2-bromo-4-iodo-1-methoxybenzene

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

Procedure: To a 100 mL round bottom flask was added copper (I) iodide (30.4 mg, 0.16 mmol), 2-(2-pyridyl)benzimidazole (31.2 mg, 0.16 mmol), cesium carbonate (625 mg, 1.92 mmol) and DMF (5.3 mL). The reaction mixture was heated to 60° C. for 1 h then (1H-pyrazol-3-yl)methanol (235 mg, 2.40 mmol) and 2-bromo-4-iodo-1-methoxybenzene (500 mg, 1.60 mmol) were added and the mixture was heated at 100° C. for 18 hours. The reaction was cooled, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc in Hepane) to afford (1-(3-bromo-4-methoxyphenyl)-1H-pyrazol-3-yl)methanol (353 mg) MS [M+2H+]=285.0. the mixture was heated at 100° C. for 18 hours The reaction was cooled filtered through celite The filtrate was concentrated in vacuo purified by silica gel chromatography (0-100% EtOAc in Hepane)

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

Procedure: To a 100 mL round bottom flask was added copper (I) iodide (30.4 mg, 0.16 mmol), 2-(2-pyridyl)benzimidazole (31.2 mg, 0.16 mmol), cesium carbonate (625 mg, 1.92 mmol) and DMF (5.3 mL). The reaction mixture was heated to 60° C. for 1 h then (1H-pyrazol-3-yl)methanol (235 mg, 2.40 mmol) and 2-bromo-4-iodo-1-methoxybenzene (500 mg, 1.60 mmol) were added and the mixture was heated at 100° C. for 18 hours. The reaction was cooled, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc in Hepane) to afford (1-(3-bromo-4-methoxyphenyl)-1H-pyrazol-3-yl)methanol (353 mg) MS [M+2H+]=285.0. the mixture was heated at 100° C. for 18 hours The reaction was cooled filtered through celite The filtrate was concentrated in vacuo purified by silica gel chromatography (0-100% EtOAc in Hepane)

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

Procedure: To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H). The resulting reaction mixture was stirred at 0° C. for 1 hr to warm up stirred at rt for 1 hr washed with 30 mL 1N HCl Organics were dried over sodium sulfate filtered concentrated Crude product was purified by silica gel chromatography

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

Procedure: To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H). The resulting reaction mixture was stirred at 0° C. for 1 hr to warm up stirred at rt for 1 hr washed with 30 mL 1N HCl Organics were dried over sodium sulfate filtered concentrated Crude product was purified by silica gel chromatography

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

Procedure: To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H). The resulting reaction mixture was stirred at 0° C. for 1 hr to warm up stirred at rt for 1 hr washed with 30 mL 1N HCl Organics were dried over sodium sulfate filtered concentrated Crude product was purified by silica gel chromatography

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

Procedure: To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H). The resulting reaction mixture was stirred at 0° C. for 1 hr to warm up stirred at rt for 1 hr washed with 30 mL 1N HCl Organics were dried over sodium sulfate filtered concentrated Crude product was purified by silica gel chromatography

Conditions: temp:80.01; pressure:0.00; stir:

Procedure: Palladium (II) acetate (0.075 g, 0.34 mmol) and racemic-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (0.223 g, 0.36 mmol) were suspended in dioxane (5mL). The mixture was evacuated and purged with nitrogen, and warmed to 50°C. In a separate vessel, 2-bromo-4-iodo-1-methoxybenzene (1.4 g, 4.47 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.547 mL, 4.47 mmol) and sodium-t- butoxide (0.645 g, 6.71 mmol) were suspended in dioxane (5ML). The resulting mixture was evacuated, purged with nitrogen and warmed to 50°C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80°C overnight. Very little product and mainly SM so reaction abandoned.

Conditions: temp:80.01; pressure:0.00; stir:

Procedure: Palladium (II) acetate (0.032 g, 0.14 mmol) and racemic-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (0.179 g, 0.29 mmol) were suspended in toluene (3 mL). The mixture was evacuated and purged with nitrogen, and warmed to 50°C. In a separate vessel, 2-bromo-4-iodo-1-methoxybenzene (0.6 g, 1.92 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.221 g, 1.92 mmol) and sodium-t- butoxide (0.276 g, 2.88 mmol) were suspended in toluene (3.5 mL). The resulting mixture was evacuated, purged with nitrogen and warmed to 50°C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80°C overnight. The mixture was filtered and purified by flash silica chromatography, elution 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 3-bromo-4-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (0.060 g, 10.42 %) as a brown solid. 60mg of product formed by LC-MS and major product is unknown but doesn't contain pyran signals in NMR and not SM iodide.

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under nitrogen atmosphere, to a solution of 20.0 g of 2-bromo-4-iodoanisole in toluene (250 ml) was added morpholine (6.12 ml), 1.29 g of tri-tert-butyl phosphine, 13.5 g of sodium tert-butoxide, and 359 mg of palladium acetate (II), and the reaction mixture was stirred for two hours at 45° C. Water and EtOAc were added to the reaction solution, liquid separation was performed and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (Chromatorex NH; mobile phase: n-hexane/EtOAc=10/1 to 3/1; v/v) to obtain 3.94 g of the title compound (colorless powder). the aqueous layer was extracted with EtOAc The combined organic layer was washed with saturated brine dried over MgSO4 the drying agent was separated by filtration the filtrate was concentrated under reduced pressure The obtained residue was purified by column chromatography (Chromatorex NH; mobile phase: n-hexane/EtOAc=10/1 to 3/1; v/v)

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

Procedure: To a 100 mL round bottom flask was added copper (I) iodide (30.4 mg, 0.16 mmol), 2-(2-pyridyl)benzimidazole (31.2 mg, 0.16 mmol), cesium carbonate (625 mg, 1.92 mmol) and DMF (5.3 mL). The reaction mixture was heated to 60° C. for 1 h then (1H-pyrazol-3-yl)methanol (235 mg, 2.40 mmol) and 2-bromo-4-iodo-1-methoxybenzene (500 mg, 1.60 mmol) were added and the mixture was heated at 100° C. for 18 hours. The reaction was cooled, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc in Hepane) to afford (1-(3-bromo-4-methoxyphenyl)-1H-pyrazol-3-yl)methanol (353 mg) MS [M+2H+]=285.0. the mixture was heated at 100° C. for 18 hours The reaction was cooled filtered through celite The filtrate was concentrated in vacuo purified by silica gel chromatography (0-100% EtOAc in Hepane)

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

Procedure: To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H). The resulting reaction mixture was stirred at 0° C. for 1 hr to warm up stirred at rt for 1 hr washed with 30 mL 1N HCl Organics were dried over sodium sulfate filtered concentrated Crude product was purified by silica gel chromatography

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

Procedure: To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H). The resulting reaction mixture was stirred at 0° C. for 1 hr to warm up stirred at rt for 1 hr washed with 30 mL 1N HCl Organics were dried over sodium sulfate filtered concentrated Crude product was purified by silica gel chromatography