1-bromo-2,2-dimethylpropane

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

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

Procedure: (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with neopentyl bromide according to Method D2a to afford (4S)-2-(N-(2,2-dimethylpropyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3-thiazoline.

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

Procedure: (1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with neopentyl bromide according to Method D2a to afford (4S)-2-(N-(2,2-dimethylpropyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3-thiazoline.

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

Procedure: To a mixture of magnesium (133 mg) and diethyl ether (10 mL) was added 1-bromo-2,2-dimethylpropane (0.68 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carbaldehyde (1.02 g) in diethyl ether (5 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (674 mg) as a pale-yellow oil. the mixture was stirred at room temperature for 2 hr the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-2-hydroxy-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (203 mg) and potassium carbonate (179 mg) in DMF (3.0 mL) was added 1-bromo-2,2-dimethylpropane (0.11 mL), and the mixture was stirred at 90° C. for 1 hr. 60% Sodium hydride (35 mg) was added at room temperature, and the mixture was stirred at 50° C. for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (128 mg) as a brown oil. the mixture was stirred at 50° C. for 3 hr the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-2-hydroxy-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (203 mg) and potassium carbonate (179 mg) in DMF (3.0 mL) was added 1-bromo-2,2-dimethylpropane (0.11 mL), and the mixture was stirred at 90° C. for 1 hr. 60% Sodium hydride (35 mg) was added at room temperature, and the mixture was stirred at 50° C. for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (128 mg) as a brown oil. the mixture was stirred at 50° C. for 3 hr the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: Under an argon atmosphere, a solution of 1-bromo-2,2-dimethylpropane (14.8 mL) in diethyl ether (120 mL) was added dropwise to magnesium (3.15 g) at a slow refluxing rate. The reaction mixture was heated under reflux for 30 min, and the obtained solution was added dropwise to a solution of 3-bromo-2-methoxypyridine (4.43 g) and PEPPSI™-SIPr (trade name) (805 mg) in THF (80 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, and saturated aqueous ammonium chloride solution was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (4.24 g) as a pale-yellow oil. This compound was used for the next step without further purification. The reaction mixture was heated under reflux for 30 min The reaction mixture was extracted with ethyl acetate the extract was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure

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

Procedure: Under an argon atmosphere, a solution of 1-bromo-2,2-dimethylpropane (23.2 mL) in diethyl ether (250 mL) was added dropwise to magnesium (4.92 g) at a slow refluxing rate, and the reaction mixture was heated under reflux further for 30 min. Under an argon atmosphere, to a solution of 2′-fluoro-5′-methoxy-4-((triisopropylsilyl)oxy)-[1,1′-biphenyl]-2-yl trifluoromethanesulfonate (19.2 g) and a PEPPSI™-SIPr catalyst (trade name) (1.26 g) in THF (200 mL) was added the solution prepared above, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crude oil. This compound was used for the next step without further purification. the reaction mixture was heated under reflux further for 30 min prepared above, and the mixture the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure

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

Procedure: Under an argon atmosphere, a solution of 1-bromo-2,2-dimethylpropane (23.2 mL) in diethyl ether (250 mL) was added dropwise to magnesium (4.92 g) at a slow refluxing rate, and the reaction mixture was heated under reflux further for 30 min. Under an argon atmosphere, to a solution of 2′-fluoro-5′-methoxy-4-((triisopropylsilyl)oxy)-[1,1′-biphenyl]-2-yl trifluoromethanesulfonate (19.2 g) and a PEPPSI™-SIPr catalyst (trade name) (1.26 g) in THF (200 mL) was added the solution prepared above, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crude oil. This compound was used for the next step without further purification. the reaction mixture was heated under reflux further for 30 min prepared above, and the mixture the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure

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

Procedure: Under an argon atmosphere, a solution of 1-bromo-2,2-dimethylpropane (9.82 mL) in diethyl ether (100 mL) was added dropwise to magnesium (1.72 g) at a slow refluxing rate, and the reaction mixture was heated under reflux further for 1 hr. Under an argon atmosphere, the obtained solution was added dropwise to a solution of 2-chloro-3-(2-fluoro-5-methoxyphenyl)-6-methoxypyridine (3.79 g) and a PEPPSI™-SIPr catalyst (trade name) (970 mg) in THF (70 mL) at room temperature, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.97 g) as a colorless oil. the reaction mixture was heated under reflux further for 1 hr the mixture was extracted with ethyl acetate The extract was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 1-bromo-2,2-dimethylpropane: 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 3.94 (s, 2H), 2.49 (s, 3H), 1.01 (s, 9H); MS (ES) m/z 295 (M+1). Synthesized

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

Procedure: In a sealed tube, dissolve p-toluenesulfinic acid sodium salt (5.71 g, 32.1 mmol) in DMF (20 mL) and water (10 mL). Add neo-pentyl bromide (6.3 mL, 48 mmol) and tetrabutylammonium iodide (592 mg, 1.60 mmol) and heat the mixture at 145° C. overnight. Cool the reaction to ambient temperature, dilute with water and extract 3 times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (3.3 g, 45%). Cool the reaction to ambient temperature extract 3 times with EtOAc Dry over anhydrous Na2SO4 concentrate in vacuo Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1)