2-amino-5-bromo-N-methylbenzamide

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

Procedure: A mixture of 2-Amino-5-bromo-N-methylbenzamide (100.0 mg, 0.4365 mmol), zinc cyanide (51.26 mg, 0.4365 mmol), Pd(PPh3)4 (75.67 mg, 0.06548 mmol) in DMF (1.5 mL) was flushed with nitrogen and irradiated in a microwave reactor at 150° C. for 5 minutes. The reaction mixture was poured into water and extracted by ethyl acetate. The combined organic layers were washed with water and brine, concentrated in vacuo and purified on an ISCO Combiflash unit to isolate the desired product (37.0 mg, 48% yield). was flushed with nitrogen irradiated in a microwave reactor at 150° C. for 5 minutes The reaction mixture was poured into water extracted by ethyl acetate The combined organic layers were washed with water and brine concentrated in vacuo purified on an ISCO Combiflash unit

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

Procedure: 2-Amino-5-bromo-N-methyl-benzamide (Compound 106A, 645.0 mg, 2.816 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester (899.2 mg, 3.379 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (229.9 mg, 0.2816 mmol) were added to a 20 mL microwave tube and taken up in 1,4-Dioxane (8 mL, 100 mmol). This mixture was treated with a solution of potassium carbonate (1167 mg, 8.447 mmol) in H2O (3 mL, 200 mmol). After sparging the mixture with N2 for 1 minute, the tube was sealed and irradiated in the Biotage microwave reactor for 30 minutes at 100° C. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to a black goo. This was taken up in DCM, treated with silica and concentrated to a plug. This plug was loaded into a sample cartridge and purified on an ISCO Combiflash unit (0-40%-70% EtOAc/Hexane) to isolate the desired product as 359 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.78 (t, J=6.44 Hz, 2H), 2.33 (br. s., 2H), 2.50-2.51 (m, J=1.80 Hz, 2H), 2.72 (d, J=4.55 Hz, 3H), 3.91 (s, 4H), 5.85 (t, J=3.92 Hz, 1H), 6.41 (s, 2H), 6.63 (d, J=8.59 Hz, 1H), 7.23 (dd, J=8.59, 2.02 Hz, 1H), 7.48 (d, J=2.27 Hz, 1H), 8.23 (d, J=4.29 Hz, 1H). MS (ES+): m/z=289.06 (100) [M+1]. HPLC: tR=2.62 min (ZQ3, polar—5 min). After sparging the mixture with N2 for 1 minute the tube was sealed irradiated in the Biotage microwave reactor for 30 minutes at 100° C The mixture was poured into water extracted twice with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated to a black goo treated with silica concentrated to a plug purified on an ISCO Combiflash unit (0-40%-70% EtOAc/Hexane)

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

Procedure: The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 106A. MS (ES+): tn/z 646.31 (100) [MH+]; HPLC: tR=1.14 min (UPLC, purity).

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

Procedure: A mixture of methyl 2-amino-5-bromobenzoate (Compound 106B, 65 g) and CH3NH2.H2O (1000 mL) was stirred at 80° C. overnight in a pressure tube. The mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were dried over MgSO4, concentrated to afford the title compound (55 g, yield: 87%) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ=2.93 (d, J=5.2 Hz, 3 H), 5.48 (s, br, 2 H), 6.04 (s, br, 1 H), 6.54 (d, J=8.4 Hz, 1 H), 7.24 (dd, J=2.0, 8.4 Hz, 1 H), 7.38 (d, J=2.0 Hz, 1 H). extracted with EtOAc (3×500 mL) The combined organic layers were dried over MgSO4 concentrated

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

Procedure: A mixture of methyl 2-amino-5-bromobenzoate (Compound 106B, 65 g) and CH3NH2.H2O (1000 mL) was stirred at 80° C. overnight in a pressure tube. The mixture was diluted with H2O (1000 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were dried over MgSO4, concentrated to afford the title compound (55 g, yield: 87%) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ=2.93 (d, J=5.2 Hz, 3 H), 5.48 (s, br, 2 H), 6.04 (s, br, 1 H), 6.54 (d, J=8.4 Hz, 1 H), 7.24 (dd, J=2.0, 8.4 Hz, 1 H), 7.38 (d, J=2.0 Hz, 1 H). extracted with EtOAc (3×500 mL) The combined organic layers were dried over MgSO4 concentrated

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

Procedure: Prepared analogously to Compound 3C using 2-amino-5-bromo-n-methyl-benzamide (Compound 8D, 300 mg, 1.31 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 383 mg, 1.44 mmol) to afford 64 mg of the title compound (17%). 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.32 (dd, J=2.0, 8.6 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.13 (br. s., 1H), 5.43 (br. s., 2H), 4.20 (t, J=6.9 Hz, 2H), 3.65-3.72 (m, 2H), 3.01 (d, J=5.1 Hz, 3H), 2.01 (quin, J=7.3 Hz, 2H), 1.58-1.67 (m, 3H).

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

Procedure: Prepared analogously to Compound 3C using 2-amino-5-bromo-n-methyl-benzamide (Compound 8D, 300 mg, 1.31 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 383 mg, 1.44 mmol) to afford 64 mg of the title compound (17%). 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.54 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.32 (dd, J=2.0, 8.6 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.13 (br. s., 1H), 5.43 (br. s., 2H), 4.20 (t, J=6.9 Hz, 2H), 3.65-3.72 (m, 2H), 3.01 (d, J=5.1 Hz, 3H), 2.01 (quin, J=7.3 Hz, 2H), 1.58-1.67 (m, 3H).

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

Procedure: Prepared analogously to Compound 1D using 2-amino-5-bromo-n-methyl-benzamide (Compound 87D, 600 mg, 2.62 mmol) to afford 335 mg of the title compound (47%). 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.76 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.38 (dd, J=2.0, 8.3 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 4.25 (t, J=6.8 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.89 (s, 3H), 2.06 (quin, J=6.5 Hz, 2H). MS (ESI): m/z 275.57 [M+H]+. UPLC: tR=0.55 min (UPLC-SQD: analytical—2 min).

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

Procedure: Prepared analogously to Compound 3C replacing Compound 3D with 2-amino-5-bromo-N-methyl-benzamide (920 mg, 4.0 mmol) to give the title compound as 0.35 g of a white solid (32%, over two steps). 1H NMR (CDCl3+CD3OD, 400 MHz): δ=7.65 (s, 1H), 7.64 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.28 (dd, J=8.4, 2.0 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 4.21 (t, J=6.6 Hz, 2H), 3.53 (t, J=5.6 Hz, 2H), 2.90 (s, 3H), 2.00 (m, 2H). MS (ESI): m/z=275.29 [M+H]+. HPLC: tR=2.50 min (ZQ3: polar—5 min).