2-fluoro-1-phenylethanone

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

Procedure: To a solution of 2.76 g of 2-fluoroacetophenone in 50 ml of ether is added dropwise over 30 minutes a solution of 3.2 g of bromine in 10 ml of chloroform. Evaporation of the reaction mixture under reduced pressure affords α-bromo-2-fluoroacetophenone. Evaporation of the reaction mixture under reduced pressure

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

Procedure: To a stirring solution of 36.2 g (0.26 mol) of 2-Fluoroacetophenone in 120 mL of ethylene glycol is added 8.6 mL (0.27 mol, 1.05 equiv.) of hydrazine. The resulting solution is stirred 2 h at RT and then heated at 165° C. for 40 h. The solution is cooled to RT, poured into CH2Cl2 (200 mL) and extracted with H2O (2×200 mL). The organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by recrystallization form hexane/CHCl3 afforded 26 g of 3-Methylindazole as a light tan solid: 1H NMR (CDCl3, 300 MHz) δ7.73 (d, 1H, J=8.1), 7.44 (m, 2H), 7.19 (dd, 1H, J=7.0,7.0), 2.67 (s, 3H). heated at 165° C. for 40 h The solution is cooled to RT extracted with H2O (2×200 mL) dried (MgSO4) the solvent removed in vacuo Purification of the crude material by recrystallization form hexane/CHCl3

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

Procedure: To a suspension of 55% sodium hydride (390 mg, 9.69 mmol) in THF (7 mL)-DMSO (20 mL) was added methyl thioglycolate (0.64 ml) under N2 atmosphere. After ceasing of bubbling, the mixture was stirred for 15 minutes at room temperature, to which was added slowly a solution of 2-fluoroacetophenone (0.89 mL, 6.46 mmol) in DMSO (5 mL). The mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a white crystal (533 mg, 36%). of bubbling The mixture was stirred at room temperature for 1 hour extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was recrystallized from ethyl acetate/hexane

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

Procedure: To a suspension of 55% sodium hydride (390 mg, 9.69 mmol) in THF (7 mL)-DMSO (20 mL) was added methyl thioglycolate (0.64 ml) under N2 atmosphere. After ceasing of bubbling, the mixture was stirred for 15 minutes at room temperature, to which was added slowly a solution of 2-fluoroacetophenone (0.89 mL, 6.46 mmol) in DMSO (5 mL). The mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a white crystal (533 mg, 36%). of bubbling The mixture was stirred at room temperature for 1 hour extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was recrystallized from ethyl acetate/hexane

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-fluoroacetophenone (19.9 g), morpholine (21 cc) and potassium carbonate (27.6 g) in dimethyl sulphoxide (32 cc) is heated at 110° C. for 30 hours. The reaction mixture is diluted with water (100 cc) and extracted with ethyl acetate (4×100 cc); the organic solution is washed with distilled water (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 9 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 250 cc fractions. Fraction 24 to 44 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2-(4-Morpholinyl)acetophenone (4.72 g) is obtained which is used as such for the subsequent syntheses. extracted with ethyl acetate (4×100 cc) the organic solution is washed with distilled water (100 cc) dried over magnesium sulphate concentrated to dryness under reduced pressure (2.7 kPa) The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 9 cm, height 40 cm) eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) collecting 250 cc fractions concentrated to dryness under reduced pressure (2.7 kPa)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-fluoroacetophenone (19.9 g), morpholine (21 cc) and potassium carbonate (27.6 g) in dimethyl sulphoxide (32 cc) is heated at 110° C. for 30 hours. The reaction mixture is diluted with water (100 cc) and extracted with ethyl acetate (4×100 cc); the organic solution is washed with distilled water (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 9 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 250 cc fractions. Fraction 24 to 44 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2-(4-Morpholinyl)acetophenone (4.72 g) is obtained which is used as such for the subsequent syntheses. extracted with ethyl acetate (4×100 cc) the organic solution is washed with distilled water (100 cc) dried over magnesium sulphate concentrated to dryness under reduced pressure (2.7 kPa) The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 9 cm, height 40 cm) eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) collecting 250 cc fractions concentrated to dryness under reduced pressure (2.7 kPa)

