1,3-dimethoxypropan-2-amine

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 65, 1 g, 2.9 mmol, 1 equiv.) in THF (7 mL) was added 1,3-dimethoxypropan-2-amine (451 mL, 2.9 mmol, 1 equiv.). This reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and re-suspended in DMF (7 mL). Potassium carbonate (1.2 g, 8.69 mmol, 3 equiv.) was added, and the reaction mixture was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and quenched with water. 1 N HCl was added until pH 4-5 was reached. The precipitate was washed with water and hexanes and dried to provide ethyl 6-bromo-1-(1,3-dimethoxypropan-2-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate as a solid (963 mg, 83%). The reaction mixture was concentrated under reduced pressure the reaction mixture was stirred at 70° C. for 3 h The reaction mixture was cooled to room temperature quenched with water 1 N HCl was added until pH 4-5 The precipitate was washed with water and hexanes dried

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

Procedure: 25 mg (0.07 mmol) of the acid from example 11-1 in 1 ml dry DMF were treated with 18 mg (0.11 mmol) 1,1′-carbonyl-diimidazole at room temperature for 2 hrs. 13 mg (0.11 mmol) 2-amino-1,3-dimethoxypropan were added and stirring was continued for 4 hrs. The solvent was removed under vacuum, the residue dissolved in dichloromethane and washed with aqueous sodium carbonate solution. The dichloromethane phase was evaporated and the residue purified by chromatography on silica in dichloromethane/methanol mixtures. The solvent was removed under vacuum the residue dissolved in dichloromethane washed with aqueous sodium carbonate solution The dichloromethane phase was evaporated the residue purified by chromatography on silica in dichloromethane/methanol mixtures

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

Procedure: 25 mg (0.07 mmol) of the acid from example 11-1 in 1 ml dry DMF were treated with 18 mg (0.11 mmol) 1,1′-carbonyl-diimidazole at room temperature for 2 hrs. 13 mg (0.11 mmol) 2-amino-1,3-dimethoxypropan were added and stirring was continued for 4 hrs. The solvent was removed under vacuum, the residue dissolved in dichloromethane and washed with aqueous sodium carbonate solution. The dichloromethane phase was evaporated and the residue purified by chromatography on silica in dichloromethane/methanol mixtures. The solvent was removed under vacuum the residue dissolved in dichloromethane washed with aqueous sodium carbonate solution The dichloromethane phase was evaporated the residue purified by chromatography on silica in dichloromethane/methanol mixtures

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

Procedure: A mixture of 4-bromo-7-(2,4-dichlorophenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazine (0.143 g, 0.387 mmol), 1,3-dimethoxypropan-2-amine (0.092 g, 0.774 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-1,1′-biphenyl-2-amine (0.011 g, 0.029 mmol), Cs2CO3 (0.176 g, 0.542 mmol) and Pd2(dba)3 (0.018 g, 0.02 mmol) in DME (5.0 mL) is refluxed for 24 h. After cooling to room temperature, to the mixture is added 1,3-dimethoxypropan-2-amine (0.092 g, 0.774 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-1,1′-biphenyl-2-amine (0.011 g, 0.029 mmol) and Pd2(dba)3 (0.018 g, 0.02 mmol). The mixture is refluxed for another 24 h. After cooling to room temperature, the mixture is filtered and washed with EtOAc. The filtrate is concentrated in vacuo to dryness, the residue is subjected to preparative TLC (silica gel, 1/5 EtOAc/heptane) to give 0.07 g (44%) of light yellow solid as the title compound: mp 154–155° C. (CH2Cl2/heptane); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.0 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.36 (d, J=8.3, 2.0 Hz, 1H), 6.35 (s, 1H), 5.65 (s, 1H), 4.88 (d, J=8.4 Hz, 1H), 3.91–3.82 (m, 1H), 3.69–3.66 (m, 2H), 3.61–3.55 (m, 2H), 3.45 (s, 3H), 3.44 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.4, 142.4, 136.4, 134.3, 134.1, 129.6, 129.3, 126.8, 123.3, 120.6, 119.3, 95.1, 88.0, 70.9, 59.3, 51.3, 22.4, 12.3; IR (diffuse reflectance) 3336, 2924, 1560, 1490, 1372, 1330, 1192, 1113, 1098, 1078, 1051, 961, 821, 811, 778 cm−1; MS (EI) m/z 407 (M+), 409 (M+); HRMS (FAB) calcd for C20H23Cl2N3O2+H 408.1245, found 408.1244; Anal. Calcd for C20H23Cl2N3O2: C, 58.83; H, 5.68; N, 10.29. Found: C, 58.90; H, 5.78; N, 10.13. is refluxed for 24 h The mixture is refluxed for another 24 h After cooling to room temperature the mixture is filtered washed with EtOAc The filtrate is concentrated in vacuo to dryness

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 65, 1 g, 2.9 mmol, 1 equiv.) in THF (7 mL) was added 1,3-dimethoxypropan-2-amine (451 mL, 2.9 mmol, 1 equiv.). This reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and re-suspended in DMF (7 mL). Potassium carbonate (1.2 g, 8.69 mmol, 3 equiv.) was added, and the reaction mixture was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and quenched with water. 1 N HCl was added until pH 4-5 was reached. The precipitate was washed with water and hexanes and dried to provide ethyl 6-bromo-1-(1,3-dimethoxypropan-2-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate as a solid (963 mg, 83%). The reaction mixture was concentrated under reduced pressure the reaction mixture was stirred at 70° C. for 3 h The reaction mixture was cooled to room temperature quenched with water 1 N HCl was added until pH 4-5 The precipitate was washed with water and hexanes dried

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chlorosulphonic acid (230 μl, 3.31 mmol) was added to a solution of the 2-anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 34; 300 mg, 1.12 mmol) in thionyl chloride (6 ml) at 5° C. The mixture was stirred at 5° C. for 30 minutes, room temperature for 1 hour and heated at reflux for 1.5 hour. The mixture was allowed to cool to room temperature and a solution of excess 1,3-dimethoxy-2-aminopropane (Method 59) in ethanol (20 ml) and dimethylethylamine (0.5 ml) were added to the residue, and the mixture stirred at room temperature for 18 hours. The volatiles were removed by evaporation. The residue was triturated with water and the solid product collected by filtration and dried under vacuum at 60° C. The residue was purified by flash silica chromatography DCM:MeOH (95:5) to give the title compound. NMR: 2.40 (s, 3H), 3.10 (s, 6H), 3.20(d, 4H), 3.32-3.28 (m, 1H), 3.98 (s, 3H), 7.20 (d, 1H), 7.55 (d, 1H), 7.65 (s, 2H), 7.74 (d, 2H), 7.90 (d, 2H), 8.44 (d, 2H), 9.89 (s, 1H); m/z 447 heated at reflux for 1.5 hour to cool to room temperature the mixture stirred at room temperature for 18 hours The volatiles were removed by evaporation The residue was triturated with water the solid product collected by filtration dried under vacuum at 60° C The residue was purified by flash silica chromatography DCM:MeOH (95:5)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Chlorosulphonic acid (230 μl, 3.31 mmol) was added to a solution of the 2-anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 34; 300 mg, 1.12 mmol) in thionyl chloride (6 ml) at 5° C. The mixture was stirred at 5° C. for 30 minutes, room temperature for 1 hour and heated at reflux for 1.5 hour. The mixture was allowed to cool to room temperature and a solution of excess 1,3-dimethoxy-2-aminopropane (Method 59) in ethanol (20 ml) and dimethylethylamine (0.5 ml) were added to the residue, and the mixture stirred at room temperature for 18 hours. The volatiles were removed by evaporation. The residue was triturated with water and the solid product collected by filtration and dried under vacuum at 60° C. The residue was purified by flash silica chromatography DCM:MeOH (95:5) to give the title compound. NMR: 2.40 (s, 3H), 3.10 (s, 6H), 3.20(d, 4H), 3.32-3.28 (m, 1H), 3.98 (s, 3H), 7.20 (d, 1H), 7.55 (d, 1H), 7.65 (s, 2H), 7.74 (d, 2H), 7.90 (d, 2H), 8.44 (d, 2H), 9.89 (s, 1H); m/z 447 heated at reflux for 1.5 hour to cool to room temperature the mixture stirred at room temperature for 18 hours The volatiles were removed by evaporation The residue was triturated with water the solid product collected by filtration dried under vacuum at 60° C The residue was purified by flash silica chromatography DCM:MeOH (95:5)

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

Procedure: 25 mg (0.07 mmol) of the acid from example 11-1 in 1 ml dry DMF were treated with 18 mg (0.11 mmol) 1,1′-carbonyl-diimidazole at room temperature for 2 hrs. 13 mg (0.11 mmol) 2-amino-1,3-dimethoxypropan were added and stirring was continued for 4 hrs. The solvent was removed under vacuum, the residue dissolved in dichloromethane and washed with aqueous sodium carbonate solution. The dichloromethane phase was evaporated and the residue purified by chromatography on silica in dichloromethane/methanol mixtures. The solvent was removed under vacuum the residue dissolved in dichloromethane washed with aqueous sodium carbonate solution The dichloromethane phase was evaporated the residue purified by chromatography on silica in dichloromethane/methanol mixtures