2-cyclopropyl-2-hydroxyacetonitrile

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

Procedure: A solution of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyanoacetamide (90 mg, 0.22 mole), cyclopropylcarboxaldehyde (18 mg, 0.26 mmole) and piperidine (22 mg, 0.26 mmole) in MeOH (5 mL) was stirred for 3 hr at room temperature. Then water was added and extracted with ethyl acetate. The organic layers were combined and washed with aq. NaHCO3 and brine, then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (3% MeOH/DCM) to provide 39 mg (38% yield) of the title compound as a white solid. LCMS m/z 466 (M+H)+. extracted with ethyl acetate washed with aq. NaHCO3 and brine dried (Na2SO4) filtered concentrated The residue was purified by column chromatography (3% MeOH/DCM)

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

Procedure: A solution of 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]benzoate (Compound 34, 9.4 mg, 0.0256 mmol), cyclopropylcarboxaldehyde (8.99 mg, 0.1282 mmol), sodium cyanoborohydride (8.06 mg, 0.1282 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature for 3 days. The solvent was removed and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.48) to give the title compound (8.03 mg, 75%) as a solid: PNMR (300 MHz, CDCl3): δ0.19 (m, 2 H), 0.49 (m, 2 H), 1.16 (d, 6 H, J=6.5 Hz), 1.30 (s, 6 H), 1.35 (t, 3 H, J=7.1 Hz), 1.73 (t, 2 H, J=6.0 Hz), 3.17 (t, 2 H, J=6.0 Hz), 3.56 (d, 2 H, J=6.5 Hz), 3.99 (sp, 1 H, J=6.6 Hz), 4.31 (q, 2 H, J=7.1 Hz), 6.43 (dd, 1 H, J=8.1, 2.0 Hz), 6.53 (d, 1 H, J=3.6 Hz), 7.71 (d, 2 H, J=9.0 Hz), 7.18 (d, 1 H, J=8.0 Hz), 7.83 (d, 2 H, J=9.0 Hz). The solvent was removed the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.48)

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

Procedure: Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (Compound 20, 0.18 g, 0.47 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (6.0 mL). The solution was treated with cyclopropylcarboxaldehyde (0.10 mL, 1.3 mmol) and then sodium cyanoborohydride (35 mg, 0.55 mmol) and the reaction was stirred at room temperature for 7 hours. 1M aqueous NaOH was added until pH=6 was reached and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified using flash column chromatography (10% ethyl acetate in hexanes) to give the title compounds (0.1 g) as an oil. the solution was extracted with ether (2×) washed with brine dried (Na2SO4) The filtered solution was concentrated under reduced pressure the residue purified

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

Procedure: 1-tert-Butyloxycarbonyl-4-[N-methyl-N-(3-amino-2-pyridinyl)amino]piperidine (1.64 g, 5.37 mmol) is dissolved in methanol (0.2M) and cooled to 0°. Cyclopropylcarboxaldehyde (0.40 ml, 5.37 mmol) is added. After stirring 5 min, sodium cyanoborohydride (337 mg, 5.37 mmol) is added. The reaction is refluxed one hour, then stirred overnight at 20°-25°. Acetic acid (53.7 mmol) is added and the reaction refluxed 3 hr. After cooling to 20°-25°, cyclopropylcarboxaldehyde (820 mg, 2.68 mmol) and sodium cyanoborohydride (168 mg 2.68 mmol) are added and the reaction stirred 16 hr at 20°-25°. The mixture is diluted with water, adjusted to pH 9 with sodium hydroxide (1N) and extracted with chloroform. The extract is filtered and concentrated. The concentrate is chromatographed (silica gel; ethyl acetate/hexane (20/80) to give the title compound; NMR (300 MHz, CD3OD) 7.39, 6.79, 3.79, 3.07, 2.80, 2.63, 2.44, 1.52, 1.33, 1.27, 0.93, 0.35 and 0.05δ. cooled to 0° The reaction is refluxed one hour stirred overnight at 20°-25° the reaction refluxed 3 hr After cooling to 20°-25° the reaction stirred 16 hr at 20°-25° extracted with chloroform The extract is filtered concentrated The concentrate is chromatographed (silica gel

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

Procedure: 3-Hydroxy-pyrrolidine (5.65 g, 65 mmol, 1.0 equiv) was dissolved in 100 mL of 1% AcOH in THF and cooled to 0° C. Na(OAc)3BH (24 g, 114 mmol, 1.75 equiv) and cyclopropylcarboxaldehyde (5.0 g, 71 mmol, 1.1 equiv) were added and the resulting mixture was stirred at 0° C. for 1 h and room temperature overnight (16 h). The reaction was diluted with 200 mL of 2 N NaOH, and the product was extracted 3×200 mL of CH2Cl2. The organic extracts were combined, dried over Na2SO4, decanted and concentrated to yield the desired product as a free-flowing oil (7.26 g, 79%) which was used without further purification; MS, m/z 142=M+1. the product was extracted 3×200 mL of CH2Cl2 dried over Na2SO4 decanted concentrated

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

Procedure: Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and cylopropyl carboxaldehyde.

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

Procedure: Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and cylopropyl carboxaldehyde.

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

Procedure: (R)-2-Methylpropane-2-sulfinamide (25) (8.63 g, 71.3 mmol) and Ti(OEt)4 (30 mL, 142.6 mmol) were added to a solution of cyclopropylcarboxaldehyde (24) (5 g, 71.3 mmol) in THF (142 mL). The reaction mixture was stirred at rt for 17 h after which brine (142 mL) was added and the resulting suspension was filtered through a pad of Celite. The filtrate was extracted with EtOAc (200 mL) and the organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give 12.7 g (quant) of (R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (26). Retention time (min)=1.459 method [1], MS (m/z) 174.1 (M+H)+. was added the resulting suspension was filtered through a pad of Celite The filtrate was extracted with EtOAc (200 mL) the organic phase was dried (Na2SO4) filtered concentrated under vacuum

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

Procedure: 3-Hydroxy-pyrrolidine (5.65 g, 65 mmol, 1.0 equiv) was dissolved in 100 mL of 1% AcOH in THF and cooled to 0° C. Na(OAc)3BH (24 g, 114 mmol, 1.75 equiv) and cyclopropylcarboxaldehyde (5.0 g, 71 mmol, 1.1 equiv) were added and the resulting mixture was stirred at 0° C. for 1 h and room temperature overnight (16 h). The reaction was diluted with 200 mL of 2 N NaOH, and the product was extracted 3×200 mL of CH2Cl2. The organic extracts were combined, dried over Na2SO4, decanted and concentrated to yield the desired product as a free-flowing oil (7.26 g, 79%) which was used without further purification; MS, m/z 142=M+1. the product was extracted 3×200 mL of CH2Cl2 dried over Na2SO4 decanted concentrated

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

Procedure: Example 319 A) To cyclopropyl carboxaldehyde in MeOH is added nitromethane and triethylamine. After stirring, the solvent is removed in vacuo and the residue is dissolved in CH2Cl2. The 2-nitro-1-cyclopropylethanol is isolated from the methylene chloride solution and added to a mixture of sodium acetate and acetic anhydride under N2After stirring, the mixture is diluted with water and extracted with EtOAc. The combined extracts are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The 2-nitroethenylcyclopropane is used without further purification. the solvent is removed in vacuo the residue is dissolved in CH2Cl2

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

Procedure: To 4.9 g (35.7 mmol) of 2-nitrotoluene in 30 ml of DMF are added, within one hour, 0.168 g (2.55 mmol; 85% purity) of KOH and simultaneously 5 g (71.34 mmol) of cyclopropylcarboxaldehyde. The mixture is stirred at room temperature (RT) for 0.5 h, then 0.5 equivalent of cyclopropylcarboxaldehyde is added and the mixture is stirred at RT for a further hour. Subsequently, a majority of the DMF is distilled off under reduced pressure, and the residue is admixed with water and extracted with ethyl acetate. After the evaporation of the solvent and chromatography using silica gel (elution with toluene/ethyl acetate mixtures), 4.2 g (yield 55% of theory, purity (GC-MS 95.9%) of 1-cyclopropyl-2-(2-nitrophenyl)ethanol were obtained in the form of an oil. the mixture is stirred at RT for a further hour Subsequently, a majority of the DMF is distilled off under reduced pressure extracted with ethyl acetate After the evaporation of the solvent and chromatography

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

Procedure: To the suspension of the product of Example 350A (1.033 g, 5.86 mmol) in methanol (58 mL) was added acetic acid (0.29 mL) and cyclopropylcarboxaldehyde (482 μL, 6.45 mmol) followed by the addition of sodium cyanoborohydride (744.6 mg, 11.85 mmol) at room temperature. The suspension was stirred at room temperature overnight and quenched with half saturated brine (100 mL) and sodium bicarbonate (425 mg, 5.06 mmol). The mixture was extracted with ethyl acetate (300 mL) and the organic layer was separated and washed with half saturated brine (2×50 mL). The combined aqueous layers were extracted with dichloromethane (2×100 mL). The combined organic solution was dried with magnesium sulfate, filtered and concentrated. The residue was used without any purification. 1H NMR (300 MHz, DMSO-d6) δ 0.09 (m, 2 H) 0.40 (m, 2 H) 0.95 (m, 1 H) 2.70 (t, J=6.43 Hz, 2 H) 5.91 (s, 1 H) 6.10 (t, J=6.07 Hz, 1 H) 7.21 (m, 1 H) 7.62 (t, J=7.17 Hz, 1 H) 7.87 (m, 2 H) 11.42 (br s, 1 H). The mixture was extracted with ethyl acetate (300 mL) the organic layer was separated washed with half saturated brine (2×50 mL) The combined aqueous layers were extracted with dichloromethane (2×100 mL) The combined organic solution was dried with magnesium sulfate filtered concentrated The residue was used without any purification