(4-fluorophenyl)hydrazine;hydrochloride

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

Procedure: Similarly prepared to Intermediate 25 from 2,6-dibromo-4-methylbenzaldehyde and (4-fluorophenyl)hydrazine hydrochloride.

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

Procedure: 2-Hydroxymethylene indan-1-one, (Example 1(ii) (a) (4.004 g; 250 mmol), p-fluorophenyl hydrazine hydrochloride (Aldrich) (4.106 g; 25.25 mmol) 10M hydrochloric acid (1 cm3) and ethanol (30 cm3), were heated under reflux for 19 hours. After cooling, the solvent was evaporated under reduced pressure, then taken up in dichloromethane and washed with 2M NaOH. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by Kugelrohr distillation (140° C.; 0.01 mmHg) afforded a yellow solid, m.p. 104-105° C. under reflux for 19 hours After cooling the solvent was evaporated under reduced pressure washed with 2M NaOH The organic layer was separated dried (Na2SO4) filtered concentrated in vacuo Purification by Kugelrohr distillation (140° C.; 0.01 mmHg) afforded a yellow solid, m.p. 104-105° C.

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

Procedure: Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester, prepared as described in U.S. Ser. No. 09/308,954, filed May 8, 1997 as Attorney Docket No. PC9798, 30 grams (97.66 mmol) was combined with 4-fluorophenyl hydrazine hydrochloride (31.76 g, 175.33 mmol) and sodium acetate (30 g, 364 mmol) in mesitylene (400 mL). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 96 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with 500 mL of diethyl ether and 600 mL of water. Organic layer was separated and aqueous layer extracted with 500 mL of ethyl acetate. Combined organic extracts were washed with water (2×600 mL), brine (1×200 mL), dried over MgSO4 and concentrated which gave a brown-red oil. Hexane (600 mL) was added to crude reaction product and the mixture boiled in a steam bath for a few minutes. This was followed by cooling still the heterogeneous mixture to room temperature and allowing to stand at room temperature for 12-14 hours. The reaction mixture was filtered, undissolved solid washed with additional hexane and filtrate which contained approximately 80% pure desired product concentrated in vacuo to give brown-yellow solid. Purification of this product on silica gel column and eluting with 15% ethyl acetate/85% hexane gave 14.1 grams of light brown-tan solid. Recrystallization from hexane gave light tan needles. mp=72-73° C.; MS (APCI) m/z 319 (base). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 96 hours concentrated under reduced pressure The crude product was diluted with 500 mL of diethyl ether and 600 mL of water Organic layer was separated aqueous layer extracted with 500 mL of ethyl acetate Combined organic extracts were washed with water (2×600 mL), brine (1×200 mL) dried over MgSO4 concentrated which gave a brown-red oil reaction product the mixture boiled in a steam bath for a few minutes by cooling still the heterogeneous mixture to room temperature The reaction mixture was filtered undissolved solid washed with additional hexane and filtrate which concentrated in vacuo to give brown-yellow solid Purification of this product on silica gel column eluting with 15% ethyl acetate/85% hexane

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

Procedure: To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.59 g, 8.79 mM) and 4-fluorophenylhydrazine hydrochloride (10.0 g, 61.5 mM) in ethanol (48 mL) was added triethylamine (9.8 mL, 70.3 mM). The resulting brown solution was refluxed for 48 hours, cooled to room temperature and diluted with ethyl acetate (150 mL) to give a white crystalline precipitate which was removed by filtration and discarded. The filtrate was washed with hydrochloric acid (3×500 mL, 1N) which caused precipitation in the ethyl acetate layer. The precipitate was collected and washed successively with ethyl acetate/ether and ether to give the 4-fluorophenylhydrazine salt of the title compound (2.14 g). This material was refluxed in glacial acetic acid (20 mL) for 2 hours. After cooling the acetic acid solution to room temperature, a precipitate formed and the solids were collected to give the title compound (1.48 g, 47%) as a yellow powder, mp 390-392° C.; MS(CI): 358 (M+H). The resulting brown solution was refluxed for 48 hours to give a white crystalline precipitate which was removed by filtration The filtrate was washed with hydrochloric acid (3×500 mL, 1N) which precipitation in the ethyl acetate layer The precipitate was collected washed successively with ethyl acetate/ether and ether

