4-(chloromethyl)benzamide

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

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-1H-pyrazole (400 mg, 2.72 mmol), 4-(chloromethyl)benzamide (462 mg, 2.72 mmol), and potassium carbonate (940 mg, 6.80 mmol) in DMF (5 mL) was stirred for 2 hours at 80° C. The reaction mixture was then cooled to ambient temperature and diluted with diethyl ether (400 mL). The mixture was washed with water (2×100 mL) and brine (25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was suspended in ethyl acetate (10 mL) and then diluted by the drop wise addition of n-heptane (40 mL). After stirring for 18 hours, the mixture was filtered and the collected solids were washed with n-heptane (3×10 mL). The collected solids were dried under reduced pressure to afford 4-((4-bromo-1H-pyrazol-1-yl)methyl)benzamide. MS ESI calcd. for C11H11BrN3O [M+H]+ 280 and 282. found 280 and 282. 1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.93 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.35 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 5.35 (s, 2H). The reaction mixture was then cooled to ambient temperature The mixture was washed with water (2×100 mL) and brine (25 mL) The organic layer was dried over magnesium sulfate filtered concentrated under reduced pressure to afford the crude product residue After stirring for 18 hours the mixture was filtered the collected solids were washed with n-heptane (3×10 mL) The collected solids were dried under reduced pressure

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

Procedure: The compound (25.0 g, 0.147 mol) obtained in Example 1, triethyl phosphite (29.4 g, 0.177 mol), potassium iodide (22.0 g, 0.133 mol) and acetonitrile (125 mL) were charged and stirred under reflux for 3 hrs. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue were added N,N-dimethylformamide (100 mL) and 1-benzyl-4-piperidone (30.6 g, 0.162 mol), and the mixture was stirred under ice-cooling. Potassium t-butoxide (23.1 g, 0.206 mol) was added in 3 portions at 15 min. intervals. The reaction mixture was stirred at room temperature for 45 min. Water (400 mL) was dropwise added under ice-cooling, and the mixture was stirred for 30 min. Crystals were collected by filtration, washed with cold water (180 mL) and dried in vacuo at 40° C. to give the title compound (38.7 g, yield 85.2%) as pale-yellow powdery crystals. under reflux for 3 hrs to return to room temperature concentrated under reduced pressure the mixture was stirred under ice- cooling The reaction mixture was stirred at room temperature for 45 min cooling the mixture was stirred for 30 min Crystals were collected by filtration washed with cold water (180 mL) dried in vacuo at 40° C.

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

Procedure: The compound (25.0 g, 0.147 mol) obtained in Example 1, triethyl phosphite (29.4 g, 0.177 mol), potassium iodide (22.0 g, 0.133 mol) and acetonitrile (125 mL) were charged and stirred under reflux for 3 hrs. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue were added N,N-dimethylformamide (100 mL) and 1-benzyl-4-piperidone (30.6 g, 0.162 mol), and the mixture was stirred under ice-cooling. Potassium t-butoxide (23.1 g, 0.206 mol) was added in 3 portions at 15 min. intervals. The reaction mixture was stirred at room temperature for 45 min. Water (400 mL) was dropwise added under ice-cooling, and the mixture was stirred for 30 min. Crystals were collected by filtration, washed with cold water (180 mL) and dried in vacuo at 40° C. to give the title compound (38.7 g, yield 85.2%) as pale-yellow powdery crystals. under reflux for 3 hrs to return to room temperature concentrated under reduced pressure the mixture was stirred under ice- cooling The reaction mixture was stirred at room temperature for 45 min cooling the mixture was stirred for 30 min Crystals were collected by filtration washed with cold water (180 mL) dried in vacuo at 40° C.

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

Procedure: The compound (44.83 g, 0.264 mol) obtained in Example 1, triethyl phosphite (53.21 g, 0.320 mol), potassium iodide (39.4 g, 0.237 mol) and acetonitrile (224 mL) were charged and stirred under reflux for 4 hrs. The reaction mixture was allowed to return to room temperature, and water (336 mL) was added. The mixture was concentrated under reduced pressure, and the residue (315 g) was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with cold water (20 mL) and dried in vacuo at 40° C. for 7 hrs. to give the title compound (66.79 g, yield 93.2%) as slightly yellow crystals. under reflux for 4 hrs to return to room temperature The mixture was concentrated under reduced pressure the residue (315 g) was stirred at room temperature for 1 hr and under ice-cooling for 1 hr The crystals were collected by filtration washed with cold water (20 mL) dried in vacuo at 40° C. for 7 hrs

