4-amino-N,N-dimethylbenzamide

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 solution of 26.4 g of 4-amino-N,N-dimethylbenzamide in 500 ml toluene and 60 g acetonylacetone is refluxed for 16 hours under a Dean-Stark water separator. The solution is washed with water and brine, dried over MgSO4, filtered and the solvent evaporated at 60° and reduced pressure. The residue is crystallized from ether-hexane 1:1 to yield 1-(4-dimethylcarbamoylphenyl)-2,5-dimethyl-1H-pyrrole, m.p. 102°-104°. The solution is washed with water and brine dried over MgSO4 filtered the solvent evaporated at 60° The residue is crystallized from ether-hexane 1:1

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,6-Dichloro-N-(2,3-difluorobenzyl)-1,2,4-triazin-5-amine (75 mg, 0.26 mmol) was dissolved in 5 mL NMP. To it was added 4-amino-N,N-dimethylbenzamide (86 mg, 0.52 mmol) and pTSA (49 mg, 0.26 mmol). The mixture was stirred at 105° C. for overnight and subjected to reverse phase preparative HPLC to isolate 4-(6-chloro-5-(2,3-difluorobenzylamino)-1,2,4-triazin-3-ylamino)-N,N-dimethylbenzamide (58 mg). MS found for C19H17ClF2N6O as (M+H)+ 419.3. UV: λ=273 nm.

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

Procedure: To a 250 mL round bottom flask, 4-amino-N,N-dimethyl-benzamide (20 g, 0.1219 mol; prepared as described in Preparation 1) and 2,2,2-trichloroethyl chloroformate (30 g, 0.1463 mol), TEA (34 mL, 0.2438 mol) and DCM (100 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude product was washed with diethyl ether and dried under reduced pressure to afford the title compound [30 g, 73%]. LC-MS (ESI): Calculated mass: 338.0; Observed mass: 341.0 (RT: 1.38 min). The compound was directly taken to the next step. washed with water The organic layer was dried over anhydrous sodium sulfate evaporated under reduced pressure to get the crude product The crude product was washed with diethyl ether dried under reduced pressure

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

Procedure: To a solution of 4-amino-N,N-dimethyl-benzamide (3.5 g, 0.0213 mol), TEA (2.15 g, 0.0213 mol) in DCM (50 mL) was added 4-bromophenyl isocyanate (5.07 g, 0.0256 mol). The reaction mixture was stirred at room temperature for 12 h. The white solid was obtained and was filtered and dried to afford the title compound [6.8 g, 88%]; LC-MS (ESI): Calculated mass: 361.0; Observed mass: 362.0 [M+H]+ (RT: 0.17 min). The white solid was obtained was filtered dried

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

Procedure: To a solution of N,N-dimethyl-4-nitro benzamide (23 g, 0.1185 mol) in MeOH (200 mL) was added Pd/C 10% (2.3 g) in portions and the Parr reaction vessel was purged with nitrogen for 10 min. The reaction vessel was fixed in Parr shaker at 60 psi pressure for 3 h. The reaction mixture was filtered through the Celite® pad and the filtrate was concentrated under reduced pressure to afford the title compound [18.0 g, 93%]; LC-MS (ESI): Calculated mass: 164.1; Observed mass: 165.2 [M+H]+ (RT: 0.17 min). the Parr reaction vessel was purged with nitrogen for 10 min The reaction mixture was filtered through the Celite® pad the filtrate was concentrated under reduced pressure

