1-bromo-3,3-dimethylbutane

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

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

Procedure: Mix 4-cyanophenol (1.2 g, 10 mmol), 1-bromo-3,3-dimethylbutane (5.3 g, 32 mmol), powdered potassium carbonate (4.14 g, 30 mmol), and powdered potassium iodide (166 mg, 1 mmol) in acetone (60 mL). Stir under inert atmosphere and heat at reflux for 48 h. Cool the reaction mixture to ambient temperature. Dilute with acetone, filter and evaporate. Purify by chromatography on silica gel eluting with hexane/EtOAc (10 and 9:1) to obtain the desired intermediate (1.8 g, 89%). MS (ES+) m/z: 221 (M+NH4)+. heat at reflux for 48 h filter evaporate Purify by chromatography on silica gel eluting with hexane/EtOAc (10 and 9:1)

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

Procedure: 1-(3,5-Dihydroxyphenyl)ethanone (3.0 g) was converted analogously to O2.031. Instead of cyclohexylbromide, however, 1-bromo-3,3-dimethylbutane was used. After chromatography, 960 mg of the title compound were obtained.

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

Procedure: 1-(3,5-Dihydroxyphenyl)ethanone (3.0 g) was converted analogously to O2.031. Instead of cyclohexylbromide, however, 1-bromo-3,3-dimethylbutane was used. After chromatography, 960 mg of the title compound were obtained.

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

Procedure: 1-(3,5-Dihydroxyphenyl)ethanone (3.0 g) were converted analogously to O2.031. Instead of cyclohexylbromide, however, 1-bromo-3,3-dimethylbutane was used. After chromatography, 960 mg of the title compound were obtained.

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

Procedure: Lithium bis(trimethylsilyl)amide (32.3 g, 193 mmol) was added to 80 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (11.6 g, 77.3 mmol) in 10 mL of tetrahydrofuran to the reaction solution was followed by addition of 1-bromo-3,3-dimethyl-butane (20.4 g, 124 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 250 mL of 1 N NaOH, washed with 250 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 17.3 g (96%) of clear oil. 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9H) 1.09 (m, 2H) 1.56 (s, 3H) 1.99 (m, 2H) 7.33 (m, 5H). the resulting solution was cooled in an ice bath The reaction vessel was removed from the cooling bath placed in a 50° C. After concentration the resulting residue was dissolved in 250 mL of 1 N NaOH washed with 250 mL of 2:1 hexane/iso-propyl acetate extracted with ethyl acetate (3×300 mL) The combined organic layers were dried over Na2SO4 concentrated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of the compound of Example 22A (11.75 g, 64.6 mmol) in tetrahydrofuran (30 mL) was added dropwise over 20 min to a −78° C. solution of lithium hexamethyldisilazide (previously prepared from hexamethyldisilazane (17.0 mL, 80.7 mmol) and n-butyllithium in hexane (2.5 M, 31.0 mL, 77.5 mmol)) in tetrahydrofuran (40 mL) and allowed to stir at that temperature for 1 h. The solution was then treated with 1-bromo-3,3-dimethylbutane (12.0 mL, 83.9 mmol), followed by stirring at −78° C. for 30 min, and then warming to 25° C. for 18 h. The solution was quenched by addition of saturated ammonium chloride solution (4 mL) and then concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was extracted with water (2×), saturated NaCl solution and dried (Na2SO4). Concentration in vacuo afforded an oil, which was distilled under reduced pressure (90-93° C./0.3 mm Hg) to afford the product (4.85 g, 28%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.86 (s, 9 H) 1.03 (m, 2 H) 1.51 (m, 3 H) 1.86 (m, 1 H) 2.00 (m, 1 H) 3.65 (m, 3H) 7.03 (m, 2 H) 7.27 (m, 2 H). by stirring at −78° C. for 30 min The solution was quenched by addition of saturated ammonium chloride solution (4 mL) concentrated in vacuo The residue was diluted with ethyl acetate and water The organic layer was extracted with water (2×), saturated NaCl solution dried (Na2SO4) Concentration in vacuo afforded an oil, which was distilled under reduced pressure (90-93° C./0.3 mm Hg)

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

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity. Cool the reaction mixture to room temperature Wash with water (1× 30 mL) and brine (1× 30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

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

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity. Cool the reaction mixture to room temperature Wash with water (1× 30 mL) and brine (1× 30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

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

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity. Cool the reaction mixture to room temperature Wash with water (1×30 mL) and brine (1×30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate

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

Procedure: 1-(3,5-Dihydroxyphenyl)ethanone (3.0 g) were converted analogously to O2.031. Instead of cyclohexylbromide, however, 1-bromo-3,3-dimethylbutane was used. After chromatography, 960 mg of the title compound were obtained.

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

Procedure: Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound : MS ES+368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity. Cool the reaction mixture to room temperature Wash with water (1×30 mL) and brine (1×30 mL) Dry the organic layer over Na2SO4 filter concentrate Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate