(2S)-1-[(2-methylpropan-2-yl)oxy]propan-2-ol

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

Procedure: To a stirred suspension of sodium bis(trimethylsilyl)amide (74.25 mmol; 14.33 g) in DMF (150 mL) at 23° C. was added (S)-tert-butoxy-2-propanol (74.25 mmoles, 9.82 g) over 15 minutes. A slight exotherm was observed (cold water cooling bath applied). A solution of 3-bromo-5-fluorobenzonitrile (49.50 mmol, 10.0 g) in DMF (40 mL) was added over 15 minutes with cold water bath still present. An exotherm (3° C.) was observed and the mixture turned from yellow to brown. DMF (10 mL) was added and the mixture stirred at ambient temperature for 1 hour. The reaction was quenched by addition of aqueous HCl (2M, 100 mL), maintaining temperature below 25° C. The mixture was diluted with water (200 mL) and extracted with 2:1 EtOAc/MTBE (3×200 mL). The organic layers were combined, washed with water (3×200 mL) and dried over MgSO4, and the solvent removed in vacuo affording the title compound as an orange oil (17.4 g). Further drying in vacuo at 23° C. gave the title product (15.5 g, ˜100%). An exotherm (3° C.) The reaction was quenched by addition of aqueous HCl (2M, 100 mL) maintaining temperature below 25° C The mixture was diluted with water (200 mL) extracted with 2:1 EtOAc/MTBE (3×200 mL) washed with water (3×200 mL) dried over MgSO4 the solvent removed in vacuo

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

Procedure: To a stirred suspension of sodium bis(trimethylsilyl)amide (74.25 mmol; 14.33 g) in DMF (150 mL) at 23° C. was added (S)-tert-butoxy-2-propanol (74.25 mmoles, 9.82 g) over 15 minutes. A slight exotherm was observed (cold water cooling bath applied). A solution of 3-bromo-5-fluorobenzonitrile (49.50 mmol, 10.0 g) in DMF (40 mL) was added over 15 minutes with cold water bath still present. An exotherm (3° C.) was observed and the mixture turned from yellow to brown. DMF (10 mL) was added and the mixture stirred at ambient temperature for 1 hour. The reaction was quenched by addition of aqueous HCl (2M, 100 mL), maintaining temperature below 25° C. The mixture was diluted with water (200 mL) and extracted with 2:1 EtOAc/MTBE (3×200 mL). The organic layers were combined, washed with water (3×200 mL) and dried over MgSO4, and the solvent removed in vacuo affording the title compound as an orange oil (17.4 g). Further drying in vacuo at 23° C. gave the title product (15.5 g, ˜100%). An exotherm (3° C.) The reaction was quenched by addition of aqueous HCl (2M, 100 mL) maintaining temperature below 25° C The mixture was diluted with water (200 mL) extracted with 2:1 EtOAc/MTBE (3×200 mL) washed with water (3×200 mL) dried over MgSO4 the solvent removed in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 3-necked round-bottomed flask (100 ml with condenser, septum thermometer and magnetic follower) was charged sodium hydride (32.96 mmol, 1.32 g). The flask was placed under an inert atmosphere and dry NMP (80 ml) was charged. To the resulting suspension was charged (S)-1-tert-butoxy-2-propanol (30.21 mmol; 3.99 g; added in 0.2 ml aliquots with temperature control to control H2 evolution). Once gas evolution had ceased 3-fluoro-5-(4-methanesulfonyl-phenoxy)benzonitrile (see Example 1, 27.46 mmol, 8.0 g) was added in one portion. The reaction mixture was heated to 70° C. for 3 hours. The reaction was cooled to room temperature and toluene (240 ml) was added followed by water (240 ml). The contents were stirred at room temperature for 30 minutes and then transferred to a separating funnel. The two layers were separated and the aqueous layer was further extracted with toluene (240 ml). The organic extracts were combined and washed once with sodium hydroxide (160 mmol, 160 ml) and then with water (4×160 ml). The toluene was removed in vacuo to leave an oil that slowly solidified (9.20 g; 83.02% yield). was charged was added in one portion The reaction was cooled to room temperature transferred to a separating funnel The two layers were separated the aqueous layer was further extracted with toluene (240 ml) The toluene was removed in vacuo to leave an oil that

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

Procedure: To a stirred suspension of sodium bis(trimethylsilyl)amide (74.25 mmol; 14.33 g) in DMF (150 mL) at 23° C. was added (S)-tert-butoxy-2-propanol (74.25 mmoles, 9.82 g) over 15 minutes. A slight exotherm was observed (cold water cooling bath applied). A solution of 3-bromo-5-fluorobenzonitrile (49.50 mmol, 10.0 g) in DMF (40 mL) was added over 15 minutes with cold water bath still present. An exotherm (3° C.) was observed and the mixture turned from yellow to brown. DMF (10 mL) was added and the mixture stirred at ambient temperature for 1 hour. The reaction was quenched by addition of aqueous HCl (2M, 100 mL), maintaining temperature below 25° C. The mixture was diluted with water (200 mL) and extracted with 2:1 EtOAc/MTBE (3×200 mL). The organic layers were combined, washed with water (3×200 mL) and dried over MgSO4, and the solvent removed in vacuo affording the title compound as an orange oil (17.4 g). Further drying in vacuo at 23° C. gave the title product (15.5 g, ˜100%). An exotherm (3° C.) The reaction was quenched by addition of aqueous HCl (2M, 100 mL) maintaining temperature below 25° C The mixture was diluted with water (200 mL) extracted with 2:1 EtOAc/MTBE (3×200 mL) washed with water (3×200 mL) dried over MgSO4 the solvent removed in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 3-necked round-bottomed flask (100 ml with condenser, septum thermometer and magnetic follower) was charged sodium hydride (32.96 mmol, 1.32 g). The flask was placed under an inert atmosphere and dry NMP (80 ml) was charged. To the resulting suspension was charged (S)-1-tert-butoxy-2-propanol (30.21 mmol; 3.99 g; added in 0.2 ml aliquots with temperature control to control H2 evolution). Once gas evolution had ceased 3-fluoro-5-(4-methanesulfonyl-phenoxy)benzonitrile (see Example 1, 27.46 mmol, 8.0 g) was added in one portion. The reaction mixture was heated to 70° C. for 3 hours. The reaction was cooled to room temperature and toluene (240 ml) was added followed by water (240 ml). The contents were stirred at room temperature for 30 minutes and then transferred to a separating funnel. The two layers were separated and the aqueous layer was further extracted with toluene (240 ml). The organic extracts were combined and washed once with sodium hydroxide (160 mmol, 160 ml) and then with water (4×160 ml). The toluene was removed in vacuo to leave an oil that slowly solidified (9.20 g; 83.02% yield). was charged was added in one portion The reaction was cooled to room temperature transferred to a separating funnel The two layers were separated the aqueous layer was further extracted with toluene (240 ml) The toluene was removed in vacuo to leave an oil that