N-(dibromomethylidene)hydroxylamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of intermediate 179, N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.350 g, 0.76 mmol) in a mixture of ethyl acetate (10 ml) and water (2 ml) was treated with potassium bicarbonate (0.230 g, 2.3 mmol) followed by dibromoformaldoxime (0.354 g, 1.75 mmol) (D. M. Vyas, Y. Chiang and T. W. Doyle, Tetrahedron Letters, 1984, 25, 487–490) and the resulting mixture stirred at 22° C. After 1 h, identical quantities of potassium bicarbonate and dibromoformaldoxime were added and the mixture stirred for another 1.5 h. The reaction mixture was then diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residue from ether gave 0.300 g (68% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.63 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.67 (2H, d, J=6.6 Hz, NCH2), 5.32 (2H, s, OCH2), 6.60 (1H, s, CH), 7.17 (1H, m, aromatic), 7.30–7.36 (4H, m, aromatics), 7.51–7.53 (2H, m, aromatics), 7.60 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 8.01 (1H, broad t, NH). HRMS (ESI+) calculated for C27H25BrFN4O5 [M+H+]: 583.0992. Found: 583.0986. the mixture stirred for another 1.5 h washed with brine dried over anhydrous magnesium sulfate concentrated under reduced pressure Crystallization of the residue from ether

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

Procedure: 20 g (0.135 mol) of ethyl allyl(P-methyl)phosphinate are dissolved in 570 ml of ethyl acetate, 49.7 g (0.6 mol) of sodium bicarbonate in 115 ml of water are added and, while stirring vigorously, a solution of 40.6 g (0.2 mol) of dibromoformaldoxime in 115 ml of ethyl acetate is slowly added dropwise. The product is isolated in the form of an oil, 15 g from the ethyl acetate phase, and a further 19 g from the aqueous phase by extraction with dichloromethane at pH 2. a further 19 g from the aqueous phase by extraction with dichloromethane at pH 2

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

Procedure: A mixture of dibromoformaldoxime(which was obtained in Example 116) (32.5 g, 160.2 mmol), 3-butyn-one (13.41 g, 197 mmol), potassium carbonate (11 g, 80.1 mmol), and methylene chloride (300 mL) was stirred at ambient temperature for 20 hours. The slurry was then treated with aqueous hydrochloric acid (2N, 200 mL) and extracted with methylene chloride. The combined organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (ethyl acetate/hexanes 5/95) gave a white solid (16.76 g, 56% yield); 1H NMR (300 MHz, CDCl3) δ 2.62 (s, 3H), 6.97 (s, 1H). extracted with methylene chloride The combined organic extracts were dried over MgSO4 Evaporation and purification by flash chromatography (ethyl acetate/hexanes 5/95)

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

Procedure: To a solution of 6-(allyloxy)-3,4-dihydroquinolin-2(1H)-one (1.85 g, 9.10 mmol) in DMF (20 mL) and water (5 mL), K2CO3 (3.77 g, 27.3 mmol) were added and the reaction mixture was cooled to 0° C. Hydroxycarbonimidic dibromide (3.69 g, 18.21 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over Na2SO4. The organic layer was concentrated and the crude material purified by flash chromatography on silica gel using ethyl acetate/hexane as eluant to give 6-((3-bromo-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (1.8 g, 59.6%). 1HNMR: 400 MHz, DMSO-d6: δ 2.40 (q, J=7.20 Hz, 2H), 2.83 (t, J=8.00 Hz, 2H), 3.18 (dd, J=7.60, 17.60 Hz, 1H), 3.50 (dd, J=10.80, 17.40 Hz, 1H), 4.01-4.09 (m, 2H), 4.98-5.03 (m, 1H), 6.72-6.81 (m, 3H), 9.92 (s, 1H). LCMS: RT 1.408 min; LCMS (ES-API), m/z 327 (M+H). washed with water, brine dried over Na2SO4 The organic layer was concentrated the crude material purified by flash chromatography on silica gel

