2,2-dimethylhexanoic acid

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

Procedure: A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50° C. The resulting grey slurry was heated to 55° C. to 60° C. using a temperature controlled heating mantle. The mixture was stirred at 55° C. to 60° C. for 5 hours. A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 680 mL of dry THF and 286.8 g of 1,1′-carbonyldiimidazole (CDI). The addition funnel was charged portion-wise with a solution of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry THF. The entire dimethyl-hexanoic acid acid/THF solution was added dropwise to the stirred CDI/THF suspension at such a rate so as to control the evolution of CO2 and to maintain the reaction at a temperature of 20° C. to 25° C. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry became a pale yellow solution. After the 5-hour reaction time, the malonate/MgCl2 reaction mixture was cooled to 20° C. to 25° C. and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged portion-wise with the dimethylhexanoic acid/CDI/THF reaction mixture. This entire reaction mixture was added dropwise to the stirred malonate/MgCl2/THF reaction mixture over about 10 minutes. After the addition was completed, the reaction mixture was heated to 35° C. to 40° C. Some effervescence was noted. The reaction mixture was stirred at 35° C. to 40° C. for 16 hour. The reaction mixture was cooled to 20° C. to 25° C. A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aq. HCl. The reaction mixture (a grey suspension) was added portion-wise to the aq. HCl solution while maintaining an internal temperature of 20° C.–25° C. The reaction temperature was moderated with an ice/water bath; the reaction mixture pH was about 1. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL); 1000 mL of water (incomplete phase separation); half saturated aq. Na2CO3 (2×1500 mL); 1000 mL water; and brine (2×1000 mL). (The aqueous base wash removed unreacted malonate ester-acid.) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and was filtered. The filtrate was concentrated under vacuum (40° C.–45° C.) to give 327 g of the titled compound as a pale yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3 H), 0.85 (d, J=6.8 Hz, 3 H), 0.99 (d, J=7.1 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H), 2.42–2.49 (m, 1 H), 3.39 (s, 2 H) 4.12 (q, J=7.16 Hz, 3 H). GC Chemical purity: 96.24%. A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet was less than 50° C The resulting grey slurry was heated to 55° C. to 60° C. controlled heating mantle A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet to maintain the reaction at a temperature of 20° C. to 25° C the addition the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry After the 5-hour reaction time was cooled to 20° C. to 25° C. the condenser was replaced with a 1 L addition funnel The addition funnel was charged portion-wise This entire reaction mixture After the addition the reaction mixture was heated to 35° C. to 40° C The reaction mixture was stirred at 35° C. to 40° C. for 16 hour The reaction mixture was cooled to 20° C. to 25° C A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer while maintaining an internal temperature of 20° C.–25° C The reaction temperature was moderated with an ice/water bath the addition the reaction mixture was stirred at 20° C. to 25° C. for 2 hours was stirred for 5 minutes The phases were separated the aqueous phase was extracted with 2000 mL of EtOAc The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL) (The aqueous base wash removed unreacted malonate ester-acid ) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present was filtered The filtrate was concentrated under vacuum (40° C.–45° C.)

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

Procedure: To a solution of tert-butyl (2S,3S,5S)-1-amino-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (350 mg, 0.76 mmol) in CH2Cl2 (15 mL), 2,2-dimethylhexanoic acid (176 mg, 1.22 mmol), HOBt (290 mg, 2.1 mmol) and EDCl (400 mg, 2.1 mmol) were added. The mixture cooled to 0° C. and DIEA (700 mg, 5.4 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 5 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl (2S,3S,5S)-1-(2,2-dimethylhexanamido)-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (335 mg, 75%). 1H NMR (400 MHz, CDCl3): 0.86 (m, 3H), 0.92 (m, 3H), 0.99 (m, 3H), 1.13 (s, 6H), 1.16 (m, 2H), 1.27 (m, 3H), 1.49 (m, 2H), 1.70 (m, 3H), 1.88 (m, 1H), 2.11 (m, 2H), 2.62 (m, 1H), 2.85 (m, 1H), 2.97 (m, 1H), 3.10 (m, 1H), 3.28 (s, 3H), 3.36 (m, 1H), 3.62 (m, 1H), 4.48 (m, 2H), 7.06 (m, 1H), 7.39 (s, 1H), 7.67 (m, 1H), 7.99 (s, 1H); MS: 588 (M++1) to warm to rt The reaction mixture was washed with water and brine dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: To a solution of tert-butyl (2S,3S,5S)-1-amino-5-(benzyloxymethyl)-2-hydroxy-6-methylheptan-3-ylcarbamate (500 mg, 1.32 mmol) in CH2Cl2 (15 mL), were added 2,2-dimethylhexanoic acid (220 mg, 1.45 mmol), HOBt (360 mg, 2.65 mmol) and EDCl (500 mg, 2.65 mmol). The mixture was cooled to 0° C. and DIEA (850 mg, 6.6 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 5 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give crude product, which was purified by column chromatography on silica gel to produce tert-butyl (2S,3S,5S)-5-(benzyloxymethyl)-1-(2,2-dimethylhexanamido)-2-hydroxy-6-methylheptan-3-ylcarbamate (310 mg, 46%); MS: 507 (M++1) to warm to rt The reaction mixture was washed with water and brine dried over Na2SO4 filtered concentrated in vacuo to give crude product, which was purified by column chromatography on silica gel

