trimethylsulfanium;iodide

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 4.84 g. of sodium hydride (57% mineral oil dispersion) in 70 ml. of dry dimethyl sulfoxide is heated at about 65° C. under argon with stirring for one hour. Dry tetrahydrofuran (75 ml.) is added and the resulting solution is cooled to -5° C. Trimethylsulfonium iodide (19 g., 92.8 mmole) is added very slowly and stirring is continued for about five minutes. A solution of 12.6 g. (92.8 mmole) of p-methoxybenzaldehyde in 120 ml. of tetrahydrofuran is added and the temperature is maintained at -5° C. After addition is completed the mixture is allowed to warm to room temperature, poured into water and extracted with ether. The extract is washed with saturated sodium chloride solution, dried and evaporated to give p-methoxystyrene oxide. A suspension of 4.84 g stirring is continued for about five minutes the temperature is maintained at -5° C After addition to warm to room temperature extracted with ether The extract is washed with saturated sodium chloride solution dried evaporated

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

Procedure: A mixture of 42.0 g. of 57% sodium hydride dispersed in oil and 700 ml. of dimethyl sulfoxide is stirred at 70°-75° C. for one to one and one-half hours. The solution is diluted with 700 ml. of dry tetrahydrofuran and cooled to 0° C., under nitrogen. A 200 g. (1.0 mole) sample of trimethylsulfonium iodide is added in portions, maintaining the temperature between 0°-5° C. The mixture is stirred for 15 minutes and then a solution of 70.4 g. (0.50 mole) of m-chlorobenzaldehyde in 300 ml. of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred at room temperature for four hours, poured into water and extracted with ether. The extract is washed with brine, dried and evaporated in vacuo to leave m-chlorostyrene oxide. A mixture of 42.0 g The solution is diluted with 700 ml maintaining the temperature between 0°-5° C The resulting mixture is stirred at room temperature for four hours extracted with ether The extract is washed with brine dried evaporated in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of trimethylsulfonium iodide (20 mg, 0.096 mmol) in CH3CN (0.3 mL) was added one drop of H2O followed KOH (s) (22 mg, 0.384 mmol). This mixture was heated at 60° C. for 10 min, then added 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-(4-oxocyclohexyl)-3,4-dihydroquinazolin-2(1H)-one (INTERMEDIATE 76) (40 mg, 0.064 mmol) in CH3CN (0.3 mL) and DMSO (0.2 mL) slowly. The reaction mixture was heated another 3.5 h, cooled to RT and diluted with CH2Cl2. It was washed with H2O followed by brine then dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography eluting with 1:3 acetone:hexane to give the title compound as a mixture of diastereomers. Mass spectrum (ESI): 633.2 (M+1). The reaction mixture was heated another 3.5 h cooled to RT It was washed with H2O then dried over Na2SO4 After removal of the solvent the crude product was purified by preparative thin layer chromatography eluting with 1:3 acetone

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

Procedure: To a mixed solution of 2-fluoro-5-methoxybenzaldehyde (0.8 ml) in tetrahydrofuran (4 ml) and dimethylsulfoxide (4 ml), 1.97 g of trimethylsulfonium iodide and 308 mg of sodium hydride were added under ice-cooling, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50:50)) to afford a crude product as a colorless oil. To a solution of the crude product in tetrahydrofuran (2 ml), 200 mg of Sodium cyanoborohydride and 0.4 ml of trifluoroborane-diethylether complex were added under ice-cooling, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (95:5-30/70)) to afford the title compound as a colorless oil. cooling the mixture was extracted with ethyl acetate The combined organic layers were washed with a saturated saline solution dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50:50)) to afford a crude product as a colorless oil cooling the reaction solution was stirred at room temperature for 2 hours the mixture was extracted with chloroform dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (95:5-30/70))

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

Procedure: To a solution of sodium hydride (1.0 g, 60% in oil) in N,N-dimethylformamide (50 ml) was added trimethylsulfonium iodide (6.1 g) at ambient temperature under N2 and stirred for 20 minutes. To the solution was added dropwise a solution of trans-1-ethoxycarbonyl-2-(3-methoxyphenyl)ethylene (5.2 g) in N,N-dimethylformamide (10 ml) and stirred for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and 1N-hydrochloric acid (100 ml). The organic layer was washed with water, saturated sodium bicarbonate aqueous solution, and brine, and then dried over magnesium sulfate. The solution was evaporated and the residue was chromatographed (hexane:ethyl acetate=4:1) to give trans-1-ethoxycarbonyl-2-(3-methoxyphenyl)cyclopropane (1.0 g). stirred for 2 hours The organic layer was washed with water, saturated sodium bicarbonate aqueous solution, and brine dried over magnesium sulfate The solution was evaporated the residue was chromatographed (hexane:ethyl acetate=4:1)