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

Procedure: To a solution of 6-(allyloxy)-3,4-dihydroquinolin-2(1H)-one (1.85 g, 9.10 mmol) in DMF (20 mL) and water (5 mL), K2CO3 (3.77 g, 27.3 mmol) were added and the reaction mixture was cooled to 0° C. Hydroxycarbonimidic dibromide (3.69 g, 18.21 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over Na2SO4. The organic layer was concentrated and the crude material purified by flash chromatography on silica gel using ethyl acetate/hexane as eluant to give 6-((3-bromo-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (1.8 g, 59.6%). 1HNMR: 400 MHz, DMSO-d6: δ 2.40 (q, J=7.20 Hz, 2H), 2.83 (t, J=8.00 Hz, 2H), 3.18 (dd, J=7.60, 17.60 Hz, 1H), 3.50 (dd, J=10.80, 17.40 Hz, 1H), 4.01-4.09 (m, 2H), 4.98-5.03 (m, 1H), 6.72-6.81 (m, 3H), 9.92 (s, 1H). LCMS: RT 1.408 min; LCMS (ES-API), m/z 327 (M+H). washed with water, brine dried over Na2SO4 The organic layer was concentrated the crude material purified by flash chromatography on silica gel

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

Procedure: Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added portionwise over 1 h 20 min to a mixture of 3-chlorobenzonitrile (3.00 g, 21.29 mmol) and NaHCO3 (2.9 g, 34.87 mmol) in toluene (3 ml) at 90° C. Stirring was continued for 3 h and then the reaction mixture was cooled to r.t., diluted with EA and washed with water. The organic phase was dried and concentrated. A mixture of 3-chlorobenzonitrile and 3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after flash chromatography (hex/EA 10:1). 1.0 g of the mixture was dissolved in MeNH2 (4 ml, 8.5 M in EtOH) and heated in a microwave reactor for 30 min at 60° C. The volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with CHCl3. The organic phase was dried and concentrated. Recrystallization from EA gave 137 mg of the title compound. 1H NMR: 3.00 (d, 3 H) 4.35 (bs, 1 H) 7.43 (t, 1 H) 7.50-7.55 (m, 1 H) 7.92 (d, 1 H) 8.03 (s, 1 H) washed with water The organic phase was dried concentrated A mixture of 3-chlorobenzonitrile

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

Procedure: Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added portionwise over 1 h 20 min to a mixture of 3-chlorobenzonitrile (3.00 g, 21.29 mmol) and NaHCO3 (2.9 g, 34.87 mmol) in toluene (3 ml) at 90° C. Stirring was continued for 3 h and then the reaction mixture was cooled to r.t., diluted with EA and washed with water. The organic phase was dried and concentrated. A mixture of 3-chlorobenzonitrile and 3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after flash chromatography (hex/EA 10:1). 1.0 g of the mixture was dissolved in MeNH2 (4 ml, 8.5 M in EtOH) and heated in a microwave reactor for 30 min at 60° C. The volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with CHCl3. The organic phase was dried and concentrated. Recrystallization from EA gave 137 mg of the title compound. 1H NMR: 3.00 (d, 3 H) 4.35 (bs, 1 H) 7.43 (t, 1 H) 7.50-7.55 (m, 1 H) 7.92 (d, 1 H) 8.03 (s, 1 H) washed with water The organic phase was dried concentrated A mixture of 3-chlorobenzonitrile