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

Procedure: To a mixture of 6-chloro-4-(3-(pyridine-2-yl)benzylamino)nicotinamide (82 mg, 0.24 mmol) in p-Dioxane (2.5 mL) was added 4-amino-N,N-dimethylbenzamide (51 mg, 0.31 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), BINAP (30 mg, 0.05 mmol) and Cs2CO3 (234 mg, 0.72 mmol). After stirred at 80° C. for 15 h, it was concentrated and purified by preparative HPLC to give 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-2-yl)benzylamino)nicotinamide. MS found for C27H26N6O2 as (M+H)+ 467.4. UV: λ=259.2, 301.6 nm. 1H NMR: (CD3OD) δ 8.75 (dd, J=11.2, 5.2 Hz, 1H), 8.34 (m, 1H), 8.23 (d, J=5.6 Hz, 1H), 8.14 (m, 1H), 7.92 (m, 2H), 7.81-7.73 (m, 1H), 7.64 (m, 1H), 7.54 (m, 1H), 7.36 (dd, J=8.4, 2.8 Hz, 2H), 7.13 (dd, J=8.4, 2.8 Hz, 2H), 6.02 (d, J=1.6 Hz, 1H), 4.65 (d, J=2.0 Hz, 2H), 3.08 (s, 3H), 2.97 (s, 3H) ppm. it was concentrated purified by preparative HPLC

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

Procedure: To a mixture of 6-chloro-4-(3-(pyridine-4-yl)benzylamino)nicotinamide (56 mg, 0.1 mmol) in p-Dioxane (2 mL) was added 4-amino-N,N-dimethylbenzamide (41 mg, 0.244 mmol), Pd(OAc)2 (7.5 mg, 0.033 mmol), BINAP (21 mg, 0.033 mmol) and Cs2CO3 (162 mg, 0.498 mmol). After stirred at 80° C. for 15 h, it was concentrated and purified by preparative HPLC to give 6-(4-(dimethylcarbamoyl)phenylamino)-4-(3-(pyridine-4-yl)benzylamino)nicotinamide. MS found for C27H26N6O2 as (M+H)+ 467.3. UV: λ=217.6, 272.7, 294.9 nm. 1H NMR: (CD3OD) δ 8.78 (dd, J=5.2, 1.2 Hz, 2H), 8.22 (s, 1H), 8.14 (dd, J=5.6, 1.2 Hz, 2H), 7.89 (bd, J=3.6 Hz, 1H), 7.85 (bs, 1H), 7.63 (t, J=3.6 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.37 (d, J=9.2 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.02 (s, 1H), 4.65 (s, 2H), 3.09 (s, 3H), 2.97 (s, 3H) ppm. it was concentrated purified by preparative HPLC

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

Procedure: A mixture of 4-(3-(1H-imidazol-1-yl)benzylamino)-6-chloronicotinamide (56 mg, 0.170 mmol), 4-amino-N,N-dimethylbenzamide (42 mg, 0.256 mmol), Cs2CO3 (110 mg, 0.337 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 120 C for 3 h. The mixture was concentrated in vacuo, the residue was purified by HPLC to give the titled compound (7 mg). MS 456.3 (M+H); UV 257.8 nm; t 0.344 min. was degassed with Ar The mixture was concentrated in vacuo the residue was purified by HPLC

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

Procedure: To a solution of 4-amino-N,N-dimethylbenzamide (74 mg, 452 μmol) in THF (0.5 mL) was added sodium hydride, 60% dispersion in mineral oil (19 μL, 452 μmol). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 5 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added slowly and the mixture was extracted with EtOAc (2×1 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in DMSO (1.0 mL) and the solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired compound, which was dissolved in MeOH (1.0 mL). Then, the solution was washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as light brown solid. MS (ESI, positive ion) m/z: 468 (M+H). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 5 min the mixture was extracted with EtOAc (2×1 mL) The combined organic extracts were dried over MgSO4 concentrated The residue was dissolved in DMSO (1.0 mL) the solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA)

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

Procedure: To a solution of 4-amino-N,N-dimethylbenzamide (74 mg, 452 μmol) in THF (0.5 mL) was added sodium hydride, 60% dispersion in mineral oil (19 μL, 452 μmol). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 5 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added slowly and the mixture was extracted with EtOAc (2×1 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in DMSO (1.0 mL) and the solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired compound, which was dissolved in MeOH (1.0 mL). Then, the solution was washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as light brown solid. MS (ESI, positive ion) m/z: 468 (M+H). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 5 min the mixture was extracted with EtOAc (2×1 mL) The combined organic extracts were dried over MgSO4 concentrated The residue was dissolved in DMSO (1.0 mL) the solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA)