4-bromo-2-iodophenol

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

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 2,6-difluoro-5-(trimethylsilyl)nicotinate (1.19 g, 4.85 mmol), 4-bromo-2-iodophenol (1.450 g, 4.85 mmol), and silver trifluoromethanesulfonate (1.496 g, 5.82 mmol) were dissolved in dry THF (40 mL) and treated with potassium carbonate (1.006 g, 7.28 mmol). The mixture was heated to 60° C. for 10 hours before being cooled to rt and filtered through a pad of celite. Water (100 mL) and diethyl ether (100 mL) were added to the filtrate and the phases were separated. The organics were dried with magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to DCM gradient) gave the desired methyl 2-(4-bromo-2-iodophenoxy)-6-fluoro-5-(trimethylsilyl)nicotinate. before being cooled to rt filtered through a pad of celite Water (100 mL) and diethyl ether (100 mL) were added to the filtrate the phases were separated The organics were dried with magnesium sulfate filtered evaporated to dryness under reduced pressure Purification

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

Procedure: The product from Example 112A and 4-pentyn-1-ol is processed as described in Example 112B to provide the title compound.

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

Procedure: The product from Example 112A and 4-pentyn-1-ol is processed as described in Example 112B to provide the title compound.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-2-iodophenol (5.00 g, 16.7 mmol), bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to the provide title compound (5.84 g, 99% yield). the mixture was extracted with ethyl acetate The organic phase was washed with water, saturated aqueous sodium chloride dried over anhydrous magnesium sulfate filtered The filtrate was concentrated to the

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-2-iodophenol (5.00 g, 16.7 mmol), bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to the provide title compound (5.84 g, 99% yield). the mixture was extracted with ethyl acetate The organic phase was washed with water, saturated aqueous sodium chloride dried over anhydrous magnesium sulfate filtered The filtrate was concentrated to the

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

Procedure: The mixture of 4-bromo-2-iodophenol (3.30 g, 11.04 mmol), 1-bromo-5-chloropentan-2-one (75% purity, 3.9 g, 14.66 mmol), and K2CO3 (2.3 g, 16.64 mmol) in acetone (66 mL) was stirred for 48 hours at ambient temperature. The insoluble material was removed by filtration and washed with EtOAc. The filtrate was evaporated in vacuo. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 25%) afforded 1-(4-bromo-2-iodophenoxy)-5-chloropentan-2-one (2.12 g). The insoluble material was removed by filtration washed with EtOAc The filtrate was evaporated in vacuo The residue was purified by silicagel column chromatography (EtOAc-hexane

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

Procedure: The mixture of 4-bromo-2-iodophenol (3.30 g, 11.04 mmol), 1-bromo-5-chloropentan-2-one (75% purity, 3.9 g, 14.66 mmol), and K2CO3 (2.3 g, 16.64 mmol) in acetone (66 mL) was stirred for 48 hours at ambient temperature. The insoluble material was removed by filtration and washed with EtOAc. The filtrate was evaporated in vacuo. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 25%) afforded 1-(4-bromo-2-iodophenoxy)-5-chloropentan-2-one (2.12 g). The insoluble material was removed by filtration washed with EtOAc The filtrate was evaporated in vacuo The residue was purified by silicagel column chromatography (EtOAc-hexane

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

Procedure: The mixture of 4-bromo-2-iodophenol (3.30 g, 11.04 mmol), 1-bromo-5-chloropentan-2-one (75% purity, 3.9 g, 14.66 mmol), and K2CO3 (2.3 g, 16.64 mmol) in acetone (66 mL) was stirred for 48 hours at ambient temperature. The insoluble material was removed by filtration and washed with EtOAc. The filtrate was evaporated in vacuo. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 25%) afforded 1-(4-bromo-2-iodophenoxy)-5-chloropentan-2-one (2.12 g). The insoluble material was removed by filtration washed with EtOAc The filtrate was evaporated in vacuo The residue was purified by silicagel column chromatography (EtOAc-hexane

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (4.03 g), 4-bromo-2-iodo-phenol (5.00 g), Pd(PPh3)2Cl2 (600 mg), copper iodide (500 mg), and triethylamine (2.35 mL) in N,N-dimethylformamide (30 mL) is heated under an argon atmosphere to 75° C. for 4 h. The reaction mixture is diluted with ice water after cooling to room temperature and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 2): tR=1.32 min; Mass spectrum (ESI+): m/z=402, 404 [M+Na]+. after cooling to room temperature extracted with ethyl acetate The combined extracts are dried over MgSO4 concentrated in vacuo The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40)

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

Procedure: The product from Example 112A and 4-pentyn-1-ol is processed as described in Example 112B to provide the title compound.