5-Chloro-2-methylphenyl isocyanate

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

Procedure: To a suspension of 2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde hydrochloride (1.43 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml) were added, at room temperature, 4-chloro-2-isocyanato-1-methylbenzene (700 mg) and one drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave N-(5-chloro-2-methylphenyl)-4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxamide (1.23 g). were added, at room temperature The aqueous phase was removed extracted with ethyl acetate The combined organic phases were dried over sodium sulphate concentrated under reduced pressure The residue was purified by chromatography

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

Procedure: To a suspension of 2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde hydrochloride (1.43 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml) were added, at room temperature, 4-chloro-2-isocyanato-1-methylbenzene (700 mg) and one drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave N-(5-chloro-2-methylphenyl)-4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxamide (1.23 g). were added, at room temperature The aqueous phase was removed extracted with ethyl acetate The combined organic phases were dried over sodium sulphate concentrated under reduced pressure The residue was purified by chromatography

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

Procedure: To a suspension of 2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde hydrochloride (1.43 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml) were added, at room temperature, 4-chloro-2-isocyanato-1-methylbenzene (700 mg) and one drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave N-(5-chloro-2-methylphenyl)-4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxamide (1.23 g). were added, at room temperature The aqueous phase was removed extracted with ethyl acetate The combined organic phases were dried over sodium sulphate concentrated under reduced pressure The residue was purified by chromatography

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

Procedure: To a suspension of 2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde hydrochloride (1.43 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml) were added, at room temperature, 4-chloro-2-isocyanato-1-methylbenzene (700 mg) and one drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave N-(5-chloro-2-methylphenyl)-4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxamide (1.23 g). were added, at room temperature The aqueous phase was removed extracted with ethyl acetate The combined organic phases were dried over sodium sulphate concentrated under reduced pressure The residue was purified by chromatography

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

Procedure: A solution of 16.7 g. of 2-methyl-5-chlorophenylisocyanate and 50 ml. of dichloromethane was added to a stirred, cooled solution of 35 g. of N-isopropyl-1,3-diaminopropane and 250 ml. of dichloromethane. The temperature was kept at -5° to 0° C. during addition. Stirring was continued at room temperature for 20 minutes. The precipitated solid was separated by filtration. The filtrate was extracted with water, then with 200 ml. of 15% hydrochloric acid (v/v). The acid extract was made basic with saturated sodium carbonate solution, then extracted with dichloromethane. The dichloromethane solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness in vacuo. The residue was triturated with ether until it solidified. The solid was recrystallized from EtOH/Et2O to obtain N-[3-(isopropylamino)propyl]-N'-(5-chloro-2-methylphenyl)urea hydrochloride, m.p. 180°-183° C. cooled solution of 35 g The temperature was kept at -5° to 0° C. during addition The precipitated solid was separated by filtration The filtrate was extracted with water The acid extract extracted with dichloromethane The dichloromethane solution was dried over magnesium sulfate evaporated to dryness The residue was dissolved in ethanol and saturated with hydrogen chloride The solution was evaporated to dryness in vacuo The residue was triturated with ether until it The solid was recrystallized from EtOH/Et2O

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

Procedure: To a suspension of 2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde hydrochloride (1.43 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml) were added, at room temperature, 4-chloro-2-isocyanato-1-methylbenzene (700 mg) and one drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave N-(5-chloro-2-methylphenyl)-4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxamide (1.23 g). were added, at room temperature The aqueous phase was removed extracted with ethyl acetate The combined organic phases were dried over sodium sulphate concentrated under reduced pressure The residue was purified by chromatography

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

Procedure: A solution of 16.7 g. of 2-methyl-5-chlorophenylisocyanate and 50 ml. of dichloromethane was added to a stirred, cooled solution of 35 g. of N-isopropyl-1,3-diaminopropane and 250 ml. of dichloromethane. The temperature was kept at -5° to 0° C. during addition. Stirring was continued at room temperature for 20 minutes. The precipitated solid was separated by filtration. The filtrate was extracted with water, then with 200 ml. of 15% hydrochloric acid (v/v). The acid extract was made basic with saturated sodium carbonate solution, then extracted with dichloromethane. The dichloromethane solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness in vacuo. The residue was triturated with ether until it solidified. The solid was recrystallized from EtOH/Et2O to obtain N-[3-(isopropylamino)propyl]-N'-(5-chloro-2-methylphenyl)urea hydrochloride, m.p. 180°-183° C. cooled solution of 35 g The temperature was kept at -5° to 0° C. during addition The precipitated solid was separated by filtration The filtrate was extracted with water The acid extract extracted with dichloromethane The dichloromethane solution was dried over magnesium sulfate evaporated to dryness The residue was dissolved in ethanol and saturated with hydrogen chloride The solution was evaporated to dryness in vacuo The residue was triturated with ether until it The solid was recrystallized from EtOH/Et2O

