potassium;cyanide

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

Procedure: To a stirred ethanol (150 mL), was added 3-(bromomethyl)-5-methylbenzonitrile (48 g, 0.228M), potassium cyanide (27 g, 0.42M), and distilled water (77 mL). The mixture was then refluxed for 3 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue was partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1)) to afford 18.3 g (51%) of 3-(cyanomethyl)-5-methylbenzonitrile as a pale yellow solid. m.p. 63-64° C. 1H NMR (300 MHz, CDCl3) δ 2.42 (3H, s), 3.77 (2H; s), 7.42 (2H, s), 7.45 (1H, s). distilled water (77 mL) The mixture was then refluxed for 3 hr the reaction mixture was evaporated in vacuo the residue was partitioned between ether and water dried with anhydrous magnesium sulfate filtered evaporated in vacuo the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1))

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

Procedure: A mixture of 3-(3,5-Dimethyl-phenyl)-acrylonitrile (93) (15.7 g, 0.1M), NBS (18.58 g, 0.11M) and benzoyl peroxide (2.42 g, 10 mmol) in carbon tetrachloride (120 ml) was refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the mixture was filtered and the filterate was evaporated in vacuo. The residue was dissolved in ether, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a light yellow solid (94). A mixture of the crude product (94) and potassium cyanide (9.75 g, 0.15M) in ethanol (60 ml) and distilled water (30 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was partitioned between EA-ether (1:1) and water. The organic layer was taken, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:1 to 2:1)) to afford 6.68 g (36%) of a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.39 (3H, s), 3.74 (2H, s), 5.91 (1H, d, J=16.5 Hz), 7.21 (3H, s), 7.34 (1H, d, J=16.5 Hz). was refluxed for 3 hr the mixture was filtered the filterate was evaporated in vacuo The residue was dissolved in ether washed with aqueous saturated sodium bicarbonate solution dried with anhydrous magnesium sulfate filtered evaporated in vacuo to give a crude product as a light yellow solid (94) distilled water (30 ml) was refluxed for 2 hr After cooling to room temperature the mixture was evaporated in vacuo the residue was partitioned between EA-ether (1:1) and water dried with anhydrous magnesium sulfate filtered evaporated in vacuo The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:1 to 2:1))

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask equipped with additional funnel, was placed potassium cyanide (29.6 g, 0.45 mol) and distilled water (55 ml). The mixture was heated up to 70° C. in an oil bath. With stirring, 1-Bromomethyl-3-chloro-5-methyl-benzene (46) (35 g, 0.16 mol) in ethanol (180 ml) was then dropwise added over 1 hr through the addition funnel. After completion of addition, the mixture was refluxed for 8 hr. After cooling to room temperature, ether was added to the mixture. The mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 20 g (77%) of a pale brown oil. 1H NMR (200 MHz, CDCl3) δ: 2.31 (3H, s), 3.66 (2H, s), 7.02 (1H, s), 7.09 (2H, s). To a flask equipped with additional funnel distilled water (55 ml) After completion of addition the mixture was refluxed for 8 hr After cooling to room temperature The mixture was washed with water dried with anhydrous magnesium sulfate filtered evaporated in vacuo the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:9))

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

Procedure: A mixture of 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.10 g, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.23 mmol) and 2-(di-tert-butylphosphino)biphenyl (0.07, 0.23 mmol), tributyltin cyanide (0.07 g, 0.23 mmol) and potassium cyanide (0.02 g, 0.23 mmol) was purged with nitrogen and anhydrous acetonitrile (10.0 mL) was added. The reaction mixture was refluxed for 16 h. After cooling down to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0 mL), washed with water (20.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The brown residue was subjected to column chromatography eluting with ethyl acetate/hexane (65%) to give the title compound (0.03 g, 33%) which was recrystallized from ether to get a colorless solid: mp 128-129° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.42-7.37 (m, 1H), 7.29-7.27 (m, 1H), 7.09 (d, 1H), 6.53 (s, 1H), 6.03 (s, 1H), 5.87 (dd, 2H), 4.91 (q, 2H), 3.86-3.63 (m, 2H), 1.74-1.62 (m, 2H), 1.43-1.26 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.5, 157.1, 149.5, 143.5, 142.4, 135.4, 129.7, 128.3, 126.4, 116.3, 114.8, 112.3, 108.8, 102.2, 93.7, 78.7, 58.3, 40.6, 28.9, 26.7, 22.2, 13.9; MS (ES+) m/z 377.5 (M+1). was purged with nitrogen and anhydrous acetonitrile (10.0 mL) was added The reaction mixture was refluxed for 16 h the reaction mixture was diluted with ethyl acetate (20.0 mL) washed with water (20.0 mL), brine (20.0 mL) dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo to dryness eluting with ethyl acetate/hexane (65%)

