Name: 75330-75-5|(S)-(1S,3R,7S,8S,8aR)-8-(2-((2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2-methylbutanoate|98%
Brand: Ambeed
SKU: A151986
Price: 5.0 USD
Availability: InStock
Rating: 95 (25 reviews)

1
*),3α,7β,8β(2S^*,4S^*,6RS^*),8aβ>>-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-<2-(tetrahydro-4,6-dihydroxy-2H-pyran-2-yl)ethyl>-1-naphthalenyl 2-methylbutanoate [ No CAS ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With Celite; silver carbonate In toluene at 85 - 95℃; for 1h;
77%	With Celite; toluene; silver carbonate In toluene at 90℃; for 1h;

Reference： [1]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]
[2]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]

2
[ 75330-75-5 ]
[ 109273-98-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 1h;
90%	With dmap; methanesulfonyl chloride In acetonitrile at 20℃;
61%	With Burgess Reagent In benzene at 60℃; for 1.5h;

460 mg

With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 1h;

Reference： [1]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]
[2]Ullrich, Thomas; Baumann, Karl; Welzenbach, Karl; Schmutz, Simone; Camenisch, Gian; Meingassner, Josef G.; Weitz-Schmidt, Gabriele [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2483 - 2487]
[3]Bartmann, W.; Beck, G.; Granzer, E.; Jendralla, H.; Kerekjarto, B. v.; Wess, G. [Tetrahedron Letters, 1986, vol. 27, # 39, p. 4709 - 4712]
[4]Location in patent: experimental part Zhu, Lin; Yau, Lee-Fong; Lu, Jing-Guang; Zhu, Guo-Yuan; Wang, Jing-Rong; Han, Quan-Bin; Hsiao, Wen-Luan; Jiang, Zhi-Hong [Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 4, p. 934 - 939]

3
[ 75330-75-5 ]
[ 79902-20-8 ]

Yield	Reaction Conditions	Operation in experiment
22.3 mg	With Wilkinson's catalyst; hydrogen In toluene at 25℃; for 144h;

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

4
[ 75330-75-5 ]
[ 79902-20-8 ]
[ 79691-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With Wilkinson's catalyst; hydrogen In toluene at 40℃; for 24h; Yield given. Yields of byproduct given;
1: 7 mg 2: 72 mg	With hydrogen In ethanol at 25℃;

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

5
[ 75330-75-5 ]
[ 85648-15-3 ]
[ 79691-10-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen In ethyl acetate for 1h; Yield given. Yields of byproduct given;

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

6
[ 75330-75-5 ]
[ 79691-09-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With (η4-1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate; hydrogen In dichloromethane at 20℃; for 1.5h;
	Multi-step reaction with 2 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 50 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature

Reference： [1]DeCamp, Ann E.; Verhoeven, Thomas R.; Shinkai, Ichiro [Journal of Organic Chemistry, 1989, vol. 54, # 13, p. 3207 - 3208]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

7
[ 75330-75-5 ]
[ 148969-22-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With lithium aluminium tetrahydride
84%	With lithium aluminium tetrahydride In tetrahydrofuran for 5h;
80%	With lithium aluminium tetrahydride In diethyl ether for 3h;

Reference： [1]Clive, Derrick L. J.; Zhang, Chengzhi [Journal of the Chemical Society. Chemical communications, 1993, # 7, p. 647 - 649]
[2]Clive, D. L. J.; Zhang, Chengzhi [Journal of Organic Chemistry, 1995, vol. 60, # 5, p. 1413 - 1427]
[3]Wagschal, Kurt; Yoshizawa, Yuko; Witter, David J.; Liu, Yaoquan; Vederas, John C. [Journal of the Chemical Society. Perkin transactions I, 1996, # 19, p. 2357 - 2363]

8
[ 79691-11-5 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogen fluoride In acetonitrile at 25℃; for 1.4h;
77%	With hydrogen fluoride In acetonitrile at 0℃; for 5h;
	With tetrabutyl ammonium fluoride; acetic acid In tetrahydrofuran

With tetrabutyl ammonium fluoride; acetic acid In tetrahydrofuran for 18h; Ambient temperature;

Reference： [1]Senanayake, Chris H.; Bill, Timothy J.; DiMichele, Lisa M.; Chen, Cheng Y.; Larsen, Robert D.; Verhoeven, Thomas R.; Reider, Paul J. [Tetrahedron Letters, 1993, vol. 34, # 38, p. 6021 - 6024]
[2]Hirama; Iwashita [Tetrahedron Letters, 1983, vol. 24, # 17, p. 1811 - 1812]
[3]Wovkulich, P. M.; Tang, P. C.; Chadha, N. K.; Batcho, A. D.; Barrish, J. C.; Uskokovic, M. R. [Journal of the American Chemical Society, 1989, vol. 111, # 7, p. 2596 - 2599]
[4]Hoffman, W. F.; Alberts, A. W.; Anderson, P. S.; Chen, J. S.; Smith, R. L.; Willard, A. K. [Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 849 - 852]

9
[ 75330-75-5 ]
[ 18162-48-6 ]
[ 79691-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole In N,N-dimethyl-formamide for 16h; Ambient temperature;
1.48 g	With 1H-imidazole In N,N-dimethyl-formamide at 35℃; for 5h;

Reference： [1]Lee, Ta-Jyh; Holtz, Willbur J.; Smith, Robert L. [Journal of Organic Chemistry, 1982, vol. 47, # 24, p. 4750 - 4757]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[3]Hirama; Iwashita [Tetrahedron Letters, 1983, vol. 24, # 17, p. 1811 - 1812]

10
[ 75330-75-5 ]
[ 109-73-9 ]
[ 134970-29-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 80℃; for 1h;
	Heating / reflux;	1 100 g Lovastatin (HPLC purity 85%) was reacted with 90 g n-butyl amine under refluxing. Un-reacted amine was distilled off. 800 ml of Hexane was added to the residue and the resultant mass was stirred to get complete crystallization. Crystallized mass was filtered and washed with hexane. 100 gram of the title compound was obtained after drying having HPLC purity 99.65%.
	Reflux;

at 70℃; for 3h; Inert atmosphere;

1.a Example I: A method for preparing simvastatin of formula (I), Step a: Under nitrogen protection, 50.0 g of lovastatin and 40 ml of n-butylamine were placed in a reaction flask, heated to 70° C. for 3 hours, and after the reaction was completed, n-butylamine was concentrated under reduced pressure, and the mixture was concentrated and 100 ml of N,N-dimethylformamide was added. The base formamide (DMF) was stirred well at room temperature to obtain a lovastatin amide DMF solution.

Reference： [1]Askin, D.; Verhoeven, T. R.; Liu, T. M.-H.; Shinkai, I. [Journal of Organic Chemistry, 1991, vol. 56, # 16, p. 4929 - 4932]
[2]Current Patent Assignee: MOREPEN LAB - WO2007/52309, 2007, A2 Location in patent: Page/Page column 6
[3]Location in patent: scheme or table Tian, Lei; Tao, Jie; Chen, Liqin [Journal of labelled compounds and radiopharmaceuticals, 2011, vol. 54, # 9, p. 625 - 628]
[4]Current Patent Assignee: XINCHANG KANGLE CHEMICALS CO., LTD. - CN104803959, 2017, B Location in patent: Paragraph 0044; 0045; 0046; 0047

11
[ 75330-75-5 ]
[ 768-33-2 ]
[ 85613-98-5 ]

Yield	Reaction Conditions	Operation in experiment
1.151 g	With 1H-imidazole In N,N-dimethyl-formamide at 35℃; for 5h;

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

12
[ 75330-75-5 ]
lovastatin acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide at 20℃; for 0.5h;
	With sodium hydroxide In water at 20℃; for 0.5h;
	With methanol; sodium hydroxide; water at 35 - 40℃;	2; 5.1; 11 Hydrolysis of Lovastatin by SEQ ID NO : 4 (100 a Scale); An exemplary reaction of the invention comprising the enzymatic hydrolysis of lovastatin to triol acid is illustrated in Figure 18E. 1. Lovastatin (10x10 g, 0.25 mol) and water (13x10 mL) were slowly added in alternating portions to a rapidly stirring mixture of MeOH (35 mL, 7% final volume) and 6M NaOH (43 mL, 0.26 mol) in a 1L 3-neck flask equipped with an overhead paddle stirrer. 2. When a homogeneous mixture was obtained, the mixture was stirred at 35°C until the pH dropped to 8 (approx. 2h) whereupon lovastatin was converted to lovastatin acid. 3. Meanwhile lyophilized enzyme (22.64 g) was reconstituted with water (final volume 180 mL). 4M Tris (4 mL) and the reconstituted enzyme solution were added to the lovastatin acid solution. Water (108 mL) was added to bring the volume to 500 mL before initiating pH control. 4. The reaction was controlled using a DASGIP AG-PRO bioreactor using 30% NH40H to maintain pH 9.5. The reaction was stirred for 48 h (Note 1, below) and maintained at 35°C, aliquots (10 IAL quenched in MeOH, 990, uL) being taken periodically to monitor progress of the reaction by HPLC (Note 2, below). 5. The reaction was terminated by transferring to a 4L beaker and diluting it with water (1L). The pH of the mixture was adjusted with 6M HC1. At pH-4. 4 the mixture became very viscous as a white solid precipitated and stirring rate was increased to prevent"gelling"of the mixture. The mixture was adjusted to pH 2.5 using a total of 120 mL 6M HC1 and stirred for a further 0.5 h. 6. The resulting slurry was filtered through Whatman 1 filter paper on a 21 cm Buchner funnel, and the damp filter cake washed with water (0.5 L). The damp filter cake was allowed air dry for-1 h; it was then transferred into 4 x 600 mL lyophilizer flasks and dried on a lyophilizer for 48 h to provide an off-white powder (98.6 g) (Note 3, below). 7. The filtrate was divided into 3 equal portions which were extracted with a single portion of EtOAc (500 mL). While the 1st extraction separated easily, the 2nd and 3rd portions formed emulsions which did not separate cleanly even after treatment with satd. NaCl (100 mL). The EtOAc extract was washed with saturated ("satd") NaCI (100 mL), dried (Na2SO4) and filtered. The filtrate was stirred under N2 and a solution of MeS03H (0.2 mL, 3.1 mmol; final concentration-7 mM) in EtOAc (5 mL) was added dropwise over a period of-5 minutes. After 4.5 h the reaction solution was washed with satd. NaHCO3 (200 mL), water (100 mL) and satd. NaCl (100 mL). The EtOAc layer was concentrated to-50 mL on a rotary evaporator and diol lactone was precipitated by the slow dropwise addition of hexanes (200 mL). The precipitated solid was collected by filtration and dried (3.36 g, 81.3% purity) ; a further 0.26 g remained in the mother liquors. 8. The total yield was determined to be 94.9% (see Note 4, below). Notes 1. HPLC indicated that reactions on a 100 g scale were ~97% complete after 22h, but were often allowed stir for longer to ensure complete hydrolysis, 2. Samples were analyzed on a Waters 1100 Series HPLC equipped with a DAD, using a ZORBAX SB-Phenyl column (4.6 x 75 mm) (45% MeCN/0.1% H3PO4 isocratic; 1 ml/min; 30°C ; 238 nm). The order of elution was: Triol acid: 1.4 min, Diol lactone: 1.9 min, Lovastatin Acid: 3.8 min, Lovastatin: 7.3 min. 3. The filter cake at this stage consists of crude triol acid and precipitated protein. 4. The total yield of product was calculated as shown in the Table: 5.; Example 5: Exemplary synthetic schemes of the invention The following example describes exemplary protocols of the invention, e. g., schemes for synthesizing simvastatin from lovastatin: STEP 1: LOVASTATIN HYDROLYSIS The invention also provided methods comprising the generation of triol acid from lovastatin, as illustrated in Figure 15A. Having identified a novel lovastatin esterase (having a sequenced as set forth in SEQ ID NO : 4 and subsequent subclones), efforts focused upon producing a scaleable enzymatic hydrolysis process. Among the required parameters for the proposed simvastatin process was that the enzymatic reaction be run at high substrate loading. Initial screening and confirmatory reactions were carried out using lovastatin acid, because of its high aqueous solubility. Reactions using lovastatin were much slower because of the lower solubility of lovastatin in water, especially at lower pH's (7-8) and high substrate loading. Lack of solubility was overcome by first chemically opening the lactone ring in sitzt. Thus a suspension of lovastatin in MeOH/water (final reaction concentration 7-10% MeOH) was treated with 1 equivalent of NaOH and the mixture stirred for a couple of hours until the lovastatin had been converted to the more soluble lovastatin acid. When ring-opening was complete, the pH of the reaction mixture was adjusted to pH 9.5 before addition of the enzyme, although adjustment was not necessary in many cases as the pH fell to an acceptable value as the ring opening proceeded. The enzymatic reaction was initiated by addition of a solution of the reconstituted enzyme. The mixture was then stirred at 35-40°C, with the pH being held constant at pH 9.5 by automatic addition of 10-30% NH40H. Under these conditions > 98% conversion of lovastatin to triol acid was generally obtained in 48 h. The reaction slows down considerably towards completion. The results for a series of large scale hydrolyses are gathered in Table 1; Runs 2 and 3 showed abnormally long reaction times. In these two cases, the lovastatin lactone opening was carried out using a large excess of NaOH and required addition of HCl to return the pH to a suitable range for the enzymatic reaction. It had previously been observed that high salt concentrations had a deleterious effect on the enzymatic hydrolysis. Furthermore, due to limited availability at the time, the initial enzyme charge (11% w/w) was less than used previously; further portions of enzyme were added to bring the final enzyme charge to 17% w/w. The reaction was terminated by diluting the reaction mixture with water and then acidifying the mixture to pH-2. Under these conditions the triol acid, denatured protein and other media/cell components precipitated from solution. For initial small scale, dilute reactions, this mixture was subjected to continuous liquid extraction with refluxing iPrOAc. Under these conditions the lactonization of triol acid occurred and the diol lactone could be easily obtained by precipitation from the concentrated iPrOAc extract. For larger scale reactions the precipitated triol acid/denatured protein mixture was isolated by filtration and, while still damp, the filter cake was suspended in iPrOAc and subjected to azeotropic distillation to effect lactonization. The insoluble, denatured protein/cell components were removed by filtration and the diol lactone 564462012840 isolated by concentration and precipitation. This procedure worked well on a 10-30 g scale to generate the diol lactone without purification of the triol acid. However as the scale of the reaction increased (50-100 g), the azeoptropic distillation required longer reflux periods in more concentrated solutions to effect lactonization. The yield of diol lactone isolated under these conditions was diminished, and the product was contaminated with increasing quantities of yellow oil, presumably caused by polymerization of the triol acid or diol lactone. At >100 g scale in the laboratory, the most convenient workup was to dilute and acidify the enzymatic reaction mixture. The insoluble materials were collected by filtration and this damp filter cake was dried; initially lyophilization was used for drying, but for additional runs the filter cake has been dried in a vacuum oven at 30-40°C. Assaying the crude product (H NMR in the presence of an internal standard) indicated that it contained-78% triol acid, the rest of the material being denatured protein, cell and media components. After filtration the filtrate could be extracted with EtOAc to recover a further-2% of product. This material could be isolated, either as the triol acid or lactonized (7 mM MeS03H) to the diol lactone, and added to the next step; Example 11: An exemplary hydrolysis protocols; This example describes exemplary protocols of the invention, including industrial scaled up processes for making simvastatin and intermediates, e. g., as in Figures 5 and 6. A protocol for the enzymatic hydrolysis of lovastatin to triol acid using SEQ ID NO : 4 (see, e. g., step 1, Figure 5) was completed, and Figure 30 illustrates the results of this exemplary lovastatin hydrolysis protocol. Enzyme source of SEQ ID NO : 4 was lysate from mini-fermentors. The protocol resulted in 99% conversion at 39 h (90% 24 h) on 12 g scale (0. 5M) with lyophilate from 10 L fermentation (214 g). Summarizing the parameters used in this study: Catalyst Load Conversion Time 56% w/w 100% about 4 h 33% w/w 97% about 24 h 22% w/w 97% about 24 h At 22% w/w lyophilate loading, using 10L fermentation hydrolyzes 1 kg lovastatin. A large-scale enzymatic hydrolysis of lovastatin to lovastatin acid to triol acid was carried out on a DasGip FEDBATCH PROTM bioreactor at constant pH 9, substrate at 500 mM, 7% MeOH, 40°C, as illustrated in Figure 31. A scaled-up 564462012840 exemplary protocol of an enzymatic hydrolysis of lovastatin to diol lactone, which can be an exemplary industrial scale process, is illustrated in the schematic of Figure 32. This reaction, with a summary of reaction parameters (reaction scale, workup, theoretical yield, product in g, % yield), is illustrated in Figure 33. Data from (a) a 50 gram (g) reaction is summarized in Figure 34A (after lactonization and concentration) and 34B (crude product), and (b) a 100 g reaction Figure 35A (triol acid) and 35B (after lactonization). Methyl (Me) 4-acetyl simvastatin was hydrolyzed enzymatically to simvastatin using a reaction as illustrated in Figure 6, step 5. Results and conclusions from this reaction are: Facile elimination at pH >7 (13% at pH 8). Enzymatic hydrolysis occurs readily, but limited by solubility. Formate > acetate-chloroacetate > methoxyacetate. 100 mM (5% w/v) hydrolyzed overnight at pH 7. 200 mM 84% conversion in 20 h in 10% MeOH at 50°C. 200 mM 89% conversion in 7 h with 50% w/w lyophilate. 400 mM biphasic with toluene. * Reactions proceed to 80-90% then stop. Insoluble simvastatin traps unreacted substrate. Summarizing these reactions (at 300 mM (14% w/v) substrate, All reactions with overhead stirring and stirrer bar below, pH 7 with 10% NH40H ; 50°C) and final conversions: 270 mM acetyl simvastatin, 13 mM homo simvastatin, with solvent as equal volumes toluene, gave a final conversion of 88. 2%. 300 mM acetyl simvastatin, with solvent as 10% methanol (MeOH), gave a final conversion of 91.3%. 300 mM acetyl simvastatin, with solvent as 10% methanol (MeOH), and addition toluene at 6 hours, gave a final conversion of 96. 1%.

