1-bromopropan-2-one

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Bromo-propan-2-one (2.26 ml) is added under an atmosphere of argon to a solution of 5-cyano-2-methylpyridine (5.0 g, 41.9 mmol) in sulfolane (30 ml). The reaction mixture is stirred for 48 hours at 45° C., then diluted with EtOAc. The precipitated salt is filtered off and dissolved in water (50 ml). The aqueous solution is washed with EtOAc, then a 10% aqueous solution of NaHCO3 (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the reaction mixture is filtered, and the filtrate is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified via flash chromatography (hexane/EtOAc 8:1, +0.2% NEt3) to afford the title compound (5.50 g, 84%). 1H NMR (400 MHz, d6-DMSO): δ=9.10-9.09 (m, 1H), 7.59 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 6.90 (dd, J=9.3/1.7 Hz, 1H), 6.55 (s, 1H), 2.39 (s, 3H). MS (ES+): 157 (M+H)+. The precipitated salt is filtered off dissolved in water (50 ml) The aqueous solution is washed with EtOAc a 10% aqueous solution of NaHCO3 (30 ml) is added the mixture is heated to reflux for 1 hour After cooling the reaction mixture is filtered the filtrate is extracted three times with EtOAc The combined organic layers are dried over Na2SO4 filtered concentrated in vacuo The residue is purified via flash chromatography (hexane/EtOAc 8:1, +0.2% NEt3)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bromoacetone (4.3 g, 31.4 mmol, 2.9 equiv) is added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-pyrazin-2-ylamine (4.0 g, 10.7 mmol) in 1,2-dimethoxyethane (20 ml) and sulfolane (20 ml). The reaction mixture is stirred overnight at 50° C. Then a 10% aqueous solution of NaHCO3 (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (hexane/EtOAc 3:1) affords the title compound (1.7 g, 40%). 1H NMR (400 MHz, d6-DMSO): δ=8.78 (d, J=0.9 Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 7.92 (s, 1H), 7.63-7.61 (m, 4H); 7.41-7.35 (m, 6H), 4.72 (s, 2H), 2.34 (s, 3H), 1.00 (s, 9H). MS (ES+): 402 (M+H)+. the mixture is heated to reflux for 1 hour After cooling the mixture is extracted three times with EtOAc The combined organic layers are washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification by flash chromatography (hexane/EtOAc 3:1)

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

Procedure: To a solution of 19.28 g (150 mmol) of 2-amino-6-chloropyridine in 150 ml of ethanol, 25 g (180 mmol) of bromoacetone was added at room temperature, followed by refluxing for 64 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was purified by recrystallization (solvent: ethanol-ethyl acetate) to yield 20.22 g (54.5%, light brown crystal) of the desired product. by refluxing for 64 hours After the reaction mixture was cooled the solvent was distilled off The residue was purified by recrystallization (solvent: ethanol-ethyl acetate)

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

Procedure: In the manner given in Example 1, 7-(trifluoromethyl) -2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with bromopropanone to give 7-(trifluoromethyl)-2-[ (2-bromo-1-methylethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.

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

Procedure: 4-Methoxy-2-methylpyridine (0.123 g, 1 mmol) and bromoacetone (0.16 mL, 1 mmol) were heated at 95° C. under N2 for 2 h. 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (0.34 mL, 2.2 mmol) in benzene (10 mL) was added. The mixture was then refluxed under N2 for 1 h, poured into ice water, and then extracted with EtOAc. The combined organic layers were washed with water and dried. After the solvent was removed in vacuo, the residue was purified on a silica gel column eluting with EtOAc:Hexane (1:9) and EtOAc to give 7-methoxy-2-methylindolizine (0.050 g, 31%). The mixture was then refluxed under N2 for 1 h extracted with EtOAc The combined organic layers were washed with water dried After the solvent was removed in vacuo the residue was purified on a silica gel column eluting with EtOAc:Hexane (1:9) and EtOAc

