3-(chloromethyl)benzamide

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

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

Procedure: A mixture of 5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one, 3-(chloromethyl)benzamide, sodium iodide, and cesium carbonate in dimethylformamide was heated to 45° C. for 16 hours. The cooled reaction mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated. The resultant residue was purified by HPLC using a CN bonded phase preparative column and by precipitation from hexane to give the title product as a white solid, identified by NMR and mass spectral analyses. The cooled reaction mixture washed with water The organic phase was dried over sodium sulfate evaporated The resultant residue was purified by HPLC by precipitation from hexane

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

Procedure: A mixture of 5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one, 3-(chloromethyl)benzamide, sodium iodide, and cesium carbonate in dimethylformamide was heated to 45° C. for 16 hours. The cooled reaction mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated. The resultant residue was purified by HPLC using a CN bonded phase preparative column and by precipitation from hexane to give the title product as a white solid, identified by NMR and mass spectral analyses. The cooled reaction mixture washed with water The organic phase was dried over sodium sulfate evaporated The resultant residue was purified by HPLC by precipitation from hexane

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

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

Procedure: A mixture of 5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one, 3-(chloromethyl)benzamide, sodium iodide, and cesium carbonate in dimethylformamide was heated to 45° C. for 16 hours. The cooled reaction mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated. The resultant residue was purified by HPLC using a CN bonded phase preparative column and by precipitation from hexane to give the title product as a white solid, identified by NMR and mass spectral analyses. The cooled reaction mixture washed with water The organic phase was dried over sodium sulfate evaporated The resultant residue was purified by HPLC by precipitation from hexane

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

Procedure: A mixture of 5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one, 3-(chloromethyl)benzamide, sodium iodide, and cesium carbonate in dimethylformamide was heated to 45° C. for 16 hours. The cooled reaction mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated. The resultant residue was purified by HPLC using a CN bonded phase preparative column and by precipitation from hexane to give the title product as a white solid, identified by NMR and mass spectral analyses. The cooled reaction mixture washed with water The organic phase was dried over sodium sulfate evaporated The resultant residue was purified by HPLC by precipitation from hexane

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

Procedure: To a solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (150 mg, 0.316 mmol) into DMF (2 mL) was added at ambient temperature potassium carbonate (87 mg, 0.63 mmol) and 3-(chloromethyl)benzamide (Maybridge) (64.4 mg, 0.380 mmol). The resulting mixture was stirred at 50° C. overnight, and then diluted with DCM (2 mL) and water (2 mL). The organic mixture was partitioned and the aqueous layer was further extracted with 2 mL of DCM. The organic solutions were combined together, dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The crude product was judged by LCMS to be pure enough to be engaged in the next step without any further purification. LCMS (System A) RT=1.37 min, ES+ve m/z 607/609 (M+H)+. In a 2 to 5 mL Biotage microwave vial were added the crude indazole product and TBAF solution in THF (1M, 3.16 mL, 3.16 mmol). The reaction vessel was sealed and heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level). The crude mixture was then diluted with 2 mL of DCM and 2 mL of water. The organic layer was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit, and evaporated under a nitrogen stream in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents NB (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (76 mg, 50%). LCMS (System A) RT=0.97 min, ES+ve m/z 477/479 (M+H)+. The organic mixture was partitioned the aqueous layer was further extracted with 2 mL of DCM dried over an hydrophobic frit evaporated under a nitrogen stream in a blowdown unit to be engaged in the next step without any further purification The reaction vessel was sealed heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level) The organic layer was separated the aqueous layer was further extracted with 2 mL of DCM The combined organic solutions were dried over an hydrophobic frit evaporated under a nitrogen stream in a blowdown unit The residue was dissolved in 1:1 MeOH DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents NB (A: Water+0.1% Formic acid, B The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus

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

Procedure: To a solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (150 mg, 0.316 mmol) into DMF (2 mL) was added at ambient temperature potassium carbonate (87 mg, 0.63 mmol) and 3-(chloromethyl)benzamide (Maybridge) (64.4 mg, 0.380 mmol). The resulting mixture was stirred at 50° C. overnight, and then diluted with DCM (2 mL) and water (2 mL). The organic mixture was partitioned and the aqueous layer was further extracted with 2 mL of DCM. The organic solutions were combined together, dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The crude product was judged by LCMS to be pure enough to be engaged in the next step without any further purification. LCMS (System A) RT=1.37 min, ES+ve m/z 607/609 (M+H)+. In a 2 to 5 mL Biotage microwave vial were added the crude indazole product and TBAF solution in THF (1M, 3.16 mL, 3.16 mmol). The reaction vessel was sealed and heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level). The crude mixture was then diluted with 2 mL of DCM and 2 mL of water. The organic layer was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit, and evaporated under a nitrogen stream in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (76 mg, 50%). LCMS (System A) RT=0.97 min, ES+ve m/z 477/479 (M+H)+. The organic mixture was partitioned the aqueous layer was further extracted with 2 mL of DCM dried over an hydrophobic frit evaporated under a nitrogen stream in a blowdown unit to be engaged in the next step without any further purification The reaction vessel was sealed heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level) The organic layer was separated the aqueous layer was further extracted with 2 mL of DCM The combined organic solutions were dried over an hydrophobic frit evaporated under a nitrogen stream in a blowdown unit The residue was dissolved in 1:1 MeOH DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus

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

Procedure: 50 mg (0.14 mmol) of the compound from Example 31A, 36 mg (0.21 mmol) of 3-(chloromethyl)benzamide and 48 mg (0.58 mmol) of sodium bicarbonate in 2.0 ml of dry DMF are reacted analogously to the preparation of the compound of Example 14.

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

Procedure: To a solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (150 mg, 0.316 mmol) into DMF (2 mL) was added at ambient temperature potassium carbonate (87 mg, 0.63 mmol) and 3-(chloromethyl)benzamide (Maybridge)(64.4 mg, 0.380 mmol). The resulting mixture was stirred at 50° C. overnight, and then diluted with DCM (2 mL) and water (2 mL). The organic mixture was partitioned and the aqueous layer was further extracted with 2 mL of DCM. The organic solutions were combined together, dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The crude product was judged by LCMS to be pure enough to be engaged in the next step without any further purification. LCMS (System A) RT=1.37 min, ES+ve m/z 607/609 (M+H)+. In a 2 to 5 mL Biotage microwave vial were added the crude indazole product and TBAF solution in THF (1M, 3.16 mL, 3.16 mmol). The reaction vessel was sealed and heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level). The crude mixture was then diluted with 2 mL of DCM and 2 mL of water. The organic layer was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit, and evaporated under a nitrogen stream in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (76 mg, 50%). LCMS (System A) RT=0.97 min, ES+ve m/z 477/479 (M+H)+. The organic mixture was partitioned the aqueous layer was further extracted with 2 mL of DCM dried over an hydrophobic frit evaporated under a nitrogen stream in a blowdown unit to be engaged in the next step without any further purification The reaction vessel was sealed heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level) The organic layer was separated the aqueous layer was further extracted with 2 mL of DCM The combined organic solutions were dried over an hydrophobic frit evaporated under a nitrogen stream in a blowdown unit The residue was dissolved in 1:1 MeOH DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus

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

Procedure: To a solution of 66.50 g (0.352 mol, 1.0 mol-equiv) 3-chloromethylbenzoylchloride in 400 mL CH2Cl2 at 0°-5° C. under argon was added 47.6 mL (0.704, 2.0 mol-equiv) concentrated aqueous NH4OH over 25 min. The resulting slurry was filtered, washed with water and the product was dried overnight at 50° C. under vacuum to provide 48.59 g (81%) of 3-chloromethylbenzamide. The resulting slurry was filtered washed with water the product was dried overnight at 50° C. under vacuum

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

Procedure: A mixture of 5-[5-acetyl-1-(3-fluoropropyl)-1H-pyrrol-3-yl]-2-amino-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one, 3-(chloromethyl)benzamide, sodium iodide, and cesium carbonate in dimethylformamide was heated to 45° C. for 16 hours. The cooled reaction mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and evaporated. The resultant residue was purified by HPLC using a CN bonded phase preparative column and by precipitation from hexane to give the title product as a white solid, identified by NMR and mass spectral analyses. The cooled reaction mixture washed with water The organic phase was dried over sodium sulfate evaporated The resultant residue was purified by HPLC by precipitation from hexane