2-tert-butyloxirane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A large (2-5 mL) microwave reactor flask was charged with 5,6-dichlorobenzimidazole (571 mg, 3.1 mmol), 1,2-epoxy-3,3-dimethylbutane (307 mg, 3.1 mmol), powdered anhydrous potassium carbonate (424 mg, 3.1 mmol) and DMF (1.5 mL). The reaction was then heated in a microwave reactor for 6 minutes at 160° C. The reaction was then diluted with ethyl acetate and extracted with water three times. The organics were dried over MgSO4 and the solvent was removed. The residue was crystallized from CH2Cl2 to afford 653 mg (73%) of product as a white solid: 1H NMR (DMSO, 400 MHz) δ 1.06 (s, 9H), 3.47 (dd, 1H, J=2.0, J2=10.4), 4.08 (dd, 1H, J1=10.5, J2=14.4), 4.47 (dd, 1H, J1=2.0, J2=14.4), 7.75 (s, 1H), 7.79 (s, 1H), 8.23 (s, 1H); HPLC-MS calcd. for C21H22Cl2N4O2 (M+H+) 287.1, found 287.3. extracted with water three times The organics were dried over MgSO4 the solvent was removed The residue was crystallized from CH2Cl2

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

Procedure: Sodium azide (10 g, 154 mmol) and ammonium chloride (3.7 g, 070 mmol) are added to a solution of 3,3-dimethyl-1,2-epoxybutane (4.26 ml, 35 mmol) in methanol:water (8:1, 315 ml), and the mixture is heated at reflux for 7 hours. The reaction is poured into ice/water (400 ml) and extracted with dichloromethane (3×200 ml). The combined organics are dried (MgSO4), filtered and evaporated to yield a clear oil (4.7 g, 94 %). the mixture is heated at reflux for 7 hours extracted with dichloromethane (3×200 ml) The combined organics are dried (MgSO4) filtered evaporated

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

Procedure: Sodium azide (10 g, 154 mmol) and ammonium chloride (3.7 g, 070 mmol) are added to a solution of 3,3-dimethyl-1,2-epoxybutane (4.26 ml, 35 mmol) in methanol:water (8:1, 315 ml), and the mixture is heated at reflux for 7 hours. The reaction is poured into ice/water (400 ml) and extracted with dichloromethane (3×200 ml). The combined organics are dried (MgSO4), filtered and evaporated to yield a clear oil (4.7 g, 94 %). the mixture is heated at reflux for 7 hours extracted with dichloromethane (3×200 ml) The combined organics are dried (MgSO4) filtered evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4,6-trichloro-pyrimidin-5-ol (400 mg, 2.01 mmol) and 2-tert-butyl oxirane (3 mL) was heated at 100° C. for 3 hours before being cooled and concentrated in vacuo. The resultant residue was triturated in hot methanol and the insoluble material removed. The filtrate was concentrated in vacuo and the resultant residue was purified by column chromatography (SiO2, 0-15% ethyl acetate in cyclohexane) to give 3,3-Dimethyl-1-(2,4,6-trichloro-pyrimidin-5-yloxy)-butan-2-ol as a white solid (275 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 4.28 (1H, dd, J=9.38, 2.19 Hz), 4.00 (1H, t, J=9.19 Hz), 3.76-3.69 (1H, m), 2.53 (1H, d, J=3.48 Hz), 0.95 (9H, s). before being cooled concentrated in vacuo The resultant residue was triturated in hot methanol the insoluble material removed The filtrate was concentrated in vacuo the resultant residue was purified by column chromatography (SiO2, 0-15% ethyl acetate in cyclohexane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4,6-trichloro-pyrimidin-5-ol (400 mg, 2.01 mmol) and 2-tert-butyl oxirane (3 mL) was heated at 100° C. for 3 hours before being cooled and concentrated in vacuo. The resultant residue was triturated in hot methanol and the insoluble material removed. The filtrate was concentrated in vacuo and the resultant residue was purified by column chromatography (SiO2, 0-15% ethyl acetate in cyclohexane) to give 3,3-Dimethyl-1-(2,4,6-trichloro-pyrimidin-5-yloxy)-butan-2-ol as a white solid (275 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 4.28 (1H, dd, J=9.38, 2.19 Hz), 4.00 (1H, t, J=9.19 Hz), 3.76-3.69 (1H, m), 2.53 (1H, d, J=3.48 Hz), 0.95 (9H, s). before being cooled concentrated in vacuo The resultant residue was triturated in hot methanol the insoluble material removed The filtrate was concentrated in vacuo the resultant residue was purified by column chromatography (SiO2, 0-15% ethyl acetate in cyclohexane)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,3-dimethyl-1,2-epoxybutane (5.0 mL, 41.0 mmol) in DMF (100 mL) was added N-hydroxyphthalimide (8.03 g, 49.2 mmol) and triethylamine (6.90 mL, 49.2 mmol). The solution was heated at 75° C. for two days. The solution was cooled to room temperature, diluted with ethyl acetate and washed with water (2×), saturated potassium carbonate (3×), brine (2×), dried over Na2SO4 and concentrated to an orange solid. Purification using flash column chromatography (dichloromethane) provided the desired product as a white solid (1.50 g, 14%). The solution was cooled to room temperature washed with water (2×), saturated potassium carbonate (3×), brine (2×) dried over Na2SO4 concentrated to an orange solid Purification