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

Procedure: A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50° C. The resulting grey slurry was heated to 55° C. to 60° C. using a temperature controlled heating mantle. The mixture was stirred at 55° C. to 60° C. for 5 hours. A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 680 mL of dry THF and 286.8 g of 1,1′-carbonyldiimidazole (CDI). The addition funnel was charged portion-wise with a solution of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry THF. The entire dimethyl-hexanoic acid acid/THF solution was added dropwise to the stirred CDI/THF suspension at such a rate so as to control the evolution of CO2 and to maintain the reaction at a temperature of 20° C. to 25° C. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry became a pale yellow solution. After the 5-hour reaction time, the malonate/MgCl2 reaction mixture was cooled to 20° C. to 25° C. and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged portion-wise with the dimethylhexanoic acid/CDI/THF reaction mixture. This entire reaction mixture was added dropwise to the stirred malonate/MgCl2/THF reaction mixture over about 10 minutes. After the addition was completed, the reaction mixture was heated to 35° C. to 40° C. Some effervescence was noted. The reaction mixture was stirred at 35° C. to 40° C. for 16 hour. The reaction mixture was cooled to 20° C. to 25° C. A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aq. HCl. The reaction mixture (a grey suspension) was added portion-wise to the aq. HCl solution while maintaining an internal temperature of 20° C.–25° C. The reaction temperature was moderated with an ice/water bath; the reaction mixture pH was about 1. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL); 1000 mL of water (incomplete phase separation); half saturated aq. Na2CO3 (2×1500 mL); 1000 mL water; and brine (2×1000 mL). (The aqueous base wash removed unreacted malonate ester-acid.) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and was filtered. The filtrate was concentrated under vacuum (40° C.–45° C.) to give 327 g of the titled compound as a pale yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3 H), 0.85 (d, J=6.8 Hz, 3 H), 0.99 (d, J=7.1 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H), 2.42–2.49 (m, 1 H), 3.39 (s, 2 H) 4.12 (q, J=7.16 Hz, 3 H). GC Chemical purity: 96.24%. A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet was less than 50° C The resulting grey slurry was heated to 55° C. to 60° C. controlled heating mantle A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet to maintain the reaction at a temperature of 20° C. to 25° C the addition the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry After the 5-hour reaction time was cooled to 20° C. to 25° C. the condenser was replaced with a 1 L addition funnel The addition funnel was charged portion-wise This entire reaction mixture After the addition the reaction mixture was heated to 35° C. to 40° C The reaction mixture was stirred at 35° C. to 40° C. for 16 hour The reaction mixture was cooled to 20° C. to 25° C A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer while maintaining an internal temperature of 20° C.–25° C The reaction temperature was moderated with an ice/water bath the addition the reaction mixture was stirred at 20° C. to 25° C. for 2 hours was stirred for 5 minutes The phases were separated the aqueous phase was extracted with 2000 mL of EtOAc The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL) (The aqueous base wash removed unreacted malonate ester-acid ) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present was filtered The filtrate was concentrated under vacuum (40° C.–45° C.)

