2-methoxy-4-(2-oxoethyl)benzonitrile

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

Procedure: 2-(Methyloxy)-4-(2-oxoethyl)benzonitrile (200 mg, 1.142 mmol), tert-butyl piperazine-1-carboxylate (532 mg, 2.85 mmol), and SODIUM CYANOBOROHYDRIDE (717 mg, 11.4 mmol) were combined in a 50 mL Flask and dissolved in MeOH. The resulting mixture was then stirred for 10 minutes followed by addition of few drops of AcOH. The mixture was stirred for overnight. The reaction mixture was concentrated to dryness, re-dissolved in EtOAc and washed with saturated NaHCO3 solution, brine, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue purified by MPLC to yield the title compound. LC-MS (IE, m/z): 346 [M+1]+; The mixture was stirred for overnight The reaction mixture was concentrated to dryness re-dissolved in EtOAc washed with saturated NaHCO3 solution, brine the organic layer was dried over Na2SO4 filtered concentrated to dryness The residue purified by MPLC

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

Procedure: To a 25 mL flask containing a stir bar was added compound 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile (0.150 g, 0.866 mmol) and MeOH (8 mL). The flask was placed in a cold bath of −78° C. Ozone was bubbled through the flask for about 10 min. followed by addition of dimethyl sulfide (1.5 mL, 0.024 mmol). The flask was taken out of the cold bath and stirred at room temperature for 1 h; LC indicated completion of the reaction. The reaction mixture was concentrated to dryness to give 2-(methyloxy)-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 176 [M+1]+; To a 25 mL flask containing a stir bar The flask was placed in a cold bath of −78° C Ozone was bubbled through the flask for about 10 min. completion of the reaction The reaction mixture was concentrated to dryness

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

Procedure: To a flask containing 3-methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one hydrochloride (123 mg, 0.40 mmol) was added in 2 mL of EtOH and NaOH (79 μl, 0.40 mmol). The solvent was removed and the free amine redissolved in DCM and filtered directly into a flask containing 2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.33 mmol). The mixture was allowed to stir for 20 minutes before sodium triacetoxyborohydride (210 mg, 0.99 mmol) was added. The reaction stirred for 1 hour before being quenched with MeOH. The crude reaction was stirred an additional 30 minutes and the excess solvent was removed. The crude material was redissolved in DCM, filtered, concentrated and purified via MPLC [10-50% (10% MeOH in DCM)/DCM)] to afford 90 mg (63% yield) of 2-methoxy-4-(2-{4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H NMR (500 MHz; DMSO): 7.80 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.65 (m, 1H), 3.88 (bs, 4H), 2.94 (m, 4H), 2.78 (m, 4H), 2.43 (m, 4H), 1.38 (d, J=6.8 Hz, 3H). LC-MS (IE, m/z): 375 [M+1]+. (0.098 μM) The solvent was removed the free amine redissolved in DCM filtered directly into a flask was added before being quenched with MeOH The crude reaction was stirred an additional 30 minutes the excess solvent was removed The crude material was redissolved in DCM filtered concentrated purified via MPLC [10-50% (10% MeOH in DCM)/DCM)]

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

Procedure: To a mixture of tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (72 mg, 0.28 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (50 mg, 0.28 mmol) in methanol (2.5 mL) at 0° C. was added sodium cyanoborohydride (25 mg, 0.40 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by column chromatography (4->30% ethyl acetate:hexanes) to provide tert-butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LC-MS (IE, m/z): 414.4 [M+1]+. The reaction mixture was concentrated purified by column chromatography (4->30% ethyl acetate:hexanes)

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

Procedure: To a mixture of 4-methyl-5-[1-(piperazin-1-yl)propan-2-yl]-2-benzofuran-1(3H)-one (25 mg, 0.080 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (17 mg, 0.097 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (7 mg, 0.113 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 434.3 [M+1]+. (0.17 μM) The reaction mixture was concentrated purified by mass-directed HPLC

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

Procedure: To a mixture of 5-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}-2-benzofuran-1(3H)-one (95 mg, 0.27 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (20 mg, 0.32 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 474.3 [M+1]+. 1H-NMR (500 MHz, CD3OD) δ ppm 7.82 (m, 1H), 7.60 (overlapping m's, 3H), 7.15 (s, 1H), 7.02 (m, 1H), 5.38 (s, 2H), 3.98 (s, 3H), 3.90 (m, 1H), 3.58 (m, 2H), 3.51 (m, 2H), 3.43 (m, 2H), 3.20 (m, 4H), 3.12 (m, 2H), 3.08 (m, 2H). (0.65 μM) The reaction mixture was concentrated purified by mass-directed HPLC

