2-(4-bromophenyl)-2-methylpropanenitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-bromophenyl)-2-methylpropanenitrile (1 g, 4.46 mmol) is dissolved in anhydrous THF (75 ml) the solution is cooled down to −100° C. with a diethyl ether-liquid nitrogen bath, n-butyl lithium 2M in c-hexane (4.0 ml, 8.0 mmol) is added and this reaction mixture stirred for 10 min., then N-methoxy-N-methyl acetamide (1.6 g, 15.6 mmol) is added and the reaction is then left to slowly warm-up to room temperature. After work-up (washing with acidic brine) and concentration the crude mixture is purified on silica gel using a 0 to 50% ethyl acetate in hexane gradient, to give the desired compound (660 mg, 78%) as a clear oil. the reaction is then left to slowly warm-up to room temperature After work-up (washing with acidic brine) and concentration the crude mixture is purified on silica gel using a 0 to 50% ethyl acetate in hexane gradient

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a suspension of sodium hydride (60% dispersion in oil, 50 g, 1.25 m) in dry N,N-dimethylformamide (400 ml under nitrogen was added with stirring a solution of 4-bromophenylacetonitrile in N,N-dimethylformamide (400 ml) keeping the temperature between 30° and 40° C. A solution of iodomethane (213 g, 1.50 m) in N,N-dimethylformamide was then added gradually keeping the temperatue between 35° C. and the mixture then stirred at ambient temperature overnight. With ice cooling 2N aqueous hydrochloric acid (800 ml) was gradually added and then the mixture was diluted with water (1200 ml). The product was extracted with ether and the extract washed with water, saturated sodium bicarbonate, aqueous sodium sulphite, water again and finally brine. After drying and concentration on vacuo an orange oil was obtained which was distilled in vacuo to give the title compound as a colourless liquid (98.05 g, 87.5%) b.pt. 98°-100°/0.4 mm. was added the temperature between 30° and 40° C between 35° C. The product was extracted with ether the extract washed with water, saturated sodium bicarbonate, aqueous sodium sulphite, water again After drying concentration on vacuo an orange oil was obtained which was distilled in vacuo

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

Procedure: To a suspension of sodium hydride (60% dispersion in oil, 50 g, 1.25 m) in dry N,N-dimethylformamide (400 ml under nitrogen was added with stirring a solution of 4-bromophenylacetonitrile in N,N-dimethylformamide (400 ml) keeping the temperature between 30° and 40° C. A solution of iodomethane (213 g, 1.50 m) in N,N-dimethylformamide was then added gradually keeping the temperatue between 35° C. and the mixture then stirred at ambient temperature overnight. With ice cooling 2N aqueous hydrochloric acid (800 ml) was gradually added and then the mixture was diluted with water (1200 ml). The product was extracted with ether and the extract washed with water, saturated sodium bicarbonate, aqueous sodium sulphite, water again and finally brine. After drying and concentration on vacuo an orange oil was obtained which was distilled in vacuo to give the title compound as a colourless liquid (98.05 g, 87.5%) b.pt. 98°-100°/0.4 mm. was added the temperature between 30° and 40° C between 35° C. The product was extracted with ether the extract washed with water, saturated sodium bicarbonate, aqueous sodium sulphite, water again After drying concentration on vacuo an orange oil was obtained which was distilled in vacuo

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

Procedure: To a solution of 2-(4-bromophenyl)-2-methylpropanenitrile (3.29 g) in toluene (33 mL) was added potassium trimethylsilanolate (8.37 g) portionwise. After being stirred at reflux temperature for 5 h, the reaction mixture was cooled to room temperature. Water(17 mL) was added to the mixture dropwise. Filtration gave the product (3.28 g, 92%). 1HNMR (CDCl3) 400 MHz δ: 7.49 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 5.52-4.93 (m, 2H), 1.57 (s, 6H). at reflux temperature for 5 h Filtration

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

Procedure: To a solution of 2-(4-bromophenyl)-2-methylpropanenitrile (3.29 g) in toluene (33 mL) was added potassium trimethylsilanolate (8.37 g) portionwise. After being stirred at reflux temperature for 5 h, the reaction mixture was cooled to room temperature. Water(17 mL) was added to the mixture dropwise. Filtration gave the product (3.28 g, 92%). 1HNMR (CDCl3) 400 MHz δ: 7.49 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 5.52-4.93 (m, 2H), 1.57 (s, 6H). at reflux temperature for 5 h Filtration

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

Procedure: To a solution of (4-bromophenyl)acetonitrile (3 g) in N,N-dimethylformamide (45 ml) chilled to 0° C. was added sodium hydride (55 wt %, 1.47 g) portionwise. The reaction mixture was stirred at the same temperature for 15 min Iodomethane (2.86 mL) was added to the mixture at 0° C. dropwise. After being stirred at 0° C. for 10 min then at room temperature for 1 h, the reaction mixture was poured into ammonium chloride aqueous solution and extracted with diisopropyl ether (3 times) and washed with saturated sodium bicarbonate aqueous solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-10% ethyl acetate in hexanes) gave the product (3.29 g, 96%). 1HNMR (CDCl3) 400 MHz δ: 7.52 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 1.71 (s, 6H). was added to the mixture at 0° C. dropwise at room temperature for 1 h extracted with diisopropyl ether (3 times) washed with saturated sodium bicarbonate aqueous solution The organics were dried over anhydrous sodium sulfate concentrated under reduced pressure Purification by column chromatography (0-10% ethyl acetate in hexanes)

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

Procedure: Following the procedure used to prepare 2-methyl-propane-2-sulfinic acid (1-{5-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-pyridin-2-yl}-cyclobutyl)-amide, 2-(4-bromo-phenyl)-2-methyl-propionitrile was reacted to give the title compound (55 mg, 99%). LCMS (Method A): RT=4.83 min, [M+H]+=553. was reacted