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

Procedure: The compound (44.83 g, 0.264 mol) obtained in Example 1, triethyl phosphite (53.21 g, 0.320 mol), potassium iodide (39.4 g, 0.237 mol) and acetonitrile (224 mL) were charged and stirred under reflux for 4 hrs. The reaction mixture was allowed to return to room temperature, and water (336 mL) was added. The mixture was concentrated under reduced pressure, and the residue (315 g) was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with cold water (20 mL) and dried in vacuo at 40° C. for 7 hrs. to give the title compound (66.79 g, yield 93.2%) as slightly yellow crystals. under reflux for 4 hrs to return to room temperature The mixture was concentrated under reduced pressure the residue (315 g) was stirred at room temperature for 1 hr and under ice-cooling for 1 hr The crystals were collected by filtration washed with cold water (20 mL) dried in vacuo at 40° C. for 7 hrs

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

Procedure: To a mixture of 28% aqueous ammonia (19.3 g, 317 mmol, 4.0 eq) and toluene (30 mL) was dropwise added a 4-chloromethylbenzoyl chloride (15.0 g, 79.3 mmol)/toluene (30 mL) solution under ice-cooling. The mixture was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with water (9 mL) and toluene (9 mL), and dried in vacuo at 40° C. to give the title compound (13.36 g, yield 99.3%) as white crystals. cooling and under ice-cooling for 1 hr The crystals were collected by filtration washed with water (9 mL) and toluene (9 mL) dried in vacuo at 40° C.

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

Procedure: To a solution of 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.816 g, 5 mmol) in DMSO (50 mL) at room temperature under nitrogen was added potassium hydroxide (0.561 g, 10.0 mmol). After stirring the resulting deep red solution for 25 min 4-(chloromethyl)benzamide (0.848 g, 5.00 mmol) was added in one portion. The reaction mixture was stirred for a further 30 min and then poured into water (250 mL), forming an emulsion. The reaction mixture was extracted using chloroform (3×250 mL). The combined organic solutions were washed with water (250 mL) and passed through hydrophobic frit. The solvent was removed in vacuo and the residue was loaded in dichloromethane to a silica (100 g) cartridge and purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane+0-20% methanol-ethyl acetate over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.18 g, 80%). LCMS: (System A) RT=0.69 min, ES+ve m/z 297 (M+H)+. at room temperature was added in one portion forming an emulsion The reaction mixture was extracted The combined organic solutions were washed with water (250 mL) The solvent was removed in vacuo purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane+0-20% methanol-ethyl acetate over 60 min evaporated in vacuo

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

Procedure: To a solution of 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.816 g, 5 mmol) in DMSO (50 mL) at room temperature under nitrogen was added potassium hydroxide (0.561 g, 10.0 mmol). After stirring the resulting deep red solution for 25 min 4-(chloromethyl)benzamide (0.848 g, 5.00 mmol) was added in one portion. The reaction mixture was stirred for a further 30 min and then poured into water (250 mL), forming an emulsion. The reaction mixture was extracted using chloroform (3×250 mL). The combined organic solutions were washed with water (250 mL) and passed through hydrophobic frit. The solvent was removed in vacuo and the residue was loaded in dichloromethane to a silica (100 g) cartridge and purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane+0-20% methanol-ethyl acetate over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.18 g, 80%). LCMS: (System A) RT=0.69 min, ES+ve m/z 297 (M+H)+. at room temperature was added in one portion forming an emulsion The reaction mixture was extracted The combined organic solutions were washed with water (250 mL) The solvent was removed in vacuo purified by chromatography on Flashmaster eluting with 0-100% ethyl acetate-cyclohexane+0-20% methanol-ethyl acetate over 60 min evaporated in vacuo

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

Procedure: The compound (25.0 g, 0.147 mol) obtained in Example 1, triethyl phosphite (29.4 g, 0.177 mol), potassium iodide (22.0 g, 0.133 mol) and acetonitrile (125 mL) were charged and stirred under reflux for 3 hrs. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue were added N,N-dimethylformamide (100 mL) and 1-benzyl-4-piperidone (30.6 g, 0.162 mol), and the mixture was stirred under ice-cooling. Potassium t-butoxide (23.1 g, 0.206 mol) was added in 3 portions at 15 min. intervals. The reaction mixture was stirred at room temperature for 45 min. Water (400 mL) was dropwise added under ice-cooling, and the mixture was stirred for 30 min. Crystals were collected by filtration, washed with cold water (180 mL) and dried in vacuo at 40° C. to give the title compound (38.7 g, yield 85.2%) as pale-yellow powdery crystals. under reflux for 3 hrs to return to room temperature concentrated under reduced pressure the mixture was stirred under ice- cooling The reaction mixture was stirred at room temperature for 45 min cooling the mixture was stirred for 30 min Crystals were collected by filtration washed with cold water (180 mL) dried in vacuo at 40° C.