1-bromo-4,4-dimethylpentan-2-one

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

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

Procedure: A stirred solution of the product from Step B (1.626 grams) in dry DMF (18 mL) was combined with 3-methoxyphenol (1.256 grams) and cesium carbonate (3.292 grams). The mixture was stirred for 2.5 hours. The reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration furnished an oil from which the title compound was isolated by chromatography over silica gel (4:1 hex/ethyl acetate). The reaction was partitioned between isopropyl acetate and pH4 The organic was washed twice with water dried over magnesium sulfate filtered Concentration

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

Procedure: A stirred solution of the product from Step B (1.626 grams) in dry DMF (18 mL) was combined with 3-methoxyphenol (1.256 grams) and cesium carbonate (3.292 grams). The mixture was stirred for 2.5 hours. The reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration furnished an oil from which the title compound was isolated by chromatography over silica gel (4:1 hex/ethyl acetate). The reaction was partitioned between isopropyl acetate and pH4 The organic was washed twice with water dried over magnesium sulfate filtered Concentration

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

Procedure: 1-bromo-4,4-dimethylpentan-2-one (500 mg, 2.6 mmol) was added to an ambient temperature solution of 2,2-difluoro-3-[4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (365 mg, 1.2 mmol) and sodium acetate (290 mg, 3.5 mmol) in 1,4-dioxane (20 mL). After stirring at reflux for 1 h, volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide. The organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.67 (dd, J=4.3, 8.8 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.45 (dt, J=2.8, 8.4, 1H) 6.69 (s, 1H), 2.39 (s, 2H), 1.77 (s, 3H), 0.84 (s, 9H). at reflux for 1 h volatiles were removed in vacuo The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide The organic phase was washed with brine dried (sodium sulfate) concentrated in vacuo

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

Procedure: 1-bromo-4,4-dimethylpentan-2-one (500 mg, 2.6 mmol) was added to an ambient temperature solution of 2,2-difluoro-3-[4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (365 mg, 1.2 mmol) and sodium acetate (290 mg, 3.5 mmol) in 1,4-dioxane (20 mL). After stirring at reflux for 1 h, volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide. The organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.67 (dd, J=4.3, 8.8 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.45 (dt, J=2.8, 8.4, 1H) 6.69 (s, 1H), 2.39 (s, 2H), 1.77 (s, 3H), 0.84 (s, 9H). at reflux for 1 h volatiles were removed in vacuo The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide The organic phase was washed with brine dried (sodium sulfate) concentrated in vacuo

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

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

Procedure: A stirred solution of the product from Step B (1.626 grams) in dry DMF (18 mL) was combined with 3-methoxyphenol (1.256 grams) and cesium carbonate (3.292 grams). The mixture was stirred for 2.5 hours. The reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration furnished an oil from which the title compound was isolated by chromatography over silica gel (4:1 hex/ethyl acetate). The reaction was partitioned between isopropyl acetate and pH4 The organic was washed twice with water dried over magnesium sulfate filtered Concentration

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

Procedure: To a stirred, −10° solution of the crude product from Step A (1.233 grams) in methylene chloride (12 mL) was added 48% HBr dropwise (1.14 mL). After gas evolution ceased, the reaction was stirred for 15 minutes at room temperature. The reaction was partitioned between isopropyl acetate and water. The organic was washed once with water, dried over magnesium sulfate and filtered. Evaporation afforded an oil containing the title compound which was used without further processing. The reaction was partitioned between isopropyl acetate and water The organic was washed once with water dried over magnesium sulfate filtered Evaporation afforded an oil

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

Procedure: To a stirred, −10° solution of the crude product from Step A (1.233 grams) in methylene chloride (12 mL) was added 48% HBr dropwise (1.14 mL). After gas evolution ceased, the reaction was stirred for 15 minutes at room temperature. The reaction was partitioned between isopropyl acetate and water. The organic was washed once with water, dried over magnesium sulfate and filtered. Evaporation afforded an oil containing the title compound which was used without further processing. The reaction was partitioned between isopropyl acetate and water The organic was washed once with water dried over magnesium sulfate filtered Evaporation afforded an oil

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

Procedure: A stirred solution of the product from Step B (1.626 grams) in dry DMF (18 mL) was combined with 3-methoxyphenol (1.256 grams) and cesium carbonate (3.292 grams). The mixture was stirred for 2.5 hours. The reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration furnished an oil from which the title compound was isolated by chromatography over silica gel (4:1 hex/ethyl acetate). The reaction was partitioned between isopropyl acetate and pH4 The organic was washed twice with water dried over magnesium sulfate filtered Concentration

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

Procedure: A stirred solution of the product from Step B (1.626 grams) in dry DMF (18 mL) was combined with 3-methoxyphenol (1.256 grams) and cesium carbonate (3.292 grams). The mixture was stirred for 2.5 hours. The reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration furnished an oil from which the title compound was isolated by chromatography over silica gel (4:1 hex/ethyl acetate). The reaction was partitioned between isopropyl acetate and pH4 The organic was washed twice with water dried over magnesium sulfate filtered Concentration

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

Procedure: 1-bromo-4,4-dimethylpentan-2-one (500 mg, 2.6 mmol) was added to an ambient temperature solution of 2,2-difluoro-3-[4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (365 mg, 1.2 mmol) and sodium acetate (290 mg, 3.5 mmol) in 1,4-dioxane (20 mL). After stirring at reflux for 1 h, volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide. The organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J=3.0 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.67 (dd, J=4.3, 8.8 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.45 (dt, J=2.8, 8.4, 1H) 6.69 (s, 1H), 2.39 (s, 2H), 1.77 (s, 3H), 0.84 (s, 9H). at reflux for 1 h volatiles were removed in vacuo The residue was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide The organic phase was washed with brine dried (sodium sulfate) concentrated in vacuo