2-amino-N-methylacetamide;hydrochloride

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

Procedure: The title compound was prepared by a procedure similar to the one described for (±)3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using glycine methyl amide HCl (1.77 g, 14.25 mmol) as the amine and with an addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (1.55 g, 33%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.97 (dd, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.57 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.98 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H); ES-HRMS m/z 491.1262 (M+H C23H22ClF2N4O4 requires 491.1292). Both (+) and (−) atropomers will be resolved and characterized. The title compound was prepared by a procedure similar to the one After reverse phase HPLC purification the organic extracts were concentrated under reduced pressure dried in vacuo

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

Procedure: To a cold solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.8 g, 1.7 mmol) in anhydrous dimethylacetamide (3.2 mL) was added isobutyl chloroformate (0.23 mL, 1.7 mmol) followed by N-methylmorpholine (0.25 mL, 2.2 mmol). The reaction mixture stirred under argon atmosphere at 0° C. for 10 min and then at room temperature for 30 min. At which time another equivalent of N-methylmorpholine (0.29 mL, 2.5 mmol) was added to reaction mixture, followed by the addition of glycine methyl amide HCl (0.33 g, 2.5 mmol) and DMAP (ca.). The reaction mixture stirred for 2 h at room temperature and then diluted with acetonitrile/water (2:1 v/v) to be purified by reverse phase HPLC using a 10–90% acetonitrile in water containing 0.5% TFA (30 min) gradient at a 80 mL/min flow rate. The appropriate fractions (M+H m/z=521) were collected and concentrated to a reduced volume. The resulting suspension was diluted with dichloromethane (30 mL) and washed with 5% NaHCO3 (2×50 mL). The organic extracts were washed with water (2×25 mL) and dried over Na2SO4 (anhydrous). The organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (364.4 mg, 37%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.96 (dd, 1H, J=2 Hz), 7.80 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.98 (s, 2H), 2.74 (s, 3H), 2.20 (s, 3H); ES-HRMS m/z 521.0650 (M+H C22H20BrF2N4O4 requires 521.0630). at room temperature for 30 min The reaction mixture stirred for 2 h at room temperature to be purified by reverse phase HPLC a 10–90% acetonitrile in water containing 0.5% TFA (30 min) gradient The appropriate fractions (M+H m/z=521) were collected concentrated to a reduced volume The resulting suspension was diluted with dichloromethane (30 mL) washed with 5% NaHCO3 (2×50 mL) The organic extracts were washed with water (2×25 mL) dried over Na2SO4 (anhydrous) The organic extracts were concentrated under reduced pressure dried in vacuo

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

Procedure: The title compound was prepared by employing a similar procedure as described for (±)3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide, substituting S-alanineamide hydrochloride for N-methylglycineamide hydrochloride. Yield 45% : 1H NMR (CD3OD/400 MHz) δ 7.96 (m, 1H), 7.73 (dd, 1H, J=2.0 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.56 (abq, 2H), 4.55 (ab q, 1H), 2.18 (s, 3H), 2.14 (s, 3H), and 1.45 (d, 3H, J=7.2 Hz); ES-HRMS m/z 535.0757 (M+H calcd for C23H22N4O4F2Br requires 535.0787). 19F NMR(CD3OD/400 MHz) −111.86(m) and −115.90 (m).

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

Procedure: To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (1.0 g, 0.022 mol) in dimethylacetamide (10.0 mL) at −20° C. was added isobutylchloroformate (0.36 g, 0.0028 mol), followed by dropwise addition of N-methylmorpholine (0.30 g, 0.003 mol) and stirred for 10 min under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 20 min, cooled to 0° C., and added N-methylmorpholine (0.30 g, 0.003 mol) followed by the addition of N-methylglycine amide hydrochloride (0.35 g, 0.0028 mol) and DMAP (0.025 g). The reaction mixture was stirred at room temperature for 4 h, and concentrated in vacuo. The resulting the residue was purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=535) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (25 mL), washed successively with 5% sodium bicarbonate (2×20 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (0.75 g, 65%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.96 (dd 1H, J=1.6 Hz, 8.0 Hz), 7.72 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.55 (abq, 2H), 3.99 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), and 2.14 (s, 3H); ES-HRMS m/z 535.0792 (M+H calcd for C23H22N4O4F2Br requires 535.0787). 19F NMR(CD3OD/400 MHz) −111.85 (m) and −115.91 (m). The reaction mixture was then stirred at room temperature for 20 min The reaction mixture was stirred at room temperature for 4 h concentrated in vacuo The resulting the residue was purified by reverse-phase 10–90% CH3CN/Water gradient (40 min) freeze-dried to give a white solid washed successively with 5% sodium bicarbonate (2×20 mL), water (2×20 mL) dried (Na2SO4) concentrated to dryness

