1-(bromomethyl)-2-iodobenzene

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: Sodium hydride (60% oil dispersion) (7.8 g) was added portionwise to a ice-water cooled solution of o-cresol (21.1 g) in tetrahydrofuran (500 mL). The mixture was stirred 20 minutes and then 1-(bromomethyl)-2-iodobenzene (58 g) was added. The mixture was warmed to 60° C. for 16 h. Additional sodium hydride (2 g) was added and the reaction mixture heated for an additional 3 h. The reaction mixture was cooled and carefully quenched with water and extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to an oil, which was triturated with cold hexane to provide a solid which was collected by filtration to yield 59.1 g (94%) of the title compound of Step B as a white solid, mp 106-108° C. the reaction mixture heated for an additional 3 h The reaction mixture was cooled carefully quenched with water extracted with ethyl acetate (2×250 mL) The combined organic extracts were dried (MgSO4) filtered concentrated under reduced pressure to an oil, which was triturated with cold hexane to provide a solid which was collected by filtration

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

Procedure: To a solution of 2-iodobenzyl alcohol (50 g) in diethyl ether (500 mL), cooled in an ice-water bath, was added dropwise phosphorus tribromide (28 mL). The reaction mixture was chilled in a refrigerator for 3.5 h, then quenched by slow addition of methanol (50 mL). The mixture was washed with water, then saturated sodium bicarbonate, then water (100 mL each). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to a white solid, which was triturated in hexane and collected by filtration to yield 58 g (91%) of the title material of Step A as a solid, mp 55-57° C. The reaction mixture was chilled in a refrigerator for 3.5 h quenched by slow addition of methanol (50 mL) The mixture was washed with water The organic phase was dried (MgSO4) filtered concentrated under reduced pressure to a white solid, which was triturated in hexane collected by filtration

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

Procedure: To a dry 100 mL 3-necked flask equipped with a nitrogen inlet and a magnetic stirrer were added 5.00 g of 2-iodobenzyl alcohol (Aldrich) and 20 mL of anhydrous CH2Cl2. The resulting suspension was cooled to 0° C. and treated with 0.71 mL of PBr3 (Aldrich) by dropwise addition over a 2 minute period. The solid slowly dissolved giving a light yellow solution which was stirred under nitrogen at 0° C. for 2 h and then allowed to warm to RT with continued stirring for 18 h. The solution was concentrated in vacuo to dryness and the residue was dissolved in 60 mL of ethyl ether. The ether solution was washed with ice cold 5% aqueous NaHCO3 (3×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 5.65 g (89%) of 2-iodobenzyl bromide as a white crystalline solid, m.p. 52-54° C. To a dry 100 mL 3-necked flask equipped with a nitrogen inlet and a magnetic stirrer The solid slowly dissolved giving a light yellow solution which to warm to RT with continued stirring for 18 h The solution was concentrated in vacuo to dryness the residue was dissolved in 60 mL of ethyl ether The ether solution was washed with ice cold 5% aqueous NaHCO3 (3×50 mL) dried over anhydrous Na2SO4 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: Stir a mixture of 2-iodobenzyl bromide (90 g, 0.29 mol), 2-bromo-5-fluorophenol (57.9 g, 0.29 mol), and potassium carbonate (63 g, 0.46 mol) in N,N-dimethylformamide (750 mL) at room temperature for 16 h. Add water (1 L), stir the resulting mixture for one hour, filter off solids, rinse with water and dry in a vacuum oven (20 mm Hg/60° C.) to obtain the title compound (121 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 5.11 (s, 2H), 6.81 (t, 1H), 7.13 (t, 1H), 7.19 (dd, 1H), 7.46 (t, 1H), 7.59 (d, 1H), 7.62 (t, 1H), 7.93 (d, 1H). filter off solids rinse with water dry in a vacuum oven (20 mm Hg/60° C.)

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

Procedure: Stir a mixture of 2-iodobenzyl bromide (90 g, 0.29 mol), 2-bromo-5-fluorophenol (57.9 g, 0.29 mol), and potassium carbonate (63 g, 0.46 mol) in N,N-dimethylformamide (750 mL) at room temperature for 16 h. Add water (1 L), stir the resulting mixture for one hour, filter off solids, rinse with water and dry in a vacuum oven (20 mm Hg/60° C.) to obtain the title compound (121 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 5.11 (s, 2H), 6.81 (t, 1H), 7.13 (t, 1H), 7.19 (dd, 1H), 7.46 (t, 1H), 7.59 (d, 1H), 7.62 (t, 1H), 7.93 (d, 1H). filter off solids rinse with water dry in a vacuum oven (20 mm Hg/60° C.)

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

Procedure: To a solution of 5-(benzylthio)-6-fluoro-1H-indazole (1-2, 1.5 g, 5.81 mmol, 1.0 equiv) in NMP (29.0 mL) was added cesium carbonate (5.68 g, 17.42 mmol, 3.0 equiv) and 1-(bromomethyl)-2-iodobenzene (2.59 g, 8.71 mmol, 1.5 equiv) and the reaction mixture was stirred at ambient temperature. Upon completion, the reaction mixture was washed with water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by normal phase chromatography followed by reverse phase chromatography (50%→100% 0.1% TFA in ACN: 0.1% TFA in water) to yield the desired regioisomer. ESI+ MS [M+H]+ C21H16FIN2S: 475.1 found, 475.3 required. Upon completion, the reaction mixture was washed with water extracted with EtOAc The organic phase was dried over Na2SO4 filtered concentrated the residue was purified by normal phase chromatography to yield the desired regioisomer

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

Procedure: 2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-iodobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.

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

Procedure: 2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-iodobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.

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

Procedure: To a stirring solution of 1,2,4-triazole (1.02 g, 14.8 mmol) and 2-iodobenzyl bromide (6.05 g, 20.3 mmol) in THF (10 mL) was added a solution of DBU (2.65 g, 17.4 mmol) in THF (2 mL) dropwise over a 1 hour period. The mixture was stirred at ambient temperature for 12 hours after which it was filtered. The filtrate was concentrated in vacuo and the resultant residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 50-60% ethyl acetate/isohexane to give the title compound as a white solid (1.45 g). 1H NMR (360 MHz, CDCl3): δ 8.15 (1H, s), 8.00 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.36 (1H, t, J=7.6 Hz), 7.13 (1H, d, J=7.7 Hz), 7.08-7.04 (1H, m), 5.43 (2H, s). was filtered The filtrate was concentrated in vacuo the resultant residue was dissolved in ethyl acetate The organic layer was washed with water and brine dried (MgSO4) evaporated in vacuo The residue was purified by flash column chromatography on silica eluting with 50-60% ethyl acetate/isohexane