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,3-dimethyl-1,2-epoxybutane (5.0 mL, 41.0 mmol) in DMF (100 mL) was added N-hydroxyphthalimide (8.03 g, 49.2 mmol) and triethylamine (6.90 mL, 49.2 mmol). The solution was heated at 75° C. for two days. The solution was cooled to room temperature, diluted with ethyl acetate and washed with water (2×), saturated potassium carbonate (3×), brine (2×), dried over Na2SO4 and concentrated to an orange solid. Purification using flash column chromatography (dichloromethane) provided the desired product as a white solid (1.50 g, 14%). The solution was cooled to room temperature washed with water (2×), saturated potassium carbonate (3×), brine (2×) dried over Na2SO4 concentrated to an orange solid Purification

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Condensation of 3,3-dimethyl-1-butene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3,3-dimethylbutylamine] (I: R= (CH3)3C, R' = H, X= (CH2)6, Z= H).

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

Procedure: A 0° C. solution of Example C9 (0.30 g, 0.696 mmol) in DMF (3 mL) was treated with NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred at RT for 0.5 h, treated drop-wise with 2-(tert-butyl)oxirane (0.139 g, 1.393 mmol), stirred at RT for 1 h, then heated at 60° C. overnight. Additional 2-(tert-butyl)oxirane (0.1 mL) was added, the mixture heated at 60° C. for 7 h, cooled to RT, treated with additional NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred for 20 min, treated with -(tert-butyl)oxirane (0.139 g, 1.393 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide (29 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6): δ 10.95 (d, J=2.7 Hz, 1 H), 8.41 (d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.57 (d, J=11.3 Hz, 1 H), 7.20 (d, J=2.5 Hz, 1 H), 6.64 (dd, J=5.7, 2.5 Hz, 1 H), 4.84 (d, J=5.5 Hz, 1 H), 3.84 (s, 3 H), 3.80 (m, 2 H), 3.58 (m, 2 H), 3.31 (m, 2 H), 3.05 (m, 1 H), 0.87 (s, 9H); MS (ESI) m/z: (M+H+): 531.2. stirred at RT for 1 h heated at 60° C. overnight the mixture heated at 60° C. for 7 h cooled to RT stirred for 20 min heated at 60° C. overnight The mixture was cooled to RT extracted with EtOAc (3×) the combined organics were washed with brine dried over Na2SO4 concentrated to dryness purified via silica gel chromatography (EtOAc, MeOH/DCM)