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

Procedure: To a stirred solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (50 mg) in methanol (1 mL) was added glycine methyl amide hydrochloride (41 mg) and acetic acid (12 μL). The mixture was stirred for 5 minutes then sodium triacetoxy borohydride (42 mg) was added and stirring was continued at room temperature overnight. Methanol was removed in vacuo and the resulting residue dissolved in DCM (20 mL) and washed with saturated sodium bicarbonate and water (1:1, 2×20 mL). The organic layer was separated, dried over sodium sulphate and evaporated to yield crude product as an oil. Purification by preparative-HPLC afforded the TFA salt of 4-[3-(methylcarbamoylmethyl-amino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a white solid (13 mg). stirring was continued at room temperature overnight Methanol was removed in vacuo the resulting residue dissolved in DCM (20 mL) washed with saturated sodium bicarbonate and water (1:1, 2×20 mL) The organic layer was separated dried over sodium sulphate evaporated to yield crude product as an oil Purification

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

Procedure: To a stirred solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (50 mg) in methanol (1 mL) was added glycine methyl amide hydrochloride (41 mg) and acetic acid (12 μL). The mixture was stirred for 5 minutes then sodium triacetoxy borohydride (42 mg) was added and stirring was continued at room temperature overnight. Methanol was removed in vacuo and the resulting residue dissolved in DCM (20 mL) and washed with saturated sodium bicarbonate and water (1:1, 2×20 mL). The organic layer was separated, dried over sodium sulphate and evaporated to yield crude product as an oil. Purification by preparative-HPLC afforded the TFA salt of 4-[3-(methylcarbamoylmethyl-amino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a white solid (13 mg). stirring was continued at room temperature overnight Methanol was removed in vacuo the resulting residue dissolved in DCM (20 mL) washed with saturated sodium bicarbonate and water (1:1, 2×20 mL) The organic layer was separated dried over sodium sulphate evaporated to yield crude product as an oil Purification

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

Procedure: The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylcarbamoylmethylamide, substituting 2-amino-N,N′-dimethylacetamide hydrochloride for 2-amino-N-methylacetamide hydrochloride. 1H-NMR (DMSO-d6) δ 8.75 (t, J=4.8 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 6.63 (d, J=9.0 Hz, 2H), 5.18 (s, 2H), 4.11 (d, J=5.4 Hz, 2H), 2.96 (s, 3H), 2.85 (s, 3H); MS LC-MS [M+H]+=315.

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

Procedure: To a solution of 4-chloropyridine-2-carbonyl choride HCl (2.00 g, 9.41 mmol) in THF (16.4 mL) and acetonitrile (9.4 mL) was added 2-amino-N-methylacetamide hydrochloride (1.29 g, 10.35 mmol, 1.1 eq) and triethylamine (5.25 mL, 37.6 mmol, 4.0 eq) at 0° C. The resulting dark brown reaction mixture was stirred at RT for 2 h. The volatile solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified on MPLC (biotage) eluted with 100% EtOAc to give 1.4 g (65.3%) of 4-chloropyridine-2-carboxylic acid methylcarbamoyl-N-methylamide as a tan solid: TLC (75% EtOAc/hex), Rf=0.14; MS LC-MS [M+H]+=228. The volatile solvent was removed under reduced pressure the residue was partitioned between EtOAc and water The organic layer was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The crude product was purified on MPLC (biotage) eluted with 100% EtOAc