	With sodium hydroxide; water	7.1 Example 7: Exemplary protocols of the invention; The following example describes exemplary protocols of the invention, including schemes for synthesizing simvastatin from lovastatin, e. g., schemes to increase the overall yield of the process outlined in Figure 5, a heterodiacylation synthetic route to simvastatin. This example describes schemes to increase the overall yield of lovastatin to simvastatin to at least 60%, and to identify where yield loss is occurring and where process improvements could be effected; STEP 1 : LOVASTATIN HYDROLYSIS; Figure 15A illustrates an exemplary reaction of the invention, hydrolysis of lovastatin to a triol acid using an esterase. In one aspect, this step involves an initial chemical opening of the lactone ring (using 1 equivalent NaOH) to form the water soluble lovastatin acid. After adjustment of pH and volumes, a slurry of the enzyme was added to the reaction, which was then maintained at pH 9.5 and 40°C until 99.5% conversion of lovastatin acid. Alternative exemplary conditions use a 10% w/v loading of substrate (0.25 M) and a 10% w/w crude enzyme/substrate loading. Previously at >100 g scale in the laboratory, the most convenient workup was to dilute and acidify the enzymatic reaction mixture. The insoluble materials were collected by filtration and this damp filter cake was dried in a vacuum oven at 30°C to 40°C. Assaying the crude product (H NMR in the presence of an internal standard) indicated that it contained-78% triol acid, the rest of the material being presumably denatured protein, cell and media components. Studies were done to answer the question as to whether unacceptable yield loss occurred at this initial step. It was suspected that the relatively high enzyme loading resulted in: (i) Irreversible absorption of product to the precipitated protein, (ii) Loss of yield due to side reactions especially if the precipitated enzyme was carried forward to Step 2, the lactonization/acetylation 564462012840 (iii) Crude enzyme preparation containing other components capable of reacting with product at this or subsequent stages. Attempts were made to improve the situation by: (i) Decreasing the enzyme loading (ii) Increase the purity of the enzyme preparation by a simple pre-treatment before use (iii) Separate the triol acid product from spent enzyme by means of ultrafiltration.
	With sodium hydroxide at 20℃; for 0.5h;
	With methanol; potassium hydroxide In water for 8h; Reflux;	1.1 Lovastatin (1, 9.0 g, 22.3 mmol) was heated with potassium hydroxide (12.6 g, 224.5 mmol) in H20/MeOH (1:6, 63 mL) underreflux for 8 h. Afier adding H20 (49.5 mL) to the mixture, MeOH was removed under reduced pressure to give compound (2). To compound (2), H20 (180 mL), CH2C12 (45 mL), and 6 M HC1 aqueous solution were added until pH reached 2. The mixture was stirred at room temperature for 4.5 h, and then neutralized with saturated NaHCO3 aqueous solution. Extracted the mixture with CH2C12. The combined organic phase was dried over anhydrous Mg504, filtered and concentrated to give a deacylation product (3) as orange oil. TLC (EtOAc) R1=0.33 The crude product (3) was treated with tert-butyldimethylsilyl chloride (8.7 g, 57.9 mmol) and imidazole (8.8 g, 129.1 mmol) in CH2C12 (82 mE) at room temperature for 5.5 h. The mixture was concentrated under reduced pressure, and the residue was extracted with CH2C12 and H20. The organic phase was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, EtOAc/hexane (2:8) to EtOAc) to give the compound (4a) (5.6 g, 58% overall yield from lovastatin).10101] C25H42O4Si; white solid, mp 141.1-142.3°C.; TEC (EtOAc/hexane (6:4)) R1=0.61; ‘H NMR (CDC13, 400 MHz) ö5.98 (1H, d, J=9.6 Hz), 5.78-5.82 (1H, m), 5.55 (1H, br s), 4.66-4.70 (1H, m), 4.29-4.30 (1H, m), 4.23-4.25 (1H, m),2.54-2.65 (2H, m), 2.35-2.45 (2H, m), 2.16-2.18 (1H, m),1.70-1.93 (7H, m), 1.44-1.55 (2H, m), 1.15 (3H, d, J=7.6 Hz),0.88-0.91 (12H, m), 0.08 (6H, d, J=1.6 Hz); ‘3C NMR (CDC13, 100 MHz) 170.4, 133.6, 131.3, 129.9, 128.4, 76.3, 65.1, 63.5, 39.2, 38.7, 36.8, 36.3, 35.7, 32.9, 30.7,27.3, 25.6 (3x), 24.2, 23.7, 17.9, 13.9, -5.0 (2x).
	With water; sodium hydroxide	Preparation of test compounds Purified lovastatin was dissolved in dH20 and 0.1 M NaOHand allowed to stir overnight, after which the solution wasadjusted to pH 7.5. A mixture of dH20, acetonitrile (ACN)and ethyl acetate (1:1:1) was used to precipitate the lovastatinb-hydroxy acid product which was then filteredthrough a 22 lM filter and dried.
	With sodium hydroxide In ethanol at 50℃; for 2h;

Reference： [1]Nagasawa, Kazuki; Muraki, Yuichi; Matsuda, Tomoko; Ohnishi, Noriaki; Yokoyama, Teruyoshi [Journal of Pharmaceutical Sciences, 2000, vol. 89, # 12, p. 1594 - 1604]
[2]Nagasawa, Kazuki; Nagai, Katsuhito; Sumitani, Yuji; Moriya, Yuka; Muraki, Yuichi; Takara, Kohji; Ohnishi, Noriaki; Yokoyama, Teruyoshi; Fujimoto, Sadaki [Journal of Pharmaceutical Sciences, 2002, vol. 91, # 12, p. 2605 - 2613]
[3]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 33-35; 48-50; 75-76
[4]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 62-63
[5]Kobayashi, Masaki; Chisaki, Ikumi; Narumi, Katsuya; Hidaka, Kazuhiro; Kagawa, Toshiki; Itagaki, Shirou; Hirano, Takeshi; Iseki, Ken [Life Sciences, 2008, vol. 82, # 17-18, p. 969 - 975]
[6]Current Patent Assignee: ACADEMIA SINICA; NATIONAL TAIWAN UNIVERSITY - US2014/206645, 2014, A1 Location in patent: Paragraph 0099; 0100; 0101
[7]Harrison, Angela T.; Kriel, Frederik H.; Papathanasopoulos, Maria A.; Mosebi, Salerwe; Abrahams, Shaakira; Hewer, Raymond [Chemical Biology and Drug Design, 2015, vol. 85, # 3, p. 290 - 295]
[8]Sokalska, Anna; Hawkins, Amanda B.; Yamaguchi, Toshia; Duleba, Antoni J. [Journal of Assisted Reproduction and Genetics, 2019, vol. 36, # 3, p. 535 - 541]

13
[ 75330-75-5 ]
(4R,6R)-4-hydroxy-6-(2-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)ethyl)tetrahydro-2H-pyran-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: lovastatin With water; lithium hydroxide at 100℃; Stage #2: With hydrogenchloride In water Stage #3: With calcium hydride In toluene at 110℃; for 1h;
73%	With lithium hydroxide In tetrahydrofuran; methanol at 66℃; for 2h; Inert atmosphere;	8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydro-naphthalen-1-yl)-ethyl]-tetrahydro-pyran-2-one(4) To a solution of lovastatin (1, 1.01 g, 2.50 mmol) in MeOH-THF (10 mL-10 mL) was addedLiOH (600 mg, 25 mmol). The resulting solution was heated to66 oC under N2 for 2 h. The reaction was diluted withdistd CH2Cl2 (50 mL) and then washed with 1N HCl(aq)(3x 25 mL), 10% NaHCO3(aq) (25 mL) and distd H2O (30 mL).The organic layer was dried over Na2SO4, filtered and thesolvent removed in vacuo. The residue was dissolved in toluene (20 mL) and theresulting solution was heated to 120 oC under N2 for 24h. The reaction mixture was concentrated in vacuo and the residue was purifiedby silica gel chromatography (MeOH: CH2Cl2=1: 99) to give4 (584 mg, 73%) as a white solid. Mp 93-95 oC (acetone). IR (KBr) 3853, 3749, 3674, 3648, 2925,2360, 2340, 1771, 1698, 1558, 1540 cm-1. 1H NMR (500 MHz, CDCl3): δ 5.97 (d, J = 9.6 Hz, 1H), 5.79 (dd, J = 6.2, 9.5 Hz, 1H), 5.53 (s, 1H), 4.70(m, 1H), 4.36 (q, J = 4.2 Hz, 1H),4.23 (q, J = 3.0 Hz, 1H), 2.72 (dd, J = 5.0, 17.6 Hz, 1H), 2.61 (ddd, J = 1.6, 3.6, 17.6 Hz, 1H), 2.44 (m, 1H),2.36 (m, 1H), 2.15 (m, 1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.82 (m, 2H), 1.79 (m, 1H),1.74 (m, 1H), 1.50 (m, 1H), 1.45 (m, 1H), 1.18 (d, J = 7.6 Hz, 3H), 0.89 (d, J= 7.1 Hz, 3H). ESI-MS m/z: 343.2 (M+Na)+.
	With lithium hydroxide for 24h; Heating;

	Multi-step reaction with 2 steps 1: aq. LiOH / Heating 2: 140 mg / toluene / 1 h / Heating
	With conc HCl In hexane; water; toluene	1.a (a) (a) 6(R)-[2-[8(S)-Hydroxy-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (2) A mixture of 20.0 g (49.4 mmol) of mevinolin and 20.7 g (0.493 mol) of LiOH H2 O in 1.5 L of water was stirred at reflux for 72 hours. The reaction mixture was cooled to 0° C., acidified by addition of 50 ml of conc HCl and then extracted with ether (3500 ml). The combined extracts were washed with water (3500 ml) and satd. brine (500 ml), dried (MgSO4) and evaporated to give a white solid. This solid was dissolved in 300 ml of toluene and heated at reflux for 2 hours in a Dean-Stark apparatus for azeotropic removal of water. After evaporation of the toluene, the residual oily solid was heated at reflux in hexane (150 ml) for 30 minutes. After cooling to 0° C., the hexane solution was filtered and the collected solid was dried in air to yield an off-white powder. An analytical sample was prepared by recrystallization of a portion of this material from 1-chlorobutane to give white clusters: m.p. 128°-131° C. (vac). Anal. Calc'd for C19 H28 O4.0.1C4 H9 Cl: C, 70.67; H, 8.84. Found: C, 70.77; H, 8.75.
	Multi-step reaction with 2 steps 1.1: lithium hydroxide / water / 68 h / Inert atmosphere; Reflux 1.2: 0 °C / pH 2 2.1: toluene / 3 h / Reflux
	With sodium hydroxide In methanol at 40℃; for 35h; Reflux;	1 Example 1Preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S),6'(R)-1',2',6',7',8',8a'(R)-hexahydronapthyl-1'(S)-ethyl]-4-(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on (Diol Lactone)NaOH (100.0 gm) was charged followed by methanol (500.0 ml) at 22° C.-25° C. Temperature rose to 55° C.-60° C. When temperature was came down to 40° C.-45° C., lovastatin (100.0 gm) was charged followed by adding methanol (200.0 ml). Temperature was raised to reflux (oil bath temp 80° C.). The reaction mass was stirred at reflux temperature till completion was observed by HPLC. The reaction was completed in 35 hours. The reaction was then cooled to 23° C.-25° C. and 150.0 ml of demineralized (DM) water was added followed by drop wise addition of conc. hydrochloric acid to adjust the pH to 7.5-8.0. Temperature rose from 24° C.-32° C. and care was taken that it does not exceed 35° C. Methanol and water was distilled out completely under vacuum at 60° C. The residue was taken in DM water (300.0 ml) and dichloromethane (150.0 ml) and pH was adjusted to 1.5-2.0 with conc. hydrochloric acid at 5° C.-10° C. The mixture was stirred for 1 hr at 5° C.-10° C. Water and dichloromethane were again distilled out completely and to the remaining residue toluene (100.0 ml) was added and then distilled completely. To this residue 4.0 liter DM water was added and the mixture stirred for 1 hr at 10° C.-15° C. The solid was filtered, washed with DM water (1000.0 ml) and dried under high vacuum at 60° C. for 24 hrs. This dried material was taken in 500.0 ml hexane and stirred for 1 hr at 15° C.-20° C. and the solid was filtered. This solid material was dried at 45° C.-50° C.
	Stage #1: lovastatin With potassium hydroxide In methanol; water for 8h; Reflux; Stage #2: With hydrogenchloride In water at 20℃; for 4.5h;
	With water; potassium hydroxide In methanol for 21h; Reflux;	1 Obtaining Monacolin J A solution of 0.7 g of potassium hydroxide in 0.5 ml of water is prepared and 3 ml of methanol are added little by little. 0.5 g of Lovastatin are subsequently added and the solution is placed under reflux for 21 hours. After the treatment of the reaction, a 50% mixture of monacolin J and the ring-opening product is obtained.
	Multi-step reaction with 2 steps 1: potassium hydroxide; methanol / water / 8 h / Reflux 2: hydrogenchloride / water; dichloromethane / 4.5 h / 20 °C / pH 2
	With potassium hydroxide In methanol; water for 8h; Reflux;	A.1.1 step 1: Preparation of intermediate 2 20 mg of lovastatin (2) (0.05 mmol) was mixed with a solution consisting of 28 g of KOH, 140 ml of methanol water (6: 1, v / v) Stirring the reaction to reflux for 8 hours to stop the reaction, Cooled to room temperature by adding 110 ml of water, The methanol was then distilled off under reduced pressure, To the residue was added 400 ml of water and 100 ml of dichloromethane, Add 6M hydrochloric acid to pH = 2 with stirring. Stirred at room temperature for 4.5 hours, Add saturated sodium bicarbonate solution neutral to neutral, Static stratification, The aqueous layer was extracted again with 100 ml of dichloromethane, The combined dichloromethane extracts were dried over anhydrous magnesium sulfate for 3 hours, Filtered and concentrated under reduced pressure to give the deacylated product intermediate (2) (orange oil) used directly in the next step.
	With water; potassium hydroxide In methanol at 100℃; for 12h;
	Stage #1: lovastatin With potassium hydroxide In methanol; water for 12h; Stage #2: With hydrogenchloride In dichloromethane; water at 20℃; for 6h;	3 Example 3: (4R,6R)-4-((tert-butyldimethylchlorosilane)oxy)-6-(2-((1S,2S,6R,8S,8αR)-8-hydroxy-2 ,6-Dimethyl-1,2,6,7,8,8α-hexahydronaphthalene-1-yl)ethyl)tetrahydro-2H-2-pyrone (8) synthesis, the route is as follows: Reagents and conditions: (i) kOH, H2O-MeOH, reflux, 12h; (ii) 6M HCl, rt, 6h; (iii) TBSCl, imidazole, CH2Cl2, rt, 6 h; (iv) p-nitrophenyl chloroformate, DMAP ,Pyridine,rt,16h; Lovastatin (18g, 44.6mmol) was added to a mixed solution of water and methanol (H2O/MeOH, 1:5, 132mL), KOH (25.2g, 449mmol) was added, and the reaction was refluxed for 12h, and the methanol was distilled off under reduced pressure. The mixture was added H2O (500mL), CH2Cl2 (100mL) and 6M HCl, adjusted pH=2. Reacted at room temperature for 6h, added saturated NaHCO3 for neutralization. Extracted with DCM, spin-dried to obtain an oil. Dissolved in DCM (85mL), added TBSCl (4.3g, 30mmol) and imidazole (3.4g, 49.6mmol) to it, reacted at room temperature for 6h. Purified by column chromatography to obtain a white solid compound 8 (7.3g, 84% yield).