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

Procedure: To a solution of 2.76 g of 2-fluoroacetophenone in 50 ml of ether is added dropwise over 30 minutes a solution of 3.2 g of bromine in 10 ml of chloroform. Evaporation of the reaction mixture under reduced pressure affords α-bromo-2-fluoroacetophenone. Evaporation of the reaction mixture under reduced pressure

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

Procedure: To a room temperature solution of [2-fluoro-1-phenylvinyl]pyrrolidine (freshly prepared before use from 2-fluoro-1-phenyl ethan-1-one (Example 152(a)), pyrrolidine and TiCl4 (see Example 30) (2.44 g, 12.7 mmol) in anhydrous toluene (15 mL) was added N,N-diisopropylethylamine (Aldrich Chemical Company) (2.0 mL, 12.7 mmol) followed by 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.61 g, 12.7 mmol). After stirring at room temperature for 2.5 h the reaction mixture was filtered through a fritted funnel. The residue was washed with hot toluene (2×30 mL) and the filtrate was concentrated under reduced pressure. The residue was dissolved with dioxane/toluene (20 mL:10 mL) and NEt3 (Aldrich Chemical Company) (2.1 mL) and piperidine (Aldrich Chemical Company) (2.0 mL, 20.3 mmol) were added. The mixture was stirred at 80° C. for 2 h under a N2 atmosphere. The SnCl2 solution was added to the reaction mixture at 80° C. The mixture was stirred at 80° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The reaction mixture was poured onto a mixture of NaOH (5 g) and crushed ice (150 mL) and stirred for 1 h. The resulting slurry was filtered through a Celite® pad, the pad was rinsed with 10:1 EtOAc/MeOH (4×60 mL). The filtrate was transferred to a seperatory funnel. The organic solution was separated, washed with H2O (3×350 mL), saturated NaCl (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc/hexanes as eluant to give 0.51 g (13%) of 7-fluoro-2-methyl-6-piperidylpyrrolo[3,2-d]pyrimidine as a brown colored foam. This compound (0.51 g, 1.60 mmol) was dissolved in 10:1 EtOAc/MeOH (35 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.60 mL, 1.60 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 270 mg (6%) of the title compound as pale green colored needles. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (br s, 6), 2.59 (s, 3), 4.07 (br s, 4), 7.53-7.57 (m, 1), 7.61 (t, 2, J=7.7), 7.87 (d, 2, J=7.5), 12.07 (s, 1), 14.56 (s, 1). MS m/z: 311 (M+1 for free base). Anal. Calcd for C18H19FN4.HCl: C, 62.33; H, 5.81; N, 16.15; Cl, 10.22. Found: C, 62.04; H, 5.95; N, 16.08; Cl, 10.02. was filtered through a fritted funnel The residue was washed with hot toluene (2×30 mL) the filtrate was concentrated under reduced pressure were added The mixture was stirred at 80° C. for 2 h under a N2 atmosphere The mixture was stirred at 80° C. for an additional 16 h to cool to room temperature stirred for 1 h The resulting slurry was filtered through a Celite® pad the pad was rinsed with 10:1 EtOAc/MeOH (4×60 mL) The filtrate was transferred to a seperatory funnel The organic solution was separated washed with H2O (3×350 mL), saturated NaCl (300 mL) dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel with 50:50 EtOAc/hexanes as eluant