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

Procedure: To a solution of 4-chloropyridine-2-carbonyl choride HCl (2.00 g, 9.41 mmol) in THF (16.4 mL) and acetonitrile (9.4 mL) was added 2-amino-N-methylacetamide hydrochloride (1.29 g, 10.35 mmol, 1.1 eq) and triethylamine (5.25 mL, 37.6 mmol, 4.0 eq) at 0° C. The resulting dark brown reaction mixture was stirred at RT for 2 h. The volatile solvent was removed under reduced pressure, and the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified on MPLC (biotage) eluted with 100% EtOAc to give 1.4 g (65.3%) of 4-chloropyridine-2-carboxylic acid methylcarbamoyl-N-methylamide as a tan solid: TLC (75% EtOAc/hex), Rf=0.14; MS LC-MS [M+H]+=228. The volatile solvent was removed under reduced pressure the residue was partitioned between EtOAc and water The organic layer was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The crude product was purified on MPLC (biotage) eluted with 100% EtOAc

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.22 mmol), H-Gly-NHMe.HCl (110 mg, 0.88 mmol), CuI (42 mg, 0.22 mmol), N,N′-dimethylethylenediamine (24 μL, 0.22 mmol), cesium carbonate (440 mg, 1.4 mmol) in 5 mL dioxane in a sealed tube was stirred for 15 hrs at 120° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C17H17ClN6O2S (M+H)+ 405.1, 407.1 (Cl pattern).

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

Procedure: Phosphoryl trichloride (1 mL, 11 mmol) was added slowly to a 0° C. solution of DMF (22 mL), followed by 2-amino-N-methylacetamide hydrochloride (2.5 g, 20 mmol). The mixture was warmed at room temperature and stirred at 60° C. before phosphoryl trichloride (35 mL, 390 mmol) was added slowly. The solution was stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into ice/water (500 mL). Solid sodium carbonate was added until pH 6-7 was reached. The mixture was extracted with DCM (4×150 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The residue was dissolved in water (10 mL) and 1,4-dioxane (20 mL) before potassium carbonate (10 g, 72.3 mmol) was added. The mixture was stirred at 60° C. for 4 hours. The mixture was evaporated to dryness. The residue was treated with 50% EtOAc/Et2O (250 mL). The solid was removed by filtration. The filtrate was recovered, evaporated, and dried in vacuo, affording 5-chloro-1-methyl-1H-imidazole-4-carbaldehyde (476 mg, 23% yield). The product was used without further purification. was added slowly After cooling to room temperature The mixture was extracted with DCM (4×150 mL) dried over MgSO4 filtered evaporated dried in vacuo The residue was dissolved in water (10 mL) The mixture was stirred at 60° C. for 4 hours The mixture was evaporated to dryness The residue was treated with 50% EtOAc/Et2O (250 mL) The solid was removed by filtration The filtrate was recovered evaporated dried in vacuo

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

Procedure: Phosphoryl trichloride (1 mL, 11 mmol) was added slowly to a 0° C. solution of DMF (22 mL), followed by 2-amino-N-methylacetamide hydrochloride (2.5 g, 20 mmol). The mixture was warmed at room temperature and stirred at 60° C. before phosphoryl trichloride (35 mL, 390 mmol) was added slowly. The solution was stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into ice/water (500 mL). Solid sodium carbonate was added until pH 6-7 was reached. The mixture was extracted with DCM (4×150 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The residue was dissolved in water (10 mL) and 1,4-dioxane (20 mL) before potassium carbonate (10 g, 72.3 mmol) was added. The mixture was stirred at 60° C. for 4 hours. The mixture was evaporated to dryness. The residue was treated with 50% EtOAc/Et2O (250 mL). The solid was removed by filtration. The filtrate was recovered, evaporated, and dried in vacuo, affording 5-chloro-1-methyl-1H-imidazole-4-carbaldehyde (476 mg, 23% yield). The product was used without further purification. was added slowly After cooling to room temperature The mixture was extracted with DCM (4×150 mL) dried over MgSO4 filtered evaporated dried in vacuo The residue was dissolved in water (10 mL) The mixture was stirred at 60° C. for 4 hours The mixture was evaporated to dryness The residue was treated with 50% EtOAc/Et2O (250 mL) The solid was removed by filtration The filtrate was recovered evaporated dried in vacuo