2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with a 1:1 mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde and 5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide (96 mg, 0.27 mmol) as prepared in step 1, 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol (40 mg, 0.14 mmol) (prepared from 2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol in a manner similar to Example 8, Step 4), potassium carbonate solution (2.0M, 0.27 mL), toluene (0.75 mL), ethanol (0.28 mL), and THF (0.28 mL) then degassed with nitrogen for 5 minutes. PddppfCl2 was then added and the reaction heated to 110° C. for 3 hours. The reaction was then cooled to rt, diluted with water and ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate×3. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then dissolved in DMSO and purified by reverse phase HPLC to provide the title compound as an ammonium salt (8.0 mg). MS (ES−): 449.1 (M−H)—HPLC retention time: 1.86 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min. then degassed with nitrogen for 5 minutes PddppfCl2 was then added The reaction was then cooled to rt diluted with water and ethyl acetate The layers were separated the aqueous extracted with ethyl acetate×3 The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo The crude residue was then dissolved in DMSO purified by reverse phase HPLC

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

Procedure: To a solution of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (300 mg, 1.16 mmol) in dichloromethane (5 mL) was added dropwise boron tribromide (580 mg, 2.32 mmol) at −78° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic layer was washed with aq. sodium bicaronate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a crude residue, which was purified by flash chromatography to give the title compound (90 mg, 32%) as a white solid. The reaction was quenched with water (10 mL) extracted with dichloromethane (20 mL) The organic layer was washed with aq. sodium dried over sodium sulfate filtered concentrated to give a crude residue, which was purified by flash chromatography

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (crude product from Step 4, containing 40% of the desired material, 75 mg, 0.12 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (45 mg, 0.14 mmol), PdCl2(dppf) (11 mg, 0.013 mmol), potassium carbonate (80 mg, 0.58 mmol), toluene (0.6 mL), ethanol (0.3 mL), water (0.3 mL), and THF (0.3 mL) was stirred at 115° C. for 2.5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (4 mL) of ethyl acetate. The extract was loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane gave the title compound (25 mg, 56% yield). MS (ES−) 386.2 (M−H)−. Retention time: 3.38 min. Column: Phenomenex Gemini-NX, 4.6 mm×50 mm, C18, 3 μm, 110A; Column Temperature 60° C. Mobile Phase A: 0.1% formic acid in water (v/v); Mobile Phase B: 0.1% formic acid in acetonitrile (v/v) Gradient Profile: Flow-1.5 mL/min. Initial conditions: A-95%, B-5%; Linear Ramp to A-0%, B-100% over 0.0-4.10 min; hold at A-0%, B-100% from 4.10-4.50 min; return to initial conditions 4.60-5.0 min. The reaction mixture was cooled to room temperature extracted with ethyl acetate (4 mL) of ethyl acetate Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane

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

Procedure: To a stirred solution of ethyl 2-(4-bromo-2-methoxyphenyl)-2-methylpropanoate (110 mg, 0.36 mmol) in THF (4 mL) was added 1M solution of lithium aluminum hydride in THF (0.4 mL, 0.4 mmol) at −60° C. and the reaction mixture was warmed up to 0° C. in 40 min (the starting material is still present by TLC) and then allowed to stir at room temperature for 4 hours—now the starting material is consumed (TLC). A solution of sodium hydroxide (105 mg) in water (0.2 mL) was added and the mixture was stirred at room temperature for 30 min. Then 3 mL of methylene chloride (3 mL), silica gel (1 g), and anhydrous magnesium sulfate (1 g) were added and the mixture was stirred for 2 hours. Solids were filtered off and mother liquor was concentrated to give the title compound (85 mg). By GCMS, this is a mixture of the target primary alcohol and de-brominated primary alcohol (40% of the desired product by GCMS). This mixture was used for the next step without purification. GCMS (ES+) 258 (M+). is consumed (TLC) A solution of sodium hydroxide (105 mg) in water (0.2 mL) was added the mixture was stirred at room temperature for 30 min Then 3 mL of methylene chloride (3 mL), silica gel (1 g), and anhydrous magnesium sulfate (1 g) were added the mixture was stirred for 2 hours Solids were filtered off mother liquor was concentrated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with a 1:1 mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde and 5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide (96 mg, 0.27 mmol) as prepared in step 1, 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol (40 mg, 0.14 mmol) (prepared from 2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol in a manner similar to Example 8, Step 4), potassium carbonate solution (2.0M, 0.27 mL), toluene (0.75 mL), ethanol (0.28 mL), and THF (0.28 mL) then degassed with nitrogen for 5 minutes. PddppfCl2 was then added and the reaction heated to 110° C. for 3 hours. The reaction was then cooled to rt, diluted with water and ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate×3. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then dissolved in DMSO and purified by reverse phase HPLC to provide the title compound as an ammonium salt (8.0 mg). MS (ES−): 449.1 (M−H)− HPLC retention time: 1.86 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min. then degassed with nitrogen for 5 minutes PddppfCl2 was then added The reaction was then cooled to rt diluted with water and ethyl acetate The layers were separated the aqueous extracted with ethyl acetate×3 The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo The crude residue was then dissolved in DMSO purified by reverse phase HPLC

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

Procedure: To a solution of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (300 mg, 1.16 mmol) in dichloromethane (5 mL) was added dropwise boron tribromide (580 mg, 2.32 mmol) at −78° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic layer was washed with aq. sodium bicaronate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a crude residue, which was purified by flash chromatography to give the title compound (90 mg, 32%) as a white solid. The reaction was quenched with water (10 mL) extracted with dichloromethane (20 mL) The organic layer was washed with aq. sodium dried over sodium sulfate filtered concentrated to give a crude residue, which was purified by flash chromatography

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (crude product from Step 4, containing 40% of the desired material, 75 mg, 0.12 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (45 mg, 0.14 mmol), PdCl2(dppf) (11 mg, 0.013 mmol), potassium carbonate (80 mg, 0.58 mmol), toluene (0.6 mL), ethanol (0.3 mL), water (0.3 mL), and THF (0.3 mL) was stirred at 115° C. for 2.5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (4 mL) of ethyl acetate. The extract was loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane gave the title compound (25 mg, 56% yield). MS (ES−) 386.2 (M−H)−. Retention time: 3.38 min. Column: Phenomenex Gemini-NX, 4.6 mm×50 mm, C18, 3 μm, 110A; Column Temperature 60° C. Mobile Phase A: 0.1% formic acid in water (v/v); Mobile Phase B: 0.1% formic acid in acetonitrile (v/v) Gradient Profile: Flow-1.5 mL/min. Initial conditions: A-95%, B-5%; Linear Ramp to A-0%, B-100% over 0.0-4.10 min; hold at A-0%, B-100% from 4.10-4.50 min; return to initial conditions 4.60-5.0 min. The reaction mixture was cooled to room temperature extracted with ethyl acetate (4 mL) of ethyl acetate Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane

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

Procedure: To a stirred solution of ethyl 2-(4-bromo-2-methoxyphenyl)-2-methylpropanoate (110 mg, 0.36 mmol) in THF (4 mL) was added 1 M solution of lithium aluminum hydride in THF (0.4 mL, 0.4 mmol) at −60° C. and the reaction mixture was warmed up to 0° C. in 40 min (the starting material is still present by TLC) and then allowed to stir at room temperature for 4 hours—now the starting material is consumed (TLC). A solution of sodium hydroxide (105 mg) in water (0.2 mL) was added and the mixture was stirred at room temperature for 30 min. Then 3 mL of methylene chloride (3 mL), silica gel (1 g), and anhydrous magnesium sulfate (1 g) were added and the mixture was stirred for 2 hours. Solids were filtered off and mother liquor was concentrated to give the title compound (85 mg). By GCMS, this is a mixture of the target primary alcohol and de-brominated primary alcohol (40% of the desired product by GCMS). This mixture was used for the next step without purification. GCMS (ES+) 258 (M+). is consumed (TLC) A solution of sodium hydroxide (105 mg) in water (0.2 mL) was added the mixture was stirred at room temperature for 30 min Then 3 mL of methylene chloride (3 mL), silica gel (1 g), and anhydrous magnesium sulfate (1 g) were added the mixture was stirred for 2 hours Solids were filtered off mother liquor was concentrated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with a 1:1 mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde and 5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide (96 mg, 0.27 mmol) as prepared in step 1, 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol (40 mg, 0.14 mmol) (prepared from 2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol in a manner similar to Example 8, Step 4), potassium carbonate solution (2.0M, 0.27 mL), toluene (0.75 mL), ethanol (0.28 mL), and THF (0.28 mL) then degassed with nitrogen for 5 minutes. PddppfCl2 was then added and the reaction heated to 110° C. for 3 hours. The reaction was then cooled to rt, diluted with water and ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate×3. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then dissolved in DMSO and purified by reverse phase HPLC to provide the title compound as an ammonium salt (8.0 mg). MS (ES−): 449.1 (M−H)—HPLC retention time: 1.86 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min. then degassed with nitrogen for 5 minutes PddppfCl2 was then added The reaction was then cooled to rt diluted with water and ethyl acetate The layers were separated the aqueous extracted with ethyl acetate×3 The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo The crude residue was then dissolved in DMSO purified by reverse phase HPLC

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottomed flask was charged with a 1:1 mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde and 5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide (96 mg, 0.27 mmol) as prepared in step 1, 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol (40 mg, 0.14 mmol) (prepared from 2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol in a manner similar to Example 8, Step 4), potassium carbonate solution (2.0M, 0.27 mL), toluene (0.75 mL), ethanol (0.28 mL), and THF (0.28 mL) then degassed with nitrogen for 5 minutes. PddppfCl2 was then added and the reaction heated to 110° C. for 3 hours. The reaction was then cooled to rt, diluted with water and ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate×3. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then dissolved in DMSO and purified by reverse phase HPLC to provide the title compound as an ammonium salt (8.0 mg). MS (ES−): 449.1 (M−H)—HPLC retention time: 1.86 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min. then degassed with nitrogen for 5 minutes PddppfCl2 was then added The reaction was then cooled to rt diluted with water and ethyl acetate The layers were separated the aqueous extracted with ethyl acetate×3 The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo The crude residue was then dissolved in DMSO purified by reverse phase HPLC

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

Procedure: To a solution of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (300 mg, 1.16 mmol) in dichloromethane (5 mL) was added dropwise boron tribromide (580 mg, 2.32 mmol) at −78° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic layer was washed with aq. sodium bicaronate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a crude residue, which was purified by flash chromatography to give the title compound (90 mg, 32%) as a white solid. The reaction was quenched with water (10 mL) extracted with dichloromethane (20 mL) The organic layer was washed with aq. sodium dried over sodium sulfate filtered concentrated to give a crude residue, which was purified by flash chromatography

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (crude product from Step 4, containing 40% of the desired material, 75 mg, 0.12 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (45 mg, 0.14 mmol), PdCl2(dppf) (11 mg, 0.013 mmol), potassium carbonate (80 mg, 0.58 mmol), toluene (0.6 mL), ethanol (0.3 mL), water (0.3 mL), and THF (0.3 mL) was stirred at 115° C. for 2.5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (4 mL) of ethyl acetate. The extract was loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane gave the title compound (25 mg, 56% yield). MS (ES−) 386.2 (M−H)−. Retention time: 3.38 min. Column: Phenomenex Gemini-NX, 4.6 mm×50 mm, C18, 3 μm, 110A; Column Temperature 60° C. Mobile Phase A: 0.1% formic acid in water (v/v); Mobile Phase B: 0.1% formic acid in acetonitrile (v/v) Gradient Profile: Flow-1.5 mL/min. Initial conditions: A-95%, B-5%; Linear Ramp to A-0%, B-100% over 0.0-4.10 min; hold at A-0%, B-100% from 4.10-4.50 min; return to initial conditions 4.60-5.0 min. The reaction mixture was cooled to room temperature extracted with ethyl acetate (4 mL) of ethyl acetate Chromatography on a silica gel column, eluting with a gradient from 10% to 40% of ethyl acetate in heptane