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

Procedure: 4-Methoxy-2-methylpyridine (0.123 g, 1 mmol) and bromoacetone (0.16 mL, 1 mmol) were heated at 95° C. under N2 for 2 h. 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (0.34 mL, 2.2 mmol) in benzene (10 mL) was added. The mixture was then refluxed under N2 for 1 h, poured into ice water, and then extracted with EtOAc. The combined organic layers were washed with water and dried. After the solvent was removed in vacuo, the residue was purified on a silica gel column eluting with EtOAc:Hexane (1:9) and EtOAc to give 7-methoxy-2-methylindolizine (0.050 g, 31%). The mixture was then refluxed under N2 for 1 h extracted with EtOAc The combined organic layers were washed with water dried After the solvent was removed in vacuo the residue was purified on a silica gel column eluting with EtOAc:Hexane (1:9) and EtOAc

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

Procedure: A mixture of 2-(5-methoxypyridin-2-yl)-1-(3,4,5-trimethoxyphenyl)ethanone (0.200 g, 0.631 mmol), 1-bromo-2-propanone (0.171 g, 1.3 mmol), and NaHCO3 (0.212 g, 2.6 mmol) in acetone (5 mL) was refluxed for 20 h. The precipitate was removed by filtration. The filtrate was concentrated to give a residue, which was purified on a silica gel column eluting with CH2Cl2 to afford compound 5 (0.213 g, 95%). was refluxed for 20 h The precipitate was removed by filtration The filtrate was concentrated to give a residue, which was purified on a silica gel column eluting with CH2Cl2

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

Procedure: A mixture of 2-(5-methoxypyridin-2-yl)-1-(3,4,5-trimethoxyphenyl)ethanone (0.200 g, 0.631 mmol), 1-bromo-2-propanone (0.171 g, 1.3 mmol), and NaHCO3 (0.212 g, 2.6 mmol) in acetone (5 mL) was refluxed for 20 h. The precipitate was removed by filtration. The filtrate was concentrated to give a residue, which was purified on a silica gel column eluting with CH2Cl2 to afford compound 5 (0.213 g, 95%). was refluxed for 20 h The precipitate was removed by filtration The filtrate was concentrated to give a residue, which was purified on a silica gel column eluting with CH2Cl2

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

Procedure: A mixture of 5 g of 2-amino pyridine and 250 ml of acetone were added at ambient temperature to a mixture of 7.25 g of 1 bromo 2-propanone and 20 ml of acetone and the mixture was refluxed for 30 minutes. Using the procedure of Stage C of Example 22, 5.3 g of the expected product were obtained in the form of an orange oil. the mixture was refluxed for 30 minutes

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

Procedure: A mixture of 5 g of 2-amino pyridine and 250 ml of acetone were added at ambient temperature to a mixture of 7.25 g of 1 bromo 2-propanone and 20 ml of acetone and the mixture was refluxed for 30 minutes. Using the procedure of Stage C of Example 22, 5.3 g of the expected product were obtained in the form of an orange oil. the mixture was refluxed for 30 minutes

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

Procedure: 1-(2,4-Difluorophenyl)-1-(6-thiocarbamoylbenzothiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (219 mg) was dissolved in ethanol (2 ml), and sodium hydrogencarbonate (42 mg) and bromoacetone (46 μl) were added to the solution. The resultant mixture was heated at 60° C. for 3 hours. Ethyl acetate and water were added to the liquid reaction mixture to separate liquid layers. An organic layer was washed with saline and then dried, and the solvent was distilled out. The residue was subjected to column chromatography on silica gel (eluting solvent: chloroform:methanol=100:1), thereby obtaining the intended compound (114 mg). Melting point: 213°-215° C. to separate liquid layers An organic layer was washed with saline dried the solvent was distilled out

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

Procedure: 1-(2,4-Difluorophenyl)-1-(6-thiocarbamoylbenzothiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol (219 mg) was dissolved in ethanol (2 ml), and sodium hydrogencarbonate (42 mg) and bromoacetone (46 μl) were added to the solution. The resultant mixture was heated at 60° C. for 3 hours. Ethyl acetate and water were added to the liquid reaction mixture to separate liquid layers. An organic layer was washed with saline and then dried, and the solvent was distilled out. The residue was subjected to column chromatography on silica gel (eluting solvent: chloroform:methanol=100:1), thereby obtaining the intended compound (114 mg). Melting point: 213°-215° C. to separate liquid layers An organic layer was washed with saline dried the solvent was distilled out