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

Procedure: 40% strength aqueous dimethylamine solution (2.66 ml, 21 mmol), 1-(4-methoxybenzyl)piperidine-4-carbaldehyde (750 mg, 3.2 mmol) and potassium cyanide (688 mg, 10.6 mmol) were added to a mixture of 4 N hydrochloric acid (1.2 ml) and methanol (5 ml), while cooling with ice. The reaction mixture was stirred at room temperature for 5 d, water (50 ml) was then added and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. while cooling with ice the mixture was extracted with ethyl acetate (3×50 ml) The combined organic phases were dried with sodium sulfate concentrated i

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

Procedure: 40 percent strength aqueous dimethylamine solution (85 ml, 0.67 mol), 1,4-dioxa-spiro[4.5]decane-8-carbaldehyde (240 g, 0.141 mol) and potassium cyanide (22.05 g, 0.338 mol) were added to a mixture of 4 N hydrochloric acid (37 ml) and methanol (22 ml), while cooling with ice. The mixture was stirred at room temperature for 4 d and then, after addition of water (80 ml), extracted with diethyl ether (4×100 ml). The organic phase was dried over sodium sulfate and concentrated i. vac. and the product was obtained as a white solid. Yield: 25.2 g (81%), melting point: 48-51° C. while cooling with ice extracted with diethyl ether (4×100 ml) The organic phase was dried over sodium sulfate concentrated i and the product was obtained as a white solid

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of potassium cyanide (1.50 g, 23.0 mmol) in dimethylsulfoxide (DMSO, 100 mL) was prepared in a 1-L 3-necked flask fitted with a reflux condenser, a heating mantle and an internal temperature probe. The 2-chlorobenzothiazole (2.6 g, 2.0 mL, 15.3 mmol) was added to the reaction flask via pipet and the reaction was heated at 80° C. (internal temperature). The reaction was monitored periodically by TLC (9:1 heptane-ethyl acetate). After 5 hours the reaction appeared to be about 50% complete. After 17 hours the reaction was judged complete by TLC analysis. The reaction mixture was allowed to cool to room temperature and was then extracted with ether (5×100 mL). The extracts were dried over sodium sulfate and concentrated to give a yellow-orange solid. The crude solid was purified on silica gel (100 g) using 9:1 heptane-ethyl acetate. Fractions containing product were pooled and concentrated to give 1.4 g (57%) of the desired product as a yellow-orange solid. The structure was confirmed by 1H NMR analysis in DMSO-d6. was prepared in a 1-L 3-necked flask fitted with a reflux condenser After 17 hours the reaction was judged complete by TLC analysis to cool to room temperature was then extracted with ether (5×100 mL) The extracts were dried over sodium sulfate concentrated to give a yellow-orange solid The crude solid was purified on silica gel (100 g) Fractions containing product concentrated

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

Procedure: To a mixture of DMF (35 mL) and MeI (74.6 g, 0.53 mol) in water (35 mL) and THF (400 mL) was added dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 0.105 mol). After the reaction mixture was refluxed for 10 min, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was kept refluxing overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (7.5 g, 36%). After the reaction mixture was refluxed for 10 min the mixture was kept refluxing overnight filtered The filtrate was washed with brine (300 mL×3) dried over Na2SO4 filtered concentrated The residue was purified by column chromatography