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

Procedure: Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester, prepared as described in U.S. Ser. No. 09/308,954, now U.S. Pat. No. 6,011,159, filed May 8, 1997 as Attorney Docket No. PC9798, 30 grams (97.66 mmol) was combined with 4-fluorophenyl hydrazine hydrochloride (31.76 g, 175.33 mmol) and sodium acetate (30 g, 364 mmol) in mesitylene (400 mL). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 96 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with 500 mL of diethyl ether and 600 mL of water. Organic layer was separated and aqueous layer extracted with 500 mL of ethyl acetate. Combined organic extracts were washed with water (2×600 mL), brine (1×200 mL), dried over MgSO4 and concentrated which gave a brown-red oil. Hexane (600 mL) was added to crude reaction product and the mixture boiled in a steam bath for a few minutes. This was followed by cooling still the heterogeneous mixture to room temperature and allowing to stand at room temperature for 12-14 hours. The reaction mixture was filtered, undissolved solid washed with additional hexane and filtrate which contained approximately 80% pure desired product concentrated in vacuo to give brown-yellow solid. Purification of this product on silica gel column and eluting with 15% ethyl acetate/85% hexane gave 14.1 grams of light brown-tan solid. Recrystallization from hexane gave light tan needles. mp=72-73° C.; MS (APCI) m/z 319 (base). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 96 hours concentrated under reduced pressure The crude product was diluted with 500 mL of diethyl ether and 600 mL of water Organic layer was separated aqueous layer extracted with 500 mL of ethyl acetate Combined organic extracts were washed with water (2×600 mL), brine (1×200 mL) dried over MgSO4 concentrated which gave a brown-red oil reaction product the mixture boiled in a steam bath for a few minutes by cooling still the heterogeneous mixture to room temperature The reaction mixture was filtered undissolved solid washed with additional hexane and filtrate which concentrated in vacuo to give brown-yellow solid Purification of this product on silica gel column eluting with 15% ethyl acetate/85% hexane

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

Procedure: To a solution of 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one (0.6 mmol) in ethanol (3 mL) was added (4-fluoro-phenyl)-hydrazine hydrochloride (0.7 mmol). The reaction mixture was heated at reflux overnight, cooled, concentrated and the residue was treated with dichloromethane and aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane and the organic layer was dried and stripped to provide an oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to yield product (0.23 mmol). 1H NMR (CDCl3, 400 MHz) δ 7.55 (m, 2H), 7.40 (s, 1H), 7.20–6.90 (m, 7H), 3.50 (br s, 2H), 3.25 (br s, 1H), 3.10 (br s, 1H), 2.95–2.6. The reaction mixture was heated at reflux overnight cooled concentrated the residue was treated with dichloromethane and aqueous sodium bicarbonate solution The aqueous layer was extracted with dichloromethane the organic layer was dried to provide an oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes

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

Procedure: To a solution of 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one (0.6 mmol) in ethanol (3 mL) was added (4-fluoro-phenyl)-hydrazine hydrochloride (0.7 mmol). The reaction mixture was heated at reflux overnight, cooled, concentrated and the residue was treated with dichloromethane and aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane and the organic layer was dried and stripped to provide an oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to yield product (0.23 mmol). 1H NMR (CDCl3, 400 MHz) δ 7.55 (m, 2H), 7.40 (s, 1H), 7.20–6.90 (m, 7H), 3.50 (br s, 2H), 3.25 (br s, 1H), 3.10 (br s, 1H), 2.95–2.6. The reaction mixture was heated at reflux overnight cooled concentrated the residue was treated with dichloromethane and aqueous sodium bicarbonate solution The aqueous layer was extracted with dichloromethane the organic layer was dried to provide an oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes

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

Procedure: 1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-fluorophenylhydrazine hydrochloride (81 mg, 0.5 mmol) with the addition of 0.5 mL of 5% sodium hydroxide solution. After reacting for 4 hrs, very little solid had formed; however, analysis of the reaction solution by TLC indicated that no starting material remained. The resulting solid was removed by filtration and the solvent was evaporated from the filtrate to yield 29 mg (20%) of the compound as a brown solid. very little solid had formed The resulting solid was removed by filtration the solvent was evaporated from the filtrate