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

Procedure: A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50° C. The resulting grey slurry was heated to 55° C. to 60° C. using a temperature controlled heating mantle. The mixture was stirred at 55° C. to 60° C. for 5 hours. A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 680 mL of dry THF and 286.8 g of 1,1′-carbonyldiimidazole (CDI). The addition funnel was charged portion-wise with a solution of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry THF. The entire dimethyl-hexanoic acid acid/THF solution was added dropwise to the stirred CDI/THF suspension at such a rate so as to control the evolution of CO2 and to maintain the reaction at a temperature of 20° C. to 25° C. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry became a pale yellow solution. After the 5-hour reaction time, the malonate/MgCl2 reaction mixture was cooled to 20° C. to 25° C. and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged portion-wise with the dimethylhexanoic acid/CDI/THF reaction mixture. This entire reaction mixture was added dropwise to the stirred malonate/MgCl2/THF reaction mixture over about 10 minutes. After the addition was completed, the reaction mixture was heated to 35° C. to 40° C. Some effervescence was noted. The reaction mixture was stirred at 35° C. to 40° C. for 16 hour. The reaction mixture was cooled to 20° C. to 25° C. A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aq. HCl. The reaction mixture (a grey suspension) was added portion-wise to the aq. HCl solution while maintaining an internal temperature of 20° C.–25° C. The reaction temperature was moderated with an ice/water bath; the reaction mixture pH was about 1. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL); 1000 mL of water (incomplete phase separation); half saturated aq. Na2CO3 (2×1500 mL); 1000 mL water; and brine (2×1000 mL). (The aqueous base wash removed unreacted malonate ester-acid.) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and was filtered. The filtrate was concentrated under vacuum (40° C.–45° C.) to give 327 g of the titled compound as a pale yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3 H), 0.85 (d, J=6.8 Hz, 3 H), 0.99 (d, J=7.1 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H), 2.42–2.49 (m, 1 H), 3.39 (s, 2 H) 4.12 (q, J=7.16 Hz, 3 H). GC Chemical purity: 96.24%. A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet was less than 50° C The resulting grey slurry was heated to 55° C. to 60° C. controlled heating mantle A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet to maintain the reaction at a temperature of 20° C. to 25° C the addition the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry After the 5-hour reaction time was cooled to 20° C. to 25° C. the condenser was replaced with a 1 L addition funnel The addition funnel was charged portion-wise This entire reaction mixture After the addition the reaction mixture was heated to 35° C. to 40° C The reaction mixture was stirred at 35° C. to 40° C. for 16 hour The reaction mixture was cooled to 20° C. to 25° C A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer while maintaining an internal temperature of 20° C.–25° C The reaction temperature was moderated with an ice/water bath the addition the reaction mixture was stirred at 20° C. to 25° C. for 2 hours was stirred for 5 minutes The phases were separated the aqueous phase was extracted with 2000 mL of EtOAc The combined organic extract was washed sequentially with: 1N aq. HCl (2×1 500 mL) (The aqueous base wash removed unreacted malonate ester-acid ) The straw colored organic solution was concentrated under vacuum (35° C.–40° C.) to give a cloudy, pale yellow oil with some white solid present was filtered The filtrate was concentrated under vacuum (40° C.–45° C.)

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

Procedure: A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50° C. The resulting grey slurry was heated to 55° C. to 60° C. using a temperature controlled heating mantle. The mixture was stirred at 55° C. to 60° C. for 5 hours. A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 680 mL of dry THF and 286.8 g of 1,1′-carbonyldiimidazole (CDI). The addition funnel was charged portion-wise with a solution of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry THF. The entire dimethyl-hexanoic acid acid/THF solution was added dropwise to the stirred CDI/THF suspension at such a rate so as to control the evolution of CO2 and to maintain the reaction at a temperature of 20° C. to 25° C. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry became a pale yellow solution. After the 5-hour reaction time, the malonate/MgCl2 reaction mixture was cooled to 20° C. to 25° C. and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged portion-wise with the dimethylhexanoic acid/CDI/THF reaction mixture. This entire reaction mixture was added dropwise to the stirred malonate/MgCl2/THF reaction mixture over about 10 minutes. After the addition was completed, the reaction mixture was heated to 35° C. to 40° C. Some effervescence was noted. The reaction mixture was stirred at 35° C. to 40° C. for 16 hour. The reaction mixture was cooled to 20° C. to 25° C. A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aq. HCl. The reaction mixture (a grey suspension) was added portion-wise to the aq. HCl solution while maintaining an internal temperature of 20° C.-25° C. The reaction temperature was moderated with an ice/water bath; the reaction mixture pH was about 1. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed sequentially with: 1N aq. HCl (2×1500 mL); 1000 mL of water (incomplete phase separation); half saturated aq. Na2CO3 (2×1500 mL); 1000 mL water; and brine (2×1000 mL). (The aqueous base wash removed unreacted malonate ester-acid.) The straw colored organic solution was concentrated under vacuum (35° C.-40° C.) to give a cloudy, pale yellow oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and was filtered. The filtrate was concentrated under vacuum (40° C.-45° C.) to give 327 g of the titled compound as a pale yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H), 1.20 (t, J=7.3 Hz, 3H), 2.42-2.49 (m, 1H), 3.39 (s, 2H) 4.12 (q, J=7.16 Hz, 3H). GC Chemical purity: 96.24%. A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet was less than 50° C The resulting grey slurry was heated to 55° C. to 60° C. controlled heating mantle A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet to maintain the reaction at a temperature of 20° C. to 25° C the addition the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry After the 5-hour reaction time was cooled to 20° C. to 25° C. the condenser was replaced with a 1 L addition funnel The addition funnel was charged portion-wise This entire reaction mixture After the addition the reaction mixture was heated to 35° C. to 40° C The reaction mixture was stirred at 35° C. to 40° C. for 16 hour The reaction mixture was cooled to 20° C. to 25° C A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer while maintaining an internal temperature of 20° C.-25° C The reaction temperature was moderated with an ice/water bath the addition the reaction mixture was stirred at 20° C. to 25° C. for 2 hours was stirred for 5 minutes The phases were separated the aqueous phase was extracted with 2000 mL of EtOAc The combined organic extract was washed sequentially with: 1N aq. HCl (2×1500 mL) (The aqueous base wash removed unreacted malonate ester-acid ) The straw colored organic solution was concentrated under vacuum (35° C.-40° C.) to give a cloudy, pale yellow oil with some white solid present was filtered The filtrate was concentrated under vacuum (40° C.-45° C.)

