1-BROMO-5-METHYLHEXANE

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 stirred suspension of samarium metal (758 mg, 5.0 mmol) and 3 Å molecular sieves (0.5 g) in anhydrous tetrahydrofuran (THF, 9.5 mL) was slowly added a solution of 1,2-diiodoethane (1.3 g, 4.6 mmol) in THF (9.5 mL) at ambient temperature. After the reaction stirred for 30 min, hexamethylphosphoramide (HPMA, 3.0 mL, 17.2 mmol) was added to the reaction mixture and continued stirring for an additional 20 min. Then, a solution of ketone 1 (500.0 mg, 1.16 mmol) in THF (6.0 mL) was added followed by a solution of 1-bromo-5-methylhexane (208.0 mg, 1.16 mmol) in THF (2.0 mL). The reaction was allowed to stir for an additional hour until the starting material was completely consumed. After this, the reaction mixture was slowly treated with saturated NaHCO3, filtered through Celite and rinsed three times with an excess amount of diethyl ether. The filtrate was treated with water and extracted with diethyl ether. The ether extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo to give a residue which was purified via silica gel chromatography. Elution with hexane-diethyl ether (4:1, v/v) afforded compound 2 (350.0 mg, 0.6 mmol, 57%) as a white powder (Honda et al. (1996) J. Chem. Soc., Perkin Trans. 1, 2291-2296). continued stirring for an additional 20 min to stir for an additional hour until the starting material was completely consumed After this, the reaction mixture was slowly treated with saturated NaHCO3 filtered through Celite rinsed three times with an excess amount of diethyl ether The filtrate was treated with water extracted with diethyl ether The ether extracts were washed with brine dried over Na2SO4 evaporated in vacuo to give a residue which was purified via silica gel chromatography Elution with hexane-diethyl ether (4:1

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

Procedure: A solution of 25 (2.30 g; 12.8 mmol) and triphenylphosphine (3.70 g; 14.1 mmol) was refluxed in toluene (12 mL) for 20 h. Then solvent was removed and the resulting crystal was washed with toluene (3 mL) and diethyl ether (3 mL) to give 4.57 g (10.4 mmol; 81% yield) of 10. m.p. 227-228° C.; 1H NMR (500 MHz, CD3CN) δ 0.82 (6H, d, J=6.6 Hz), 1.16 (2H, m), 1.42-1.52 (3H, m), 1.59 (2H, m), 3.30 (2H, m), 7.72 (12H, m), 7.85 (3H, m); 13C NMR (125 MHz, CD3CN) δ 22.7, 23.2, 28.4, 28.8, 28.9, 38.6, 131.2, 131.3, 134.7, 134.7, 136.0. Then solvent was removed the resulting crystal was washed with toluene (3 mL) and diethyl ether (3 mL)

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

Procedure: A solution of 25 (2.30 g; 12.8 mmol) and triphenylphosphine (3.70 g; 14.1 mmol) was refluxed in toluene (12 mL) for 20 h. Then solvent was removed and the resulting crystal was washed with toluene (3 mL) and diethyl ether (3 mL) to give 4.57 g (10.4 mmol; 81% yield) of 10. m.p. 227-228° C.; 1H NMR (500 MHz, CD3CN) δ 0.82 (6H, d, J=6.6 Hz), 1.16 (2H, m), 1.42-1.52 (3H, m), 1.59 (2H, m), 3.30 (2H, m), 7.72 (12H, m), 7.85 (3H, m); 13C NMR (125 MHz, CD3CN) δ 22.7, 23.2, 28.4, 28.8, 28.9, 38.6, 131.2, 131.3, 134.7, 134.7, 136.0. Then solvent was removed the resulting crystal was washed with toluene (3 mL) and diethyl ether (3 mL)

Conditions: temp:50.01; 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-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool die reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), 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+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 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=12.4 min, 97.7% purity. increase the temperature to 80° C. for 3.5 hours Cool die reaction mixture to room temperature Wash with water (1× 30 mL), 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:50.01; 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-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool die reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), 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+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 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=12.4 min, 97.7% purity. increase the temperature to 80° C. for 3.5 hours Cool die reaction mixture to room temperature Wash with water (1× 30 mL), 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:50.01; 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-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool die reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), 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+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 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=12.4 min, 97.7% purity. increase the temperature to 80° C. for 3.5 hours Cool die reaction mixture to room temperature Wash with water (1×30 mL), 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:50.01; 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-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), 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+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 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=12.4 min, 97.7% purity. increase the temperature to 80° C. for 3.5 hours Cool the reaction mixture to room temperature Wash with water (1×30 mL), 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: To a solution of methyl cyclopentanecarboxylate (300 mg, 2.3 mmol) in THF (20 ml) at −78° C. was added LHMDS (4.6 mL, 4.6 mmol) and stirred for 30 min, and followed by 1-bromo-5-methylhexane (626 mg, 3.5 mmol). The mixture was stirred from −78° C. to rt over 16 hr, before 30 ml of H2O was added and then was extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with water, dried over MgSO4, filtered and concentrated, then purified using flash chromatography to give an oil (110 mg, 21%). MS [M+H]+333. was added was extracted with CH2Cl2 (2×30 mL) The combined extracts were washed with water dried over MgSO4 filtered concentrated purified

Conditions: temp:50.01; 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-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool die reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), 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+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 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=12.4 min, 97.7% purity. increase the temperature to 80° C. for 3.5 hours Cool die reaction mixture to room temperature Wash with water (1×30 mL), 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: