT=1.30 min (no mass ion detected). separated the aqueous extracted with Et2O (4×50 mL) the organic layers were combined washed with water (50 mL) dried over Na2SO4 filtered evaporated to afford beige solid The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in isohexane Pure fractions were evaporated to dryness

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 34.5 g (121 mmole) of 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 25.3 g (121 mmole) of 1-tosylethyl isocyanide, 200 ml of dimethyl sulfoxide and 400 ml of ether was added dropwise to a suspension of 8.9 g (184 mmole) of 50% sodium hydride in mineral oil and 450 ml of ether. When the addition was complete stirring was continued for 2 hr. The mixture was diluted with water and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a dark oil. Crystallization from ether gave off-white crystals. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°. When the addition the ether layer was separated The aqueous solution was extracted with ether The combined ether extracts were washed with water dried over anhydrous sodium sulfate concentrated at reduced pressure to give a dark oil Crystallization from ether gave off-white crystals A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium hydride (60%, 0.096 g) in diethyl ether (3 mL) were added a solution of 1-(toluene-4-sulfonyl)ethylisocyanide (0.42 g) and 2-heptenenitrile (0.22 g) in a mixed solvent of diethyl ether (3 mL) and dimethylsulfoxide (3 mL) at room temperature, and this mixture was stirred at room temperature for 1 hour. To this reaction mixture was added water (15 mL). This mixture was extracted with ethyl acetate, and this organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (0.19 g). This mixture was extracted with ethyl acetate this organic layer was washed with brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of toluene-4-sulfonylmethylisocyanide (15 g), methyl iodide (109 g) benzyl trimethyl ammonium chloride (3.5 g) in dichloromethane (300 mL) was added 5 mol/L aqueous sodium hydroxide solution (307 mL) under ice cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water and this mixture was extracted with diethyl ether. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (16 g). this mixture was extracted with diethyl ether This organic layer was washed with water and brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of toluene-4-sulfonylmethylisocyanide (15 g), methyl iodide (109 g) benzyl trimethyl ammonium chloride (3.5 g) in dichloromethane (300 mL) was added 5 mol/L aqueous sodium hydroxide solution (307 mL) under ice cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water and this mixture was extracted with diethyl ether. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (16 g). this mixture was extracted with diethyl ether This organic layer was washed with water and brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 34.5 g (121 mmole) of 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 25.3 g (121 mole) of 1-tosylethyl isocyanide, 200 ml of dimethyl sulfoxide and 400 ml of ether was added dropwise to a suspension of 8.9 g (184 mmole) of 50% sodium hydride in mineral oil and 450 ml of ether. When the addition was complete stirring was continued for 2 hr. The mixture was diluted with water and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a dark oil. Crystallization from ether gave off-white crystals. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°. When the addition the ether layer was separated The aqueous solution was extracted with ether The combined ether extracts were washed with water dried over anhydrous sodium sulfate concentrated at reduced pressure to give a dark oil Crystallization from ether gave off-white crystals A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 34.5 g (121 mmole) of 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 25.3 g (121 mole) of 1-tosylethyl isocyanide, 200 ml of dimethyl sulfoxide and 400 ml of ether was added dropwise to a suspension of 8.9 g (184 mmole) of 50% sodium hydride in mineral oil and 450 ml of ether. When the addition was complete stirring was continued for 2 hr. The mixture was diluted with water and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a dark oil. Crystallization from ether gave off-white crystals. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°. When the addition the ether layer was separated The aqueous solution was extracted with ether The combined ether extracts were washed with water dried over anhydrous sodium sulfate concentrated at reduced pressure to give a dark oil Crystallization from ether gave off-white crystals A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluoro-4-(trifluoromethyl)benzaldehyde (0.96 g, 5.0 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.05 g, 5.00 mmol), and potassium carbonate (0.898 g, 6.50 mmol) was heated to reflux for 2 hours in methanol (25 mL). After this time, the reaction mixture was cooled to room temperature and poured into water, then extracted with ether. Chromatography on silica gel (20 to 40% ethyl acetate-hexane, eluant) afforded the title compound as an off-white solid (1.01 g, 82% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.90 (m, 1H), 7.68 (m, 2H), 2.43 (s, 3H). MS (DCI+) m/z 246 (M+H), 263 (M+NH4). was heated extracted with ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (30 mg), 1-[(1-isocyanoethyl)sulfonyl]-4-methylbenzene (17.6 mg), potassium carbonate (17 mg) in MeOH (1 ml) was refluxed for 1.5 hours. After cooling, the mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH3-4 by adding 1N HCl and extracted with CHCl3. The organic layer was washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of MeOH and CHCl3 (1:10). Crystallization from EtOAc-n-hexane gave 3-[1-ethyl-6-(4-methyl-1,3-oxazol-5-yl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoic acid (10 mg) as a colorless crystal. was refluxed for 1.5 hours After cooling extracted with EtOAc by adding 1N HCl extracted with CHCl3 The organic layer was washed with water dried over anhydrous MgSO4 concentrated in vacuo The residue was purified by preparative thin layer chromatography eluting with a mixture of MeOH and CHCl3 (1:10) Crystallization from EtOAc-n-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 34.5 g (121 mmole) of 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 25.3 g (121 mmole) of 1-tosylethyl isocyanide, 200 ml of dimethyl sulfoxide and 400 ml of ether was added dropwise to a suspension of 8.9 g (184 mmole) of 50% sodium hydride in mineral oil and 450 ml of ether. When the addition was complete stirring was continued for 2 hr. The mixture was diluted with water and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a dark oil. Crystallization from ether gave off-white crystals. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°. When the addition the ether layer was separated The aqueous solution was extracted with ether The combined ether extracts were washed with water dried over anhydrous sodium sulfate concentrated at reduced pressure to give a dark oil Crystallization from ether gave off-white crystals A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 34.5 g (121 mmole) of 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 25.3 g (121 mmole) of 1-tosylethyl isocyanide, 200 ml of dimethyl sulfoxide and 400 ml of ether was added dropwise to a suspension of 8.9 g (184 mmole) of 50% sodium hydride in mineral oil and 450 ml of ether. When the addition was complete stirring was continued for 2 hr. The mixture was diluted with water and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a dark oil. Crystallization from ether gave off-white crystals. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°. When the addition the ether layer was separated The aqueous solution was extracted with ether The combined ether extracts were washed with water dried over anhydrous sodium sulfate concentrated at reduced pressure to give a dark oil Crystallization from ether gave off-white crystals A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 201°-202°