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

Procedure: To a mixture of 5-chloro-2-methylphenyl isocyanate (100 μL, 0.73 mmol) in CCl4 (2 mL) was added sulfuryl chloride (118 μL, 0.88 mmol) and 2,2′-azobis(isobutyronitrile) (catalytic amount) and the resulting mixture was refluxed for 20 h. The mixture was allowed to obtain room temperature, then diluted with CH2Cl2, washed with saturated aqueous NaHCO3-solution, dried (Na2SO4) and concentrated. The mixture was taken up in benzene (2 mL) and a mixture of AlCl3 (160 mg, 1.2 mmol) in benzene (1 mL) was added. The resulting mixture was stirred at 80° for 4 h, and then allowed to obtain room temperature. The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1) to give 25 mg (14%) of the title compound (189JO59). 1H NMR (CDCl3) δ 8.18 (bs, 1 H), 7.92 (dd, 1 H, J=1.2, 7.8 Hz), 7.46 (dt 1 H, J=1.4, 7.4 Hz), 7.34 (dt, 1 H, J=1.2, 7.4 Hz), 7.23 (m, 2 H), 7.07 (m, 2 H), 3.92 (s 2 H). MS (ESI) 244 (MH+). the resulting mixture was refluxed for 20 h to obtain room temperature washed with saturated aqueous NaHCO3-solution dried (Na2SO4) concentrated was added to obtain room temperature The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1)

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

Procedure: To a mixture of 5-chloro-2-methylphenyl isocyanate (100 μL, 0.73 mmol) in CCl4 (2 mL) was added sulfuryl chloride (118 μL, 0.88 mmol) and 2,2′-azobis(isobutyronitrile) (catalytic amount) and the resulting mixture was refluxed for 20h. The mixture was allowed to obtain room temperature, then diluted with CH2Cl2, washed with saturated aqueous NaHCO3-solution, dried (Na2SO4) and concentrated. The mixture was taken up in benzene (2 mL) and a mixture of AlCl3 (160 mg, 1.2 mmol) in benzene (1 mL) was added. The resulting mixture was stirred at 80° for 4 h, and then allowed to obtain room temperature. The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1) to give 25 mg (14%) of the title compound (189JO59). 1H NMR (CDCl3) d 8.18 (bs, 1H), 7.92 (dd, 1H, J=1.2, 7.8 Hz), 7.46 (dt 1H, J=1.4, 7.4 Hz), 7.34 (dt, 1H, J=1.2, 7.4 Hz), 7.23 (m, 2H), 7.07 (m, 2H), 3.92 (s 2H). MS (ESI) 244 (MH+). the resulting mixture was refluxed for 20h to obtain room temperature washed with saturated aqueous NaHCO3-solution dried (Na2SO4) concentrated was added to obtain room temperature The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1)

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

Procedure: To a suspension of 2-{3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde hydrochloride (1.43 g) in dichloromethane (30 ml) and diisopropylethylamine (0.73 ml) were added, at room temperature, 4-chloro-2-isocyanato-1-methylbenzene (700 mg) and one drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The mixture was stirred at room temperature overnight, and water was then added. The aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave N-(5-chloro-2-methylphenyl)-4-{4-[5-(2-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxamide (1.23 g). were added, at room temperature The aqueous phase was removed extracted with ethyl acetate The combined organic phases were dried over sodium sulphate concentrated under reduced pressure The residue was purified by chromatography

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

Procedure: To a mixture of 5-chloro-2-methylphenyl isocyanate (100 μL, 0.73 mmol) in CCl4 (2 mL) was added sulfuryl chloride (118 μL, 0.88 mmol) and 2,2′-azobis(isobutyronitrile) (catalytic amount) and the resulting mixture was refluxed for 20 h. The mixture was allowed to obtain room temperature, then diluted with CH2Cl2, washed with saturated aqueous NaHCO3-solution, dried (Na2SO4) and concentrated. The mixture was taken up in benzene (2 mL) and a mixture of AlCl3 (160 mg, 1.2 mmol) in benzene (1 mL) was added. The resulting mixture was stirred at 80° for 4 h, and then allowed to obtain room temperature. The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1) to give 25 mg (14%) of the title compound (189JO59). 1H NMR (CDCl3) δ 8.18 (bs, 1H), 7.92 (dd, 1H, J=1.2, 7.8 Hz), 7.46 (dt 1H, J=1.4, 7.4 Hz), 7.34 (dt, 1H, J=1.2, 7.4 Hz), 7.23 (m, 2H), 7.07 (m, 2H), 3.92 (s 2H). MS (ESI) 244 (MH+) the resulting mixture was refluxed for 20 h to obtain room temperature washed with saturated aqueous NaHCO3-solution dried (Na2SO4) concentrated was added to obtain room temperature The mixture was filtered through a short column (SiO2, heptane:EtOAc, 1:1)

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

Procedure: A solution of 16.7 g. of 2-methyl-5-chlorophenylisocyanate and 50 ml. of dichloromethane was added to a stirred, cooled solution of 35 g. of N-isopropyl-1,3-diaminopropane and 250 ml. of dichloromethane. The temperature was kept at -5° to 0° C. during addition. Stirring was continued at room temperature for 20 minutes. The precipitated solid was separated by filtration. The filtrate was extracted with water, then with 200 ml. of 15% hydrochloric acid (v/v). The acid extract was made basic with saturated sodium carbonate solution, then extracted with dichloromethane. The dichloromethane solution was dried over magnesium sulfate, then evaporated to dryness. The residue was dissolved in ethanol and saturated with hydrogen chloride. The solution was evaporated to dryness in vacuo. The residue was triturated with ether until it solidified. The solid was recrystallized from EtOH/Et2O to obtain N-[3-(isopropylamino)propyl]-N'-(5-chloro-2-methylphenyl)urea hydrochloride, m.p. 180°-183° C. cooled solution of 35 g The temperature was kept at -5° to 0° C. during addition The precipitated solid was separated by filtration The filtrate was extracted with water The acid extract extracted with dichloromethane The dichloromethane solution was dried over magnesium sulfate evaporated to dryness The residue was dissolved in ethanol and saturated with hydrogen chloride The solution was evaporated to dryness in vacuo The residue was triturated with ether until it The solid was recrystallized from EtOH/Et2O