Reference： [1]Barriuso, Jorge; Nguyen, Don T.; Li, Jesse W.-H; Roberts, Joseph N.; MacNevin, Gillian; Chaytor, Jennifer L.; Marcus, Sandra L.; Vederas, John C.; Ro, Dae-Kyun [Journal of the American Chemical Society, 2011, vol. 133, # 21, p. 8078 - 8081]
[2]Lin, Ruo-Kai; Lin, Yuh-Feng; Hsu, Ming-Jen; Hsieh, Chang-Lin; Wang, Chen-Yu; Huang, Chih-Chiang; Huang, Wei-Jan [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5528 - 5533]
[3]Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 12, p. 1527 - 1531]
[4]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]
[5]Current Patent Assignee: MERCK & CO INC - US4665091, 1987, A
[6]Tian, Lei; Tao, Jie; Chen, Liqin [Journal of labelled compounds and radiopharmaceuticals, 2011, vol. 54, # 9, p. 625 - 628]
[7]Current Patent Assignee: STERLING BIOTECH RESEARCH CENTRE - US2011/282074, 2011, A1 Location in patent: Page/Page column 5
[8]Chen, Jhih-Bin; Chern, Ting-Rong; Wei, Tzu-Tang; Chen, Ching-Chow; Lin, Jung-Hsin; Fang, Jim-Min [Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3645 - 3655]
[9]Current Patent Assignee: NEURON BIOPHARMA SA - US2013/197073, 2013, A1 Location in patent: Paragraph 0102; 0103;
[10]Current Patent Assignee: ACADEMIA SINICA; NATIONAL TAIWAN UNIVERSITY - US2014/206645, 2014, A1
[11]Current Patent Assignee: BEIJING LABWORLD BIOMEDICAL TECHNOLOGY CO LTD - CN104529971, 2017, B Location in patent: Paragraph 0074; 0075; 0076
[12]Current Patent Assignee: UPPTHERA - WO2021/201577, 2021, A1 Location in patent: Paragraph 463-466
[13]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN113527273, 2021, A Location in patent: Paragraph 0058-0061

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[ 75330-75-5 ]
[ 132748-10-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium hydroxide In methanol at 20℃; Reflux;	1; 2; 3 Example 2 Preparation of Compound III Add Compound II (0.120mol) to the reaction flask.Add potassium hydroxide solution (0.260mol),180ml of methanol, heated to reflux,The reaction was lowered to room temperature for 4-5 hours, adjusted to pH = 2 with hydrochloric acid, and the methanol was removed under reduced pressure.Get solid, dry in vacuum,39.80 g of compound III was obtained with a yield of 98% and a purity of 99.5%.
93%	Stage #1: lovastatin In ethanol; water at 20℃; for 12.5 - 17h; Heating / reflux; Stage #2: With hydrogenchloride; water In diethyl ether at 5 - 10℃; for 1h;	1 EXAMPLE 1; Hydrolysis of Lovastatin And Formation of Trihydroxy Acid Intermediate (Reaction 4)Under the protection of nitrogen, 20.0 gram of lovastatin was dissolved in 200 ml of heated ethanol. At room temperature, 100 ml of cooled aqueous solution of potassium hydroxide (36 g) was slowly added into the above reaction solution. The reaction mixture was stirred for 0.5 to 1 hour under the protection of nitrogen in room temperature, and then refluxed for 12 to 16 hours. Additionally, added 300 ml of water, vaporized to remove 500 ml of solvent, then cooled to a temperature of 510° C. Then added 80 ml of ether, and adjusted pH value to 5.0 by slowly adding concentrated hydrochloric acid, meanwhile controlling temperature within a range from 5 to 10° C. Stirred for another 1 hour, then the trihydroxy acid intermediate in ether crystallized and precipitated, and the solid product obtained was washed with water and dried in vacuum, weighed 15.6 gram (yield: 93%).Melting point (m.p.): 127129° C.1H-NMR (δ, CDCl3): 5.96 (d, 1H), 5.79 (dd, 1H), 5.54 (br, 1H), 4.33 (m, 1H), 4.28 (m, 1H), 3.96 (m, 1H), 2.2-2.6 (m, 7H), 1.1-1.9 (m, 10H), 1.18 (d, 3H), 0.91 (d, 3H).
90%	Stage #1: lovastatin With potassium hydroxide In water; isopropyl alcohol at 80℃; for 7h; Stage #2: With hydrogenchloride In water at 12 - 17℃; for 2h; Cooling with ice;	2 Example 2 Preparation of Monacolin J Hydroxy Acid from Lovastatin Example 2 Preparation of Monacolin J Hydroxy Acid from Lovastatin (0118) To lovastatin (30 g, 0.074 mol) in a 3-neck round bottom flask (RBF) fitted with a condenser was added isopropanol (IPA, 250 mL). KOH pellets (33.2 g, 0.593 mol) and water (3 mL, 0.1 vol) were then added to the stirred suspension. The reaction was stirred at 80° C. (internal temperature) for 7 h. The reaction was then cooled to 50° C. and IPA was removed under reduced pressure (35° C., 50 mbar) until a final volume of 100 mL (3.3 vol) was achieved. Water (110 mL, 3.7 vol) was added to the residue and the solution was cooled to 10° C. in an ice-water bath. 6 M HCl (92 mL, 3.0 vol) was added dropwise to the solution while maintaining the internal temperature between 12-17° C. The pH of the solution was thereby adjusted to a final pH between 3 and 4. The mixture was then stirred in an ice-bath for 2 h. The solid obtained was filtered off and washed with water (60-90 mL, 2-3 vol) and then with heptane (60 mL, 2 vol). The filter cake was dried in a vacuum oven at 25° C. for 24 h to yield a white solid (22.4 g, 90% yield) with >99% purity by HPLC analysis.

83%	for 23 - 40.5h; Enzymatic reaction;	9.1 Example 9: Enzymatic hydrolysis of Lovastatin; The following example provides an exemplary protocol of the invention comprising the enzymatic hydrolysis of lovastatin. Step 1 : Enzymatic Hydrolysis of Lovastatin A. Separation of Spent Enzyme from Triol Acid Heat Treatment After enzymatic hydrolysis was complete, 4 x 10 g reactions were heated to 80-85°C for 1 h. There was no obvious precipitation of denatured protein; the reactions remained a cloudy greenish/black color. Cooling to RT resulted in no apparent change in the color or viscosity of the reaction mixtures. 564462012840 pH Manipulation A solution of 10 g of enzyme powder in 10% MeOH/water at pH 10.5 does not filter easily when treated with CELIEZ diatomaceous earth (3 g). Adjusting to pH 6 results in a heavy precipitation which does not filter easily even after prolonged stirring with an equal weight of CELITE diatomaceous earth. After adjusting to pH 6 and centrifugation, the supernatant still contains material which precipitates on lowering the pH further. 'Triol acid is soluble at 2M in the range pH 9.5-3.5. Microfiltration After centrifugation to remove a small amount of insolubles, 4 x 10 g combined enzymatic hydrolyses were filtered through a Spectrum Labs polysulfone hollow fiber bundle (10K MW cutoff ; 1050 cm2). This is a convenient method for removing the high MW materials from the reaction mixture before precipitation of the triol acid. The solution filters at a reasonable rate (-3-4 h for ~1L solution). After microfiltration, decreasing the pH of the effluent does not lead to precipitation until-pH 4. The precipitated triol acid is easily filtered and dried under vacuum. B. Performance of Enzyme Batches * 4 lots of lovastatin esterase were used. * Comparison of the 4 enzyme lots at 0. 5M/20% enzyme load and 0.25M/10% enzyme load showed comparable behavior for all lots with 99% conversion at 23 h and >99.5% conversion in 23-40.5 h. Two enzyme use tests (4 x 10 g and 5 X 10 g) were subjected to the microfiltration workup. The isolated triol acid, in both cases, was only 82.7 and 83.8% pure when assayed against a working standard of triol acid. Only 83-86% of the material could be accounted for when the residues were assayed.
73.7%	Stage #1: lovastatin With lithium hydroxide In water for 68h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride In water at 0℃;
	With lithium hydroxide Heating;
	Stage #1: lovastatin With methanol; water for 48h; Alkaline conditions; Enzymatic reaction; Stage #2: In methanol Acidic conditions;	1; 6.1 EXAMPLES; Example 1: Chemoenzymatic production of Simvastatin; The following example describes an exemplary protocol of the invention, e. g., for the chemoenzymatic production of Simvastatin. Enzymatic Hydrolysis of Lovastatin The enzyme having a sequence as set forth in SEQ ID NO : 4 (encoded by SEQ ID NO : 3) was evaluated at 0.1 to 0.5 M concentrations of lovastatin or lovastatin acid in 7-10% MeOH/buffer, with the reaction being maintained at pH 9-9.5 by automatic addition of base. For example, at 0. 5M lovastatin on a 500 mL scale using a lyophilized preparation of enzyme SEQ ID NO : 4 (centrifuged supernatant from lysed cells) containing 14 mg/mL total protein, complete conversion of substrate was observed after 48 h. The reaction mixture was acidified (pH 2), and the precipitate collected by centrifugation and dried. The filtrate was extracted with iPrOAc and the organic extract was added to the dried filter cake. The resulting suspension was heat to reflux in a Dean- Stark apparatus until lactonization was complete. The resulting solution was filtered through a Celite pad, and the filtrate was washed with satd. NaHCO3. The resulting iPrOAc solution was concentrated until (x 0.5), diluted with hexanes and cooled to 0°C. The precipitated solid was filtered and air-dried to yield diol lactone (63 g, 79.5% isolated yield; another 10.3 g of product was identified in various washes and mother liquors). The product contained <1% lovastatin; Example 6: Exemplary processes of the invention; The following example describes exemplary protocols of the invention, including schemes for synthesizing simvastatin from lovastatin. The invention provides a method for making lovastatin acid from lovastatin, and triol acid from lovastatin acid, as illustrated in Figure 16A, or"Step 1."In this aspect, the protocol effects complete (>99%) removal of the methylbutyrate sidechain. This can be important because of the difficulty in separating lovastatin and simvastatin, and the low allowable levels of lovastatin in simvastatin API (some procedures for the hydrolysis of lovastatin have required the use of high temperatures and long reaction times for a complete (>99%) reaction). Lovastatin is hydrolyzed under mild conditions using a hydrolase enzyme (e. g., as described herein), resulting in hydrolysis of the lactone ring and complete removal of the side-chain in the 8-position. Three exemplary hydrolase enzymes that can be used in this enzymatic hydrolysis of the methylbutyrate sidechain are the esterase enzymes: SEQ ID NO : 4 (encoded by, e. g., SEQ ID NO : 3), SEQ ID NO : 6 (encoded by, e. g., SEQ ID NO : 5), and SEQ ID NO : 2 (encoded by, e. g., SEQ ID NO : 1). SEQ ID NO : 4 (encoded by, e. g., SEQ ID NO : 3). Each has been subcloned and expressed in different hosts and fermented at different scales, including at 200 liter (L) scale. Lovastatin shows poor solubility under the aqueous conditions necessary for enzymatic activity. Alternatively, in one aspect, a suspension of lovastatin in water is raised to pH >12 to effect a rapid hydrolysis of the lactone ring resulting in the ire-site formation of the more soluble lovastatin acid salt. In practice, a suspension of lovastatin in water/MeOH is treated with a solution of 1 mole equivalent of NaOH in water and stirred until dissolution is complete. The pH of the reaction mixture is then readjusted to a range suitable for the enzymatic reaction and the enzyme is added. In alternative aspects, enzymatic hydrolysis conditions can be applied to mixtures of lovastatin and/or lovastatin acid extracted directly from fermentation broth, or the enzyme may be added to the fermentation broth and the triol acid isolated directly. After hydrolysis, the reaction mixture is carefully acidified, and the triol acid is isolated by extraction and/or filtration. In one aspect, it is used directly in the next step, or it is isolated as a solid after a suitable crystallization/precipitation step. The invention provides a method for making diol lactone from triol acid, as illustrated in Figure 16B, or"Step 2. "In one aspect, the triol acid is re-lactonized by heating in a suitable solvent, driving the equilibrium to the lactone form by removal of water by conventional means. Alternatively, in one aspect the triol acid is re-lactonized by stirring in the presence of a suitable acid. This also will effect closure of the lactone ring. The diol lactone may be purified at this stage by crystallization/precipitation from suitable solvent (s). The invention provides a method for making acyl lactone from diol lactone, as illustrated in Figure 16C, or"Step 3. "In one aspect, regioselective acylation of the hydroxyl group in the 4'-position is carried out enzymatically using an enzyme with the desired activity and selectivity. The nature of the acyl group can be varied to impart suitable properties, e. g., acetate for ease of removal, benzoate for enhanced crystallinity, formate for enhanced water solubility. In an alternative aspect, as illustrated in Figure 16D (steps 2 and 3, above, combined), in a"telescoped variation"of this protocol of the invention, lactonization and acylation at the lactone 4-position is carried out in a single pot. When treated with 2 equivalents of an anhydride in the presence of a base (e. g., DMAP) the triol acid first undergoes lactonization followed by a regioselective acylation at the lactone 4-OH to form 4-acyllactone. This product is then isolated and purified by crystallization/precipitation from suitable solvent (s). The invention provides a method for making acyl simvastatin from acyl lactone by, e. g., chemical or enzymatic acylation, as illustrated in Figure 16E, or"Step 4. "A combination of a dimethylbutyric acid derivative with a suitable acylation catalyst can be used to install the desired side-chain, e. g., the simvastatin side-chain. While the combination of dimethylbutyryl chloride/dimethylaminopyridine has been described, the reaction times are excessive, the conditions are harsh and lead to the formation of unacceptable levels of by-products. In contrast, the invention's combination of dimethylbutyric anhydride/Lewis acid (e. g., Bi (triflate) 3, Cu (triflate) 2), BF3. Et2O results in rapid reaction at room temperature. Screening of suitable Lewis acids and reaction conditions (temperature, solvent etc.) can identify the optimum conditions for this acylation. In one aspect, enzyme-catalyzed acylation of the acyl lactone is used to install the dimethylbutyrate group at the 8-position under very mild conditions (rt-40°C, organic solvent) without formation of side products. The invention provides a method for making simvastatin ammonium salt from acyl simvastatin, and simvastatin from simvastatin ammonium salt, as illustrated in Figure 16F, or"Step 5. "The final steps require the selective removal of the acyl group at the 4'-position. The acyl group at the 4'-position is highly susceptible to base-catalyzed elimination, even under only slightly basic conditions. Consequently, enzymatic hydrolysis has been the most convenient method for regioselective removal of this acyl group. It was demonstrated that the esterase that hydrolyzes lovastatin (SEQ ID NO : 4, encoded, e. g., by SEQ ID NO : 3) in step 1 (above) can also effectively catalyze the selective hydrolysis of acyl groups at the lactone 4'-position. When carried out at pH 7, this enzymatic hydrolysis yields simvastatin with the lactone ring substantially intact. Any assay known in the art can be used for screening, characterization, etc. For example, enzyme screening can use any standard HPLC and TLC analyses, many of which are known to those skilled in the art. The following describes another exemplary protocol and alternative conditions for practicing the methods of the invention; Enzymatic Hydrolysis of Lovastatin to Triol Acid (Step 1); SEQ ID NO : 4 (encoded, e. g., by SEQ ID NO : 3) was evaluated at 0.1-0.5 M concentrations of lovastatin or lovastatin acid in 7-10% MeOH/buffer, with the reaction being maintained at pH 9-9.5 by automatic addition of base. The best result was obtained at 0. 5M lovastatin on a 500 mL scale using a lyophilized preparation of enzyme SEQ ID NO : 4 (encoded by SEQ ID NO : 3) (centrifuged supernatant from lysed cells) containing 14 mg/mL total protein; complete conversion of substrate was observed after 48 h.
	for 4 - 39h; Enzymatic reaction;	11 Example 11: An exemplary hydrolysis protocols; This example describes exemplary protocols of the invention, including industrial scaled up processes for making simvastatin and intermediates, e. g., as in Figures 5 and 6. A protocol for the enzymatic hydrolysis of lovastatin to triol acid using SEQ ID NO : 4 (see, e. g., step 1, Figure 5) was completed, and Figure 30 illustrates the results of this exemplary lovastatin hydrolysis protocol. Enzyme source of SEQ ID NO : 4 was lysate from mini-fermentors. The protocol resulted in 99% conversion at 39 h (90% 24 h) on 12 g scale (0. 5M) with lyophilate from 10 L fermentation (214 g). Summarizing the parameters used in this study: Catalyst Load Conversion Time 56% w/w 100% about 4 h 33% w/w 97% about 24 h 22% w/w 97% about 24 h At 22% w/w lyophilate loading, using 10L fermentation hydrolyzes 1 kg lovastatin. A large-scale enzymatic hydrolysis of lovastatin to lovastatin acid to triol acid was carried out on a DasGip FEDBATCH PROTM bioreactor at constant pH 9, substrate at 500 mM, 7% MeOH, 40°C, as illustrated in Figure 31. A scaled-up 564462012840 exemplary protocol of an enzymatic hydrolysis of lovastatin to diol lactone, which can be an exemplary industrial scale process, is illustrated in the schematic of Figure 32. This reaction, with a summary of reaction parameters (reaction scale, workup, theoretical yield, product in g, % yield), is illustrated in Figure 33. Data from (a) a 50 gram (g) reaction is summarized in Figure 34A (after lactonization and concentration) and 34B (crude product), and (b) a 100 g reaction Figure 35A (triol acid) and 35B (after lactonization). Methyl (Me) 4-acetyl simvastatin was hydrolyzed enzymatically to simvastatin using a reaction as illustrated in Figure 6, step 5. Results and conclusions from this reaction are: Facile elimination at pH >7 (13% at pH 8). Enzymatic hydrolysis occurs readily, but limited by solubility. Formate > acetate-chloroacetate > methoxyacetate. 100 mM (5% w/v) hydrolyzed overnight at pH 7. 200 mM 84% conversion in 20 h in 10% MeOH at 50°C. 200 mM 89% conversion in 7 h with 50% w/w lyophilate. 400 mM biphasic with toluene. * Reactions proceed to 80-90% then stop. Insoluble simvastatin traps unreacted substrate. Summarizing these reactions (at 300 mM (14% w/v) substrate, All reactions with overhead stirring and stirrer bar below, pH 7 with 10% NH40H ; 50°C) and final conversions: 270 mM acetyl simvastatin, 13 mM homo simvastatin, with solvent as equal volumes toluene, gave a final conversion of 88. 2%. 300 mM acetyl simvastatin, with solvent as 10% methanol (MeOH), gave a final conversion of 91.3%. 300 mM acetyl simvastatin, with solvent as 10% methanol (MeOH), and addition toluene at 6 hours, gave a final conversion of 96. 1%.
	With methanol; sodium hydroxide for 45.5h; tris-HCl buffer; Enzymatic reaction;	10 Example 10: Fractional factorial design of grz=atic h; The enzymatic hydrolysis of lovastatin was subjected to fractional factorial design for optimization of the reaction. The fractional factorial design was done with DESIGN EXPERTTM software on 0. 35M lovastatin acid, Na salt, the results are illustrated in Figure 24. Notes for Figure 24 are: 1 Enzyme activity was measured on methyl umbelliferyl butyrate and expressed as the slope obtained for 0.1 jug total protein. 2 Rate of triol acid formation up to 3 h. 3 Triol acid formed at 45.5 h (%). Four factors affect lovastatin acid hydrolysis: % Triol acid formed, enzyme concentration, buffer concentration, and the amount of MeOH, as illustrated in Figure 25, where all reactions performed with clarified lysate of E. coli containing SEQ ID NO : 4, and reactions carried out under pH-stat conditions in a DasGip FEDBATCH- PROS system. A Response Surface Analysis (RSA) was performed using central composite design for hydrolysis of 0.35 M Lovastatin using DESIGN EXPERT software, the results are illustrated in Figure 26. Notes for Figure 26 are: 1 Enzyme activity was measured on methyl umbelliferyl butyrate and expressed as the slope obtained for 0.1 jug total protein (RFU/s). 2 Rate of triol acid formation up to 3 h. 3 Triol acid formed at 45.5 h (%). The iia sitaa hydrolysis of lovastatin with SEQ ID NO : 4 was optimized such that insignificant amounts of NaCl generated: 0.85 g lovastatin in MeOH and equimolar NaOH added. Clarified lysate of E. coli containing SEQ ID NO : 4 was added to lovastatin acid. Significant factors were: methanol concentration ( [MeOH]), enzyme concentration ( [Enzyme]) was highly significant, and buffer concentration ( [Buffer]) had a slight effect at low [Enzyme]. See Figure 27 for an illustration summary of the results. The results of Response Surface Analysis (RSA) can be applied to large- scale hydrolysis of lovastatin, e. g., using a protocol as illustrated in Figure 28: -Reaction performed successfully on 100 g scale (0.5 M); 97. 5% conversion in 27 h; Productivity : x g/g esterase/h ; Specific activity: 0.084 pmol/mg esterase/min. Substrate specificities of SEQ ID NO : 4 were studies: many 4-acyl derivatives of simvastatin are actively hydrolyzed by SEQ ID NO : 4, as illustrated in Figure 29. Chemical hydrolysis of Acetylsimvastatin results in dehydration of the lactone ring.