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

Procedure: To a solution of 2,2-Dimethyl-hexanoic acid (10.15 g, 0.07 mol) in ether (150 mL) was added (trimethylsilyl)diazomethane (46 ml, 2M in hexanes, 0.092 mol) drop wise. The mixture was stirred for 3 h, and ether was evaporated without applying reduced pressure. Fractional distillation of the residue provided the title ester 11.12 g (b.p. 90-95° C./1 mmHg). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 3H), 1.1-1.2 (m, 2H), 1.13 (s, 6H), 1.21-1.31 (m, 2H), 1.44-1.51 (m, 2H), 3.72 (s, 3H). ether was evaporated Fractional distillation of the residue

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

Procedure: A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 1390 mL of dry THF and 389.3 g of potassium ethyl malonate. MgCl2 (217.8 g) was added in three equal portions so that the internal temperature was less than 50° C. The resulting grey slurry was heated to 55° C. to 60° C. using a temperature controlled heating mantle. The mixture was stirred at 55° C. to 60° C. for 5 hours. A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet, and thermometer, was charged with 680 mL of dry THF and 286.8 g of 1,1′-carbonyldiimidazole (CDI). The addition funnel was charged portion-wise with a solution of 219.9 g of (2R,3R)-2,3-dimethyl-hexanoic acid in 350 mL of dry THF. The entire dimethyl-hexanoic acid acid/THF solution was added dropwise to the stirred CDI/THF suspension at such a rate so as to control the evolution of CO2 and to maintain the reaction at a temperature of 20° C. to 25° C. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry became a pale yellow solution. After the 5-hour reaction time, the malonate/MgCl2 reaction mixture was cooled to 20° C. to 25° C. and the condenser was replaced with a 1 L addition funnel. The addition funnel was charged portion-wise with the dimethylhexanoic acid/CDI/THF reaction mixture. This entire reaction mixture was added dropwise to the stirred malonate/MgCl2/THF reaction mixture over about 10 minutes. After the addition was completed, the reaction mixture was heated to 35° C. to 40° C. Some effervescence was noted. The reaction mixture was stirred at 35° C. to 40° C. for 16 hour. The reaction mixture was cooled to 20° C. to 25° C. A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer and thermometer, was charged with 3060 mL of 2N aq. HCl. The reaction mixture (a grey suspension) was added portion-wise to the aq. HCl solution while maintaining an internal temperature of 20° C.-25° C. The reaction temperature was moderated with an ice/water bath; the reaction mixture pH was about 1. Following the addition, the reaction mixture was stirred at 20° C. to 25° C. for 2 hours. The reaction mixture was subsequently charged with 4000 mL of EtOAc and was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with 2000 mL of EtOAc. The combined organic extract was washed sequentially with: 1N aq. HCl (2×1500 mL); 1000 mL of water (incomplete phase separation); half saturated aq. Na2CO3 (2×1500 mL); 1000 mL water; and brine (2×1000 mL). (The aqueous base wash removed unreacted malonate ester-acid.) The straw colored organic solution was concentrated under vacuum (35° C.-40° C.) to give a cloudy, pale yellow oil with some white solid present. The oil was redissolved in 1500 mL of n-heptane and was filtered. The filtrate was concentrated under vacuum (40° C.-45° C.) to give 327 g of the titled compound as a pale yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) d ppm 0.82 (t, J=7.1 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H), 1.20 (t, J=7.3 Hz, 3H), 2.42-2.49 (m, 1H), 3.39 (s, 2H) 4.12 (q, J=7.16 Hz, 3H). GC Chemical purity: 96.24%. A 5 L 3-neck round bottom flask, equipped with a reflux condenser, mechanical stirrer, nitrogen inlet was less than 50° C The resulting grey slurry was heated to 55° C. to 60° C. controlled heating mantle A 2 L 3-neck round bottom flask, equipped with a 500 mL addition funnel, mechanical stirrer, nitrogen inlet to maintain the reaction at a temperature of 20° C. to 25° C the addition the reaction mixture was stirred at 20° C. to 25° C. for 1 hour, during which the slurry After the 5-hour reaction time was cooled to 20° C. to 25° C. the condenser was replaced with a 1 L addition funnel The addition funnel was charged portion-wise This entire reaction mixture After the addition the reaction mixture was heated to 35° C. to 40° C The reaction mixture was stirred at 35° C. to 40° C. for 16 hour The reaction mixture was cooled to 20° C. to 25° C A 12 L 3-neck round bottom flask, equipped with a mechanical stirrer while maintaining an internal temperature of 20° C.-25° C The reaction temperature was moderated with an ice/water bath the addition the reaction mixture was stirred at 20° C. to 25° C. for 2 hours was stirred for 5 minutes The phases were separated the aqueous phase was extracted with 2000 mL of EtOAc The combined organic extract was washed sequentially with: 1N aq. HCl (2×1500 mL) (The aqueous base wash removed unreacted malonate ester-acid ) The straw colored organic solution was concentrated under vacuum (35° C.-40° C.) to give a cloudy, pale yellow oil with some white solid present was filtered The filtrate was concentrated under vacuum (40° C.-45° C.)