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

Procedure: To a room temperature solution of [2-fluoro-1-phenylvinyl]pyrrolidine (freshly prepared before use from 2-fluoro-1-phenyl ethan-1-one (Example 152(a)), pyrrolidine and TiCl4 (see Example 30) (2.44 g, 12.7 mmol) in anhydrous toluene (15 mL) was added N,N-diisopropylethylamine (Aldrich Chemical Company) (2.0 mL, 12.7 mmol) followed by 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.61 g, 12.7 mmol). After stirring at room temperature for 2.5 h the reaction mixture was filtered through a fritted funnel. The residue was washed with hot toluene (2×30 mL) and the filtrate was concentrated under reduced pressure. The residue was dissolved with dioxane/toluene (20 mL:10 mL) and NEt3 (Aldrich Chemical Company) (2.1 mL) and piperidine (Aldrich Chemical Company) (2.0 mL, 20.3 mmol) were added. The mixture was stirred at 80° C. for 2 h under a N2 atmosphere. The SnCl2 solution was added to the reaction mixture at 80° C. The mixture was stirred at 80° C. for an additional 16 h then the heating was discontinued and the mixture was allowed to cool to room temperature. The reaction mixture was poured onto a mixture of NaOH (5 g) and crushed ice (150 mL) and stirred for 1 h. The resulting slurry was filtered through a Celite® pad, the pad was rinsed with 10:1 EtOAc/MeOH (4×60 mL). The filtrate was transferred to a seperatory funnel. The organic solution was separated, washed with H2O (3×350 mL), saturated NaCl (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc/hexanes as eluant to give 0.51 g (13%) of 7-fluoro-2-methyl-6-piperidylpyrrolo[3,2-d]pyrimidine as a brown colored foam. This compound (0.51 g, 1.60 mmol) was dissolved in 10:1 EtOAc/MeOH (35 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.60 mL, 1.60 mmol). The solution was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 270 mg (6%) of the title compound as pale green colored needles. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (br s, 6), 2.59 (s, 3), 4.07 (br s, 4), 7.53-7.57 (m, 1), 7.61 (t, 2, J=7.7), 7.87 (d, 2, J=7.5), 12.07 (s, 1), 14.56 (s, 1). MS m/z: 311 (M+1 for free base). Anal. Calcd for C18H19FN4.HCl: C, 62.33; H, 5.81; N, 16.15; Cl, 10.22. Found: C, 62.04; H, 5.95; N, 16.08; Cl, 10.02. was filtered through a fritted funnel The residue was washed with hot toluene (2×30 mL) the filtrate was concentrated under reduced pressure were added The mixture was stirred at 80° C. for 2 h under a N2 atmosphere The mixture was stirred at 80° C. for an additional 16 h to cool to room temperature stirred for 1 h The resulting slurry was filtered through a Celite® pad the pad was rinsed with 10:1 EtOAc/MeOH (4×60 mL) The filtrate was transferred to a seperatory funnel The organic solution was separated washed with H2O (3×350 mL), saturated NaCl (300 mL) dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel with 50:50 EtOAc/hexanes as eluant

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

Procedure: To a solution of 2.76 g of 2-fluoroacetophenone in 50 ml of ether is added dropwise over 30 minutes a solution of 3.2 g of bromine in 10 ml of chloroform. Evaporation of the reaction mixture under reduced pressure affords α-bromo-2-fluoroacetophenone. Evaporation of the reaction mixture under reduced pressure

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

Procedure: 100 g of fluoro-acetophenone in 400 mL of ethylene glycol was stirred at room temperature with hydrazine (0.624 mol, 20 g) for 4 h after which the reaction mixture was heated to 150 C for 48 h. TLC analysis indicated complete reaction. Partitioned the reaction mixture into dichloromethane and brine. Dried organic phase over sodium sulphate and evaporated to a solid. Re-crystallized from hexane/dicholomethane gave indazole. was heated to 150 C for 48 h reaction Partitioned the reaction mixture into dichloromethane and brine Dried organic phase over sodium sulphate and evaporated to a solid

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

Procedure: 100 g of fluoro-acetophenone in 400 mL of ethylene glycol was stirred at room temperature with hydrazine (0.624 mol, 20 g) for 4 h after which the reaction mixture was heated to 150 C for 48 h. TLC analysis indicated complete reaction. Partitioned the reaction mixture into dichloromethane and brine. Dried organic phase over sodium sulphate and evaporated to a solid. Re-crystallized from hexane/dicholomethane gave indazole. was heated to 150 C for 48 h reaction Partitioned the reaction mixture into dichloromethane and brine Dried organic phase over sodium sulphate and evaporated to a solid