Reference： [1]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN110563680, 2019, A Location in patent: Paragraph 0011; 0025-0033
[2]Current Patent Assignee: PFICKER PHARMACEUTICALS - US2009/43115, 2009, A1 Location in patent: Page/Page column 5; 9
[3]Current Patent Assignee: CODEXIS INC - US9399785, 2016, B2 Location in patent: Page/Page column 23; 24
[4]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 71-72
[5]Location in patent: experimental part Tian, Lei; Tao, Jie; Chen, Liqin [Journal of labelled compounds and radiopharmaceuticals, 2011, vol. 54, # 9, p. 625 - 628]
[6]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]
[7]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 31-32; 60
[8]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 75-76
[9]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 74-75

15
[ 3282-30-2 ]
[ 75330-75-5 ]
[ 479482-41-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With pyridine In toluene at 20℃;
77%	With pyridine In toluene at 20℃; for 24h; Inert atmosphere;	Generalprocedure for the preparation of 2b-i General procedure: To a solution of lovastatin (1, 2.02 g, 5.00 mmol) in toluene (25 mL) was addedpyridine (0.9 mL, 11.00 mmol) and the appropriate acyl chloride (10.00 mmol).The resulting solution was stirred at RT under N2 for 24 h. Thereaction mixture was diluted with toluene (50 mL) and then washed with 1N HCl(aq)(3x 25 mL), 10% NaHCO3(aq) (25 mL), and distd H2O (30 mL).The organic layer was dried over Na2SO4, filtered and thesolvent removed in vacuo. The residue was purified by silica gel chromatography(EtOAc: n-hexane=1: 4). (S)-2-Methyl-butyricacid (3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-(tert-butyl-carbaloxy) -6-oxo-tetrahydro-pyran-2yl]-ethyl}-3,7-dimetyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester (2b) Yield: 77%. Mp 95-100 °C (acetone). IR (KBr) 3749, 3648, 2969, 1730, 1456, 1375 cm-1. 1H NMR (500 MHz, CDCl3): δ 5.99 (d, J = 9.7 Hz, 1H), 5.78(dd, J = 6.1, 9.5 Hz, 1H), 5.53 (s, 1H),5.37 (d, J = 2.6 Hz, 1H), 5.22 (dt, J = 3.3, 5.9 Hz, 1H), 4.44 (m, 1H), 2.27(dd, J = 5.8, 18.3 Hz, 1H), 2.68 (dq,J = 1.2, 3.0, 18.0 Hz, 1H), 2.44 (m, 1H),2.34 (m, 2H), 2.26 (dd, J = 2.3, 12.0Hz, 1H), 2.00 (m, 2H), 1.92 (dd, J =1.9, 7.9 Hz, 1H), 1.82 (m, 1H), 1.78 (dd, J= 3.3, 14.8 Hz, 1H), 1.72 (m, 1H), 1.65 (m, 1H), 1.49 (m, 1H), 1.45(m, 2H),1.28 (m, 1H), 1.20 (s, 9H), 1.10 (d, J= 6.8 Hz, 3H), 1.08 (d, J = 7.4 Hz, 3H),0.89 (d, J = 7.0 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H). EI-MS m/z: 488.3 (M)+.

Reference： [1]Dabak, Kadir; Adiyaman, Mustafa [Helvetica Chimica Acta, 2003, vol. 86, # 3, p. 673 - 677]
[2]Lin, Ruo-Kai; Lin, Yuh-Feng; Hsu, Ming-Jen; Hsieh, Chang-Lin; Wang, Chen-Yu; Huang, Chih-Chiang; Huang, Wei-Jan [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5528 - 5533]

16
[ 98-88-4 ]
[ 75330-75-5 ]
[ 81189-93-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With pyridine In toluene at 20℃; for 18h;
85%	With pyridine In toluene at 20℃; for 24h; Inert atmosphere;	Generalprocedure for the preparation of 2b-i General procedure: To a solution of lovastatin (1, 2.02 g, 5.00 mmol) in toluene (25 mL) was addedpyridine (0.9 mL, 11.00 mmol) and the appropriate acyl chloride (10.00 mmol).The resulting solution was stirred at RT under N2 for 24 h. Thereaction mixture was diluted with toluene (50 mL) and then washed with 1N HCl(aq)(3x 25 mL), 10% NaHCO3(aq) (25 mL), and distd H2O (30 mL).The organic layer was dried over Na2SO4, filtered and thesolvent removed in vacuo. The residue was purified by silica gel chromatography(EtOAc: n-hexane=1: 4).

Reference： [1]Dabak, Kadir; Adiyaman, Mustafa [Helvetica Chimica Acta, 2003, vol. 86, # 3, p. 673 - 677]
[2]Lin, Ruo-Kai; Lin, Yuh-Feng; Hsu, Ming-Jen; Hsieh, Chang-Lin; Wang, Chen-Yu; Huang, Chih-Chiang; Huang, Wei-Jan [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5528 - 5533]

17
[ 75330-75-5 ]
[ 121-44-8 ]
(3R,5S)-7-[(1S,2S,6R,8S,8aR)-2,6-Dimethyl-8-((S)-2-methyl-butyryloxy)-1,2,6,7,8,8a-hexahydro-naphthalen-1-yl]-3,5-dihydroxy-heptanoic acid; compound with triethyl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: lovastatin With sodium hydroxide In methanol; water at 20℃; for 2h; Stage #2: triethylamine In ethyl acetate at 20℃; for 4h;

Reference： [1]Dabak, Kadir; Keskin, Hulya [Heterocyclic Communications, 2004, vol. 10, # 1, p. 29 - 34]

18
[ 75330-75-5 ]
simvastatin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: NaOH / methanol; H₂O / 2 h / 20 °C 1.2: 98 percent / ethyl acetate / 4 h / 20 °C 2.1: pyrrolidine; n-BuLi / tetrahydrofuran; hexane / -30 - 35 °C 2.2: tetrahydrofuran / 1 h / -30 °C 2.3: 90 percent / NH₄OH / ethyl acetate; H₂O; methanol / 2 h / 20 °C 3.1: 92 percent / toluene / 4 h / 90 °C
	Multi-step reaction with 4 steps 1.1: 92 percent / pyridine / toluene / 20 °C 2.1: 48 percent / (EtO)3CH; H₂SO₄ / tetrahydrofuran / 20 °C 3.1: pyrrolidine BuLi / tetrahydrofuran; hexane / -30 °C 3.2: tetrahydrofuran / -30 - -10 °C 3.3: 84 percent / H₂O / tetrahydrofuran / 0 °C 4.1: 92 percent / aq. HCl / tetrahydrofuran / 3 h / 20 °C
	Multi-step reaction with 4 steps 1.1: 91 percent / pyridine / toluene / 18 h / 20 °C 2.1: 51 percent / (EtO)3CH; H₂SO₄ / tetrahydrofuran / 48 h / 20 °C 3.1: pyrrolidine; BuLi / tetrahydrofuran; hexane / 2 h / -30 °C 3.2: tetrahydrofuran / 2.5 h / -30 - -10 °C 3.3: 85 percent / H₂O / tetrahydrofuran / 0.33 h / 0 °C 4.1: 92 percent / aq. HCl / tetrahydrofuran / 3 h / 20 °C

	In piperidine	3.I Preparation of Simvastatin (II) from Lovastatin using piperidine as the secondary amine Step I: Preparation of Compound IIb3 A solution of Lovastatin (10 g) in piperidine (75 mL) was refluxed for 5 hours. Excess piperidine was removed under reduced pressure, and the residue was purified by column chromatography using 60-120 silica gel to give the pure amide intermediate IIb3. Compound IIb3 was converted to Simvastatin by subjecting it to steps II-IV described in Example 1.
	Multi-step reaction with 4 steps 1: sodium hydroxide / methanol / 35 h / 40 °C / Reflux 2: 1H-imidazole / N,N-dimethyl-formamide / 15 - 20 °C / Inert atmosphere 3: dmap; pyridine / n-heptane / 36 h / Inert atmosphere; Reflux 4: water; hydrogen fluoride / acetonitrile / 2.5 h / 0 - 25 °C
	Multi-step reaction with 4 steps 1.1: 8 h / 40 - 42 °C / Inert atmosphere 2.1: n-butyllithium; pyrrolidine / tetrahydrofuran; hexane / 1 h / -45 - -20 °C / Inert atmosphere 2.2: 1 h / -35 - -30 °C / Inert atmosphere 3.1: sodium hydroxide / methanol / 3 h / 75 - 78 °C / Inert atmosphere 3.2: 10 - 15 h / pH 4 / Inert atmosphere 3.3: 1.5 h / 22 - 25 °C / Inert atmosphere 4.1: toluene / 5 h / 105 °C / Acidic conditions
	Multi-step reaction with 6 steps 1.1: 3 h / 70 °C / Inert atmosphere 2.1: 1H-imidazole / 3 h / 68 °C / Inert atmosphere 3.1: n-butyllithium; pyrrolidine / tetrahydrofuran; methyl cyclohexane / 3.5 h / -45 - -30 °C / Inert atmosphere 3.2: 1 h / -45 - -20 °C 4.1: hydrogenchloride / methanol; water / 3 h / 20 °C / pH 2 - 3 5.1: sodium hydroxide / water / 2.5 h / 75 °C 5.2: 0.5 h 6.1: methanesulfonic acid / dichloromethane / 3 h / 10 - 20 °C

Reference： [1]Dabak, Kadir; Keskin, Hulya [Heterocyclic Communications, 2004, vol. 10, # 1, p. 29 - 34]
[2]Dabak, Kadir; Adiyaman, Mustafa [Helvetica Chimica Acta, 2003, vol. 86, # 3, p. 673 - 677]
[3]Dabak, Kadir; Adiyaman, Mustafa [Helvetica Chimica Acta, 2003, vol. 86, # 3, p. 673 - 677]
[4]Current Patent Assignee: BIOCON LIMITED - US6573385, 2003, B1
[5]Current Patent Assignee: STERLING BIOTECH RESEARCH CENTRE - US2011/282074, 2011, A1
[6]Thaper, Rajesh K.; Kumar, Yatendra; Kumar, S.M. Dileep; Misra, Satyananda; Khanna, Jag Mohan [Organic Process Research and Development, 1999, vol. 3, # 6, p. 476 - 479]
[7]Current Patent Assignee: XINCHANG KANGLE CHEMICALS CO., LTD. - CN104803959, 2017, B

19
[ 75330-75-5 ]
[ 79902-31-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: aq. LiOH / Heating 2: 140 mg / toluene / 1 h / Heating 3: 74 percent / imidazole / dimethylformamide / 18 h / 20 °C
	Multi-step reaction with 3 steps 1.1: lithium hydroxide / water / 68 h / Inert atmosphere; Reflux 1.2: 0 °C / pH 2 2.1: toluene / 3 h / Reflux 3.1: 1H-imidazole / N,N-dimethyl-formamide / 20 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium hydroxide / methanol / 35 h / 40 °C / Reflux 2: 1H-imidazole / N,N-dimethyl-formamide / 15 - 20 °C / Inert atmosphere

	Multi-step reaction with 2 steps 1.1: potassium hydroxide / water; methanol / 8 h / Reflux 1.2: 4.5 h / 20 °C 2.1: 1H-imidazole / dichloromethane / 5.5 h / 20 °C
	Multi-step reaction with 2 steps 1: water; potassium hydroxide / methanol / 21 h / Reflux 2: 1H-imidazole / dichloromethane / 24 h
	Multi-step reaction with 3 steps 1: potassium hydroxide; methanol / water / 8 h / Reflux 2: hydrogenchloride / water; dichloromethane / 4.5 h / 20 °C / pH 2 3: 1H-imidazole / dichloromethane / 5.5 h / 20 °C
	Multi-step reaction with 2 steps 1: potassium hydroxide / methanol; water / 8 h / Reflux 2: 1H-imidazole / dichloromethane / 5.5 h / 20 °C
	Multi-step reaction with 2 steps 1: potassium hydroxide; water / methanol / 12 h / 100 °C 2: 1H-imidazole / 12 h / 20 °C
	Multi-step reaction with 2 steps 1.1: potassium hydroxide / water; methanol / 12 h 1.2: 6 h / 20 °C / pH 2 2.1: 1H-imidazole / dichloromethane / 6 h / 20 °C

Reference： [1]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]
[2]Tian, Lei; Tao, Jie; Chen, Liqin [Journal of labelled compounds and radiopharmaceuticals, 2011, vol. 54, # 9, p. 625 - 628]
[3]Current Patent Assignee: STERLING BIOTECH RESEARCH CENTRE - US2011/282074, 2011, A1
[4]Chen, Jhih-Bin; Chern, Ting-Rong; Wei, Tzu-Tang; Chen, Ching-Chow; Lin, Jung-Hsin; Fang, Jim-Min [Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3645 - 3655]
[5]Current Patent Assignee: NEURON BIOPHARMA SA - EP2628737, 2013, A1
[6]Current Patent Assignee: ACADEMIA SINICA; NATIONAL TAIWAN UNIVERSITY - US2014/206645, 2014, A1
[7]Current Patent Assignee: BEIJING LABWORLD BIOMEDICAL TECHNOLOGY CO LTD - CN104529971, 2017, B
[8]Current Patent Assignee: UPPTHERA - WO2021/201577, 2021, A1
[9]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN113527273, 2021, A