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

Procedure: 1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-fluorophenylhydrazine hydrochloride (81 mg, 0.5 mmol) with the addition of 0.5 mL of 5% sodium hydroxide solution. After reacting for 4 hrs, very little solid had formed; however, analysis of the reaction solution by TLC indicated that no starting material remained. The resulting solid was removed by filtration and the solvent was evaporated from the filtrate to yield 29 mg (20%) of the compound as a brown solid. very little solid had formed The resulting solid was removed by filtration the solvent was evaporated from the filtrate

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

Procedure: In a 5 mL round-bottomed flask the above prepared 6-cyclobutoxy-5-furan-2-yl-nicotinic acid (0.050 g, 174 μmol, Eq: 1.00) was combined with THF (2 mL) to give a colorless solution. TBTU (83.6 mg, 260 μmol, Eq: 1.5) and N,N-diisopropylamine (112 mg, 152 μL, 868 μmol, Eq: 5) were added. The reaction mixture was stirred for 10 min at RT before (4-fluorophenyl)-hydrazine hydrochloride (33.9 mg, 208 μmol, Eq: 1.2) was added and the reaction allowed to proceed at RT overnight. The mixture was poured into 15 mL 1 M HCl and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 1 M NaOH, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) to yield 40 mg of the title compound as white solid; MS (EI) 368.4 (M+H)+. to give a colorless solution was added extracted with EtOAc (2×25 mL) washed with 1 M NaOH dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane)

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

Procedure: In a 5 mL round-bottomed flask the above prepared 6-cyclobutoxy-5-furan-2-yl-nicotinic acid (0.050 g, 174 μmol, Eq: 1.00) was combined with THF (2 mL) to give a colorless solution. TBTU (83.6 mg, 260 μmol, Eq: 1.5) and N,N-diisopropylamine (112 mg, 152 μL, 868 μmol, Eq: 5) were added. The reaction mixture was stirred for 10 min at RT before (4-fluorophenyl)-hydrazine hydrochloride (33.9 mg, 208 μmol, Eq: 1.2) was added and the reaction allowed to proceed at RT overnight. The mixture was poured into 15 mL 1 M HCl and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 1 M NaOH, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) to yield 40 mg of the title compound as white solid; MS (EI) 368.4 (M+H)+. to give a colorless solution was added extracted with EtOAc (2×25 mL) washed with 1 M NaOH dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane)

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

Procedure: A mixture of 3-hydroxy-4-isobutyryl-2-oxo-1-phenyl-2,5-dihydropyrrole (0.350 g, 1.43 mmole), 4-fluorophenylhydrazine hydrochloride (0.245 g, 1.50 mmole) and sodium methoxide (39 mg, 0.72 mmole) in ethanol (10 ml) was heated to reflux. After 16 hours the solvent was removed by rotory evaporation under reduced pressure, and the crude residue was chromatographed on a silica column using 1:3 ethyl acetate/hexane as eluent to give 210 mg of the title compound along with 80 mg of the 2-(4-fluorophenyl)-3-isopropyl-6-oxo-5-phenyl-4,6-dihydro-2H-pyrazolo[3,4-c]pyrrole regioisomer (M.P. 223°-224° C.). The title compound was recrystallized from ether to give a pale yellow solid. M.P. 150°-151° C.; 1H NMR (250 Mhz, CDCl3) δ1.38 (d, J=7.0 Hz, 6H), 3.18 (heptet, J=7.0 Hz, 1H), 4.78 (s, 2H), 7.15 (dd, J=8.3, 9.1 Hz, 2H), 7.21 (m, 1H), 7.43 (t, J=7.9 Hz, 2H), 7.74 (d, J=7.8 Hz, 2H), 8.20 (dd, J=4.8, 9.1 Hz, 2H); MS m/z (M+) 336. was heated to reflux After 16 hours the solvent was removed by rotory evaporation under reduced pressure the crude residue was chromatographed on a silica column