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

Procedure: 0.233 g Allyl-[7-(3,4,dimethoxy-phenyl)-[1,6]-naphthyridin-5-yl]-amine (I.35) were placed in 2.9 mL ethyl acetate at ambient temperature, then 0.265 g sodium hydrogen carbonate and 0.220 g dibromoformaldoxime were added. The reaction was stirred at ambient temperature for 21 h. After this time the reaction was poured onto water and extracted with ethyl acetate (×2). The combined organic fractions were dried with sodium sulfate and the solvent was removed from the filtrate under reduced pressure to provide 1.36 as a mixture of enantiomers which was used without further purification. The crude material was placed in 6 mL tetrahydrofuran at ambient temperature, then 23.9 mL of 1M sodium hydroxide and 23.8 mg tetrabutylammonium hydrogensulfate were added. The reaction was heated to 80° C. where it was maintained for 22 h. After this time, reaction mixture was cooled to ambient temperature and washed with diethyl ether (×2). The aqueous phase was acidified to pH ˜6 using 4M hydrochloric acid and extracted with dichloromethane (×4). The combined organic fractions were dried with sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by silica gel chromatography (methanol/dichloromethane: 2-5%) gave the title compound as a mixture of enantiomers. After this time the reaction was poured onto water extracted with ethyl acetate (×2) The combined organic fractions were dried with sodium sulfate the solvent was removed from the filtrate under reduced pressure to provide 1.36 as a mixture of enantiomers which was used without further purification was placed in 6 mL tetrahydrofuran at ambient temperature 23.9 mL of 1M sodium hydroxide and 23.8 mg tetrabutylammonium hydrogensulfate were added The reaction was heated to 80° C. where it was maintained for 22 h After this time, reaction mixture was cooled to ambient temperature washed with diethyl ether (×2) extracted with dichloromethane (×4) The combined organic fractions were dried with sodium sulfate filtered the solvent was removed from the filtrate under reduced pressure Purification by silica gel chromatography (methanol/dichloromethane: 2-5%)

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

Procedure: 0.233 g Allyl-[7-(3,4,dimethoxy-phenyl)-[1,6]-naphthyridin-5-yl]-amine (I.35) were placed in 2.9 mL ethyl acetate at ambient temperature, then 0.265 g sodium hydrogen carbonate and 0.220 g dibromoformaldoxime were added. The reaction was stirred at ambient temperature for 21 h. After this time the reaction was poured onto water and extracted with ethyl acetate (×2). The combined organic fractions were dried with sodium sulfate and the solvent was removed from the filtrate under reduced pressure to provide 1.36 as a mixture of enantiomers which was used without further purification. The crude material was placed in 6 mL tetrahydrofuran at ambient temperature, then 23.9 mL of 1M sodium hydroxide and 23.8 mg tetrabutylammonium hydrogensulfate were added. The reaction was heated to 80° C. where it was maintained for 22 h. After this time, reaction mixture was cooled to ambient temperature and washed with diethyl ether (×2). The aqueous phase was acidified to pH ˜6 using 4M hydrochloric acid and extracted with dichloromethane (×4). The combined organic fractions were dried with sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by silica gel chromatography (methanol/dichloromethane: 2-5%) gave the title compound as a mixture of enantiomers. After this time the reaction was poured onto water extracted with ethyl acetate (×2) The combined organic fractions were dried with sodium sulfate the solvent was removed from the filtrate under reduced pressure to provide 1.36 as a mixture of enantiomers which was used without further purification was placed in 6 mL tetrahydrofuran at ambient temperature 23.9 mL of 1M sodium hydroxide and 23.8 mg tetrabutylammonium hydrogensulfate were added The reaction was heated to 80° C. where it was maintained for 22 h After this time, reaction mixture was cooled to ambient temperature washed with diethyl ether (×2) extracted with dichloromethane (×4) The combined organic fractions were dried with sodium sulfate filtered the solvent was removed from the filtrate under reduced pressure Purification by silica gel chromatography (methanol/dichloromethane: 2-5%)

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

Procedure: In a similar manner dibromoformaldoxime is reacted with propargyl alcohol, ethyl propiolate, phenylacetylene, 1-pentyn-3-ol, 1-hexyn-1-ol, 3-butyn-1-ol, n-butyl 2-hydroxy-3-butanoate, and dichloroformaldoxime is reacted with 3-butyn-2-ol and propargyl alcohol, to afford the following compounds respectively: to afford the following compounds respectively

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

Procedure: In a similar manner dibromoformaldoxime is reacted with propargyl alcohol, ethyl propiolate, phenylacetylene, 1-pentyn-3-ol, 1-hexyn-1-ol, 3-butyn-1-ol, n-butyl 2-hydroxy-3-butanoate, and dichloroformaldoxime is reacted with 3-butyn-2-ol and propargyl alcohol, to afford the following compounds respectively: to afford the following compounds respectively