20
[ 75330-75-5 ]
6(R)-<2-<1,2,4a,5,6,7,8,8a(S)-Octahydro-2(S),6(S)-dimethyl-8(S)-<<2(S)-methylbutyryl>oxy>-1(S)-naphthyl>ethyl>-3,4,5,6-tetrahydro-4(R)-<(tert-butyldimetylsilyl)oxy>-2H-pyran-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: aq. LiOH / Heating 2: 140 mg / toluene / 1 h / Heating 3: 74 percent / imidazole / dimethylformamide / 18 h / 20 °C 4: 86 percent / H₂ / Ir(cod)py(Pcy₃)PF₆ / CH₂Cl₂; methanol 5: 72 percent / DMAP; pyridine / CH₂Cl₂ / 72 h / 20 °C

Reference： [1]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]

21
[ 75330-75-5 ]
4a,5-dihydromonacolin j [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: aq. LiOH / Heating 2: 140 mg / toluene / 1 h / Heating 3: 74 percent / imidazole / dimethylformamide / 18 h / 20 °C 4: 86 percent / H₂ / Ir(cod)py(Pcy₃)PF₆ / CH₂Cl₂; methanol 5: 60 percent / TBAF; glacial AcOH / tetrahydrofuran / 4 h / 0 - 20 °C

Reference： [1]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]

22
[ 75330-75-5 ]
4a,5-dihydrolovastin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: aq. LiOH / Heating 2: 140 mg / toluene / 1 h / Heating 3: 74 percent / imidazole / dimethylformamide / 18 h / 20 °C 4: 86 percent / H₂ / Ir(cod)py(Pcy₃)PF₆ / CH₂Cl₂; methanol 5: 72 percent / DMAP; pyridine / CH₂Cl₂ / 72 h / 20 °C 6: 85 percent / HCl / methanol / 1 h / 20 °C

Reference： [1]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]

23
[ 75330-75-5 ]
4a,5-dihydro(tert-butyldimethylsiloxy)monacolin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: aq. LiOH / Heating 2: 140 mg / toluene / 1 h / Heating 3: 74 percent / imidazole / dimethylformamide / 18 h / 20 °C 4: 86 percent / H₂ / Ir(cod)py(Pcy₃)PF₆ / CH₂Cl₂; methanol

Reference： [1]Sorensen, John L.; Auclair, Karine; Kennedy, Jonathan; Hutchinson, C. Richard; Vederas, John C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 1, p. 50 - 59]

24
[ 116996-47-5 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 2: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 3: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 3 steps 1: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 2: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 3: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

25
[ 116996-48-6 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 2: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 2 steps 1: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 2: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

26
<4R-<4α*(1R^*,2S^*)>6α>>-6-<2-<<(1,1-dimethylethyl)diphenylsilyl>oxy>ethyl>-2,2-dimethyl-α-(2-methyl-5-oxo-3-cyclohexen-1-yl)-1,3-dioxane-4-propanal [ No CAS ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1: 50 percent / (Ph₃P)3RhCl / toluene; acetonitrile / 2.5 h / Heating 2: 1.) LDA / 1.)Et₂O, -78 deg C, 45 min; 2.) -78 deg C, 10 min 3: 85 percent / i-Pr₂NH / DMAP / diethyl ether / 24 h / Ambient temperature 4: 1.) O₃; 2.) Ph₃P / 1.) CH₂Cl₂, -78 deg C; 2.) -78 deg C -> r.t., 3 h 5: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / r.t., 5 h; reflux, 4 h 6: 1.) Bu₄NF ; 2.) t-BuPh₂SiCl, Et₃N / 2.) DMAP / 1.) THF, r.t., 22 h; 2.) CH₂Cl₂, r.t., 24 h 7: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 8: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 9: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 10: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 11: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 12 steps 1: 50 percent / (Ph₃P)3RhCl / toluene; benzonitrile / 2.5 h / Heating 2: 1.) lithium diisopropylamide (LDA) / 1.) ether, -78 deg C, 45 min, 2.) -78 deg C, 10 min 3: 85 percent / diisopropylamine, 4-(dimethylamino)pyridine (DMAP) / diethyl ether / 24 h / Ambient temperature 4: 85 percent / 1.) O₃, 2.) triphenylphosphine / CH₂Cl₂ / 1.) -78 deg C, 5 min, 2.) 3 h 5: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / 1.) RT, 5 h, 2.) reflux, 4 h 6: 99 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 22 h / Ambient temperature 7: Et₃N, 4-(dimethylamino)pyridine (DMAP) / CH₂Cl₂ / 24 h / Ambient temperature 8: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 9: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 10: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 11: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 12: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

27
[ 116996-45-3 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 2: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 3: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 4: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 5: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 5 steps 1: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 2: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾*F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 3: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 4: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 5: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

28
[ 117020-88-9 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: 85 percent / i-Pr₂NH / DMAP / diethyl ether / 24 h / Ambient temperature 2: 1.) O₃; 2.) Ph₃P / 1.) CH₂Cl₂, -78 deg C; 2.) -78 deg C -> r.t., 3 h 3: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / r.t., 5 h; reflux, 4 h 4: 1.) Bu₄NF ; 2.) t-BuPh₂SiCl, Et₃N / 2.) DMAP / 1.) THF, r.t., 22 h; 2.) CH₂Cl₂, r.t., 24 h 5: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 6: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 7: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 8: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 9: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 10 steps 1: 85 percent / diisopropylamine, 4-(dimethylamino)pyridine (DMAP) / diethyl ether / 24 h / Ambient temperature 2: 85 percent / 1.) O₃, 2.) triphenylphosphine / CH₂Cl₂ / 1.) -78 deg C, 5 min, 2.) 3 h 3: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / 1.) RT, 5 h, 2.) reflux, 4 h 4: 99 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 22 h / Ambient temperature 5: Et₃N, 4-(dimethylamino)pyridine (DMAP) / CH₂Cl₂ / 24 h / Ambient temperature 6: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 7: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 8: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 9: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 10: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

29
[ 116996-44-2 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 1.) Bu₄NF ; 2.) t-BuPh₂SiCl, Et₃N / 2.) DMAP / 1.) THF, r.t., 22 h; 2.) CH₂Cl₂, r.t., 24 h 2: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 3: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 4: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 5: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 6: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 7 steps 1: 99 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 22 h / Ambient temperature 2: Et₃N, 4-(dimethylamino)pyridine (DMAP) / CH₂Cl₂ / 24 h / Ambient temperature 3: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 4: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 5: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 6: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 7: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

30
[ 116996-46-4 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 2: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 3: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 4: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 4 steps 1: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾*F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 2: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 3: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 4: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

31
[ 117020-89-0 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: 1.) O₃; 2.) Ph₃P / 1.) CH₂Cl₂, -78 deg C; 2.) -78 deg C -> r.t., 3 h 2: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / r.t., 5 h; reflux, 4 h 3: 1.) Bu₄NF ; 2.) t-BuPh₂SiCl, Et₃N / 2.) DMAP / 1.) THF, r.t., 22 h; 2.) CH₂Cl₂, r.t., 24 h 4: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 5: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 6: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 7: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 8: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 9 steps 1: 85 percent / 1.) O₃, 2.) triphenylphosphine / CH₂Cl₂ / 1.) -78 deg C, 5 min, 2.) 3 h 2: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / 1.) RT, 5 h, 2.) reflux, 4 h 3: 99 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 22 h / Ambient temperature 4: Et₃N, 4-(dimethylamino)pyridine (DMAP) / CH₂Cl₂ / 24 h / Ambient temperature 5: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 6: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 7: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 8: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 9: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

32
[ 116996-43-1 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / r.t., 5 h; reflux, 4 h 2: 1.) Bu₄NF ; 2.) t-BuPh₂SiCl, Et₃N / 2.) DMAP / 1.) THF, r.t., 22 h; 2.) CH₂Cl₂, r.t., 24 h 3: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 4: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 5: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 6: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 7: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 8 steps 1: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / 1.) RT, 5 h, 2.) reflux, 4 h 2: 99 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 22 h / Ambient temperature 3: Et₃N, 4-(dimethylamino)pyridine (DMAP) / CH₂Cl₂ / 24 h / Ambient temperature 4: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 5: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 6: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 7: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 8: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

33
[ 116996-32-8 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: 1.) LDA / 1.)Et₂O, -78 deg C, 45 min; 2.) -78 deg C, 10 min 2: 85 percent / i-Pr₂NH / DMAP / diethyl ether / 24 h / Ambient temperature 3: 1.) O₃; 2.) Ph₃P / 1.) CH₂Cl₂, -78 deg C; 2.) -78 deg C -> r.t., 3 h 4: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / r.t., 5 h; reflux, 4 h 5: 1.) Bu₄NF ; 2.) t-BuPh₂SiCl, Et₃N / 2.) DMAP / 1.) THF, r.t., 22 h; 2.) CH₂Cl₂, r.t., 24 h 6: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 7: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 8: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 9: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 10: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C
	Multi-step reaction with 11 steps 1: 1.) lithium diisopropylamide (LDA) / 1.) ether, -78 deg C, 45 min, 2.) -78 deg C, 10 min 2: 85 percent / diisopropylamine, 4-(dimethylamino)pyridine (DMAP) / diethyl ether / 24 h / Ambient temperature 3: 85 percent / 1.) O₃, 2.) triphenylphosphine / CH₂Cl₂ / 1.) -78 deg C, 5 min, 2.) 3 h 4: 86 percent / C₈K, TiCl₃ / 1,2-dimethoxy-ethane / 1.) RT, 5 h, 2.) reflux, 4 h 5: 99 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 22 h / Ambient temperature 6: Et₃N, 4-(dimethylamino)pyridine (DMAP) / CH₂Cl₂ / 24 h / Ambient temperature 7: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 8: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 9: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 10: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 11: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]
[2]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

34
[ 84131-91-9 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 97 percent / Et₃N / DMAP / CH₂Cl₂ / 88 h / Ambient temperature 2: 95 percent / Bu₄NF / tetrahydrofuran / 3 h / Ambient temperature 3: 1.) (COCl)2; 2.) Et₃N / 1.) DMSO, CH₂Cl₂, -78 deg C, 20 min; 2.) -78 deg C, 10 min, -78 deg C -> r.t., 20 min 4: 97 percent / 1.3N HCl / tetrahydrofuran / 4 h / Ambient temperature 5: 77 percent / Ag₂CO₃/Celite, PhMe / toluene / 1 h / 90 °C

Reference： [1]Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil V. J. da; et al. [Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6914 - 6916]

35
[ 75330-75-5 ]
[ 134970-30-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 100 percent / 1 h / 80 °C 2: 99 percent / imidazole / dimethylformamide / 6 h / 60 °C
	Multi-step reaction with 2 steps 1: Reflux 2: 1H-imidazole
	Multi-step reaction with 2 steps 1: 3 h / 70 °C / Inert atmosphere 2: 1H-imidazole / 3 h / 68 °C / Inert atmosphere

Reference： [1]Askin, D.; Verhoeven, T. R.; Liu, T. M.-H.; Shinkai, I. [Journal of Organic Chemistry, 1991, vol. 56, # 16, p. 4929 - 4932]
[2]Tian, Lei; Tao, Jie; Chen, Liqin [Journal of labelled compounds and radiopharmaceuticals, 2011, vol. 54, # 9, p. 625 - 628]
[3]Current Patent Assignee: XINCHANG KANGLE CHEMICALS CO., LTD. - CN104803959, 2017, B

36
[ 75330-75-5 ]
[ 85613-99-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 72 mg / H₂ / Pd/CaCO₃ / ethanol / 25 °C / 760 Torr 2: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C
	Multi-step reaction with 3 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 50 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C
	Multi-step reaction with 2 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 97 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[3]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

37
[ 75330-75-5 ]
[ 85614-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 72 mg / H₂ / Pd/CaCO₃ / ethanol / 25 °C / 760 Torr 2: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 3: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C 4: 109.5 mg / boron trifluoride etherate / benzene; diethyl ether / 2 h / 2 °C 5: 119 mg / lithium tri-tert-butoxyaluminum hydride / tetrahydrofuran / 5 h / 0 °C
	Multi-step reaction with 5 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 97 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C 4: 109.5 mg / boron trifluoride etherate / benzene; diethyl ether / 2 h / 2 °C 5: 119 mg / lithium tri-tert-butoxyaluminum hydride / tetrahydrofuran / 5 h / 0 °C
	Multi-step reaction with 6 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 50 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 4: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C 5: 109.5 mg / boron trifluoride etherate / benzene; diethyl ether / 2 h / 2 °C 6: 119 mg / lithium tri-tert-butoxyaluminum hydride / tetrahydrofuran / 5 h / 0 °C

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[3]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

38
[ 75330-75-5 ]
[ 85614-08-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 72 mg / H₂ / Pd/CaCO₃ / ethanol / 25 °C / 760 Torr 2: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 3: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C 4: 109.5 mg / boron trifluoride etherate / benzene; diethyl ether / 2 h / 2 °C
	Multi-step reaction with 4 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 97 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C 4: 109.5 mg / boron trifluoride etherate / benzene; diethyl ether / 2 h / 2 °C
	Multi-step reaction with 5 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 50 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 4: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C 5: 109.5 mg / boron trifluoride etherate / benzene; diethyl ether / 2 h / 2 °C

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[3]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

39
[ 75330-75-5 ]
[ 85648-19-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 72 mg / H₂ / Pd/CaCO₃ / ethanol / 25 °C / 760 Torr 2: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 3: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C
	Multi-step reaction with 3 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 97 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C
	Multi-step reaction with 4 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 50 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 4: 162 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[3]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

40
[ 75330-75-5 ]
[ 85614-07-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 72 mg / H₂ / Pd/CaCO₃ / ethanol / 25 °C / 760 Torr 2: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 3: 362 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C
	Multi-step reaction with 3 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 97 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 362 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C
	Multi-step reaction with 4 steps 1: 1.48 g / imidazole / dimethylformamide / 5 h / 35 °C 2: 50 mg / triethylsilane, trifluoroacetic acid / CH₂Cl₂ / 24 h / Ambient temperature 3: 55 mg / imidazole / dimethylformamide / 5 h / 35 °C 4: 362 mg / m-chloroperbenzoic acid, sodium bicarbonate / CH₂Cl₂ / 5 h / 4 °C

Reference： [1]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[2]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]
[3]Kuo, C. H.; Patchett, A. A.; Wendler, N. L. [Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 1991 - 1998]

41
[ 125975-03-3 ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: Et₃N, 4-(dimethylamino)pyridine (DMAP) / CH₂Cl₂ / 24 h / Ambient temperature 2: 91 percent / 4-(dimethylamino)pyridine (DMAP), triethylamine / CH₂Cl₂ / 72 h / Ambient temperature 3: 95 percent / 1.1 M Bu₄N⁽¹⁺⁾*F^(1-) / tetrahydrofuran / 3 h / Ambient temperature 4: 97 percent / (COCl)2, DMSO / CH₂Cl₂ / 0.33 h / -78 °C 5: 97 percent / 10percent aq. HCl / tetrahydrofuran / 4 h / Ambient temperature 6: 77 percent / Ag₂CO₃/Celite / toluene / 1 h / 85 - 95 °C

Reference： [1]Clive; Murthy; Wee; Prasad; Da Silva; Majewski; Anderson; Evans; Haugen; Heerze; Barrie [Journal of the American Chemical Society, 1990, vol. 112, # 8, p. 3018 - 3028]

42
[ 75330-75-5 ]
[ 100-46-9 ]
[ 476468-68-5 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene at 80℃; for 1h;	3.I EXAMPLE 3; Hydroxyacid ammonium salt of Formula II required in lactonization is prepared by the following procedure: Step-I; PREPARATION OF N-BENZYL-7-[1,2,6,7,8,8a(R)-HEXAHYDRO-2(S),6(R)-DIMETHYL-8(S)-[[2(S)-METHYLBUTANOYL]OXY]-NAPHTHYL]-3(R),5(R)-DIHYDROXY HEPTANOIC ACID AMIDE (LOVASTATIN BENZYLAMIDE); EXAMPLE 3; Hydroxyacid ammonium salt of Formula II required in lactonization is prepared by the following procedure: Step-I; PREPARATION OF N-BENZYL-7-[1,2,6,7,8,8a(R)-HEXAHYDRO-2(S),6(R)-DIMETHYL-8(S)-[[2(S)-METHYLBUTANOYL]OXY]-NAPHTHYL]-3(R),5(R)-DIHYDROXY HEPTANOIC ACID AMIDE (LOVASTATIN BENZYLAMIDE); A mixture of Lovastatin (50 g, 0.124 mol) and benzylamine (46.32 g, 0.432 mol) was mixed with toluene (25 ml) and heated to 80° C. under nitrogen atmosphere for 1 hour. Absence of Lovastatin was monitored by HPLC. Excess benzylamine and toluene were distilled off at 85-90° C. under reduced pressure (5-10 mm Hg). The residue was mixed with xylenes (50 ml) and distilled again at 85-90° C. under reduced pressure (5-10 mm Hg) to get product, lovastatin benzylamide, as light brown viscous liquid. Yield: 67.5 g.
	In toluene at 80 - 90℃; for 4h;	4 Preparation of lovastatin benzylamide Example 4 Preparation of lovastatin benzylamide Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of benzylamine (2.94 g, 3 ml, 27.5 mmol) and toluene (25 ml) and the resulting mixture was heated to 80-90° C. to obtain a solution. The solution was stirred at this temperature for 4 hours under nitrogen atmosphere to complete the reaction and obtain a solution including lovastatin benzylamide.