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

Procedure: 2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 420.2 [M+1]+. (0.035 μM)

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

Procedure: A solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (100 mg, 0.57 mmol), 1-[2-(4-Nitrophenyl)ethyl]piperazine (134 mg, 0.51 mmol) in 60 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (362 mg, 1.71 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-methoxy-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.14 (d, J=8.6 Hz, 2H), 7.35˜7.47 (m, 3H), 6.79˜6.85 (m, 2H), 3.12 (s, 3H), 2.48˜2.96 (m, 16H). MS m/z: 395 (M+1)+. (0.052 μM) was stirred overnight Concentrated the residue was purified via prep-TLC

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

Procedure: A solution of ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate (400 mg, 1.6 mmol) in 5 mL of dry ethanol was cooled to 0° C. Freshly prepared EtONa (2.1 mmol) in 4 mL of ethanol was added and stirred at 0° C. for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0° C. for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 10 mL of water and added 10 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford crude 2-methoxy-4-(2-oxoethyl)benzonitrile. MS m/z: 176 (M+1)+. stirred at 0° C. for 2 hours the sodium salt of the epoxy compound was filtered The sodium salt of the epoxy compound was then dissolved in 10 mL of water added 10 mL of 1 N of HCl and 20 mL of toluene The mixture was heated to reflux for 2 hours The organic phase was separated washed by saturated sodium chloride dried over Na2SO4 distilled off solvent

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

Procedure: To a stirred solution of 1.48 g (8.47 mmol) of 2-methoxy-4-(2-oxoethyl)benzonitrile in dichloromethane (30 mL) at 0° C. was added 2.82 mL (8.47 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to RT and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.47 (d, 1H, J=7.8 Hz), 6.85 (dd, 1H, J=3.4 Hz), 6.82 (s, 1H), 4.05 (m, 1H), 3.93 (d, 2H), 3.91 (s, 3H), 1.25 (d, 2H, J=6.1 Hz). LC-MS (IE, m/z): 192.3 [M+1)+. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid extracted with dichloromethane (2×30 mL) The combined organic extracts were dried with magnesium sulfate filtered concentrated in vacuo The crude residue was purified on silica (30% EtOAc/hexanes as eluent)

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

Procedure: To a 25 ml, flask containing a stir bar was added compound 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile (0.15 g, 0.87 mmol) and MeOH (8 mL). The flask was placed in a cold bath of −78° C. Ozone was bubbled through the flask for about 10 min. followed by addition of dimethyl sulfide (1.5 mL, 24 mmol). The flask was taken out of the cold bath and stirred at room temperature for 1 h; LC indicated completion of the reaction. The reaction mixture was concentrated to dryness to give 2-(methyloxy)-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 176 [M+1]+. To a 25 ml, flask containing a stir bar The flask was placed in a cold bath of −78° C Ozone was bubbled through the flask for about 10 min. completion of the reaction The reaction mixture was concentrated to dryness

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

Procedure: 5-[1-(Ethyloxy)-2-piperazin-1-ylethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride (50 mg, 0.16 mmol), 2-(methyloxy)-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol), sodium cyanoborohydride (14 mg, 1.7 mmol) and a stir bar were added to a 25 mL flask and few drops of AcOH. The resulting mixture was then dissolved in MeOH (3 mL) and stirred for 12 h; Analysis by LC indicated that reaction had gone to completion. The reaction mixture was treated with EtOAc (20 mL) and washed with aq. NaHCO3 and aq. NaCl. The organic phase was then dried over Na2SO4, filtered and concentrated to dryness; the resulting residue was then dissolved in MeOH (3.5 mL), filtered and shot into Mass-directed HPLC for separation to give the desired product. LC-MS (IE, m/z): 464 [M+1]+. Analysis by LC indicated that reaction washed with aq. NaHCO3 and aq. NaCl The organic phase was then dried over Na2SO4 filtered concentrated to dryness the resulting residue was then dissolved in MeOH (3.5 mL) filtered shot into Mass-directed HPLC for separation