Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16]CC1C=CC=CC=1)(=[O:15])[CH3:14].C([N-]C(C)C)(C)C.[Li+].[CH3:32][CH:33]([CH3:47])[C:34](=[O:46])/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-])=O)=[CH:39][CH:38]=1.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.[C]>C1COCC1.CO.C(O)(=O)C.O>[NH2:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][C:34]([OH:46])([CH:33]([CH3:47])[CH3:32])[CH2:14][C:13]([OH:16])=[O:15])=[CH:38][CH:39]=1
Reactant: CC(=O)OCc1ccccc1
Reactant: CC(C)C(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [C]
Solvent: O
Solvent: CO
Solvent: CC(C)NC(C)C
Product: CC(C)C(O)(CCc1ccc(N)cc1)CC(=O)O
Temperature: 86.5 °C
Reaction time: 6 h

Procedure:
Methyl isobutyrylacetate (40.0 Kg), methyl tert-butyl ether (10 L) and water (60 L) were charged to a still under an inert atmosphere and the mixture stirred and cooled to 17° C. Sodium hydroxide (60 Kg of a 50% aqueous solution) was added over 2 hours while maintaining the temperature between 17 and 25° C. The mixture was stirred overnight at 24-25° C. and then cooled to 0° C. Hydrochloric acid (75 Kg of a 37% aqueous solution) was added while maintaining the temperature below 5° C. to adjust the pH to 0.9. After settling, the aqueous layer was separated and treated with sodium chloride (3 Kg) and extracted with methyl tert-butyl ether (5 L). The combined organic layers were added to a mixture of E-nitrobenzaldehyde (26.0 Kg, 172 mmol) and pyridine (51 Kg) over 2.5 hours while maintaining the temperature between 2 and −4° C. The resulting mixture was stirred over the weekend at −1 to 4° C. and then warmed to 30-35° C. where it was held for 5 hours. Toluene (60 L) was charged to the mixture which was then cooled to 15° C. and extracted with a solution of sodium carbonate (3 Kg) in water (30 L) followed by a solution of sodium chloride (12 Kg) in water (30 L). The remaining organic layer was dried over sodium carbonate (10 Kg). After filtration to remove the sodium carbonate, the salt was washed with toluene (60 L) and the wash combined with the filtrate to provide a solution of (+/−)-1-hydroxy-4-methyl-1-(4-nitrophenyl)pentan-3-one (12) in toluene, pyridine and methyl tert-butyl ether. This was cooled to 0° C. and acetic anhydride (33.0 Kg) added over 45 minutes while maintaining the temperature between 2 and −1° C. The resulting mixture was stirred overnight while maintaining the temperature between 2 and 1° C. thus providing a solution of (+/−)-1-acetoxy-4-methyl-1-(4-nitrophenyl)pentan-3-one (13) in toluene and methyl tert-butyl ether and pyridine. This was heated to 85-88° C. where it was held for 6 hours. After cooling to 15° C., water (40 L) was added with stirring. After settling, the aqueous layer was separated and the organic layer was extracted with a solution 37% hydrochloric acid (39 Kg) and water (75 L) while including a 10 L toluene rinse to aid in transfer of the organic solution of the product. The latter was treated with 37% hydrochloric acid (13 Kg), water (55 L), toluene (10 L), ADP carbon (4 Kg) and Supercel Hyflo (12 Kg). After stirring the mixture was filtered and the residue rinsed with toluene (30 L). The combined filtrate and rinse were allowed to settle and the aqueous layer separated from the organic layer. The latter was extracted with water (25 L) and concentrated under vacuum to remove solvent. This provides (E)-4-methyl-1-(4-nitrophenyl)-1-penten-3-one (17) as a solid. The 17 was dissolved in tetrahydrofuran (75 L). A solution of the lithium enolate anion of benzyl acetate was prepared starting with 21.0 Kg diisopropylamine in 65 L THF followed by treatment of this solution with 15.4 Kg 10 M n-butyl lithium in hexanes at −10 to −38° C. followed by addition of 28.8 Kg benzyl acetate to the resulting solution of lithium diisopropylamide at −61 to −70° C. The solution of 17 in THF was added to this benzyl acetate enolate anion solution over an 80 minute period while maintaining the temperature between −61 to −69° C. The mixture was stirred another 50 minutes at −61 to −63° C. and acetic acid (19 Kg) was added while maintaining the temperature between −57 to −64° C. Methanol (61 L) was added and the mixture stirred and warmed to 17° C. The mixture was treated with ADP carbon (8 Kg) and Supercel Hyflo (8 Kg) and diluted with THF (20 L) and methanol (20 L). The resulting mixture was stirred I hour at 20-30° C. and then concentrated under vacuum to a volume of 250-280 L. The mixture was filtered and the residue washed with a mixture of THF (50 L) and methanol (40 L). The combined filtrates containing (+/−)-3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester (18) in methanol-THF solvent were hydrogenated over 5.5 Kg 20% palladium hydroxide catalyst 50% water wet at 26-37° C. under 50 psi hydrogen gas. The hydrogenation mixture was filtered to remove catalyst and the catalyst washed with methanol (40 L) and this combined with the whole to give a solution of (+/−)-3-[2-(4-aminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (19) in THF and methanol. The latter was cooled to 3° C. and acetic anhydride (25.0 Kg) added over 30 minutes while maintaining the temperature below 16° C. The resulting solution was concentrated under vacuum to remove solvent and the residue treated with toluene (20 L), methyl tert-butyl ether (10 L) and water (150 L). Sodium hydroxide 50% aqueous solution (34.6 Kg) was added to adjust the pH to 12.1 while maintaining the temperature below 19° C. The resulting mixture was heated to 60-80° C. where it was held overnight. The mixture was cooled to 18° C. and the layers separated and the organic layer extracted with water (20 L) and then discarded. The combined aqueous layers were treated with ethyl acetate (90 L) and 37% hydrochloric acid (55.8 Kg) was added to bring the pH to 2.7 while maintaining the temperature below 16° C. The aqueous layer was separated and extracted with ethyl acetate (70 L) and then discarded. The combined ethyl acetate extracts were washed twice with a solution of 3 Kg 37% hydrochloric acid in 30 L water followed by 30 L water and then concentrated under vacuum to a volume of 50-80 L. Toluene (80 L) was charged to the still and the vacuum distillation continued to reduce the volume again to 50-80 L. Ethyl acetate (30 L) was added to the still and the mixture stirred and cooled overnight to 6° C. The mixture was filtered and the solid washed with ethyl acetate (40 L and 30 L) and vacuum dried at 35-55° C. until the LOD was less than 0.5%. This provides 28.9 Kg (98.5 mmol, 57.3%) of (+/−)-3-[2-(N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (11a): mp: 160-161° C.; Assay (HPLC): 98.7 area %; ROI: 0. 18%. A second crop was isolated from the mother liquors: 1.3 Kg (4.4 mmol, 2.6%); mp: 158-160° C.; Assay (HPLC): 97.4 area %; ROI: 0.04%.