Reference： [1]Current Patent Assignee: AUROBINDO PHARMA LIMITED - US2004/19225, 2004, A1 Location in patent: Page 3
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2007/129437, 2007, A1 Location in patent: Page/Page column 11/2

43
[ 75330-75-5 ]
7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3(R),5 (R)-dihydroxy heptanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium <i>tert</i>-butylate In tetrahydrofuran; water at -30 - 20℃; for 5h;	1 EXAMPLE 1Preparation of 7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3 (R),5 (R)-dihydroxy heptanoic acid EXAMPLE 1 Preparation of 7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3 (R),5 (R)-dihydroxy heptanoic acid To a mixed solution of 500 ml of tetrahydrofuran and 4.7 ml of water cooled to -30° C., was added 111 g of potassium t-butoxide, following 50 g of lovastatin.After the reaction mixture was stirred at room temperature for 5 hrs, it was cooled to 0° C. and 200 ml of water was added and concentrated.The reaction mixture was acidified to PH 2.0 with 6N HCl and stirred for 1 hr in cooled condition.The reaction mixture was filtered, washed with 100 ml of water and 100 ml of dichloromethane and then dried to obtain 39.3 g (94%) of white solid compound. mp 127-128° C.;

Reference： [1]Current Patent Assignee: CHONG KUN DANG PHARMACEUTICAL CORP. - US2004/68123, 2004, A1 Location in patent: Page 5

44
lovastatin acid [ No CAS ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
76.12%	With phosphoric acid In water; toluene at 20 - 55℃; for 19h;	1; 2 Example 1; Lactonisation of Mevinolinic Acid (In to impure Lovastatin (I); (Broth extraction process); Lovastatin broth [4500gms ; containing (34.2) gms of mevinolinic acid (II)] was added into a flask and cooled to 20C, and the pH was adjusted to 3.5 0.1 by addition of 85% orthophosphoric acid (60gms). Toluene (11250ml) was added and the mixture agitated to 55 5 C for 19.0 hours in a nitrogen atmosphere. The organic layer was separated and washed twice with 2.5% aqueous sodium bicarbonate solution (580 ml). The organic layer was washed with water (580ml) and the organic layer concentrated under vacuum at 35-40C. Toluene (260ml) was added to the residue and the mixture was cooled to-5 C for complete crystallization of Lovastatin (I) in a period of 4.0 hours. The mixture was filtered and the wet cake washed with chilled toluene (50ml). The wet cake was dried at 35-40°C to give impure Lovastatin (1) 26.6gm ; % Yield 76 12; % purity 93.7.; Example-2; Lactonisation of Mevinolinic acid (II) to impure Lovastatin (I); (Cake extraction process); Lovastatin broth [4500gms; containing (34. 2) gms of mevinolinic acid (II) ] was added in a flask. The broth was cooled to 20 C and the pH of the mixture adjusted to 3.5 0.01 by adding 85% orthophosphoric acid (60gms). The broth was filtered and toluene (6200ml) was added to the mycelia cake. The mixture was agitated at 55 5 C for 19 hours in a nitrogen atmosphere. The organic layer was separated and washed twice with 2.5% aqueous sodium bicarbonate solution (580ml). The organic layer was separated and washed with water (580ml) and concentrated. Toluene (260ml) was added to the residue and cooled to-5°C. The mixture was agitated at same temperature for 4.0 hours for complete crystallization of Lovastatin (I). The mixture was filtered and washed with chilled toluene (50ml). The wet cake was dried at 35-40°C to give impure Lovastatin (I) 26.6gm ; % Yield: 76.12 ; purity 93.7%.
	With trifluoroacetic acid In ethyl acetate for 0.166667h;

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2005/35515, 2005, A1 Location in patent: Page/Page column 17-18
[2]Balraj, Janani; Jairaman, Karunyadevi; Kalieswaran, Vidhya; Jayaraman, Angayarkanni [3 Biotech, 2018, vol. 8, # 8]

45
ammonium mevinolinic acid [ No CAS ]
[ 75330-75-5 ]

Yield	Reaction Conditions	Operation in experiment
78.2%	Stage #1: ammonium mevinolinic acid With phosphoric acid In toluene; butanone at 20 - 82℃; for 2 - 2.5h; Stage #2: With triethylamine In water; toluene; butanone at 20℃;	3 Ammonium-7- [l, 2,6, 7, 8, 8a (R-hexahydro-2 (S), 6 (R)- dimethyl-8 (S) - (2- methylbutyryloxy)-1 (S)-naphthyl]-3 (R), 5 (R) -dihydroxyheptanoate (lovastatin ammonium salt) (lOgms ; 0. 023moles) was added to a mixture of toluene (140ml) and methyl ethyl ketone (60ml). Nitrogen gas was bubbled into the reaction mixture followed by drop wise addition of orthophosphoric acid (2. 4gms; 0. 24 moles) at room temperature. The reaction mixture was agitated at 80 2°C, for 2.0-2. 5 hours with HPLC monitoring. The reaction mixture was cooled to 20°C and water (20ml) followed by triethyl amine (2.3gms ; 0. 023 moles) was added to the mixture. The aqueous layer was separated and the organic layer was distilled under reduced pressure to completely evaporate the solvent mixture. Cyclohexane (50ml) was added and distilled again to completely strip off toluene/methyl ketone mixture. Cyclohexane (50ml) was added to the syrupy mass and stirred for 30 minutes for complete crystallization of the product. The product was filtered and washed with cyclohexane (lOml). The wet cake was added to cyclohexane (200ml) and refluxed for 10-15 minutes. The mixture was gradually cooled to 25-30°C and stirred for 3.0 hours. The mixture was cooled to 10-15°C and filtered. The wet cake was washed with cyclohexane. The wet cake obtained was dissolved in methanol (1000ml). Butylated hydroxy toluene (0. 5mgms) and butylated hydroxy anisole (0. 5mgms) was added to the mixture and after optional carbon treatment was filtered and cooled to 25-30°C. Water was added gradually to the filtrate in 45 minutes and cooled to 0-5°C. The mixture was agitated at same temperature for 90 minutes and filtered. The wet cake was washed with a (4: 1) mixture of water: methanol (200ml). The wet cake was dried at 40-45°C. Yield: 7. 2gms; % Yield : 78. 2; Purity: 99.7%
	With sulfuric acid In acetonitrile at -22 - -17℃; for 0.5h;	5 Example 5: Lovastatin A suspension of Lovastatin ammonium salt (10 Kg, 22.7 mol) and butylated hydroxyanisole (100 g) in acetonitrile (60 L) was chilled to about - 20° C. concentrated sulphuric acid (1.67 Kg, 17.02 mol) was added to the suspension in one portion and stirred for 30 minutes maintaining the temperature between-17 TO-22° C. After completion of reaction (by TLC), product was filtered, the cake washed with water (until pH of filtrate is neutral) and dried. Yield: 9.0 Kg; Purity by HPLC: 99.6 %

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2005/95374, 2005, A1 Location in patent: Page/Page column 27; 28
[2]Current Patent Assignee: BIOCON LIMITED - WO2005/12279, 2005, A1 Location in patent: Page/Page column 9-10

46
[ 75330-75-5 ]
[ 75225-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water at 50℃; for 2h;	The lactone forms of Lovastatin (Calbiochem) and Simvastatin (Calbiochem) were hydrolysed by alkaline hydrolysis in 1M NaOH at 50° C. for 2 hours, followed by dilution in water. Atorvastatin (Pfizer), Pravastatin (Chempacific Corporation) and Cerivastatin (Sequoia Research Products Ltd.) were dissolved in water.
	With sodium hydroxide at 20℃;	2 A 10-gm lovastatin crystal isolated from Example 1, and a molar equivalent of NaOH were added while stirring at room temperature. After the mixture turns into a solution, it was taken to dryness in vacuo to yield the sodium salt of the free acid form hereinafter referred to as Compound I.
	With sodium hydroxide In ethanol; water at 20℃;	1 Example 1Preparation of Sildenafil-Lovastatinic Acid Complex Salt (8)Lovastatin (8.8 g) is dissolved in ethanol (50 mL), under room temperature the aqueous solution of sodium hydroxide (4 g/60 ml) is added to result an ethanol solution of Lovastatinic acid sodium (300 mL) for use.In a flask equipped with a magnetic stirrer, Sildenafil citrate (13.2 g) is dissolved in a mixture of ethanol (100 mL) and water (30 mL), an ethanol solution of Lovastatinic acid sodium is added then reacted at 50° C. for 20 mins. After cooling, a white precipitate is obtained and the sodium citrate is removed by filtration. The methanol (100 mL) is added under room temperature and being incubated over night for re-precipitation. The Sildenafil-Lovastatinic acid complex salt (16.8 g) is obtained after filtering the crystal.

Reference： [1]Current Patent Assignee: PFIZER INC - US2005/85528, 2005, A1 Location in patent: Page/Page column 4
[2]Current Patent Assignee: JJ PHARMA INC - US2005/101561, 2005, A1 Location in patent: Page/Page column 9
[3]Current Patent Assignee: KAOHSIUNG MEDICAL UNIVERSITY - US2012/108604, 2012, A1 Location in patent: Page/Page column 7

47
C₂₇H₃₀N₂O₂ [ No CAS ]
[ 75330-75-5 ]
C₅₁H₆₆N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine at 20℃; for 24h;	1.E A mixture of lovastatin 4 (commercially available from Merck & Co. as MEVACOR ) (0.039g, 0.1 MMOL) and 0.045 g of amine 3 (0.11 MMOL) in 19 mg of pyridine was stirred for 24 h at room temperature. The reaction was chromatographed twice over SI02 eluting with 2-5% methanol in DICHLOROMETHANE to give 0.028 g of the desired product 5 (m. p. = 67-68°C).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2004/81002, 2004, A1 Location in patent: Page 50

48
[ 75330-75-5 ]
lovastatin acid [ No CAS ]
(4R,6R)-4-hydroxy-6-(2-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)ethyl)tetrahydro-2H-pyran-2-one [ No CAS ]
[ 132748-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: lovastatin With methanol; sodium hydroxide; 2,6-di-tert-butyl-4-methyl-phenol at 50℃; for 1h; Stage #2: With methanol; ammonia; water at 40℃; for 43h; Stage #3: With hydrogenchloride In methanol; water at 12℃;	13 Example 13: An Exemplary Process for Making Simvastatin; This example describes an exemplary process of the invention for making simvastatin, simvastatin intermediates, or equivalent compounds. This exemplary process 564462012840 of the invention comprises a method for (i) Hydrolysis of Lovastatin by lovastatin esterase and the subsequent"one-pot/one-step"lactonization/acetylation (as Steps 1 and 2), (ii) Acylation of 4-acetyllactone with dimethylbutyric anhydride with BF3 (Et20) (A) or Cu (OTf) 2 (B) catalyst (as Step 3). The acylation with dimethylbutyric anhydride/pyndine/DMAP (C) was included for comparison to demonstrate advantages of this method. (iii) Hydrolysis of acetylsimvastatin with lovastatin esterase (as Step 4); 4-Acetyllactone (50 g Scale); An exemplary process for making 4-Acetyllactone, as illustrated in Figure 19, comprises : 1. Lovastatin (50.05 g, 124 mmol) was weighed into a 1-L 3-neck flask equipped with a magnetic stir bar and N2 inlet. 2M NaOH (65 mL, 130 mmol) was added and the slurry stirred. MeOH (10 mL) and BHT (0.25 g) was added and the slurry was stirred in a water bath at 50°C for 1 hour. By this time all the lovastatin had dissolved to give a viscous, slightly yellow solution. The solution was diluted with water (175 mL) and the temperature adjusted to 40°C. 2. Meanwhile, lovastatin esterase (5.0 g of a crude enzyme lyophilizate) was weighed into a polypropylene centrifuge bottle, suspended in water (100 mL) and stirred at room temperature for 30 min. The mixture was then centrifuged at 10,000 rpm at 4°C for 15 minutes. The supernatant was added to the lovastatin acid reaction mixture. The centrifuge bottle was rinsed with a further portion of water (150 mL) which was added to the reaction mixture. (see Note 1, below) 3. The pH of the reaction was adjusted to pH 9.5 and was maintained at 40° and pH 9.5 on a DASGIP AG FEDBATCH-PRO bioreactorby automatic addition of 10% NH40H. 4. Aliquots (25 pL) of the reaction mixture were removed periodically, diluted with MeOH and examined by HPLC (see Note 2, below). After 26.5 h, 0.5% of unreacted lovastatin acid remained. The reaction was terminated after 43 h. 5. The reaction mixture was diluted to 800 mL in a 1-L beaker and cooled to +12°C. With vigorous stirring the pH was reduced to pH 2.5 with 6M HC1. The precipitated solid was filtered under N2, washed with water (300 mL) and the damp filter cake was dried in a vacuum oven at 40°C (see Note 3, below). 6. The crude triol acid filter cake was suspended in CH2Cl2 (500 mL) in a 1-L 3- neck flask equipped with a thermometer, addition funnel, magnetic stir bar and N2 inlet. The slurry was cooled in an ice bath and stirred under N2. 7. Dimethylaminopyndine (2.24 g, 18.3 mmol; 0.15 equiv.) was added to the reaction mixture. Acetic anhydride (35 mL, 0.37 mol; 3 equiv.) was placed in the addition funnel and was added dropwise to the reaction mixture over a period 12 minutes, the temperature remaining at 8.5-9. 2°C. 8. Aliquots (25 IlL) of the reaction mixture were removed every 30 minutes, diluted with MeOH and examined by HPLC (see Note 4, below). 9. After 30 minutes the cooling bath was removed and the reaction stirred at room temperature (see Note 5, below). The reaction was terminated 6.25 h after the addition of Ac20 (see Note 6, below). The reaction mixture was filtered through a pad of Celite and the pad washed with CH2C12 (2 x 100 mL). The combined filtrates were washed with water (200 mL), 1.2 M HC1 (200 mL) and water (100 mL). 10. The organic layer was concentrated on a rotovap (250 mL removed) and diluted with EtOAc (300 mL). Water (400 mL and solid NaHCO3 (53 g) was added to the organic solution and the mixture stirred for 30 min. Separated the organic layer. The aqueous layer was diluted with water (400 mL) and extracted with EtOAc (150 mL). The EtOAc extracts were combined and washed with a mixture of water (100 mL) and saturated (satd.) NaCL (50 mL) and then with satd. NaCI (100 mL). The organic layer was dried (Na2SO4), filtered and concentrated (420 mL removed from a 600 mL volume). 11. The pale yellow concentrated solution was stirred with an overhead stirrer and hexanes (200 mL) was added quickly, forming a dense white precipitate. A further portion of hexanes (300 mL) was added and the mixture cooled in an ice bath for 1.5 h. 12. The precipitate solid was filtered, washed with cold 20% EtOAc/hexanes (80 mL), air dried for 0.5 h then dried in a vacuum oven at 40°C overnight. 13. The mother liquors were evaporated to dryness. The resulting yellow oil was redissolved in EtOAc (25 mL) and a second crop was precipitated by dropwise addition of hexanes (175 mL). The precipitated solid was collected by filtration and dried in a vacuum oven at 40°C (see Note 7, below). Notes 1. Total volume of the reaction was 500 mL, corresponding to a substrate concentration of 0. 25M (10% w/v substrate) and a crude enzyme load of 10% w/w. 2. Samples were analyzed on a Waters 1100 Series HPLC equipped with a DAD, using a ZORBAX SB-Phenyl column (4.6 x 75 mm) (45% MeCN/0.5% AcOH isocratic; 1 ml/min ; 30°C ; 238 nm). The order of elution was : Triol acid: 1.4 min, Diol lactone: 1.9 min, Lovastatin Acid: 3.8 min, Lovastatin: 7.3 min. 3. The filter cake (43.61 g) at this stage consists of crude triol acid and precipitated protein. HPLC analysis versus a working standard of triol acid indicated that the aqueous filtrate contained 0.69 g triol acid (1.6%) and 0.69 g diol lactone (1. 8%). 4. Samples were analyzed on a Waters 1100 Series HPLC equipped with a DAD, using a ZORBAX SB-Phenyl column (4.6 x 75 mm) (45% MeCN/0. 5% AcOH isocratic; 1 ml/min ; 30°C ; 238 nm). The order of elution was: Triol acid: 1.4 min, Diol lactone: 1.9 min, Diacetate Acid/Elimination: 3.6 min, 4-Acetyllactone: 4.1 min; Diacetate, 7.6 min. 5. The reaction mixture is initially lumpy, but vigorous stirring breaks up the major lumps After 2 h the reaction mixture was sonicated to disperse some smaller lumps which persisted. Milling of the crude triol acid filter cake before suspending it in solvent is suggested. The final reaction mixture was a milky white suspension. 6. HPLC before quenching indicated the presence of 1. 1% Diol lactone, 3.9% Diacetate acid/Elimination, and 1. 2% Diacetate. 7. The total yield of product was calculated as shown in the following Table:

