2-amino-4-fluoro-N-methylbenzamide

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino 4-fluoro benzoic acid (2.5 g, 16.13 mmol) and 1,3 dimethyl urea (5.85 g, 66.5 mmol) was heated at 150° C. for 24 hours. The reaction was diluted with water, filtered and extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with ethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid (670 mg, 25%) filtered extracted twice with ethyl acetate The organic extracts were dried over magnesium sulfate concentrated at reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino 4-fluoro benzoic acid (2.5 g, 16.13 mmol) and 1,3 dimethyl urea (5.85 g, 66.5 mmol) was heated at 150° C. for 24 hours. The reaction was diluted with water, filtered and extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with ethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid (670 mg, 25%) filtered extracted twice with ethyl acetate The organic extracts were dried over magnesium sulfate concentrated at reduced pressure

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

Procedure: A suspension of sodium hydride (60% in mineral oil, 368 mg, 9.2 mmol) in dimethylformamide (12 mL) was cooled to 0° C. and treated with 2-amino-4-fluoro-N-methylbenzamide [Intermediate 137] (0.67 g, 4.0 mmol). Phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added over 40 minutes. After 1 hour a further portion of phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added. The reaction was allowed to warm to room temperature and stir for two hours. The reaction was slowly added to 200 mL of ice. The solid was filtered, washed with methanol to obtain the product (395 mg, 51%). to warm to room temperature The solid was filtered washed with methanol

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

Procedure: A suspension of sodium hydride (60% in mineral oil, 368 mg, 9.2 mmol) in dimethylformamide (12 mL) was cooled to 0° C. and treated with 2-amino-4-fluoro-N-methylbenzamide [Intermediate 137] (0.67 g, 4.0 mmol). Phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added over 40 minutes. After 1 hour a further portion of phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added. The reaction was allowed to warm to room temperature and stir for two hours. The reaction was slowly added to 200 mL of ice. The solid was filtered, washed with methanol to obtain the product (395 mg, 51%). to warm to room temperature The solid was filtered washed with methanol

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

Procedure: This compound was prepared from N-(1,3-dimethylpyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine and 2-amino-4-fluoro-N-methylbenzamide. 54 mg, 33%; triturated in tBuOMe; NMR Spectrum: (DMSOd6) 2.08 (s, 3H), 2.76 (d, 3H), 3.55 (s, 3H), 6.04 (s, 1H), 6.76 (s, 1H), 6.95 (ddd, 1H), 7.39 (dd, 1H), 7.79 (dd, 1H), 8.27 (s, 1H), 8.69 (q, 1H), 9.06 (s, 1H), 10.65 (s, 1H); Mass spectrum: MH+ 423. triturated in tBuOMe

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

Procedure: This compound was prepared from N-(1,3-dimethylpyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine and 2-amino-4-fluoro-N-methylbenzamide. 54 mg, 33%; triturated in tBuOMe; NMR Spectrum: (DMSOd6) 2.08 (s, 3H), 2.76 (d, 3H), 3.55 (s, 3H), 6.04 (s, 1H), 6.76 (s, 1H), 6.95 (ddd, 1H), 7.39 (dd, 1H), 7.79 (dd, 1H), 8.27 (s, 1H), 8.69 (q, 1H), 9.06 (s, 1H), 10.65 (s, 1H); Mass spectrum: MH+ 423. triturated in tBuOMe

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

Procedure: Carbonyl-1,1′-diimidazole (1.26 g) was added to 2-amino-4-fluorobenzoic acid (1.0 g) in THF (16.3 mL). After stirring overnight a solution of methylamine in THF (2M, 4.9 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The phases were separated and the organics were washed with water (2×100 mL) and then saturated aqueous brine (30 mL). The organics were dried (MgSO4, 15 g), filtered and concentrated in vacuo to give crude product (0.9 g). This material was purified by column chromatography (SiO2, 40 g, eluent 3% MeOH in DCM) to give 2-amino-4-fluoro-N-methylbenzamide (0.6 g). 1H NMR spectrum (270 MHz, DMSO): 2.69 (d, 3H), 6.28 (ddd, 1H), 6.42 (dd, 1H), 6.74 (bs, 2H), 7.48 (dd, 1H), 8.16 (q, 1H); Mass spectrum: ESI+ MH+ 169. was added The reaction was concentrated in vacuo the residue dissolved in EtOAc (100 mL) The phases were separated the organics were washed with water (2×100 mL) The organics were dried (MgSO4, 15 g) filtered concentrated in vacuo to give crude product (0.9 g) This material was purified by column chromatography (SiO2, 40 g, eluent 3% MeOH in DCM)

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

Procedure: Carbonyl-1,1′-diimidazole (1.26 g) was added to 2-amino-4-fluorobenzoic acid (1.0 g) in THF (16.3 mL). After stirring overnight a solution of methylamine in THF (2M, 4.9 mL) was added and the reaction stirred for 3 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The phases were separated and the organics were washed with water (2×100 mL) and then saturated aqueous brine (30 mL). The organics were dried (MgSO4, 15 g), filtered and concentrated in vacuo to give crude product (0.9 g). This material was purified by column chromatography (SiO2, 40 g, eluent 3% MeOH in DCM) to give 2-amino-4-fluoro-N-methylbenzamide (0.6 g). 1H NMR spectrum (270 MHz, DMSO): 2.69 (d, 3H), 6.28 (ddd, 1H), 6.42 (dd, 1H), 6.74 (bs, 2H), 7.48 (dd, 1H), 8.16 (q, 1H); Mass spectrum: ESI+ MH+ 169. was added The reaction was concentrated in vacuo the residue dissolved in EtOAc (100 mL) The phases were separated the organics were washed with water (2×100 mL) The organics were dried (MgSO4, 15 g) filtered concentrated in vacuo to give crude product (0.9 g) This material was purified by column chromatography (SiO2, 40 g, eluent 3% MeOH in DCM)

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

Procedure: The title compound was prepared using the procedure from Compound 102A with 4-Fluoro-N-methyl-2-nitrobenzamide (Compound 103B). MS (ES+): m/z 169.07 [MH+] (TOF, polar).

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

Procedure: The title compound was prepared using the procedure from Compound 102A with 4-Fluoro-N-methyl-2-nitrobenzamide (Compound 103B). MS (ES+): m/z 169.07 [MH+] (TOF, polar).

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

Procedure: The title compound was prepared using the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 2-Amino-4-fluoro-N-methylbenzamide. 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6H), 2.77 (d, J=4.55 Hz, 3 H), 3.16-3.24 (m, 2 H), 3.78 (s, 3 H), 3.92-4.01 (m, 4 H), 6.83 (d, J=7.83 Hz, 1 H), 6.93 (br. s., 1 H), 6.99 (s, 1 H), 7.53 (br. s., 1 H), 7.78 (t, J=7.33 Hz, 1 H), 8.25-8.48 (m, 2 H), 8.62-9.04 (m, 2 H), 11.86 (br. s., 1H). MS (ES+): m/z 586.18 [MH+] (TOF, polar).

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino 4-fluoro benzoic acid (2.5 g, 16.13 mmol) and 1,3 dimethyl urea (5.85 g, 66.5 mmol) was heated at 150° C. for 24 hours. The reaction was diluted with water, filtered and extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with ethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid (670 mg, 25%) filtered extracted twice with ethyl acetate The organic extracts were dried over magnesium sulfate concentrated at reduced pressure