Reaction SMILES: [C:1]([CH2:6]C(OC)=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1(C)C=CC=CC=1.N1C=CC=CC=1.O.C(OC)(C)(C)C>[OH:22][CH:21]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:24][CH:23]=1)[CH2:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)C(=O)CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: 17 °C
Reaction time: 3.5 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 18 and 25° C. The mixture was stirred overnight at 22-35° C. and then cooled to 1° C. Hydrochloric acid (77 Kg of a 37% aqueous solution) was added while maintaining the temperature below 10° C. to adjust the pH to 0.2. After settling the aqueous layer was separated and treated with sodium chloride (5 Kg) and extracted with methyl tert-butyl ether (5 L). The combined organic layers were added to a mixture of p-nitrobenzaldehyde (26.0 Kg, 172 mmol) and pyridine (49 Kg) over 35 minutes while maintaining the temperature between 1 and −4° C. The resulting mixture was stirred overnight at 2-3° C. and then warmed to 30-35° C. where it was held for 3.5 hours. Toluene (60 L) was charged to the mixture which was then cooled to 8° 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 carbonate 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 40 minutes while maintaining the temperature between 0 and −2° C. The resulting mixture was stirred overnight while maintaining the temperature between 2 and 3° C. Water (80 L) was added with stirring. After settling, the aqueous layer was separated and the organic layer extracted twice with a solution 37% hydrochloric acid (22 Kg) and water (50 L) while including 10 L of toluene to aid in transfer of the organic solution of the product. The latter was extracted with water (40 L) to give a solution of (+/−)-1-acetoxy-4-methyl-1-(4-nitrophenyl)pentan-3-one (13) in toluene and methyl tert-butyl ether. This solution was added to 4.4 Kg of 20% palladium hydroxide on carbon, 50% water wet, in tetrahydrofuran (50 L) and toluene (40 L) and the mixture hydrogenated at 14-25° C. under 50 psi hydrogen gas. The mixture was filtered to remove catalyst and the catalyst washed with toluene (30 L) and this combined with the whole. The resulting solution containing 1-(4-aminophenyl)-4-methylpentan-3-one (14) was cooled to 3° C. and treated with acetic anhydride (24.0 Kg) while holding the temperature below 20° C. This solution was stirred overnight at 15-20° C. 4-Dimethylaminopyridine (0.4 Kg) and water (4 L) were added and the resulting solution distilled under vacuum to a volume of 190-200° F. The remaining solution was cooled to 2° C. and extracted with a solution of 26 Kg 50% sodium hydroxide in 58 L water followed by extraction with a solution of 13 Kg 50% sodium hydroxide in 29 L water, a solution of 7 Kg 37% hydrochloric acid in 15 L water and finally a solution of 12 Kg sodium chloride in 30 L water. The remaining organic layer was concentrated under vacuum to remove solvent while holding the batch temperature below 53° C. The residue was dissolved in tetrahydrofuran (155 L) to give 172 Kg of a solution of 1-(4-N-acetylaminophenyl)-4-methylpentan-3-one (15a) in THF. A solution of the lithium enolate anion of benzyl acetate was prepared starting with 29.0 Kg diisopropylamine in 350 L THF followed by treatment of this solution with 20.7 Kg of 10 m n-butyl lithium in hexanes at −9 to −35° C. followed by addition of 40.0 Kg benzyl acetate to the resulting solution of lithium diisopropylamide at −63 to −69° C. A 86.8 Kg portion of the solution of 15a in THF was added to this lithium enolate of benzyl acetate over a 1.5 hour period at −56 to −70° C. After stirring an additional 15-20 minutes at −52 to −56° C., the mixture was quenched by addition to a cold (0-5° C.) solution of toluene (43 L), ethyl acetate (43 L), acetic acid (34 L), and water (65 L) while holding the temperature below 5° C. The low temperature reaction vessel was rinsed with tetrahydrofuran (5 L) and the rinse added to the quench solution. After mixing, the solution was allowed to settle and the aqueous layer separated and discarded. This provides a solution of (+/−)-3-[2-(N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid benzyl ester (16a) in toluene, THF, and ethyl acetate. In a similar way a second part lot of (16a) was prepared using the remaining amount (85.1 Kg) of 15a in THF by addition to the lithium enolate anion of benzyl acetate (prepared from 29.0 Kg diisopropylamine in 350 L THF followed by treatment with 20.0 Kg of 10 M n-butyl lithium in hexanes followed by addition of 40.0 Kg benzyl acetate) and finally quenching into (43 L), ethyl acetate (43 L), acetic acid (34 L), and water (65 L) and separation of the aqueous layer. The combined part lots of 16a in toluene, THF and ethyl acetate were extracted with a solution of acetic acid (8 Kg) in water (110 L) followed by extraction with water (65 L). The remaining organic layer was concentrated under vacuum at 25-30° C. to 200-220° L and then added to 4.0 Kg of 20% palladium hydroxide on carbon, 50% water wet, in tetrahydrofuran (30 L), and toluene (30 L) and the mixture hydrogenated at 18-24° C. under 50 psi hydrogen gas. The mixture was filtered to remove the catalyst and the catalyst washed with tetrahydrofuran (40 L) and this combined with the whole which was then cooled to 6° C. The resulting solution was extracted with three separate portions of a solution of 45% potassium hydroxide (23 Kg) dissolved in water (64 L). The combined basic extracts were back extracted with toluene (30 L) and then treated with ethyl acetate (80 L). This ethyl acetate/aqueous KOH solution was acidified to pH 4.2 using 42.7 Kg of 37% hydrochloric acid while holding the temperature below 20° C. The layers were separated and the aqueous layer extracted with ethyl acetate (80 L). The combined ethyl acetate extracts were washed with water (30 L) and concentrated under vacuum to about 55 L while maintaining the temperature below 25° C. Additional ethyl acetate (13 Kg) was added back to the thick slurry of the product to assist agitation. The mixture was stirred and cooled overnight to 20° C. and filtered on a centrifuge. The product was washed with ethyl acetate (40 L and 10 L) and vacuum dried at 20-42° C. until the LOD was less than 0.5%. This gave 34.9 Kg (119 mmol, 69% yield for the six steps) of (+/−)-3-[2-N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (11a): mp: 158-162° C.; Assay (HPLC): 98.8 area %; ROI: 0.07%.