2-aminoacetamide;hydrochloride

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

Procedure: tert-butyl 6-carboxy-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (7.50 g, 20.8 mmol), glycinamide hydrochloride (2.76 g, 24.9 mmol), EDCI (4.78 g, 24.9 mmol), HOBT (3.78 g, 24.9 mmol), and TEA (5.80 ml, 41.6 mmol) were suspended in DMF (75 ml) and stirred at room temperature for 23 h. After removal of the solvent, the residue was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with saturated NaHCO3 aq. and brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was triturated with MeOH-Et2O and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid. After removal of the solvent the residue was diluted with EtOAc and H2O The aqueous layer was extracted with EtOAc the combined organic layer was washed with saturated NaHCO3 aq. and brine dried over MgSO4 The desiccant was removed through filtration the filtrate was concentrated under reduced pressure The residue was triturated with MeOH-Et2O the insoluble solid was collected through filtration

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

Procedure: Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 559.8 (M+H)+

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

Procedure: Prepared by the method of Example 231, using the product of Example 219 and glycinamide hydrochloride. Prepared by the method of Example 231

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

Procedure: In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and glycinamide hydrochloride (95 mg, 0.84 mmol) were reacted to give the title compound as colorless oil (40 mg, 50%). were reacted

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

Procedure: N-benzyloxycarbonylglycine (3 g, 14.4 mmole) were dissolved in 200 mL of dichloromethane and 4.5 g (21.6 mmole) of DCC were added. The mixture was stirred at room temperature for 2 hours, the insoluble materials were removed and 3.2 g (28.8 mmole) of glycinamide hydrochloride and 2.93 g (28.8 mmole) of TEA (triethylamine) were added to the filtrate. The reaction was stirred for 24 hours at room temperature, the insoluble materials were filtered and the filtrate was evaporated to dryness in vacuum. The residue was recrystallized from distilled water to get a pure product 1.9 g (7.2 mmole), yield of 50%. the insoluble materials were removed The reaction was stirred for 24 hours at room temperature the insoluble materials were filtered the filtrate was evaporated to dryness in vacuum The residue was recrystallized from distilled water

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

Procedure: N-Acetylglycine (5 g, 43 mmole) and 9.5 g (86 mmole) of glycinamide hydrochloride were dissolved in a 150 mL of a mixture of water-acetonitrile (50:50), 8.65 g (86 mmole) of triethylamine (TEA) and 12.6 g (64 mmole) of 1-ethyl-3(3-dimethyl aminopropyl)carbodiimide (EDC) as a coupling reagent were added to the mixture and the mixture was refluxed for 12 hours. The mixture was left to cool at room temperature, the insoluble materials were filtered and the filtrate was evaporated to dryness in vacuum. The residue was recrystallized from a big fraction of acetonitrile to get a mixture of the product with the salt TEA:HCl, the solid crystals were dissolved in distilled water and purified from the salt by a strong cation exchange chromatography (120 plus). The water fractions were collected and the water was removed by lyophilization to get a pure product 4.5 g (26 mmole), yield of 60%. were added to the mixture the mixture was refluxed for 12 hours The mixture was left the insoluble materials were filtered the filtrate was evaporated to dryness in vacuum The residue was recrystallized from a big fraction of acetonitrile to get purified from the salt by a strong cation exchange chromatography (120 plus) The water fractions were collected the water was removed by lyophilization

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

Procedure: To a solution of 2 g (11.4 mmole) of N-(tert-butoxycarbonyl)-glycine (Boc-glycine) and 1.26 g (22.8 mmole) of glycinamide hydrochloride in 100 mL of DMF at neutral pH, 3.54 g (17.1 mmole) of dicyclohexylcarbodiimide (DCC) was added and 0.28 g (2.3 mmole) of 4-dimethylaminopyridine (DMAP) was added as a catalyst. The reaction mixture was stirred for 24 hours at room temperature, the insoluble materials were filtered and the filtrate was evaporated to dryness in vacuum. the insoluble materials were filtered the filtrate was evaporated to dryness in vacuum

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 amide HCl (1.2 g, 10.95 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 (1.79 g, 52%) 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), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 4.01 (d, 2H, J=1.6 Hz), 2.18 (s, 3H), 2.13 (s, 3H); ES-HRMS m/z 477.1128 (M+H C22H20ClF2N4O4 requires 477.1136). 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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(+)-3-pyrrolidinol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.31 (d, 1H, J=7.6 Hz), 7.62 (m, 2H), 7.52 (m, 2H), 7.01 (m, 2H), 5.51 (m, 2H), 4.42 (m, 1H), 3.65 (m, 4H), 2.19 (s, 3H), 2.00 (m, 2H). ESHRMS m/z 476.1175 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).

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

Procedure: The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting 2-methoxyethylamine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.91 (m, 1H), 7.75 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.55 (s, 4H), 3.35 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 464.1142 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).

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

Procedure: The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-3-hydroxypyrrolidine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.31 (d, 1H, J=7.6 Hz), 7.62 (m, 2H), 7.52 (m, 2H), 7.01 (m, 2H), 5.59 (m, 2H), 4.42 .(m, 1H), 3.64 (m, 4H), 2.19 (s, 3H), 2.00 (m, 2H). ESHRMS m/z 476.1147 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).

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

Procedure: The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(−)-1-amino-2-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.94 (m, 1H), 3.30 (m, 2H), 2.20 (s, 3H), 1.18 (s, 3H). ESHRMS m/z 464.1167 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).