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

Procedure: To a solution of 2,2-Dimethyl-hexanoic acid (10.15 g, 0.07 mol) in ether (150 mL) was added (trimethylsilyl)diazomethane (46 ml, 2M in hexanes, 0.092 mol) drop wise. The mixture was stirred for 3 h, and ether was evaporated without applying reduced pressure. Fractional distillation of the residue provided the title ester 11.12 g (b.p. 90-95° C./1 mmHg). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 3H), 1.1-1.2 (m, 2H), 1.13 (s, 6H), 1.21-1.31 (m, 2H), 1.44-1.51 (m, 2H), 3.72 (s, 3H). ether was evaporated Fractional distillation of the residue

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

Procedure: A 2-L flask is charged with 4.9 g (200 g-atom) of magnesium turnings, 75 mL of methanol and a crystal of iodine. The mixture is heated to reflux until all the magnesium has reacted leaving a grey slurry of magnesium methoxide. After cooling, 35.2 g (400 mmol) of isobutyric acid is added followed by 250 mL of toluene. A condenser is attached set for downward distillation and the methanol and some toluene are distilled until 250 mL of distillate is collected and the distillation temperature reaches ~110° C. The mixture is cooled, 400 mL of anhydrous tetrahydrofuran is added along with 41 g (400 mmol) of diisopropylamine ad the resulting homogeneous solution is cooled in an ice bath. Finally, 240 mL of a standard solution of n-butyllithium in heptane (1.67 mmol/mL; 400 mmol) is added by injection at a temperature <10° C. The ice bath is retained for 10 minutes and then the mixture is warmed to 30°-35 ° C. for 30 minutes to complete the metalation. The ice bath is replaced and 54.8 g (400 mmol)) of 1-bromobutane is added over 15 minutes at 0° C. No exothermic reaction is observed. The ice bath is retained for 30 minutes and then the mixture is heated to 30°-35° C. for 18 hours overnight. At the conclusion of the reaction period, 150 mL of 6N hydrochloric acid solution (0.90 mmol)) is added at a temperature <10° C. followed by 280 mL of water. The aqueous layer is separated extracted with 200 mL of diethyl ether and the combined organic layers ar washed with 150 mL of 2N hydrochloric acid solution, 200 mL of saturated sodium chloride, dried (magnesium sulfate) and evaporated. This affords 64 g of product. Distillation through a 6" vacuum jacketed vigreux column affords 42.7 g of 2,2-dimethylhexanoic acid; bpD 103°-105°/5 mm; n25 1.4245. After cooling A condenser is attached set for downward distillation the methanol and some toluene are distilled until 250 mL of distillate is collected reaches ~110° C The mixture is cooled is cooled in an ice bath the mixture is warmed to 30°-35 ° C. for 30 minutes No exothermic reaction the mixture is heated to 30°-35° C. for 18 hours overnight is added at a temperature <10° C. The aqueous layer is separated extracted with 200 mL of diethyl ether the combined organic layers ar washed with 150 mL of 2N hydrochloric acid solution, 200 mL of saturated sodium chloride dried (magnesium sulfate) evaporated Distillation through a 6" vacuum

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

Procedure: A 2-L flask is charged with 4.9 g (200 g-atom) of magnesium turnings, 75 mL of methanol and a crystal of iodine. The mixture is heated to reflux until all the magnesium has reacted leaving a grey slurry of magnesium methoxide. After cooling, 35.2 g (400 mmol) of isobutyric acid is added followed by 250 mL of toluene. A condenser is attached set for downward distillation and the methanol and some toluene are distilled until 250 mL of distillate is collected and the distillation temperature reaches ~110° C. The mixture is cooled, 400 mL of anhydrous tetrahydrofuran is added along with 41 g (400 mmol) of diisopropylamine ad the resulting homogeneous solution is cooled in an ice bath. Finally, 240 mL of a standard solution of n-butyllithium in heptane (1.67 mmol/mL; 400 mmol) is added by injection at a temperature <10° C. The ice bath is retained for 10 minutes and then the mixture is warmed to 30°-35 ° C. for 30 minutes to complete the metalation. The ice bath is replaced and 54.8 g (400 mmol)) of 1-bromobutane is added over 15 minutes at 0° C. No exothermic reaction is observed. The ice bath is retained for 30 minutes and then the mixture is heated to 30°-35° C. for 18 hours overnight. At the conclusion of the reaction period, 150 mL of 6N hydrochloric acid solution (0.90 mmol)) is added at a temperature <10° C. followed by 280 mL of water. The aqueous layer is separated extracted with 200 mL of diethyl ether and the combined organic layers ar washed with 150 mL of 2N hydrochloric acid solution, 200 mL of saturated sodium chloride, dried (magnesium sulfate) and evaporated. This affords 64 g of product. Distillation through a 6" vacuum jacketed vigreux column affords 42.7 g of 2,2-dimethylhexanoic acid; bpD 103°-105°/5 mm; n25 1.4245. After cooling A condenser is attached set for downward distillation the methanol and some toluene are distilled until 250 mL of distillate is collected reaches ~110° C The mixture is cooled is cooled in an ice bath the mixture is warmed to 30°-35 ° C. for 30 minutes No exothermic reaction the mixture is heated to 30°-35° C. for 18 hours overnight is added at a temperature <10° C. The aqueous layer is separated extracted with 200 mL of diethyl ether the combined organic layers ar washed with 150 mL of 2N hydrochloric acid solution, 200 mL of saturated sodium chloride dried (magnesium sulfate) evaporated Distillation through a 6" vacuum

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

Procedure: A solution of 14.4 g (100 mmol) of 2,2-dimethylhexanoic acid (XXIX) in 100 ml of dry ether was stirred a 0° C. under argon as 130 ml (237 mol) of a solution of methyllithium (1.82 M) in ether was added dropwise. The resultant mixture was stirred with ice-bath cooling for 1 hour and then without cooling overnight. It was then poured into a vigorously stirred 500 ml portion of water in a large beaker. The phases were separated and the aqueous phase was back-extracted twice with ether. The combined extract was dried (MgSO4) and evaporated in vacuo. The residue was distilled at 20 mm to yield 12.7 g of XXX as a colorless oil, bp 125°-130°; Rf (CHCl3) 0.54; nmr 0.9 (3, broad t, J=6.0 Hz), 1.12 (6, s), 1.0-1.8 (6, m) and 2.14 (3, s); ir (film) 8.85, 7.45, 6.80, 5.85, 3.50, 3.41 and 3.38μ. was added dropwise cooling for 1 hour without cooling overnight The phases were separated the aqueous phase was back-extracted twice with ether The combined extract was dried (MgSO4) evaporated in vacuo The residue was distilled at 20 mm