Reference： [1]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 77-80

49
[ 75330-75-5 ]
[ 761354-04-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: lovastatin With potassium hydroxide; ethanol; water In isopropyl alcohol at 20℃; for 6.5h; Heating / reflux; Stage #2: With hydrogenchloride In water; isopropyl alcohol for 1h;	1 Example 1; Synthesis of 3, 5-dihydroxy-7- (8-hydroxy-2, 6-dimethyl- 14267, 88a-hexahydro-naphthalen-l-vl . heptanoic acid [step 1] 10 g (24.7 mmol) of lovastatin was added with 70 ml of 2- propanol/ethanol and 8.16 g (123.5 mmol) of potassium hydroxide, and then the resultant was stirred at room temperature for 30 minutes. The solution was heated to the reflux temperature, and then stirred at the temperature for 6 hours. After the reaction was finished, the resultant was cooled to room temperature, and then completely dissolved by adding 300 ml of water. The solution was added with concentrated hydrochloric acid to adjust the pH to 3 or lower and then stirred to crystallize. After stirring for 1 hour, the resultant was filtrated and then dried completely to yield 7.53 g (90%) of the title compound as white crystal. The obtained substance was used in the next process without further recrystallization. 'H NMR (CDCl3, 400MHz) : 85. 94 (d, 1H, J = 9. 6Hz, naphtha C-4H), 5.75 (dd, 1H, J = 9.6Hz, naphtha C-3H), 5.52 (t, 1H, J = 3. 0Hz, naphtha C-5H), 4.69 (m, 1H), 4.36 (q, 1H), 4.21 (q, 1H), 2.62 (dd, 2H, -CH2-), 2.50-2. 30 (m, 2H), 2.13 (m, 1H), 2.00-2. 30 (m, 12H), 1.46 (m, 2H), 1.15 (d, 3H,-CH3), 0.86 (s, 3H,- CH3)

Reference： [1]Current Patent Assignee: UK CHEMIPHARM - WO2005/58861, 2005, A1 Location in patent: Page/Page column 8-9

50
[ 75330-75-5 ]
(4R,6R)-4-hydroxy-6-(2-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)ethyl)tetrahydro-2H-pyran-2-one [ No CAS ]
[ 132748-10-8 ]

Yield	Reaction Conditions	Operation in experiment
89.4%	Stage #1: lovastatin With ammonia; water at 40℃; for 18.75 - 27h; Enzymatic reaction; Stage #2: In water Acidic aqueous solution;	8.1 Example 8 : Enzymatic hydrolysis of Lovastatin; The following example provides an exemplary protocol of the invention comprising the hydrolysis of lovastatin; Step 1: Enzymatic Hydrolysis; A 50 g and 2 x 150 g scale hydrolyses of lovastatin were carried out. The reactions were run at 0. 5M substrate, pH 9.5, 40°C with pH maintained constant by addition of 10% NH40H All 3 reactions behaved similarly, achieving >99% conversion (by normalized HPLC peak area) in-24 h. The reaction mixtures were acidified to pH-2. 5. Depending on the scale of the reaction, the efficiency/power of the stirring and the extent of dilution, the reaction mixture may"solidify"during this operation, requiring further dilution. 'The precipitated product was easily filtered and the damp filter cake dried at-40°C in a vacuum oven. 'On standing, more triol acid and diol lactone precipitated from the acidic aqueous filtrate (1-4%) Discussion Although the reactions are run at 0.5 M (20 w/v) substrate, the reaction mixture must be diluted with up to an equal volume of water to prevent solidification of the reaction mixture during workup. The volumetric efficiency may be improved by running the reaction at 0.25M from the beginning. The 50 g reaction showed an abnormally high amount of triol acid in the aqueous filtrate (estimated at 12%), resulting in a lower overall yield at the next step; Hydrolysis of Crude Lovastatin ; The hydrolysis of crude lovastatin (91 %) was carried out on 4 x 10 g scale using two lots of enzyme (SEQ ID NO : 4, encoded by, e. g., SEQ ID NO : 3) at pH 9. 5/40°C. Reactions with this enzyme resulted in 99.5% conversion in this time period (one lot showed 96% conversion after 27 h, another lot at 20% loading showed 99.4% conversion in 18. 75 h). * 3 reactions were combined and processed as described herein. Assay indicated an 89.4% yield of triol acid as a crude filter cake with an estimated 5% lost to the aqueous filtrates. The crude triol acid was lactonized/acetylated under conditions as described herein.
	Stage #1: lovastatin With methanol; sodium hydroxide; water at 20℃; Stage #2: With hydrogenchloride In methanol; water Stage #3: With hydrogenchloride; methanol; methanesulfonic acid; ammonia; water more than 3 stages;	2 Hydrolysis of Lovastatin by SEQ ID NO : 4 (150 _ Scale); 1. Lovastatin (150 g, 0. 37 mol) and water (300 mL) were slowly added in alternating portions to a rapidly stirring mixture of MeOH (52.5 mL) and 50% w/w NaOH (30 mL, 0.57 mol) in a 1L 3-neck flask equipped with an overhead paddle stirrer. The reaction was stirred at room temperature overnight and the clear mixture then acidified to pH No. 7-8 using conc. HC1 (-25 mL) (Note 1, below). 2. SEQ ID NO : 4 (17 g) was reconstituted in water (50 ml water) and added to the reaction. A further portion of water (300 rnL) to bring the volume of the reaction to a total of 750 mL. 3. The reaction was controlled using a DASGIP AG FEDBATCH-pro'» using 30% NH4OH to maintain pH 9.5. The reaction was stirred and maintained at 35°C, aliquots (10 liL quenched in MeOH, 990 uL) being taken periodically to monitor progress of the reaction by HPLC (Note 2, below). 4. After 86. 3 h, HPLC indicated-1 % lovastatin acid remained and the reaction was terminated. The reaction mixture was transferred to a 4 L beaker, diluted with water (1 L) and vigorously stirred. The mixture was acidified to pH 2.5 with 6M HC1 (160 mL) and stirred at room temperature for a further 1.5 h. 5. The slurry was filtered through Whatman No.1 filter paper on a 19 cm Buchner funnel and the damp filter cake washed with water (0.5 L). The mixture filtered easily to give a cream-colored filter cake and a golden yellow filtrate. The damp filter cake was allowed air dry forNo.1 h; it was then transferred into 4 x 600 mL lyophilizer flasks and dried on a lyophilizer to provide an off-white powder (154.8 g) (Note 3, below). 6. The filtrate was divided into 3 equal portions which were extracted with a single portion of EtOAc (600 mL). The EtOAc extract was washed with satd. NaCl (100 mL), dried ( ? 2804), filtered and concentrated to-250 mL. The filtrate was stirred under N2 and a solution of MeSO3H (0.2 mL, 3.1 mmol ; final concentration-15 mM) in EtOAc (4 mL) was added dropwise over a period of-5 minutes. After 70 min. the reaction solution was washed with satd. NaHCO3 (200 mL), and satd. NaCl (50 mL). The EtOAc solution was allowed stand overnight, decanted, and concentrated to -120 mL on a rotary evaporator. The diol lactone was precipitated by the slow dropwise addition of hexanes (200 mL). The precipitated solid was filtered and dried (3.22 g, 92.3% purity) ; a further 0.47 g remained in the mother liquors. 7. The total yield was determined to be 98.9% (see Note 4, below). The total yield of product was calculated as shown in the following Table:
	With water; potassium hydroxide In methanol for 21h; Reflux;	1.2 1.2. Obtaining monacolin J 1.2. Obtaining monacolin J [0066] [0067] A solution of 0.7 g of potassium hydroxide in 0.5 ml of water is prepared and 3 ml of methanol are added little by little. 0.5 g of Lovastatin are subsequently added and the solution is placed under reflux for 21 hours. After the treatment of the reaction, a 50% mixture of monacolin J and the ring-opening product is obtained. NMR (CDCl3) data of the monacolin J

Reference： [1]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 69-70; 71
[2]Current Patent Assignee: WIRAINIM - WO2005/40107, 2005, A2 Location in patent: Page/Page column 35-36
[3]Current Patent Assignee: NEURON BIOPHARMA SA - EP2628737, 2013, A1 Location in patent: Paragraph 0066-0067

51
[ 75330-75-5 ]
[ 75-64-9 ]
lovastatin tert-butylamine salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With water at 50 - 55℃; for 3.5h;	1; 5 Preparation of Tert-butylamine Salt of Lovastatin Into a 4-neck round-bottom flask, lovastatin (25 g) was added with water (250 ml) and tert-butylamine (13 ml). The reaction mixture was slowly heated to a temperature of about 50° C. over about 30 minutes. The reaction mixture was maintained at a temperature ranging between about 50° C. and about 55° C. for about 3 hours. After the completion of reaction as determined by TLC, the water was distilled out at a temperature below about 60° C., and the residue was stripped twice using acetone (2*50 ml). The residue was charged in acetone (200 ml) and stirred for about 1 hour at a temperature ranging from about 20° C. to about 25° C. The residue was filtered and washed with acetone. The material was dried at a temperature ranging from about 50° C. to about 55° C. This process yielded the tert-butylamine salt of lovastatin (27.2 g). Yield of about 88%. HPLC purity greater than 99%. IR (KBr) cm-1:3513, 3326 (OH & NH str); 1715 (C=O str); 1537 (C-O str) 1H NMR spectrum (CDCl3) 300 MHz: δ6.0(d, J=9.3, 1H) δ5.8 (dd, J=6.3, 1H) δ5.51(br s, 1H) δ5.37(d, J=2.7, 1H) δ4.12(m, 1H) δ3.78 (m, 1H) δ2.42-1.45(m, 17H) δ1.34(s, 9H) 1.08(m, 6H), δ0.87(m, 6H). Mass: m/z 496.4(M+).

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - US2005/239885, 2005, A1 Location in patent: Page/Page column 11-12

52
diaza-bicyclo-undecane [ No CAS ]
[ 75330-75-5 ]
(S)-2-Methyl-butyric acid (1S,3R,7S,8S,8AR)-8-[2-((R)-1-benzyl-4-methyl-6-oxo-piperidin-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With methyllithium; acetic anhydride In methanol	68 (S)-2-Methyl-butyric acid (1S,3R,7S,8S,8aR)-8-[2-((R)-1-benzyl-4-methyl-6-oxo-piperidin-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester EXAMPLE 68 (S)-2-Methyl-butyric acid (1S,3R,7S,8S,8aR)-8-[2-((R)-1-benzyl-4-methyl-6-oxo-piperidin-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester Mevinolin is treated with acetic anhydride to give the α,β-unsaturated lactone. This is treated with cuprous bromide dimethylsulfide complex and methyl lithium to affect conjugate addition. The methylated lactone compound is treated with methanol and diazabicycloundecane to give the ring opened methylated hydroxy ester. The hydroxy group of which is then oxidized with sulfur trioxide pyridine complex to the corresponding ketone. The ketone reductively aminated (as described for Example 76b) to give the title compound. MS(El): 491 (M)

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2002/37895, 2002, A1

53
[ 100-39-0 ]
[ 75330-75-5 ]
2-Methyl-butyric Acid 8-[2-(5-Benzyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane	2 2-Methyl-butyric Acid 8-[2-(5-Benzyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester EXAMPLE 2 2-Methyl-butyric Acid 8-[2-(5-Benzyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester To a stirred, cooled (-77° C.) solution of 101 mg (1.00 mmol) of diisopropylamine in 5 ml of THF under argon are added 0.63 ml (1.0 mmol) of a 1.6 M butyllithium solution in hexane. After 15 minutes, 202 mg (0.50 mmol) of mevinolin are added and the reaction mixture is kept at -77° C. for 30 minutes. Then 171 mg (1.0 mmol) benzyl bromide are added. After 2 hours the reaction is let come to room temperature and poured onto 0.1 N aqueous HCl. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product is purified by silica gel chromatography (diethyl ether/hexane 2/1) to afford the desired product as a colorless oil. MS (FAB) 495 (M+H), 393.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US6630492, 2003, B1

54
[ 75330-75-5 ]
2-Methyl-butyric Acid 8-[2-(4-Hydroxy-tetrahydro-pyran-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester [ No CAS ]
2-methyl-butyric acid 3,7-dimethyl-8-(3,5,7-trihydroxy-heptyl)-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium borohydride In ethanol	3 2-Methyl-butyric Acid 8-[2-(4-Hydroxy-tetrahydro-pyran-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester EXAMPLE 3 2-Methyl-butyric Acid 8-[2-(4-Hydroxy-tetrahydro-pyran-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester To a solution of 65 mg (0.15 mmol) of mevinolin in 5 ml of ethanol are added 22 mg (1.0 mmol) lithium borohydride and the resulting mixture is stirred overnight at room temperature. The reaction is quenched with 0.1 N aqueous HCl. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product purified by silica gel chromatography (ethyl acetate) to afford 2-methyl-butyric acid 3,7-dimethyl-8-(3,5,7-trihydroxy-heptyl)-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester as an oil. MS (ESI) 431 (M+Na), 409 (M+H).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US6630492, 2003, B1

55
[ 75330-75-5 ]
lovastatin amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N-butylamine	1 Preparation of Lovastatin Amide EXAMPLE 1 Preparation of Lovastatin Amide Lovastatin (about 20 Kg) was dissolved in n-butylamine (about 10 L to about 15 L of an about 99% pure liquid) at about 45° C. to about 95° C., preferably at about 50° C. to about 70° C., until the reaction was completed. Then, the lovastatin amide solution was concentrated at about 440 mm/Hg to remove unreacted butylamine, e.g. by distillation.

Reference： [1]Current Patent Assignee: FERMIC DE C V - US6472542, 2002, B1

56
[ 67000-01-5 ]
[ 75330-75-5 ]
2-methyl-butyric acid 3,7-dimethyl-8-[2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic anhydride In pyridine	6 2-Methyl-butyric Acid 8-[3-Hydroxy-5-(2-hydroxy-ethylamino)-6-(2-hydroxy-ethylcarbamoyl)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester EXAMPLE 6 2-Methyl-butyric Acid 8-[3-Hydroxy-5-(2-hydroxy-ethylamino)-6-(2-hydroxy-ethylcarbamoyl)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl Ester To a stirred solution of 4.0 g (10 mmol) mevinolin in 20 ml pyridine at room temperature are added 20 ml acetic acid anhydride. After 1 h the reaction mixture is concentrated in-vacuo. The residue is dissolved with 10 ml methyl-t-butyl ether and washed successively with water, 0.1 N HCl and brine. The organic phase is then dried over sodium sulfate and the solvent removed in vacuo. The crude product is purified by silica gel chromatography (methyl-t-butyl ether 1/3) to afford 2-methyl-butyric acid 3,7-dimethyl-8-[2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester) as a white powder.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US6630492, 2003, B1

57
[ 75330-75-5 ]
[ 98-80-6 ]
lovastatin phenylboronate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene	1 Preparation of Lovastatin Phenylboronate Example 1 Preparation of Lovastatin Phenylboronate A suspension of lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g, 0.909 mmol) and toluene (1.75 L) was heated with agitation under a nitrogen atmosphere. A reflux temperature of 100-105° C. was maintained for 55 minutes as water was collected and separated from the reaction mixture. The solution was cooled and 1.39 L of toluene was removed by vacuum distillation at 40-50° C. The concentrated solution was treated with hexanes (3.15 L) between 40-50° C. The resulting suspension was cooled to 0-5° C. for 2 hours and the product was filtered and washed with 0-5° C. hexanes (350 mL). The product was dried at 35-40° C. under vacuum to provide 427.9 g (37%) of lovastatin phenylboronate at >99% purity by HPLC.

Reference： [1]Current Patent Assignee: APOTEX INC - US6307066, 2001, B1

58
[ 75330-75-5 ]
lovastatin potassium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide In tetrahydrofuran	6.1 Step 1 Step 1 Preparation of Lovastatin Potassium Salt A solution of lovastatin (99% pure; 25 g; 60.57 mmol) in 325 mL tetrahydrofuran (THF) was prepared under nitrogen then cooled to 5° C. An aqueous solution (6.1 ml) of 10.01M potassium hydroxide was added over 15 min then the mixture was warmed to 25° C. and aged, with stirring, until complete (>99%) conversion to the potassium salt (by HPLC analysis) had occurred.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US5223415, 1993, A

59
[ 3970-21-6 ]
[ 75330-75-5 ]
C₂₈H₄₄O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 45℃; for 6h;	II Diisopropylethylamine ( 12.82 ml, 74.1 mmoles) was added to a stirred solution of lovastatin (1O g, 24.7 mmoles) in methylenedichloride. 2-Methoxyethoxy methyl chloride (8.3 ml, 80%) was introduced into the reaction mixture and heated at 450C for six hours. The reaction mixture was cooled to room temperature and quenched with water (75 ml). Melhylenedichloride layer was separated and aqueous layer was extracted with methylenedichloride (100 ml). The combined organic layer was washed with water followed by brine solution and then dried over sodium sulphate. Removal of organic layer gave crude liquid product. Further purified by column chromatography to yield lovastatin MEM ether

Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2006/123355, 2006, A2 Location in patent: Page/Page column 21-22

60
[ 75330-75-5 ]
monacophenyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: lovastatin With chloro-trimethyl-silane; sodium iodide In acetonitrile at -10 - 20℃; for 2h; Stage #2: With water In acetonitrile for 0.166667h;	I To a stirred solution of Lovastatin (12 g, 29.6 mmoles) in acetonitrile (60 ml) at -50C to - 100C was added sodium iodide (8 g, 53.4 mmoles) and lrimethyl silyl chloride (6.75 g, 53.4 mmoles). The reaction mixture was then allowed to stir at room temperature for 2.0 hours. D. M water (50 ml) added to the reaction mixture and stirred for 10 minutes. Acelonitrile was removed under vacuum at about 5O0C and aqueous solution was extracted with ethyl acetate. The combined organic layer was washed with 10 % sodium thiosulphate solution, followed by water and brine solution, and dried over sodium sulphate and filtered. The solvent was removed under vacuum to obtain crude product. The crude product was purified by column chromatography to get a compound of formula I-A.

Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2006/123355, 2006, A2 Location in patent: Page/Page column 21

61
[ 75330-75-5 ]
6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6-dimethyl-3-oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.IV IV. Additionally, the sodium salt of 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid, the sodium salt of ring opened lovastatin, was subjected to analogous bioconversion reactions utilizing both N. autotrophic subsp. amethystina ATCC 35204 (MA6180) and N. autotrophic subsp. canberrica ATCC 35203 (MA6181) to afford 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6-dimethyl-3-oxo-1,2,3,7,8,8a(R)-hexahydronaphthyl-1(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
		1.IV IV. Additionally, the sodium salt of 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid, the sodium salt of ring opened lovastatin, was subjected to analogous bioconversion reactions utilizing both N. autotrophica subsp. amethystina ATCC 35204 (MA6180) and N. autotrophic subsp. canberrica ATCC 35203 (MA6181) to afford 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S),6-dimethyl-3-oxo-1,2,7,8,8a(R)-pentahydronaphthyl-1(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US4968693, 1990, A Current Patent Assignee: MERCK & CO INC - US5001241, 1991, A
[2]Current Patent Assignee: MERCK & CO INC - EP408806, 1991, A1

62
[ 288-32-4 ]
[ 75330-75-5 ]
[ 18162-48-6 ]
[ 79691-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	In <i>N</i>-methyl-acetamide; hexane	1.A Step A Step A Preparation of 6(R)-[2-(8(S)-(2(S)-methylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S))-ethyl]-4(R)-(dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one Mevinolin (4.04 g, 0.01 mol) was dissolved in 25 ml of dry dimethylformamide (DMF) and treated with 2.7 g (0.04 mol) of imidazole and 3 g (0.02 mol) of dimethyl-tert-butylsilyl chloride, and the solution was stirred under nitrogen overnight. The mixture was poured into 200 ml of ether, washed with 250 ml of water, 125 ml of 1N hydrochloric acid, 125 ml of saturated aqueous sodium carbonate and 250 ml of brine, dried over MgS04 and concentrated to dryness. The residue was chromatographed on a "Still" column of silica gel (6.0*17.7 cm, 230-400 mesh) by elution with 45% ether in hexane (V/V) collecting 20 ml fractions. The fractions containing the product (21-52) were combined and concentrated to dryness to give 5.2 of oil.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US5053525, 1991, A

63
LiOH-H₂ O [ No CAS ]
[ 75330-75-5 ]
(4R,6R)-4-hydroxy-6-(2-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)ethyl)tetrahydro-2H-pyran-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With conc HCl In hexane; water; toluene	1.a (a) (a) 6(R)-[2-[8(S)-Hydroxy-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (2) A mixture of 20.0 g (49.4 mmol) of mevinolin and 20.7 g (0.493 mol) of LiOH-H2 O in 1.5 L of water was stirred at reflux for 72 hours. The reaction mixture was cooled to 0° C., acidified by addition of 50 ml of conc HCl and then extracted with ether (3500 ml). The combined extracts were washing with water (3500 ml) and satd. brine (500 ml), dried (MgSO4) and evaporated to give a white solid. This solid was dissolved in 300 ml of toluene and heated at reflux for 2 hours in a Dean-Stark apparatus for azeotropic removal of water. After evaporation of the toluene, the residual oily solid was heated at reflux in hexane (150 ml) for 30 minutes. After cooling to 0° C., the hexane solution was filtered and the collected solid was dried in air to yield an off-white powder. An analytical sample was prepared by recrystallization of a portion of this material from 1-chlorobutane to give white clusters: m.p. 128°-131° C. (vac). Anal. Calc'd for C19 H28 O4.0.1C4 H9 Cl: C, 70.67; H, 8.84. Found: C, 70.77; H, 8.75.

Reference： [1]Current Patent Assignee: MERCK & CO INC - US4668699, 1987, A

64
[ 108-91-8 ]
[ 75330-75-5 ]
[ 163448-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene at 80 - 90℃; for 5h;	1 Preparation of lovastatin cyclohexylamide Example 1 Preparation of lovastatin cyclohexylamide Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of cyclohexylamine (2.6 g, 3.0 ml, 26.3 mmol) and toluene (25 ml) and the reaction mixture was heated to a temperature of 80-90° C. to obtain a solution. The solution was stirred at this temperature for 5 hours under nitrogen atmosphere to complete the reaction and obtain a solution including lovastatin cyclohexamide.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2007/129437, 2007, A1 Location in patent: Page/Page column 11/1

65
[ 75330-75-5 ]
[ 151005-85-5 ]
(4R,6R)-4-hydroxy-6-(2-((1S,2S,6R,8S,8aR)-8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)ethyl)tetrahydro-2H-pyran-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; potassium hydroxide In methanol for 21h; Reflux;	1.2 1.2. Obtaining monacolin J; [Show Image] A solution of 0.7 g of potassium hydroxide in 0.5 ml of water is prepared and 3 ml of methanol are added little by little. 0.5 g of Lovastatin are subsequently added and the solution is placed under reflux for 21 hours. After the treatment of the reaction, a 50% mixture of monacolin J and the opened product is obtained.

Reference： [1]Current Patent Assignee: NEURON BIOPHARMA SA - EP2241561, 2010, A1 Location in patent: Page/Page column 12-13

66
fosinopril [ No CAS ]
[ 75330-75-5 ]
C₅₃H₇₈NO₁₁P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: fosinopril With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 2℃; for 0.0666667h; Stage #2: lovastatin In dichloromethane at 0℃;	1 Codrug offosinopril with lovastatin. To a stirred solution offosinopril (320 mg) in 7 mL of anhydrous dichloromethane at 0-2 °C was added EDCI (133 mg) and DMAP (5 mg). After 4 minutes lovastatin (135 mg) was added and the resulting mixture was stirred in an ice-bath for 5 hr and left in refrigerator overnight. The solvent was evaporated to dryness and the residue was dissolved in ethyl acetate. The organic solution was washed with water, brine and dried over anhydrous sodium sulfate. Evaporation afforded 413 mg of the colorless crude product, which was purified bypassing through short pad of silica gel to yield 300 mg of codrug.

Reference： [1]Current Patent Assignee: EYEPOINT PHARMACEUTICALS INC - WO2007/16306, 2007, A2 Location in patent: Page/Page column 23

67
[ 110-87-2 ]
[ 75330-75-5 ]
[ 109-73-9 ]
[ 936945-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,4-dihydro-2<i>H</i>-pyran With sulfuric acid In tetrahydrofuran for 0.25h; Stage #2: lovastatin In tetrahydrofuran at 38℃; for 0.416667h; Stage #3: N-butylamine In tetrahydrofuran at 49℃; for 2h;	1 Preparation of Hydroxy-Protected Lovastatin Amide (Formula IV) 20 ml of tetrahydrofuran (THF) and 25 ml of 3,4-dihydropyran were placed into a round bottom flask and subjected to stirring for a period of 5 minutes. 5 ml of THF and 0.03 ml of sulphuric acid were added to the above solution over a period of about 10 minutes. 50 g of lovastatin was added to the obtained reaction solution and heated to a temperature of about 38 C. for a period of 25 minutes. 17 ml of n-butyl amine was added to the obtained reaction mass and it was heated to a temperature of 49 C. for a period of 2 hours. The reaction mixture was subjected to distillation at 45 C. by applying vacuum to afford 74 g of the title compound.

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - US2007/117996, 2007, A1 Location in patent: Page/Page column 9/1

68
[ 75330-75-5 ]
[ 221192-13-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With samarium diiodide; water; triethylamine In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;

Reference： [1]Szostak, Michal; Collins, Karl D.; Fazakerley, Neal J.; Spain, Malcolm; Procter, David J. [Organic and Biomolecular Chemistry, 2012, vol. 10, # 30, p. 5820 - 5824]

69
[ 75330-75-5 ]
(1S,3R,7S,8S,8aR)-8-((3R,5R)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (S)-2-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydroxylamine In tetrahydrofuran; water for 72h;	7 (l_lS,3i?,7_lS,8_lS,8ai?)-8-((3i?,5i?)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl)-3,7- dimethyl- 1 ,2,3,7,8,8a-hexahydronaphthalen- 1 -yl (5)-2-methylbutanoate 41 To a solution of lovastatin (50 mg, 0.12 mmol) (0494) in THF (0.5 mL) was added hydroxylamine (50% in (0495) water, 20 μ, 0.62 mmol). The resulting mixture was (0496) stirred for 72 h. Next, the mixture was concentrated (0497) under reduced pressure, stripped with CHCI3 and (0498) dried in vacuo to yield compound 41 (53 mg, 98%>) as a white foam. FontWeight="Bold" FontSize="10" H NMR (400 MHz, (0499) CDCI3) δ 5.98 (d, J = 9.7 Hz, 1H), 5.78 (dd, J = 9.4, 6.1 Hz, 1H), 5.54-5.48 (m, 1H), 5.46-5.39 (m, 1H), 4.29-4.20 (m, 1H), 3.83-3.72 (m, 1H), 2.53-2.19 (m, 6H), 1.99-1.89 (0500) (m, 2H), 1.72-1.37 (m, 7H), 1.33-1.12 (m, 2H), 1.10 (d, J= 6.9 Hz, 3H), 1.08 (d, J= 7.4 (0501) Hz, 3H), 0.93-0.82 (m, 6H).
92%	With hydroxylamine In tetrahydrofuran; water at 20℃; for 1h;

Reference： [1]Current Patent Assignee: RADBOUD UNIVERSITY NIJMEGEN; STICHTING RADBOUD UNIVERSITEIT - WO2017/137469, 2017, A1 Location in patent: Page/Page column 61
[2]Chen, Jhih-Bin; Chern, Ting-Rong; Wei, Tzu-Tang; Chen, Ching-Chow; Lin, Jung-Hsin; Fang, Jim-Min [Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3645 - 3655]

70
[ 6217-54-5 ]
[ 75330-75-5 ]
[ 1580444-10-5 ]

Yield	Reaction Conditions	Operation in experiment
60.2%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 3h; Inert atmosphere;	Lovastatin-docosahexaenoate-(LOV-DHA) conjugate synthesis and characterization At 25 °C under N2, DCC (188mg; 0.91mM) and DMAP (167mg; 1.4mM) were added to a solution containing 150mg (0.46mM) docosahexaenoic acid (DHA) in 10mL anhydrous CH2Cl2. The reaction mixture was stirred at 25°C for 30 min followed by the addition of 100mg (0.26mM) of lovastatin. The reaction mixture was stirred at 25°C for another 3h, and then 20mL CH2Cl2 was added. The resulting solution was filtered and washed with three 20-mL portions of 0.2N HCl, and then three 20-mL portions of brine. The organic layer was dried (NaSO4) and concentrated under diminished pressure. The residue was purified with flash column chromatography eluted with 90:10 hexane-ethyl acetate to 80:20 hexane-ethyl acetate, and presented LOV-DHA as a colorless oil: yield 110mg (60.2%); 1H NMR (CDCl3) δ 0.79-0.86 (m, 6H), 0.90 (tri, 3H, J=7.5Hz), 1.02-1.07 (m, 6H), 1.23 (m, 1H), 1.37-1.44 (m, 3H), 1.61-1.70 (m, 4H), 1.87-1.92 (m, 2H), 1.98-2.05 (m, 3H), 2.20-2.35 (m, 8H), 2.60-2.70 (m, 2H), 2.72-2.80 (m, 10H), 4.42 (m, 1H), 5.20 (m, 1H, H-3), 5.25-5.38 (m, 13H), 5.48 (m, 1H), 5.73 (m, 1H), 5.94 (d, 1H, J=9.6Hz); 13C NMR (CDCl3) δ 11.6, 13.8, 14.2, 16.2, 20.4, 22.5, 22.7, 24.1, 25.4, 25.5, 26.7, 27.4, 30.6, 32.5, 33.0, 33.2, 34.0, 35.3, 36.5, 37.1, 41.3, 65.4 (C-3), 67.6, 76.4, 126.9, 127.3, 127.7, 127.8, 127.9, 128.1, 128.2, 128.4, 129.5, 131.4, 131.9, 132.8, 168.6 (C-1), 172.0 (DHA,C=O), 176.4; Mass spectrum (HR ESI), m/z 715.4949 (M+H)+ (C46H66O6 requires 714.4859)

Reference： [1]Siddiqui, Rafat A.; Harvey, Kevin A.; Xu, Zhidong; Natarajan, Selvamuthu K.; Davisson, V. Jo [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 6, p. 1899 - 1908]

71
[ 75330-75-5 ]
(1S,3R,7S,8S,8aR)-7,7-dideuterio-3,7-dimethyl-8-((3R,5S)-3,5,7-trihydroxyheptyl)-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With samarium diiodide; water-d2 In tetrahydrofuran at 23℃; for 2h; Inert atmosphere; chemoselective reaction;

Reference： [1]Szostak, Michal; Spain, Malcolm; Procter, David J. [Organic Letters, 2014, vol. 16, # 19, p. 5052 - 5055]

72
[ 36823-88-8 ]
[ 75330-75-5 ]
(S)-2-methyl-butyric acid (3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-(4-trifluoromethoxybenzoyloxy)-6-oxo-tetrahydro-pyran-2yl]-ethyl}-3,7-dimetyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With pyridine; In toluene; at 20℃; for 24h;Inert atmosphere;	General procedure: To a solution of lovastatin (1, 2.02 g, 5.00 mmol) in toluene (25 mL) was addedpyridine (0.9 mL, 11.00 mmol) and the appropriate acyl chloride (10.00 mmol).The resulting solution was stirred at RT under N2 for 24 h. Thereaction mixture was diluted with toluene (50 mL) and then washed with 1N HCl(aq)(3x 25 mL), 10% NaHCO3(aq) (25 mL), and distd H2O (30 mL).The organic layer was dried over Na2SO4, filtered and thesolvent removed in vacuo. The residue was purified by silica gel chromatography(EtOAc: n-hexane=1: 4).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5528 - 5533

73
[ 75330-75-5 ]
[ 122-04-3 ]
(S)-2-methyl-butyric acid (3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-(4-nitrobenzoyloxy)-6-oxo-tetrahydro-pyran-2yl]-ethyl}-3,7-dimetyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With pyridine In toluene at 20℃; for 24h; Inert atmosphere;	Generalprocedure for the preparation of 2b-i General procedure: To a solution of lovastatin (1, 2.02 g, 5.00 mmol) in toluene (25 mL) was addedpyridine (0.9 mL, 11.00 mmol) and the appropriate acyl chloride (10.00 mmol).The resulting solution was stirred at RT under N2 for 24 h. Thereaction mixture was diluted with toluene (50 mL) and then washed with 1N HCl(aq)(3x 25 mL), 10% NaHCO3(aq) (25 mL), and distd H2O (30 mL).The organic layer was dried over Na2SO4, filtered and thesolvent removed in vacuo. The residue was purified by silica gel chromatography(EtOAc: n-hexane=1: 4).