3-chloro-2-methylbenzonitrile

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

Procedure: To a refluxing solution of 3-chloro-2-methylbenzonitrile (2.0 g, 13.2 mmol) in 20 mL of CCl4 was added 2.6 g (14.4 mmol, 1.1 eq) of N-bromosuccinimide and 0.2 g of AIBN. The solution was refluxed for 3 hours and then cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (1.4 g, 46%) as a yellow oil. The solution was refluxed for 3 hours cooled washed with 200 mL of H2O and 200 mL of brine The organic phase was dried over MgSO4 filtered concentrated in vacuo chromatographed with 5:1 hexane/ethyl acetate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add a 2M solution of lithium diisopropylamide in tetrahydrofuran (62.6 mL, 461.8 mmol) to tetrahydrofuran (1 L) at −78° C. Slowly add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (19.94 mL, 164.91 mmol) followed by drop-wise addition of 3-chloro-2-methyl-benzonitrile (20 g, 131.93 mmol). Maintain the mixture at −78° C. with stirring for 5 min. Purge the reaction vessel with carbon dioxide (1 L; 25.65 moles) for 15 min. Add water (100 mL) and stir for 2 hr. Add 10M aqueous solution of sodium hydroxide to increase the pH of the aqueous phase to >12. Separate the aqueous layer and wash with diethyl ether. Acidify the aqueous layer with concentrated hydrochloric acid to pH-1 and extract with ethyl acetate. Separate the organic phase and dry over sodium sulfate. Filter and concentrate to dryness to yield the title compound as an off white solid (16.0 g; 81.80 mmol). MS (m/z): 195.9 (M+1). to increase the pH of the aqueous phase to >12 Separate the aqueous layer wash with diethyl ether extract with ethyl acetate Separate the organic phase dry over sodium sulfate Filter concentrate to dryness

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

Procedure: To a refluxing solution of 3-chloro-2-methylbenzonitrile (2.0 g,13.2 mmol) in 20 mL of CCl4 was added 2.6 g (14.4 mmol, 1.1 eq) of N-bromosuccinimide and 0.2 g of AIBN. The solution was refluxed for 3 hours and then cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (1.4 g, 46%) as a yellow oil. The solution was refluxed for 3 hours cooled washed with 200 mL of H2O and 200 mL of brine The organic phase was dried over MgSO4 filtered concentrated in vacuo chromatographed with 5:1 hexane/ethyl acetate

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

Procedure: Sodium cyanide (58 g, 1.18 mol) in 90 ml of water is added to cuprous chloride (44 g, 0.44 mol) in 180 ml of water while stirring mechanically in a 5 l. 3-necked flask. Evolution of heat results and the cuprous chloride dissolves. This is then cooled in an ice bath to 0° C. A milky suspension of cuprous cyanide results. To this is added 90 ml of toluene. 6 N Hydrochloric acid (125 ml) is added slowly to 3-chloro-2-methylaniline (50 g, 0.35 mol) in a 2 l. erlenmeyer flask, while cooling and swirling. A solution of sodium nitrite (25 g, 0.36 mol) in 70 ml of water is added dropwise to the hydrochloride suspension. Ice is added when required, keeping the temperature at 0° C. Anhydrous sodium carbonate is added until the diazonium hydrochloride solution is neutral to pH paper. This is then added slowly to the cold stirring cuprous cyanide suspension, the temperature not being allowed to rise above 5° C. The reaction is then stirred at 0°-5° C. for 0.5 hr, allowed to reach room temperature over a 2 hr period and then heated to 50° C. on the steam bath. After remaining at room temperature overnight, the product is steam distilled off. The distillate is extracted with benzene, washed with 10% hydrochloric acid, dried and evaporated to afford 28 g of the title compound that solidified on standing. Evolution of heat results results erlenmeyer flask, while cooling Ice is added when at 0° C This is then added slowly to the to rise above 5° C The reaction is then stirred at 0°-5° C. for 0.5 hr heated to 50° C. on the steam bath After remaining at room temperature overnight distilled off The distillate is extracted with benzene washed with 10% hydrochloric acid dried evaporated