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.60 ml of a 1.6 M solution of n-butyllithium in hexane are introduced dropwise into a suspension of 2.71 g of trimethylsulfonium iodide (13.3 mmol) in 25 ml of tetrahydrofuran cooled to -15° C. The solution is stirred at -15° C. for 20 minutes under nitrogen, and then a solution of 1.57 g of 2-[1,3]dioxolan-2-yl-6-vinylpyridine (8.90 mmol) in 5 ml of tetrahydrofuran is added dropwise. After stirring for 1 hour at -15° C., the suspension is stirred for 3 hours at room temperature. The tetrahydrofuran is evaporated off, the residue is taken up in water and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: hexane/ethyl acetate; 50:50). 1.24 g of a colorless oil are obtained. After stirring for 1 hour at -15° C. the suspension is stirred for 3 hours at room temperature The tetrahydrofuran is evaporated off the mixture is extracted with ethyl acetate The organic phase is washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate filtered concentrated under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of potassium tert-butoxide (3.22 g, 28.7 mmol) in tetrahydrofuran (40 ml) was added dropwise to a mixture of 4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl) oxyethyl]amino]-3-nitrobenzotrifluoride (5.00 g, 14.4 mmol), trimethylsulfonium iodide (5.86 g, 28.7 mmol) and N,N-dimethylformamide (80 ml) with stirring at 15°-20° C. After stirring at 15°-16° C. for another 1 hour, the reaction mixture was cooled to 0° C. The reaction mixture was poured into cold water and extracted three times with ethyl acetate. The extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 3/97) to obtain an oil of 2-methyl-4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl) oxyethyl]amino]-3-nitrobenzotrifluoride. After stirring at 15°-16° C. for another 1 hour extracted three times with ethyl acetate The extract solution was washed twice with a 5% aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 3/97)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10 ml of abs. DMSO are added dropwise at 10° C. to 2 g (10 mmol) of trimethylsulphonium iodide and 0.2 g (7 mmol) of sodium hydride (80% in oil). The mixture is stirred for 1 h at 20° C. After this, a solution of 1 g (5 mmol) of 1-cyanocyclopropyl 2-phenylethyl-ketone (compound II-16, Example 32) in 5 ml of abs. DMSO is added dropwise and the mixture is allowed to react for 4 h at 20° C. The solution is poured into water and extracted using ethyl acetate, the organic phase is dried with Na2SO4 and the solvent is evaporated in vacuo. 0.8 g (75% of theory) is obtained in the form of a colorless oil, to react for 4 h at 20° C extracted the organic phase is dried with Na2SO4 the solvent is evaporated in vacuo 0.8 g (75% of theory) is obtained in the form of a colorless oil

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 2.99 g (8.79 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-formylphenyl)-pyridin-2-ylamine, 1.79 g (8.79 mmol) trimethylsulfonium iodide, 0.98 9 (17.59 mmol) powdered potassium hydroxide, 44 mL acetonitrile, and 0.5 mL water. The reaction was heated to 60° C. for 2.5 hours, then cooled, filtered, and evaporated. The yellow oil was used directly, 3.3 g (˜100%). To a 100 mL round-bottomed flask equipped with condenser and N2 inlet cooled filtered evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 2.99 g (8.79 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-formylphenyl)-pyridin-2-ylamine, 1.79 g (8.79 mmol) trimethylsulfonium iodide, 0.98 9 (17.59 mmol) powdered potassium hydroxide, 44 mL acetonitrile, and 0.5 mL water. The reaction was heated to 60° C. for 2.5 hours, then cooled, filtered, and evaporated. The yellow oil was used directly, 3.3 g (˜100%). To a 100 mL round-bottomed flask equipped with condenser and N2 inlet cooled filtered evaporated

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

Procedure: To an ice-cooled suspension of potassium tert-butoxide (0.82 g) in tetrahydrofuran (6.6 ml) was added trimethylsulfonium iodide (98% purity; 1.5 g) in dimethyl sulfoxide (6.6 ml). After the addition was complete, piperonal (1.0 g) in tetrahydrofuran (3.3 ml) was added dropwise to the mixture while the internal temperature was maintained below 5° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted once with ethyl acetate. The extract was washed twice with water and once with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 3,4-methylenedioxyphenyloxirane (1.0 g), which was used for next reaction without further purification. After the addition was maintained below 5° C extracted once with ethyl acetate The extract was washed twice with water and once with brine dried over anhydrous sodium sulfate concentrated in vacuo

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

Procedure: To an ice-cooled suspension of potassium tert-butoxide (0.82 g) in tetrahydrofuran (6.6 ml) was added trimethylsulfonium iodide (98% purity; 1.5 g) in dimethyl sulfoxide (6.6 ml). After the addition was complete, piperonal (1.0 g) in tetrahydrofuran (3.3 ml) was added dropwise to the mixture while the internal temperature was maintained below 5° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted once with ethyl acetate. The extract was washed twice with water and once with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 3,4-methylenedioxyphenyloxirane (1.0 g), which was used for next reaction without further purification. After the addition was maintained below 5° C extracted once with ethyl acetate The extract was washed twice with water and once with brine dried over anhydrous sodium sulfate concentrated in vacuo