4,4-dimethylcyclohexan-1-ol

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

Procedure: Prepared analogously to III.1 from 2 ml 2,4-difluoro-nitrobenzene and 2.339 g 4,4-dimethyl-cyclohexanol.

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

Procedure: To a mixture of 4,4-Dimethylcyclohexanol (63.2 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (100 mg, 0.0004 mol), triphenylphosphine (129 mg, 0.000493 mol), and tetrahydrofuran (4 mL, 0.05 mol), diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred at room temperature overnight. The mixture was diluted with EA and washed with 5% citric acid and brine then dried with magnesium sulfate and concentrated. The crude was taken up into DCM and subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product. was added dropwise washed with 5% citric acid and brine then dried with magnesium sulfate concentrated subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product

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

Procedure: In a 500 ml three necked round bottom flask was charged 4,4-dimethyl-cyclohexanol (100 g, 0.78 mol) and heated up to 160° C., while adding over 4 hours tBuOOtBu (11.4 g, 0.08 mol) and ethylacrylate (39.2 g, 0.39 mol). 10 minutes after the end of the addition, the mixture was cooled to 50° C. and lights were distilled off. Then, 30% w/w aqueous NaOH (61 g) and MTBE (200 g) were added. Stirring was continued during the night at 40° C. and the aqueous phase was separated. The aqueous phase was re-extracted four times with MTBE (200 g). Afterwards, MTBE (200 g) was added to the aqueous phase, and the pH adjusted to 1 with 50% w/w aqueous H2SO4. The organic phase was washed with water and concentrated to yield 49.4 g of crude 8,8-dimethyl-1-oxa-spiro[4.5]decan-2-one (GC purity: 96.3%). 10 minutes after the end of the addition the mixture was cooled to 50° C. lights were distilled off Then, 30% w/w aqueous NaOH (61 g) and MTBE (200 g) were added was continued during the night at 40° C. the aqueous phase was separated The aqueous phase was re-extracted four times with MTBE (200 g) Afterwards, MTBE (200 g) was added to the aqueous phase The organic phase was washed with water concentrated

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

Procedure: Prepared analogously to III.1 from 2 ml 2,4-difluoro-nitrobenzene and 2.339 g 4,4-dimethyl-cyclohexanol.

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

Procedure: To a mixture of 4,4-Dimethylcyclohexanol (63.2 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (100 mg, 0.0004 mol), triphenylphosphine (129 mg, 0.000493 mol), and tetrahydrofuran (4 mL, 0.05 mol), diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred at room temperature overnight. The mixture was diluted with EA and washed with 5% citric acid and brine then dried with magnesium sulfate and concentrated. The crude was taken up into DCM and subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product. was added dropwise washed with 5% citric acid and brine then dried with magnesium sulfate concentrated subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product

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

Procedure: To a mixture of 4,4-Dimethylcyclohexanol (63.2 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (100 mg, 0.0004 mol), triphenylphosphine (129 mg, 0.000493 mol), and tetrahydrofuran (4 mL, 0.05 mol), diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred at room temperature overnight. The mixture was diluted with EA and washed with 5% citric acid and brine then dried with magnesium sulfate and concentrated. The crude was taken up into DCM and subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product. was added dropwise washed with 5% citric acid and brine then dried with magnesium sulfate concentrated subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product

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

Procedure: The title compounds were prepared following the procedure described in step-1, Intermediate-10 using 1-chloro-5-nitroisoquinoline (Intermediate-1, step-1, 200 mg, 0.96 mmol) and 4,4-dimethylcyclohexanol (135 mg, 1.05 mmol) and NaH (42 mg, 1.05 mmol, 60% in mineral oil) in THF (10 mL) to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.65 (d, J=7.8 Hz, 1H), 8.47 (d, J=7.8 Hz, 1H), 8.18 (d, J=6.6 Hz, 1H), 7.94 (d, J=6.3 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 5.33 (m, 1H), 2.04-1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.43-1.39 (m, 4H), 1.02 (s, 3H), 0.99 (s, 3H).

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

Procedure: To a solution of 4,4-dimethylcyclohexanol (140 mg, 1.097 mmol) in THF (2 mL) was added NaH (43 mg, 1.097 mmol, 60% in mineral oil) at 0° C. Then the reaction mixture was stirred at that temperature for 20 min and 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 115 mg, 0.549 mmol) was added to the reaction mixture. Then the reaction mixture was stirred at 0-5° C. for 4 h and then at rt for 12 h. Then the reaction mixture was quenched with water and was extracted with chloroform. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography using chloroform to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.89 (s, 1H), 8.49-8.46 (d, J=7.8 Hz, 1H), 8.45-8.42 (d, J=7.8 Hz, 1H), 7.86-7.80 (t, J=8.4 Hz, 1H), 5.41 (m, 1H), 1.94 (m, 2H), 1.82-1.79 (m, 2H), 1.54 (m, 2H), 1.37-1.34 (m, 2H), 0.99 (s, 3H), 0.67 (s, 3H); MS (m/z): 301.93 (M+H)+. Then the reaction mixture was stirred at 0-5° C. for 4 h at rt for 12 h Then the reaction mixture was quenched with water was extracted with chloroform The organic layer was washed with brine separated dried filtered concentrated The residue was purified by column chromatography

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

Procedure: To a mixture of 4,4-Dimethylcyclohexanol (63.2 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (100 mg, 0.0004 mol), triphenylphosphine (129 mg, 0.000493 mol), and tetrahydrofuran (4 mL, 0.05 mol), diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred at room temperature overnight. The mixture was diluted with EA and washed with 5% citric acid and brine then dried with magnesium sulfate and concentrated. The crude was taken up into DCM and subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product. was added dropwise washed with 5% citric acid and brine then dried with magnesium sulfate concentrated subjected to ISCO combiflash purification with EtOAc/hexane (0-70) to give product

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

Procedure: In a 500 ml three necked round bottom flask was charged 4,4-dimethyl-cyclohexanol (100 g, 0.78 mol) and heated up to 160° C., while adding over 4 hours tBuOOtBu (11.4 g, 0.08 mol) and ethylacrylate (39.2 g, 0.39 mol). 10 minutes after the end of the addition, the mixture was cooled to 50° C. and lights were distilled off. Then, 30% w/w aqueous NaOH (61 g) and MTBE (200 g) were added. Stirring was continued during the night at 40° C. and the aqueous phase was separated. The aqueous phase was re-extracted four times with MTBE (200 g). Afterwards, MTBE (200 g) was added to the aqueous phase, and the pH adjusted to 1 with 50% w/w aqueous H2SO4. The organic phase was washed with water and concentrated to yield 49.4 g of crude 8,8-dimethyl-1-oxa-spiro[4.5]decan-2-one (GC purity: 96.3%). 10 minutes after the end of the addition the mixture was cooled to 50° C. lights were distilled off Then, 30% w/w aqueous NaOH (61 g) and MTBE (200 g) were added was continued during the night at 40° C. the aqueous phase was separated The aqueous phase was re-extracted four times with MTBE (200 g) Afterwards, MTBE (200 g) was added to the aqueous phase The organic phase was washed with water concentrated

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

Procedure: Prepared analogously to III.1 from 2 ml 2,4-difluoro-nitrobenzene and 2.339 g 4,4-dimethyl-cyclohexanol.