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

Procedure: A solution of methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (1.21 g, 3.07 mmol), potassium cyanide (0.799 g, 12.27 mmol) and potassium iodide (0.25 g) in 50 mL of DMF was heated to 95° C. under argon with stirring for 24 hours. The reaction mixture was cooled and poured into 500 mL of water. The aqueous mix was extracted three times with EtOAc, and the combined organic phases were washed with water, saturated brine, and dried (MgSO4). Evaporation of the solvent under reduced pressure gave an oil that was purified by elution on silica gel (hexanes:EtOAc 1:1). Removal of the solvent under reduced pressure yielded 0.950 g (2.97 mmol, 95.1% of 3-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-propionitrile as a white crystalline solid. MS: 326 (M+H)+. The reaction mixture was cooled The aqueous mix was extracted three times with EtOAc the combined organic phases were washed with water, saturated brine dried (MgSO4) Evaporation of the solvent under reduced pressure gave an oil that was purified by elution on silica gel (hexanes:EtOAc 1:1) Removal of the solvent under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-fluorobenzaldehyde (35.38 g, 285.07 mmol) in 35 mL dimethylformamide (DMF) was added to a heated (48° C.) solution of methyl acrylate (26.28 mL, 25.03 g, 290.7 mmol) and powdered KCN under Argon. The reaction mixture was stirred at 40° C. for 2 hours and then poured into 500 mL of water. This aqueous phase was extracted twice with 500 mL of Et2O and once with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, and then dried over MgSO4. The solvent was evaporated under reduced pressure to give 50.89 g (242.2 mmol, 84.93%) of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methyl ester as an oil. MS: 211 (M+H)+. This aqueous phase was extracted twice with 500 mL of Et2O and once with 250 mL of EtOAc The combined organic layers were washed with water and saturated brine dried over MgSO4 The solvent was evaporated under reduced pressure

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

Procedure: To a stirred solution of 4-bromo-1-(bromomethyl)-2-chlorobenzene (7.19 g, 25.3 mmol) in dichloromethane (60 mL) and water (60 mL) is added tetrabutylammonium bromide (0.82 g, 2.53 mmol). Potassium cyanide (4.94 g, 75.8 mmol) in water (60 mL) is then added. The resulting solution is stirred 4 h at room temperature and quickly turned orange. A saturated solution of NaHCO3 aq. is then added and the mixture extracted with CH2Cl2 (3×100 mL). The combined organic layer is washed with brine, dried over anhydrous MgSO4 and filtered on a silica gel pad. The pad is rinsed with CH2Cl2 and the filtrate concentrated under reduced pressure to provide the expected product 2-(4-bromo-2-chlorophenyl)acetonitrile (5.38 g, 92%) contaminated with bromoform. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.60 (1H, d, J=1.9 Hz), 7.47 (1H, dd, J=8.3, 1.9 Hz), 7.39 (1H, d, J=8.3 Hz), 3.79 (2H, s). the mixture extracted with CH2Cl2 (3×100 mL) The combined organic layer is washed with brine dried over anhydrous MgSO4 filtered on a silica gel pad The pad is rinsed with CH2Cl2 the filtrate concentrated under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-tert-Butyl —N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide (444 mg, 0.899 mmol) was dissolved in DMF (5 mL). KCN (300 mg, 4.6 mmol) was then added and the reaction mixture was heated to 60° C. for 2 hours. Additional KCN (110 mg, 1.7 mmol) was then added and the reaction was stirred for another 2 hours. The solvent was removed under reduced pressure and the resulting brown oil purified by column (1:4 EtOAc/hexanes) to give 172 mg (0.345 mmol, 38% yield). MS calc'd for C24H24ClN4O4S (MH+): 499.1, found 499.1. The solvent was removed under reduced pressure the resulting brown oil purified by column (1:4 EtOAc/hexanes) to give 172 mg (0.345 mmol, 38% yield)