[ CAS No. 852821-06-8 ] {[proInfo.proName]}

Name: 852821-06-8|(4AS,8aS,9S)-3-(benzyloxy)-4a-((tert-butyldimethylsilyl)oxy)-9-(dimethylamino)-8a,9-dihydronaphtho[2,3-d]isoxazole-4,5(4aH,8H)-dione|97%
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Quality Control of [ 852821-06-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 852821-06-8 ]

Product Details of [ 852821-06-8 ]

CAS No. :	852821-06-8	MDL No. :	MFCD28023585
Formula :	C₂₆H₃₄N₂O₅Si	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SLXLVVLJLQJWFG-JCWFFFCVSA-N
M.W :	482.64	Pubchem ID :	11363682
Synonyms :

Calculated chemistry of [ 852821-06-8 ]

Physicochemical Properties

Num. heavy atoms :	34
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.5
Num. rotatable bonds :	7
Num. H-bond acceptors :	7.0
Num. H-bond donors :	0.0
Molar Refractivity :	132.52
TPSA :	81.87 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.71 cm/s

Lipophilicity

Log Po/w (iLOGP) :	4.3
Log Po/w (XLOGP3) :	4.98
Log Po/w (WLOGP) :	4.48
Log Po/w (MLOGP) :	1.86
Log Po/w (SILICOS-IT) :	2.61
Consensus Log Po/w :	3.65

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-5.75
Solubility :	0.000864 mg/ml ; 0.00000179 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.44
Solubility :	0.000176 mg/ml ; 0.000000365 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-6.74
Solubility :	0.0000884 mg/ml ; 0.000000183 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	5.75

Safety of [ 852821-06-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 852821-06-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 852821-06-8 ]
Downstream synthetic route of [ 852821-06-8 ]

[ 852821-06-8 ] Synthesis Path-Upstream 1~7

1
[ 856906-36-0 ]
[ 69739-34-0 ]
[ 852821-06-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 2,6-dimethylpyridine In dichloromethane; water at 23℃; for 3 h; Aqueous potassium phosphate buffer solution	2,6-Lutidine (75.0 μL, 0.640 mmol, 5.0 equiv) and tert- butyldimethylsilyl trifluoromethanesulfonate (88.0 μL, 0.380 mmol, 3.0 equiv) were added in sequence to a solution of the cyclohexenone DRS5 (47.0 mg, 0.130 mmol, 1.0 equiv) in dichloromethane (3 mL) at 23 °C. The mixture was stirred at 23 °C for 3 h, then an aqueous potassium phosphate buffer solution (pH 7.0,0.2 M, 15 mL) was added. The biphasic mixture was extracted with dichloromethane (2 x 20 mL) and the organic extracts were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, affording the silyl- cyclohexenone DRS6 as a white crystalline solid (56.0 mg, 91percent). [00141] Mp 157-158 °C (dec) ; Rf 0.54 (1: 3 ethyl acetate-hexanes) ; ¹H NMR (500 MHz, CDC13) 8 7.51 (d, 2H, J= 1.5 Hz, ArH), 7.50-7.34 (m, 3H, ArH), 6.94 (m, 1H, =CHCH2), 6.10 (ddd, 1H, J= 10.3,1.5, 1.5 Hz, =CHC(O)), 5.36 (m, 2H, OCH2Ar), 3.79 (d, 1H, J= 10.7 Hz, CHN(CH3)2), 2.83 (m, 2H, =CCH2), 2.78 (m, 1H, C3CH), 2.46 (s, 6H, N(CH3)2), 0.84 (s, 9H, C(CH3)3), 0.27 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3); ¹³C NMR (125 MHz, CDC13) No. 193.4,187.9, 181.6, 167.7, 149.5, 135.2, 128.8, 128.8, 128.8, 128.6, 108.6, 83.5, 72.8, 59.8, 48.1, 42.2, 26.3, 25.8, 19.3, -2.2,-3.8; FTIR (neat), cm-1 2942 (s), 1719 (s, C=O), 1678 (s, C=O), 1602 (m), 1510 (s), 1053 (s, C-O), 733 (s) ; HRMS (ES) m/z calcd for (C26H34N2O5Si+H)+ 483.2315, found 483.2321.

Reference： [1] Patent: WO2005/112945, 2005, A2, . Location in patent: Page/Page column 94-95
[2] Organic Process Research and Development, 2017, vol. 21, # 3, p. 377 - 386
[3] Patent: WO2010/126607, 2010, A2, . Location in patent: Page/Page column 123/251

2
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[ 852821-06-8 ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: With boron tribromide In dichloromethane at -78℃; for 0.2 h; Stage #2: With water In dichloromethaneAqueous phosphate buffer Stage #3: With 2,6-dimethylpyridine In dichloromethane at 0 - 23℃; for 1.16667 h;	Protected Enone 10:[0098] A solution of boron tribromide in dichloromethane (1.0 M, 1.54 mL, 1.54 mmol, 2.00 equiv) was added to a solution of ketone JDB9 (294 mg, 0.770 mmol, 1 equiv) in dichloromethane (7.7 mL) at -78 ⁰C. The yellow reaction solution was stirred for 12 min, then was partitioned between aqueous potassium phosphate buffer (pH 7.0, 0.05 M, 30 mL) and and dichloromethane (50 mL). The aqueous layer was separated and further extracted with dichloromethane (30 mL). The organic layers were combined and the combined layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was dissolved in dichloromethane (15.4 mL) and the resulting solution was cooled to 0 ⁰C. 2,6-Lutidine (382 μL, 3.48 mmol, 4.5 equiv) and tert-butyldimethylsilyl trifluoromethanesulfonate (444 μL, 1.93 mmol, 2.5 equiv) were added sequentially to the cooled solution. The reaction solution was stirred at 0 ⁰C for 5 min and then the cooling bath was removed. The reaction solution was stirred at 23 ⁰C for 65 min, then was partitioned between aqueous potassium phosphate buffer (pH 7.0, 0.05 M, 20 mL) and dichloromethane (40 mL). The aqueous layer was separated and further extracted with dichloromethane (20 mL). The organic layers were combined and the combined layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography on silica gel (2.5 percent ethyl acetate-hexanes, grading to 7.5 percent ethyl acetate-hexanes) to furnish the enone JDBlO (170 mg, 46percent over two steps) as a white solid.TLC (20percent ethyl acetate-hexanes) R_/= 0.34 (UV, CAM).HNMR (500 MHz, CDCl₃), δ: 7.51 (d, 2H, J= 1.5 Hz, ArH), 7.50-7.34 (m, 3H, ArH),6.94 (m, IH, =CHCH₂), 6.10 (ddd, IH, J= 10.3, 1.5,1.5 Hz, =CHC(O)), 5.36 (m, 2H, OCH₂Ph), 3.79 (d, IH,J= 10.7 Hz, CHN(CH₃)₂), 2.83 (m, 2H, =CHCH₂), 2.78(m, IH, CHCHN(CHs)₂), 2.46 (s, 6H, N(CH₃)₂), 0.84(s, 9H, SiC(CH₃)₃), 0.27 (s, 3H, SiCH₃), 0.06 (s, 3H,SiCH₃).3 XNMR (100 MHz, CDCl₃), δ: 193.4, 187.9, 181.6, 167.7, 149.5, 135.2, 128.8, 128.8,128.8, 128.6, 108.6, 83.5, 72.8, 59.8, 48.1, 42.2, 26.3,25.8, 19.3,-2.2,-3.8.IR (neat), cm^" 2942 (s), 1719 (s), 1678 (s), 1602 (m), 1510 (s), 1053(S), 733 (S).HRMS (ESI): Calcd for (C₂₆H₃₄N₂C^H)⁺: 483.2315Found: 483.2321.

Reference： [1] Patent: WO2008/127361, 2008, A2, . Location in patent: Page/Page column 72-73

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Reference： [1] Patent: WO2008/127361, 2008, A2, . Location in patent: Page/Page column 85-86

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Reference： [1] Organic Letters, 2007, vol. 9, # 18, p. 3523 - 3525

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[ 1072297-56-3 ]
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Reference： [1] Patent: WO2008/127361, 2008, A2,
[2] Patent: WO2008/127361, 2008, A2,

6
[ 1253798-65-0 ]
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Reference： [1] Patent: WO2010/126607, 2010, A2,

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[ 69739-34-0 ]
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Reference： [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 377 - 386

[ 852821-06-8 ] Synthesis Path-Downstream 1~67

1
[ 856906-36-0 ]
[ 69739-34-0 ]
[ 852821-06-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 2,6-dimethylpyridine; In dichloromethane; water; at 23℃; for 3h;pH 7.0;Aqueous potassium phosphate buffer solution;	2,6-Lutidine (75.0 muL, 0.640 mmol, 5.0 equiv) and tert- butyldimethylsilyl trifluoromethanesulfonate (88.0 muL, 0.380 mmol, 3.0 equiv) were added in sequence to a solution of the cyclohexenone DRS5 (47.0 mg, 0.130 mmol, 1.0 equiv) in dichloromethane (3 mL) at 23 C. The mixture was stirred at 23 C for 3 h, then an aqueous potassium phosphate buffer solution (pH 7.0,0.2 M, 15 mL) was added. The biphasic mixture was extracted with dichloromethane (2 x 20 mL) and the organic extracts were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, affording the silyl- cyclohexenone DRS6 as a white crystalline solid (56.0 mg, 91%). [00141] Mp 157-158 C (dec) ; Rf 0.54 (1: 3 ethyl acetate-hexanes) ; ¹H NMR (500 MHz, CDC13) 8 7.51 (d, 2H, J= 1.5 Hz, ArH), 7.50-7.34 (m, 3H, ArH), 6.94 (m, 1H, =CHCH2), 6.10 (ddd, 1H, J= 10.3,1.5, 1.5 Hz, =CHC(O)), 5.36 (m, 2H, OCH2Ar), 3.79 (d, 1H, J= 10.7 Hz, CHN(CH3)2), 2.83 (m, 2H, =CCH2), 2.78 (m, 1H, C3CH), 2.46 (s, 6H, N(CH3)2), 0.84 (s, 9H, C(CH3)3), 0.27 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3); ¹3C NMR (125 MHz, CDC13) No. 193.4,187.9, 181.6, 167.7, 149.5, 135.2, 128.8, 128.8, 128.8, 128.6, 108.6, 83.5, 72.8, 59.8, 48.1, 42.2, 26.3, 25.8, 19.3, -2.2,-3.8; FTIR (neat), cm-1 2942 (s), 1719 (s, C=O), 1678 (s, C=O), 1602 (m), 1510 (s), 1053 (s, C-O), 733 (s) ; HRMS (ES) m/z calcd for (C26H34N2O5Si+H)+ 483.2315, found 483.2321.
91%	With 2,6-dimethylpyridine; In dichloromethane; at 23℃; for 3h;Inert atmosphere;	(0170) (0171) 2,6-Lutidine (75.0 muL, 0.640 mmol, 5.0 equiv) and tert-butyldimethylsilyl trifluoromethanesulfonate (88.0 muL, 0.380 mmol, 3.0 equiv) were added in sequence to a solution of the cyclohexenone DRS5 (47.0 mg, 0.130 mmol, 1.0 equiv) in dichloromethane (3 mL) at 23 C. The mixture was stirred at 23 C for 3 h, then an aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 15 mL) was added. The biphasic mixture was extracted with dichloromethane (2 × 20 mL) and the organic extracts were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, affording the silyl-cyclohexenone DRS6 as a white crystalline solid (56.0 mg, 91%). Mp 157-158 C (dec); Rf 0.54 (1:3 ethyl acetate-hexanes); 1H NMR (500 MHz, CDCl3) delta 7.51 (d, 2H, J = 1.5 Hz, ArH), 7.50-7.34 (m, 3H, ArH), 6.94 (m, 1H, =CHCH2), 6.10 (ddd, 1H, J = 10.3, 1.5, 1.5 Hz, =CHC(O)), 5.36 (m, 2H, OCH2Ar), 3.79 (d, 1H, J = 10.7 Hz, CHN(CH3)2), 2.83 (m, 2H, =CCH2), 2.78 (m, 1H, C3CH), 2.46 (s, 6H, N(CH3)2), 0.84 (s, 9H, C(CH3)3), 0.27 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3); 13C NMR (125 MHz, CDCl3) delta 193.4, 187.9, 181.6, 167.7, 149.5, 135.2, 128.8, 128.8, 128.8, 128.6, 108.6, 83.5, 72.8, 59.8, 48.1, 42.2, 26.3, 25.8, 19.3, -2.2, -3.8; FTIR (neat), cm-1 2942 (s), 1719 (s, C=O), 1678 (s, C=O), 1602 (m), 1510 (s), 1053 (s, C-O), 733 (s); HRMS (ES) m/z calcd for (C26H34N2O5Si+H)+ 483.2315, found 483.2321.
	With 2,6-dimethylpyridine; In dichloromethane; at 0 - 23℃; for 0.583333h;Inert atmosphere;	Epimerization. A 100-mL, single-necked, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar was flushed with argon. The flask was charged with a solution of alcohol 11 (1.46 g, 3.96 mmol, 1 equiv) in tetrahydrofuran (10 mL), methanol (10 mL), and a 2 M aqueous sodium dihydrogen phosphate solution (6 mL). The resulting biphasic mixture was degassed by bubbling with argon for 30 min. The mixture was stirred at 52 0C for 15 h. The flask was removed from the heating bath and the product mixture allowed to cool to 23 0C, then water (15 mL), dipotassium hydrogenphosphate (7.83 g), and dichloromethane (40 mL) was added and the resulting biphasic mixture was stirred for 10 min. The layers were separated. The aqueous layer was extracted with two 40-mL portions of dichloromethane. The organic layers were combined and the combined layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to provide a purple residue that was used directly in the next step. Silylation. A 100-mL, single-necked, round-bottomed flask equipped with aTeflon-coated magnetic stirring bar was flame-dried, then allowed to cool to 23 0C under argon. The flask was charged with a solution of the product obtained above in dichloromethane (20 mL). The solution was cooled to 0 C, whereupon 2,6-Lutidine (0.813 mL, 7.14 mmol, 1.8 equiv) and terf-butyldimethylsilyl trifluoromethanesulfonate (1.28 mL, 5.56 mmol, 1.4 equiv) were added sequentially dropwise by syringe. The reaction mixture was stirred for 15 min at 0 0C, then the cooling bath was removed. The reaction solution was stirred for 20 min at 23 0C, then was partitioned between aqueous potassium phosphate buffer solution (pH 7, 0.05 M, 40 mL) and dichloromethane (35 mL). The layers were separated. The aqueous layer was extracted with one 40-mL portion of dichloromethane. The organic layers were combined and the combined layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash- column chromatography on silica gel (100% dichloromethane, grading to 2% ethyl acetate-dichloromethane) to provide the enone 12A (990 mg, 50% yield over 3 steps) as a light-yellow foam. TLC (20% ethyl acetate-hexanes): R7= 0.34 (UV3 CAM). 1H NMR (600 MHz, CDCl3), delta: 7.51 (d, 2H, J= 1.5 Hz, ArH), 7.50-7.34 (m, 3H, ArH), 6.94 (m, IH, =CHCH2), 6.10 (ddd, IH, J= 10.3, 1.5, 1.5 Hz, =CHC(O)), 5.36 (m, 2H, OCH2Ph), 3.79 (d, IH, J= 10.7 Hz, CHN(CH3)2), 2.83 (m, 2H, =CHCH2), 2.78 (m, IH, CHCHN(CH3)2), 2.46 (s, 6H, N(CH3)2), 0.84 (s, 9H, SiC(CH3)3), 0.27 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3).

Reference： [1]Patent: WO2005/112945,2005,A2 .Location in patent: Page/Page column 94-95
[2]Patent: EP2016044,2020,B1 .Location in patent: Paragraph 0058; 0140; 0170-0171
[3]Organic Process Research and Development,2017,vol. 21,p. 377 - 386
[4]Patent: WO2010/126607,2010,A2 .Location in patent: Page/Page column 123/251

2
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[ 852821-22-8 ]
[ 852821-27-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With n-butyllithium; In tetrahydrofuran; hexane; at -100 - 0℃; for 1.16667h;	A solution of n-butyllithium in hexanes (2.65 M, 107 muL, 0.284 mmol, 4.03 equiv) was added to a solution of phenyl 3-(bromomethyl)-1-methoxynaphthalene- 2-carboxylate (105 mg, 0.283 mmol, 4.02 equiv) and enone 7 (34.0 mg, 0.0705 mmol, 1 equiv) in tetrahydrofuran (2.80 mL) at -100 C. The resulting light-red reaction mixture was allowed to warm to 0 C over 70 min. The ice-cold product solution was then partitioned between aqueous potassium phosphate buffer solution (pH 7.0,0.2 M, 15 mL) and dichloromethane (15 mL). The organic phase was separated and the aqueous phase was further extracted with two 15-mL portions of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered, and the filtrate was concentrated, affording a yellow solid. The product was purified by preparatory HPLC on a Coulter Ultrasphere ODS column [10 mum, 250 x 10 mm, UV detection at 350 nm, Solvent A: water, Solvent B: methanol, two separate injections (750 muL each, acetonitrile), isochratic elution with 94% B for 20 min followed by a linear gradient elution with 94No.100% B over 20 min, flow rate: 3.5 mL/min]. Fractions eluting at 24-38 min were collected and concentrated, affording the hexacyclic addition product in diastereomerically pure form (36.1 mg, 75%, a white solid). [00242] Rf 0.37 (3: 7 ethyl acetate-hexanes); 'H NMR (500 MHz, CDC13) 8 16.25 (s, 1 H, enol-OH), 8.30 (d, 1 H, J = 8.3 Hz, ArH), 7.75 (d, 1 H, J = 7.8 Hz, ArH), 7.59- 7.34 (m, 7H, ArH), 7.26 (s, 1H, ArH), 5.38 (s, 2H, OCH2Ph), 4.02 (s, 3H, OCH3), 3.99 (d, 1H, J= 10.7 Hz, CHN(CH3)2), 3.08-3.05 (m, 2H, CHCH2CHCHN(CH3)2, CHH'CHCH2CHCHN(CH3)2), 2.95-2.90 (m, 1H, CHH'CHCH2CHCHN(CH3)2), 2.58 (dd, 1H, J= 10.7, 5.9 Hz, CHCHN(CH3)2), 2.51 (s, 6H, N(CH3)2), 2.50-2.48 (m, 1H, CHH'CHCHN(CH3)2), 2.20-2.14 (m, 1H, CHH'CHCHN(CH3)2), 0.82 (s, 9H, TBS), 0.29 (s, 3H, TBS), 0.13 (s, 3H, TBS) ; '(at)C NMR (125 MHz, CDC13) No. 187.9, 184.1, 183.0,182.0, 167.8, 159.2, 137.5, 136.7, 135.3, 129.5,128.8, 128.7,128.5, 127.5, 126.4,124.2, 121.8, 119.5, 108.7, 108.7, 82.4, 72.8,63.8, 61.6,46.8, 42.1, 40.7, 29.3, 26.2, 23.1, 19.3,-2.2, -3.5; FTIR (neat film), cm-1 2934 (m), 2852 (m), 1718 (s, C=O), 1610 (s), 1513 (s), 1472 (m), 1452 (m), 1369 (m), 1339 (w), 1293 (m), 1252 (m), 1190 (w), 1159 (m), 1067 (m), 1026 (w), 1011 (w) ; HRMS (ES) m/z calcd for (C39H44N207Si+H) (at) 681.2996, found 681.2985.
75%	With n-butyllithium; In tetrahydrofuran; hexane; at -100 - 0℃; for 1.16667h;Inert atmosphere;	(0269) (0270) A solution of n-butyllithium in hexanes (2.65 M, 107 muL, 0.284 mmol, 4.03 equiv) was added to a solution of phenyl 3-(bromomethyl)-1-methoxynaphthalene-2-carboxylate (105 mg, 0.283 mmol, 4.02 equiv) and enone 7 (34.0 mg, 0.0705 mmol, 1 equiv) in tetrahydrofuran (2.80 mL) at -100 C. The resulting light-red reaction mixture was allowed to warm to 0 C over 70 min. The ice-cold product solution was then partitioned between aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 15 mL) and dichloromethane (15 mL). The organic phase was separated and the aqueous phase was further extracted with two 15-mL portions of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered, and the filtrate was concentrated, affording a yellow solid. The product was purified by preparatory HPLC on a Coulter Ultrasphere ODS column [10 mum, 250 × 10 mm, UV detection at 350 nm, Solvent A: water, Solvent B: methanol, two separate injections (750 muL each, acetonitrile), isochratic elution with 94% B for 20 min followed by a linear gradient elution with 94?100% B over 20 min, flow rate: 3.5 mL/min]. Fractions eluting at 24-38 min were collected and concentrated, affording the hexacyclic addition product in diastereomerically pure form (36.1 mg, 75%, a white solid). Rf 0.37 (3:7 ethyl acetate-hexanes); 1H NMR (500 MHz, CDCl3) delta 16.25 (s, 1H, enol-OH), 8.30 (d, 1H, J = 8.3 Hz, ArH), 7.75 (d, 1H, J = 7.8 Hz, ArH), 7.59-7.34 (m, 7H, ArH), 7.26 (s, 1H, ArH), 5.38 (s, 2H, OCH2Ph), 4.02 (s, 3H, OCH3), 3.99 (d, 1H, J = 10.7 Hz, CHN(CH3)2), 3.08-3.05 (m, 2H, CHCH2CHCHN(CH3)2, CHH'CHCH2CHCHN(CH3)2), 2.95-2.90 (m, 1H, CHH'CHCH2CHCHN(CH3)2), 2.58 (dd, 1H, J = 10.7, 5.9 Hz, CHCHN(CH3)2), 2.51 (s, 6H, N(CH3)2), 2.50-2.48 (m, 1H, CHH'CHCHN(CH3)2), 2.20-2.14 (m, 1H, CHH'CHCHN(CH3)2), 0.82 (s, 9H, TBS), 0.29 (s, 3H, TBS), 0.13 (s, 3H, TBS); 13C NMR (125 MHz, CDCl3) delta 187.9, 184.1, 183.0, 182.0, 167.8, 159.2, 137.5, 136.7, 135.3, 129.5, 128.8, 128.7, 128.5, 127.5, 126.4, 124.2, 121.8, 119.5, 108.7, 108.7, 82.4, 72.8, 63.8, 61.6, 46.8, 42.1, 40.7, 29.3, 26.2, 23.1, 19.3, - 2.2, -3.5; FTIR (neat film), cm-1 2934 (m), 2852 (m), 1718 (s, C=O), 1610 (s), 1513 (s), 1472 (m), 1452 (m), 1369 (m), 1339 (w), 1293 (m), 1252 (m), 1190 (w), 1159 (m), 1067 (m), 1026 (w), 1011 (w); HRMS (ES) m/z calcd for (C39H44N2O7Si+H)+ 681.2996, found 681.2985.

Reference： [1]Patent: WO2005/112945,2005,A2 .Location in patent: Page/Page column 152-153
[2]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927
[3]Patent: EP2016044,2020,B1 .Location in patent: Paragraph 0058; 0251; 0269-0270

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C₃₄H₄₀N₂O₆Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; water; at -95 - 0℃; for 0.5h;pH 7.0;Aqueous potassium phosphate buffer solution;	N,N-dimethylformamide (20 muL) was added was added to a solution of the carboxylic acid JDB1-113-SM (500 mg, 3.67 mmol, 1.0 equiv) and oxalyl chloride (367 mul, 4.22 mmol, 1.15 equiv) in dichloromethane (20 mL) at 23 C. Vigorous gas evolution was observed. After stirring for 80 min at 23 C, phenol (863 mg, 9.18 mmol, 2.5 equiv), pyridine (890 muL, 11.0 mmol, 3.0 equiv), and dimethylaminopyridine (3 mg) were added in sequence. The resulting solution was stirred for 90 min at 23 C, whereupon an aqueous potassium phosphate buffer solution (pH 7.05,0.2 M, 5.0 mL) was added. The resulting mixture was partitioned between water (30 mL) and ethyl acetate (50 mL). The aqueous phase was extracted with an additional 50-mL portion of ethyl acetate. The organic layers were combined and washed with an aqueous sodium hydroxide solution (50 mL, 1M), brine (50 mL), and then dried over anhydrous sodium sulfate. The dried solution was decanted and concentrated, affording a colorless oil (850 mg). The product was purified by flash column chromatography (25: 75 ethyl acetate-hexanes), providing the ester JDB1-113 as a colorless oil (774 mg, 99%). [00211] Rf 0.43 (3: 7 ethyl acetate-hexanes); 'H NMR (300 MHz, CDCl3) No. 8.18 (d, 1H, J = 8.1 Hz, ArH), 7.49-7.20 (m, 8H, ArH, OArH), 2.69 (s, 3H, ArCH3); ¹3C NMR (100 MHz, CDC13) No. 165.8, 150.9, 141.3, 132.7,132.0, 131.2, 129.5, 128.5, 125.9, 125.8, 121.8, 22.0; FTIR (neat film), cm-1 3046 (w), 2923 (w), 1739 (s), 1594 (m), 1487 (m), 1287 (m), 1241 (s), 1189 (s), 1159 (m), 1041 (s), 733 (s) ; HRMS (ES) m/z calcd for (C14H12O2+NH4) + 230.1181, found 230.1187. [00212] A solution of n-butyllithium in hexanes (1.47 M, 38.0 muL, 0.0565 mmol, 8.26 equiv) was added to a solution of diisopropylamine (7.4 muL, 0.057 mmol, 8.3 equiv) in tetrahydrofuran (0.50 mL) at -78 C. The reaction mixture was briefly (10 min) transferred to an ice bath, with stirring, then was cooled to -78 C. Hexamethylphosphoramide (13.9 muL, 0.113 mmol, 16.5 equiv) was added to the mixture prepared above at -78 C. The resulting mixture was stirred for 5 minutes whereupon a colorless solution was formed. The resulting solution was added dropwise via cannula to a solution of the ester JDB1-113 (10.0 mg, 0.0471 mmol, 6.88 equiv), and the enone DRS6 (3.3 mg, 0.00684 mmol, 1.00 equiv) in tetrahydrofuran (0.50 mL) at -95 C dropwise via cannula. The light red mixture was allowed to warm to -70 C over 30 min and was then partitioned between an aqueous potassium phosphate buffer solution (pH 7.0,0.2 M, 5.0 mL) and dichloromethane (20 mL). The organic phase was separated and the aqueous phase was further extracted with an additional 20-mL portion of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was decanted and concentrated, affording a yellow solid. The product was purified by preparatory HPLC on a Coulter Ultrasphere ODS column (10 mum, 250 x 10 mm, 3.5 mL/min, Solvent A: water, Solvent B: methanol, UV detection at 350 nm) using an injection volume of 500 muL methanol and a linear gradient elution of 85-100% B over 30 min. The peak at 25- 30 min was collected and concentrated to give enol JDBI-87 as a white solid (3.5 mg, 85%). [00213] Rf 0.46 (3:7 acetate-hexanes) ; ¹H NMR (500 MHz, CD2C12) No. 15.53 (s, 1H, enol), 7.94 (d, 1H, J= 7.9 Hz, ArH), 7.54 - 7.28 (m, 8H, ArH, OCH2ArH), 5.37-5.34 (m, 2H, OCH2Ph), 4.05 (d, 1H, J= 10.7 Hz, CHN(CH3)2), 3.24- 3.18 (m, 1H, CHCH2CHCHN(CH3)2), 2.99 (dd, 1H, J= 15.5, 5.6 Hz, CHH'CHCH2CHCHN(CH3)2), 2.88 (dd, 1H, J= 15.5, 15.5 Hz, CHH'CHCH2CHCHN (CH3)2), 2.61 (dd, 1H, J= 4.4, 10.7 Hz, CHCHN(CH3)2), 2.54- 2.44 (m, 7H, N(CH3)2, CHH'CHCHN(CH3)2), 2.14 (d, 1H, J= 14.3 Hz, CHH'CHCHN(CH3)2), 0.86 (s, 9H, TBS), 0.25 (s, 3H, TBS), 0.12 (s, 3H, TBS) ; ¹3C NMR (100 MHz, CD2Cl2) No. 187.8, 183.0, 182.8, 182.4, 167.7, 141.7, 135.4,133.4, 130.9, 129.0, 128.9, 128.9,128.1, 127.5,126.5, 108.5, 106.8, 82.1, 72.8, 61.5, 58.5, 46.9, 41.9, 38.6, 29.0, 25.9, 23.1, 19.1, -2.6,-3.7; HRMS (ES) m/z calcd for (C34H40N3O6Si+H) + 601.2734, found 601.2730. [00214] Hydrofluoric acid (1.1 mL, 48% aqueous) was added to a polypropylene reaction vessel containing a solution of the enol JDB1-114 (15.1 mg, 0.0251 mmol, 1.0 equiv) in acetonitrile (10 mL) at 23 C. The resulting mixture was stirred vigorously at 23 C for 12 hr, then was poured into water (50 mL) containing K2HP04 (4.7 g). The resulting mixture was extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, furnishing the intermediate alcohol as a yellow solid (12.2 mg, 99%). Pd black was added in one portion to a solution of the residue in methanol-dioxane (1:1, 3.0 mL). An atmosphere of hydrogen was introduced by briefly evacuating the flask, then flushing with pure hydrogen (1 atm). The mixture was stirred at 23 C for 20 min. Within 5 min, the color changed from light yellow to...
85%	With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -95 - -70℃; for 0.5h;	(0242) A solution of n-butyllithium in hexanes (1.47 M, 38.0 muL, 0.0565 mmol, 8.26 equiv) was added to a solution of diisopropylamine (7.4 muL, 0.057 mmol, 8.3 equiv) in tetrahydrofuran (0.50 mL) at -78 C. The reaction mixture was briefly (10 min) transferred to an ice bath, with stirring, then was cooled to -78 C. Hexamethylphosphoramide (13.9 muL, 0.113 mmol, 16.5 equiv) was added to the mixture prepared above at -78 C. The resulting mixture was stirred for 5 minutes whereupon a colorless solution was formed. The resulting solution was added dropwise via cannula to a solution of the ester JDB1-113 (10.0 mg, 0.0471 mmol, 6.88 equiv), and the enone DRS6 (3.3 mg, 0.00684 mmol, 1.00 equiv) in tetrahydrofuran (0.50 mL) at -95 C dropwise via cannula. The light red mixture was allowed to warm to -70 C over 30 min and was then partitioned between an aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 5.0 mL) and dichloromethane (20 mL). The organic phase was separated and the aqueous phase was further extracted with an additional 20-mL portion of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was decanted and concentrated, affording a yellow solid. The product was purified by preparatory HPLC on a Coulter Ultrasphere ODS column (10 mum, 250 × 10 mm, 3.5 mL/min, Solvent A: water, Solvent B: methanol, UV detection at 350 nm) using an injection volume of 500 muL methanol and a linear gradient elution of 85-100% B over 30 min. The peak at 25-30 min was collected and concentrated to give enol JDB1-87 as a white solid (3.5 mg, 85%). Rf 0.46 (3:7 ethyl acetate-hexanes); 1H NMR (500 MHz, CD2Cl2) delta 15.53 (s, 1H, enol), 7.94 (d, 1H, J = 7.9 Hz, ArH), 7.54 - 7.28 (m, 8H, ArH, OCH2ArH), 5.37-5.34 (m, 2H, OCH2Ph), 4.05 (d, 1H, J = 10.7 Hz, CHN(CH3)2), 3.24-3.18 (m, 1H, CHCH2CHCHN(CH3)2), 2.99 (dd, 1H, J = 15.5, 5.6 Hz, CHH'CHCH2CHCHN(CH3)2), 2.88 (dd, 1H, J = 15.5, 15.5 Hz, CHH'CHCH2CHCHN(CH3)2), 2.61 (dd, 1H, J = 4.4, 10.7 Hz, CHCHN(CH3)2), 2.54-2.44 (m, 7H, N(CH3)2, CHH'CHCHN(CH3)2), 2.14 (d, 1H, J = 14.3 Hz, CHH'CHCHN(CH3)2), 0.86 (s, 9H, TBS), 0.25 (s, 3H, TBS), 0.12 (s, 3H, TBS); 13C NMR (100 MHz, CD2Cl2) delta 187.8, 183.0, 182.8, 182.4, 167.7, 141.7, 135.4, 133.4, 130.9, 129.0, 128.9, 128.9, 128.1, 127.5, 126.5, 108.5, 106.8, 82.1, 72.8, 61.5, 58.5, 46.9, 41.9, 38.6, 29.0, 25.9, 23.1, 19.1, -2.6, -3.7; HRMS (ES) m/z calcd for (C34H40N3O6Si+H)+ 601.2734, found 601.2730.

Reference： [1]Patent: WO2005/112945,2005,A2 .Location in patent: Page/Page column 131-134
[2]Patent: EP2016044,2020,B1 .Location in patent: Paragraph 0058; 0242

4
C₂₁H₂₂N₂O₅ [ No CAS ]
[ 69739-34-0 ]
[ 852821-06-8 ]

Yield	Reaction Conditions	Operation in experiment
46%		Protected Enone 10:[0098] A solution of boron tribromide in dichloromethane (1.0 M, 1.54 mL, 1.54 mmol, 2.00 equiv) was added to a solution of ketone JDB9 (294 mg, 0.770 mmol, 1 equiv) in dichloromethane (7.7 mL) at -78 0C. The yellow reaction solution was stirred for 12 min, then was partitioned between aqueous potassium phosphate buffer (pH 7.0, 0.05 M, 30 mL) and and dichloromethane (50 mL). The aqueous layer was separated and further extracted with dichloromethane (30 mL). The organic layers were combined and the combined layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was dissolved in dichloromethane (15.4 mL) and the resulting solution was cooled to 0 0C. 2,6-Lutidine (382 muL, 3.48 mmol, 4.5 equiv) and tert-butyldimethylsilyl trifluoromethanesulfonate (444 muL, 1.93 mmol, 2.5 equiv) were added sequentially to the cooled solution. The reaction solution was stirred at 0 0C for 5 min and then the cooling bath was removed. The reaction solution was stirred at 23 0C for 65 min, then was partitioned between aqueous potassium phosphate buffer (pH 7.0, 0.05 M, 20 mL) and dichloromethane (40 mL). The aqueous layer was separated and further extracted with dichloromethane (20 mL). The organic layers were combined and the combined layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography on silica gel (2.5 % ethyl acetate-hexanes, grading to 7.5 % ethyl acetate-hexanes) to furnish the enone JDBlO (170 mg, 46% over two steps) as a white solid.TLC (20% ethyl acetate-hexanes) R/= 0.34 (UV, CAM).HNMR (500 MHz, CDCl3), delta: 7.51 (d, 2H, J= 1.5 Hz, ArH), 7.50-7.34 (m, 3H, ArH),6.94 (m, IH, =CHCH2), 6.10 (ddd, IH, J= 10.3, 1.5,1.5 Hz, =CHC(O)), 5.36 (m, 2H, OCH2Ph), 3.79 (d, IH,J= 10.7 Hz, CHN(CH3)2), 2.83 (m, 2H, =CHCH2), 2.78(m, IH, CHCHN(CHs)2), 2.46 (s, 6H, N(CH3)2), 0.84(s, 9H, SiC(CH3)3), 0.27 (s, 3H, SiCH3), 0.06 (s, 3H,SiCH3).3 XNMR (100 MHz, CDCl3), delta: 193.4, 187.9, 181.6, 167.7, 149.5, 135.2, 128.8, 128.8,128.8, 128.6, 108.6, 83.5, 72.8, 59.8, 48.1, 42.2, 26.3,25.8, 19.3,-2.2,-3.8.IR (neat), cm" 2942 (s), 1719 (s), 1678 (s), 1602 (m), 1510 (s), 1053(S), 733 (S).HRMS (ESI): Calcd for (C26H34N2C^H)+: 483.2315Found: 483.2321.

Reference： [1]Patent: WO2008/127361,2008,A2 .Location in patent: Page/Page column 72-73

5
[ 852821-06-8 ]
[ 1095276-67-7 ]
[ 1095276-69-9 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927

6
[ 852821-06-8 ]
[ 1095277-67-0 ]
[ 1095277-68-1 ]

Yield	Reaction Conditions	Operation in experiment
64%		A solution of lithium diisopropylamide (1.8 M, 1.27 mL, 2.28 mmol, 3.0 eq) in heptane/ethylbezene/THF was added drop wise via syringe to a solution of ester S4-5 (760 mg, 1.52 mol, 2.0 eq), enone (366 mg, 0.759 mol, 1.0 eq) and TMEDA (682 muL, 4.55 mmol, 6.0 eq) in tetrahydrofuran (38 mL) at -78 C. The resulting orange mixture was allowed to warm slowly to -50 C over 3.5 h, then was poured into a mixture of saturated ammonium chloride (30 mL) and brine (30 mL). The resulting mixture was extracted with EtOAc (3 x 40 mL). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by preparative reverse phase HPLC on a Waters Autopurifcation system using a Sunfire Prep Cl 8 OBD column [5 mum, 19^50 mm; flow rate, 20 mL/min; Solvent A: H2O; Solvent B: MeOH; injection volume: 3.0 mL (CH3CN); gradient: 90% B for 2 min, 90-» 100% B over 6 min, then 100% B for 7 min; mass-directed fraction collection]. Fractions with the desired MW, were collected and concentrated on a RotaVap at it to afford the desired product S4-6 (430 mg, 64%) as a yellow solid: R/= 0.50 (30% ethyl acetate-hexanes). 1H NMR (600 MHz, CDCl3) delta 15.91 (br s, 1H), 8.28 (br s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 9.0, 2.4 Hz, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.44-7.37 (m, 3H), 5.42 (d, J = 12.0 Hz, 1H), 5.39 (d, J = 12.0 Hz, 1H), 4.07 (d, J = 10.8 Hz, 1H), 3.33 (dd, J = 15.6, 3.6 Hz, 1H), 3.05 (br s, 7H), 2.69 (t, J = 15.6 Hz, 1H), 2.63-2.54 (m, 8H), 2.24 (d, J - 13.8 Hz, 1H), 1.63 (s, 9H), 0.89 (s, 9H), 0.33 (s, 3H), 0.19 (s, 3H). HRMS-ESI (m/z) [M+H]+ calcd for C45H55BrN3O9Si, 888.2891 ; found, 888.2856.

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 88; 91-92
[2]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927

7
[ 852821-06-8 ]
[ 1095276-98-4 ]
[ 1095276-99-5 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927

8
[ 852821-06-8 ]
[ 852821-18-2 ]
C₄₆H₅₆N₂O₁₀Si [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927

9
[ 852821-06-8 ]
[ 852821-18-2 ]
[ 852821-23-9 ]

Yield	Reaction Conditions	Operation in experiment
83%		(0226) (0227) A solution of n-butyllithium in hexanes (1.45 M, 47 muL, 0.068 mmol, 6.8 equiv) was added to a solution of diisopropylamine (10 muL, 0.071 mmol, 7.1 equiv) and N,N,N',N'-tetramethylethylenediamine (10 muL, 0.066 mmol, 6.6 equiv) in tetrahydrofuran (300 muL) at -78 C. The resulting solution was stirred at -78 C for 30 min whereupon a solution of the ester CDL-I-299 (17 mg, 0.050 mmol, 5.0 equiv) in tetrahydrofuran (200 muL) was added, forming a deep red solution. The solution was stirred at -78 C for 75 min, then a solution of the enone DRS6 (5.0 mg, 0.010 mmol, 1.0 equiv) in tetrahydrofuran (100 muL) was added at -78 C. The color of the reaction mixture remained deep red following the addition. The mixture was allowed to warm to 0 C over 150 min. Upon reaching 0 C, an aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 15 mL) was added. The resulting yellow mixture was extracted with dichloromethane (3 × 15 mL). The organic layers were combined and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, providing a yellow oil. The product was purified by preparatory HPLC on a Coulter Ultrasphere ODS column (5 mum, 250 × 10 mm, flow rate 3.5 mL/min, Solvent A: water, Solvent B: methanol, UV detection at 350 nm) using an injection volume of 500 muL methanol with an isochratic elution of 89.5% B. The peak eluting at 31-40 min was collected and concentrated affording the Michael-Dieckmann product CDL-I-287 as a light yellow solid (6.1 mg, 83%), mp 114 C. Rf 0.37 (2:8 tetrahydrofuran-hexanes); 1H NMR (500 MHz, CDCl3) delta (s, 1H, 16.24, enol-OH), 7.55-7.50 (m, 3H, ArH), 7.40-7.35 (m, 4H, ArH), 7.10 (d, 1H, J = 7.8 Hz, ArH), 5.39-5.34 (m, 2H, OCH2Ph), 3.92 (d, 1H, J = 10.7 Hz, CHN(CH3)2), 2.81-2.71 (m, 2H, CH3CH, CH3CHCH), 2.55 (dd, 1H, J = 10.7, 5.7 Hz, CHCHN(CH3)2), 2.48 (s, 6H, N(CH3)2), 2.40 (d, 1H, J = 14.7 Hz, CHH'CHCHN(CH3)2), 2.31 (ddd, 1H, J = 14.7, 9.3, 5.7, CHH'CHCHN(CH3)2), 1.56 (s, 3H, CH3), 1.55 (s, 9H, Boc), 0.84 (s, 9H, TBS), 0.27 (s, 3H, TBS), 0.13 (s, 3H, TBS); 13C NMR (125 MHz, CDCl3) delta 187.4, 183.1, 182.8, 181.6, 167.6, 151.7, 150.2, 147.4, 135.0, 134.0, 128.5, 128.5, 123.4, 123.0, 122.4, 108.3, 107.4, 94.8, 83.9, 81.5, 72.5, 61.5, 46.4, 41.9, 39.5, 34.9, 27.7, 26.0, 20.7, 19.0, 16.0, -2.6, -3.7; FTIR (neat film), cm-1 2923 (m), 2841 (m), 1759 (s, C=O), 1718 (s, C=O), 1605 (s), 1508 (s), 1467 (m), 1456 (m), 1369 (m), 1277 (s), 1262 (m), 1231 (s), 1144 (s), 1005 (w); HRMS (ES) m/z calcd for (C40H50N2O9Si+H)+ 731.3364, found 731.3370.

Reference： [1]Patent: EP2016044,2020,B1 .Location in patent: Paragraph 0226-0227; 0251; 0261-0262
[2]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927

10
[ 852821-06-8 ]
C₁₉H₁₈BrFO₅ [ No CAS ]
[ 1095277-35-2 ]

Yield	Reaction Conditions	Operation in experiment
90%		A solution of phenyllithium in di-n-butyl ether (1.22 mL, 1.8 M, 2.20 mmol, 3.0 equiv) was added dropwise via a syringe to a solution of S19-1 (0.94 g, 2.20 mmol, 3.0 equiv) and enone S1-9 (0.35 g, 0.73 mmol, 1.0 equiv) in THF (37 mL) at -100 C. The orange reaction mixture was allowed to warm to -78 C. over 10 min. Then a solution of LHMDS in hexanes (0.73 mL, 1.0 M/THF, 0.73 mmol, 1.0 equiv) was added dropwise at -78 C. The reaction mixture was allowed to warm slowly to -10 C. over 50 min, and then partitioned between aqueous potassium phosphate buffer solution (pH 7, 0.2 M, 50 mL) and EtOAc (120 mL). The phases were separated and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C18 OBD column [5 mum, 19×50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; injection volume: 3.0 mL (CH3CN); gradient: 80?100% B in A over 10 min; mass-directed fraction collection]. Fractions containing the desired product, eluting at 4.3-6.8 min, were collected and concentrated to yield compound S19-2 (0.49 g, 90%): 1H NMR (400 MHz, CDCl3) delta 15.69 (s, 1 H), 7.49-7.47 (m, 2 H), 7.38-7.32 (m, 3 H), 6.84 (d, J=7.9 Hz, 1 H), 6.80 (d, J=8.5 Hz, 1 H), 5.34 (s, 2 H), 3.92 (d, J=10.4 Hz, 1 H), 3.10-3.03 (m, 1 H), 2.94-2.78 (m, 2 H), 2.52-2.40 (m, 8 H), 2.07 (d, J=14.6 Hz, 1 H), 1.98 (s, 9 H), 1.53 (s, 9 H), 0.26 (s, 3 H), 0.11 (s, 3 H); MS (ESI) m/z 735.35 (M+H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 329; 330; 331
[2]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927

11
[ 852821-06-8 ]
[ 34124-08-8 ]
C₃₄H₄₀N₂O₆Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With n-butyllithium; In tetrahydrofuran; hexane; at -100 - 0℃; for 0.5h;Inert atmosphere;	(0277) (0278) A solution of n-butyllithium in hexanes (2.65 M, 59 muL, 0.16 mmol, 4.0 equiv) was added to a solution of phenyl 2-(bromomethyl)benzoate (45.6 mg, 0.157 mmol, 3.97 equiv) and enone 7 (19.0 mg, 0.0394 mmol, 1 equiv) in tetrahydrofuran (1.57 mL) at -100 C. The resulting light-red solution was allowed to warm to 0 C over 30 min. The ice-cold product solution was then partitioned between aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 5 mL) and dichloromethane (25 mL). The organic phase was separated and the aqueous phase was further extracted with an additional 15-mL portion of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, affording a yellow solid. The product was purified by preparatory HPLC on a Coulter Ultrasphere ODS column [10 mum, 250 × 10 mm, Solvent A: water, Solvent B: methanol, injection volume: 1.0 mL (methanol), gradient elution with 85?100% B over 30 min, UV detection at 350 nm, flow rate: 3.5 mL/min]. Fractions eluting at 25-30 min were collected and concentrated, affording the pentacyclic addition product in diastereomerically pure form (19.2 mg, 81%, a white solid). Rf 0.46 (3:7 ethyl acetate-hexanes); 1H NMR (500 MHz, CD2Cl2) delta 15.53 (s, 1H, enol), 7.94 (d, 1H, J = 7.9 Hz, ArH), 7.54 - 7.28 (m, 8H, ArH, OCH2ArH), 5.37-5.34 (m, 2H, OCH2Ph), 4.05 (d, 1H, J = 10.7 Hz, CHN(CH3)2), 3.24-3.18 (m, 1H, CHCH2CHCHN(CH3)2), 2.99 (dd, 1H, J = 15.5, 5.6 Hz, CHH'CHCH2CHCHN(CH3)2), 2.88 (dd, 1H, J = 15.5, 15.5 Hz, CHH'CHCH2CHCHN(CH3)2), 2.61 (dd, 1H, J = 4.4, 10.7 Hz, CHCHN(CH3)2), 2.54-2.44 (m, 7H, N(CH3)2, CHH'CHCHN(CH3)2), 2.14 (d, 1H, J = 14.3 Hz, CHH'CHCHN(CH3)2), 0.86 (s, 9H, TBS), 0.25 (s, 3H, TBS), 0.12 (s, 3H, TBS); 13C NMR (100 MHz, CD2Cl2) delta 187.8, 183.0, 182.8, 182.4, 167.7, 141.7, 135.4, 133.4, 130.9, 129.0, 128.9, 128.9, 128.1, 127.5, 126.5, 108.5, 106.8, 82.1, 72.8, 61.5, 58.5, 46.9, 41.9, 38.6, 29.0, 25.9, 23.1, 19.1, -2.6, -3.7; HRMS (ES) m/z calcd for (C34H40N3O6Si+H)+ 601.2734, found 601.2730.

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 17913 - 17927
[2]Patent: EP2016044,2020,B1 .Location in patent: Paragraph 0151; 0251; 0277-0278

12
[ 852821-06-8 ]
[ 1207284-90-9 ]
[ 1207284-91-0 ]

Yield	Reaction Conditions	Operation in experiment
41%		Compound 2-5A THF solution (6.5 mL) of 2-4 (875 mg, 2.03 mmol, 1.25 equiv) was added to a freshly-prepared solution of LDA in THF (0.051 M, 2.03 mmol, 40 ml,, 1.25 equiv) and TMEDA (304 muL, 2.03 mmoi, 1.25 equiv) at -78 C. The reaction was stirred at -78 C for 15 min. A THF solution (6.5 mL) of enone (784 mg, 1.62 mmol, 1.0 equiv) was added to the reaction mixture dropwise, followed by addition of LHMDS solution (1.0 M in TFfF, 2.03 mL, 2.03 mmol, 1.25 equiv). The reaction was stirred from -78 C to -10 C for 1 h, quenched with saturated MH4Cl (6 mL), and warmed to 25 C. The solution was poured into saturated NH4CI (20 mL) and extracted with EtOAc (2 x 75 mL). The combined EtOAc extracts were dried (Na2SO4), filtered, and concentrated to yield the crude product. Preparative reverse phase HPLC purification on a Waters Autopurification system using a Sunfire Prep C 18 OBD column [5 mum, 19 * 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; injection volume: 4x 3.6- 4.2 mL (CH3CN); gradient: 88-?100% B over 12 mm; mass-directed fraction collection]. Fractions with the desired MW, eluting at 6.6-10.6 min, were collected and lyophilized to give 552 mg of pure 2-5 (41 %): 1H NMR (400 MHz, CDCl3) delta 16.22 (s, 1 H), 7.49-7.47 (m, 4 H), 7.37-7.31 (m, 6 H), 6.80 (d, J = 1 1.0 Hz, 1 H), 5.76-5.64 (m, 2 H), 5.35 (s, 2 H)3 5.17-5.1 1 (m, 4 H), 4.98 (d, ./= 9.2, 1 H), 4.87 (d, J = 9.8 Hz, 1 H), 3.96 (m, J = 10.4 Hz, 1 H), 3.83-3 71 (m, 4 H), 3. 14 (dd, J = 14.7, 4.3 Hz, 1 H), 3.0-2.87 (m, 1 H), 2.55-2 35 (m, 9 H), 2. 1 1 (d, J = 14.7 Hz, 1 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H); MS (ESl) tn/z 820.55 (M+H).

Reference： [1]Patent: WO2010/17470,2010,A1 .Location in patent: Page/Page column 70; 73-74
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 606 - 622

13
[ 852821-06-8 ]
C₃₀H₃₅FO₄Si [ No CAS ]
C₅₀H₆₃FN₂O₈Si₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%		Compound 9-4 n-BuLi (1.3 niL, 2.07 mmol, 5.5 equiv) was added to a TIIF solution (5 mL) of diisopropylamine (0.3 mL, 2.07 mmol, 5.5 equiv) at 0 C. The reaction was stirred at 0 C for 30 min and cooled to -78 C. TMEDA (0.8 rnL, 5.64 mmol, 15 equiv) was added to the mixture. To the resulting solution was added a THF solution (5 mL) of 9-3 (475 mg, 0.94 mmol, 2.5 equiv). The reaction was stirred at -78 C for 10 min. A THF solution (5 mL) of enone (181 mg, 0.376 mmol) was added to the reaction at -78 C. The reaction was stirred at -78 C for 30 min and allowed to warm to 25 C over 1 h, quenched with saturated NH4CI, and extracted with EtOAc. The combined EtOAc extracts were dried (Na2SO4) and concentrated to yield the crude product. Preparative reverse phase HPLC purification on a Waters Autopurifi cation system using a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.3% HCO2H; injection volume: 4.0 mL (CH3CN); gradient: 100?100% B over 15 min; mass-directed fraction collection]. Fractions with the desired MW were collected and concentrated on aRotaVap at 25 C to remove most of the acetonitrile. The resulting mostly aqueous solution was extracted with EtOAc. The combined EtOAc extracts were dried (Na2SO4) and concentrated to give 200 mg of 9-4 (59%).

Reference： [1]Patent: WO2010/17470,2010,A1 .Location in patent: Page/Page column 122-125

14
[ 852821-06-8 ]
[ 1207283-56-4 ]
[ 1207283-57-5 ]

Yield	Reaction Conditions	Operation in experiment
35%		Compound 5A THJF solution (6 mL) of 4 (487 mg, 1.40 mmol, 2.0 cquiv) was added to a THF solution (5 mL) of LDA (6.30 mL, 10% wt, 4.20 mmol, 6.0 equiv) and TMEDA (1.70 mL, 11.20 mmol, 16.0 equiv) at -78 C. The reaction was stirred at -78 C for 5 min. A THF solution of enone (339 mg, 0.70 mmol, 1.0 equiv) was added to the reaction mixture dropwise. The reaction was stirred from -78 C to 25 C for 1 h, quenched with saturated NH4CI, and extracted with EtOAc. The combined EtOAc extracts were dried (Na2SO4) and concentrated to yield the crude product. Preparative reverse phase HPLC purification on a Waters Autopurification system using a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; injection volume: 4.0 mL (CH3CN); gradient: 80? 100% B over 15 min; mass-directed fraction collection]. Fractions with the desired MW, eluting at 6.3- 8.0 min, were collected and concentrated on a RotaVap at rt to remove most of the acetonitrile. The resulting mostly aqueous solution was extracted with EtOAc. The combined EtOAc extracts were dried (Na2SO4) and concentrated to give 185 mg of pure 5 (35%): 1H NMR (400 MHz, CDCl3) delta 15.67 (s, 1 H), 7.51-7.46 (m, 2 H), 7.39-7.29 (m, 3 H), 7.21 (dd, J = 8.9, 8.9 Hz, 1 H), 7.03 (dd, J= 8.9, 4.0 Hz, 1 H), 5.34 (s, 2 H), 3.93 (d, J= 10.4 Hz, 1 H), 3.30-3.21 (m, I H), 3.10-3.00 (m, I H), 2.57-2.41 (m, 3 H), 2.48 (s, 6 H), 2.17-2.12 (m, 1 H), 1.53 (s, 9 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 735.45 (M+H).

Reference： [1]Patent: WO2010/17470,2010,A1 .Location in patent: Page/Page column 47; 49-50
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 597 - 605

15
[ 505-23-7 ]
[ 852821-06-8 ]
[ 75-77-4 ]
[ 1253798-69-4 ]

Yield	Reaction Conditions	Operation in experiment
90%		A solution of n-butyllithium in hexanes (2.5 M, 2.91 mL, 7.27 mmol, 1.15 equiv) was added to a solution of 1,3-dithiane (862 mg, 6.95 mmol, 1.1 equiv) in tetrahydrofuran (60 mL) at -78 C. The resulting solution was stirred at this temperature for 30 min, at which point hexamethylphosphoramide (2.44 mL, 13.9 mmol, 2.2 equiv) was added dropwise. After stirring at -78 C for a further 2 min, a solution of the AB enone 1 (3.05 g, 6.32 mmol, 1 equiv) in tetrahydrofuran (15 mL) was added to the reaction solution dropwise via syringe. The brownish-yellow reaction mixture was stirred at -78 C for 40 min whereupon chlorotrimethylsilane (1.20 mL, 9.48 mmol, 1.5 equiv) was added. After stirring at -78 C for 40 min, aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 100 mL) was added to the reaction solution. The resulting mixture was allowed to warm to 23 C, then was extracted with dichloromethane (3×100 mL). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The product was purified by flash-column chromatography (8% ethyl acetate/hexanes), affording beta-(1,3-dithian-2-yl) trimethylsilyl enol ether 8 as a white foam (3.85 g, 90%). Rf=0.53 (30% ethyl acetate/hexanes); 1H NMR (500 MHz, CDCl3) delta 7.48 (d, 2H, J=7.0 Hz), 7.38-7.31 (m, 3H), 5.36 (AB quartet, 2H), 4.98 (d, 1H, J=3.0 Hz), 4.12 (d, 1H, J=5.0 Hz), 3.89 (d, 1H, J=9.5 Hz), 2.96-2.82 (m, 5H), 2.46 (s, 6H), 2.34-2.29 (m, 1H), 2.28-2.23 (m, 2H), 2.15-2.09 (m, 1H), 1.90-1.80 (m, 1H), 0.86 (s, 9H), 0.21 (s, 3H), 0.10 (s, 3H), -0.01 (s, 9H); 13C NMR (125 MHz, CDCl3) delta 189.4, 181.5, 167.3, 149.5, 135.1, 128.7, 128.5, 128.4, 108.5, 104.8, 81.0, 72.3, 61.3, 54.9, 46.1, 41.9, 37.1, 31.1, 30.8, 26.1, 25.7, 21.8, 18.9, -0.4, -2.7, -3.6; FTIR (neat film), cm-1 2953 (w), 1721 (s), 1653 (w), 1614 (w), 1510 (s), 1472 (w), 1454 (w), 1254 (s), 1204 (w), 1150 (w), 1024 (w), 934 (s), 901 (s), 835 (s); HRMS-ESI (m/z): [M+H]+ calcd for C33H51N2O5S2Si2, 675.2772; found, 675.2783.
90%		A solution of H-butyllithium in hexanes (2.5 M, 2.91 mL, 7.27 mmol, 1.15 equiv) was added to a solution of 1,3-dithiane (862 mg, 6.95 mmol, 1.1 equiv) in tetrahydrofuran (60 mL) at -78 0C. The resulting solution was stirred at this temperature for 30 min, at which point hexamethylphosphoramide (2.44 mL, 13.9 mmol, 2.2 equiv) was added. After stirring at -78 0C for a further 2 min, a solution of the AB enone 16 (3.05 g, 6.32 mmol, 1 equiv) in tetrahydrofuran (25 mL) was added dropwise via syringe to the reaction solution. The brownish-yellow reaction mixture was stirred at -78 0C for 40 min whereupon trimethylsilyl chloride (1.20 mL, 9.48 mmol, 1.5 equiv) was added. After stirring at -78 0C for 40 min, aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 100 mL) was added to the reaction solution. The resulting mixture was allowed to warm to 23 0C, then was extracted with dichloromethane (3 x 100 mL). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The product was purified by flash-column chromatography (8% ethyl acetate-hexanes), affording the Michael addition product 17 as a foamy white solid (3.85 g, 90%). R/= 0.53 (30% ethyl acetate-hexanes); 1H NMR (500 MHz, CDCl3) delta 7.48 (d, 2H, J= 7.0 Hz), 7.38-7.31 (m, 3H), 5.36 (AB quartet, 2H, J= 12.0 Hz, Deltav = 34.0 Hz), 4.98 (d, IH, J= 3.0 Hz), 4.12 (d, IH, J= 5.0 Hz), 3.89 (d, IH, J= 9.5 Hz), 2.96-2.82 (m, 5H), 2.46 (s, 6H), 2.34-2.29 (m, I H), 2.28-2.23 (m, 2H), 2.15-2.09 (m, IH), 1.90-1.80 (m, IH), 0.86 (s, 9H), 0.21 (s, 3H), 0.10 (s, 3H), -0.01 (s, 9H); 13C NMR (125 MHz, CDCl3) delta 189.4, 181.5, 167.3, 149.5, 135.1, 128.7, 128.5, 128.4, 108.5, 104.8, 81.0, 72.3, 61.3, 54.9, 46.1, 41.9, 37.1, 31.1 , 30.8, 26.1 , 25.7, 21.8, 18.9, -0.4, -2.7, -3.6; FTIR (neat film), cm"1 2953 (w), 1721 (s), 1653 (w), 1614 (w), 1510 (s), 1472 (w), 1454 (w), 1254 (s), 1204 (w), 1 150 (w), 1024 (w), 934 (s), 901 (s), 835 (s); HRMS-ESI (m/z): [M+H]+ calcd for C33H51N2O5S2Si2, 675.2772; found, 675.2783.

Reference： [1]Tetrahedron,2011,vol. 67,p. 9853 - 9869
[2]Patent: WO2010/126607,2010,A2 .Location in patent: Page/Page column 127/251-128/251

16
[ 852821-06-8 ]
[ 108-98-5 ]
[ 1253799-26-6 ]

Yield	Reaction Conditions	Operation in experiment
97%		To a solution of enone 56 (1.94 g, 4.03 mmol, 1 equiv) in dichloromethane (9 mL) was added triethylamine (56 muL, 0.40 mmol, 0.1 equiv). The solution was cooled to 0 0C then thiophenol (434 muL, 4.23 mmol, 1.05 equiv) was added dropwise and the reaction was stirred at 0 0C. After forty minutes, additional thiophenol was added (40 muL, 0.39 mmol, 0.1 equiv). Seven minutes later, acetic acid (26 muL, 0.40 mmol, 0.1 equiv) was added, and the reaction was concentrated under reduced pressure to remove the solvent. Purification of the resulting crude oil via flash column chromatography on silica gel (Biotage, 100 g, 5 to 30% EtOAc in hexane gradient) provided enone 57 as a white foam (2.33 g, 97%, 6: 1 -mixture of-diastereomers)^H-NMR-(400-MHz1-GDGl3^-mixture-of-diastereomers,-6:-l-H:H-)- delta 7.43-7.37 (m, 2H + 2H'), 7.36-7.19 (m, 8H, 8H'), 5.29 (s, 2 H), 5.26 (s, 2H'), 4.31 (d, J = 9.2 Hz, 1 H), 3.84-3.73 (m, 1 H), 3.63 (d, J= 11.6 Hz, 1 H'), 3.42-3.31 (m, 1 H'), 3.25 (dd, J = 6.7, 14.0, 1 H), 3.12 (t, J= 12.8 Hz, 1 H'), 2.63-2.47 (m, 2H + 2 H'), 2.40 (s, 6 H), 2.38 (s, 6 H'), 2.33-2.21 (m, 2 H + 2 H'), 0.81 (s, 9 H'), 0.79 (s, 9 H), 0.050 (s, 3 H'), 0.037 (s, 3 H), 0.02 (s, 3 H'), 0.00 (s, 3 H); MS (ESI) m/z 591.31 (M-H).

Reference： [1]Patent: WO2010/126607,2010,A2 .Location in patent: Page/Page column 162/251-163/251

17
[ 852821-06-8 ]
[ 69739-34-0 ]
[ 1253799-71-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; In 1,2-dichloro-ethane; for 16h;Inert atmosphere; Reflux;	To a stirred solution of the AB enone 12A (1.055 g, 2.19 mmol) in dry 1,2- dichloroethane (25 mL) under an atmosphere of Ar was added triethylamine (2.44 mL, 8.0eq.) and f-butyldimethylsilyl trifluoromethanesulfonate (2.0 mL, 4.0 eq.). The resultant solution was heated to relux and stirred 16h under an inert atmosphere. The reaction mixture was poured over NaHCO3 sat. aq. (60 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organics were washed with NaHCO3 sat. aq., brine (60 mL), dried (Na2SO4), and concentrated in vacuo. Flash column chromatography (SiO2, 10% ethyl acetate in hexanes) of the residue provided the silyl dienol ether 92 ((4aS,8aS,9S)-3-(benzyloxy)-5-((tert- butyldimethylsilyl)oxy)-9-(dimethylamino)-4a-hydroxy-8a,9-dihydronaphtho[2,3-d]isoxazol- 4(4aH)-one) as a waxy off-white solid (1.12 g, 86%): Rf= 0.68 (20% ethyl acetate in hexanes); Rf= 0.79 (20% ethyl acetate in hexanes); IR (neat) 2929, 1716, 1510, 1247 cm"1; 1H NMR (500 MHz, CDCl3) delta 7.48 (d, J= 7.8 Hz, 2H), 7.35 (m, 3H), 5.98 (dd, J= 9.3, 5.9 Hz, IH), 5.87 (dd, J= 9.3, 5.9 Hz, IH), 5.32 (m, 2H), 5.25 (d, J= 5.8 Hz, IH), 3.78 (d, J= 10.3 Hz, IH), 2.83 (dd, J= 9.8, 5.9 Hz, IH), 2.48 (s, 6H), 0.82 (s, 9H), 0.77 (s, 9H), 0.15 (s, 6H), 0.13 (s, 3H), -0.04 (s, 3H); 13C NMR (500 MHz, CDCl3) delta 188.7, 181.8, 167.7, 151.0, 139.3, 135.1, 128.9, 128.5, 128.4, 123.0, 122.9, 107.9, 103.4, 94.7, 81.7, 72.3, 64.2, 48.1, 42.4, 25.8, 25.4, 18.9, 17.8, -2.8, -3.4, -4.5, -5.3; HRMS for C32H48N2O5Si2 [MH+] m/z calc. 597.31745, found 596.31789.

Reference： [1]Patent: WO2010/126607,2010,A2 .Location in patent: Page/Page column 188/251

18
[ 852821-06-8 ]
[ 1253799-65-3 ]
[ 1254367-51-5 ]

Yield	Reaction Conditions	Operation in experiment
35%		Synthesis ofS3-2-l.Lithium diisopropylamide was prepared at -78 0C from rc-butyllithium (1.6 M solution in hexane, 0.495 mL, 0.792 mmol) and diisopropylamine (0.1 12 mL, 0.792 mmol) in THF (5 mL). TMEDA (0.318 mL, 2.11 mmol) was added, followed by drop wise addition of a solution of intermediate Sl-4 (169 mg, 0.529 mmol) in THF (2 mL). This resulted in a deep red colored solution. After 5 min, a solution of S3-1 (128 mg, 0.264 mmol) in THF (2 mL) was added. After complete addition, the reaction mixture was allowed to warm to -10 C over 1 h. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution, 20 mL) and was extracted with EtOAc (2 x 20 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 80?100% B; mass- directed fraction collection], yielding 65.5 mg (35%) of the desired product S3-2-1 as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.77 (s, 1 H), 8.36 (s, 1 H), 8.16 (s, 1 H), 7.55-7.24 (m, 10 H), 5.40-5.25 (m, 4 H), 3.93 (d, J= 1 1.0 Hz, 1 H), 3.16- 3.04 (m, 1 H), 2.98-2.90 (m, 1 H), 2.76-2.64 (m, 1 H), 2.60-2.40 (m, 8 H), 2.12 (d, J = 14 Hz, 1 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 708.72 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 43-44
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

19
[ 852821-06-8 ]
[ 1254367-61-7 ]
[ 1254367-62-8 ]

Yield	Reaction Conditions	Operation in experiment
35%		Synthesis ofS6-3.S6-3A solution of intermediate S6-2 (95 mg, 0.22 mmol) in THF (1 mL) was added drop wise to a -78 C solution of lithium diisopropylamide (10 wt% suspension in hexanes, 0.48 mL, 0.32 mmol) and TMEDA (0.13 mL, 0.86 mmol) in THF (2 mL), resulting in an immediate purple colored solution. After 2 min, a solution of S3-1 (52 mg, 0.108 mmol) in THF (1 mL) was added drop wise over -30 seconds. The color gradually lightened to orange. After complete addition, the reaction mixture was allowed to warm to -10 C over ~45 min. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution), was diluted with water, and was extracted with EtOAc (2 x). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep C 18 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 90?100% B; mass- directed fraction collection], yielding 31.1 mg (35%) of the desired product as a yellow solid. MS (ESI) m/z 829.44, 831.43 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 63-64

20
[ 852821-06-8 ]
[ 1254367-64-0 ]
[ 1254367-65-1 ]

Yield	Reaction Conditions	Operation in experiment
20%		Synthesis of S7-3.A solution of intermediate S7-2 (24 mg, 0.047 mmol) in THF (0.5 mL) was added drop wise to a -78 0C solution of lithium diisopropylamide (0.5 M solution in THF, 0.102 mL, 0.051 mmol) and TMEDA (0.041 mL, 0.27 mmol) in THF (2 mL), resulting in a yellowish orange colored solution. After 10 min, a solution of S3-1 (16.4 mg, 0.034 mmol) in THF (0.5 mL) was added drop wise. After complete addition, the reaction mixture was allowed to warm to -20 0C over ~45 min. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution) and was extracted with EtOAc (2 x). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 * 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 90?100% B; mass- directed fraction collection], yielding 6.1 mg (20%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.56 (s, 1 H), 7.52-7.24 (m, 10 H), 5.36 (s, 2 H), 4.99-4.64 (m, 2 H), 4.02 (d, J= 11.0 Hz, 1 H), 3.10-2.81 (m, 2 H), 2.78 (s, 6 H), 2.62-2.40 (m, 10 H), 2.20-2.14 (m, 1 H), 1.80-1.45 (m, 2 H), 1.44-1.15 (m, 1 1 H), 1.00-0.70 (m, 12 H), 0.25 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 908.65 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 64-67
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

21
[ 852821-06-8 ]
[ 1254367-70-8 ]
[ 1254367-71-9 ]

Yield	Reaction Conditions	Operation in experiment
45%	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - -20℃; for 1.78333h;	Synthesis o/S8-6.LHMDS solution (1.0 M, 0.621 mL, 0.621 mmol) was added over ~2 min to a -78 C solution of intermediate S8-5 (86 mg, 0.207 mmol) and S3-1 (99 mg, 0.207 mmol) in THF (2 mL). After 45 min, the reaction mixture was allowed to slowly warm to -20 C over 1 hr. The reaction mixture was quenched by the addition of NH4Cl (saturated, aqueous solution) and was extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1%HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 80?100% B; mass-directed fraction collection], yielding 75.3 mg (45%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.55 (s, 1 H), 7.56-7.26 (m, 10 H), 5.36 (s, 2 H), 5.02 (s, 2 H), 3.88 (d, J= 10.4 Hz, 1 H), 3.18-3.04 (m, 2 H), 2.62-2.58 (m, 1 H), 2.58-2.40 (m, 8 H), 2.17 (d, J= 14.6 Hz, 1 H), 0.81 (s, 9 H), 0.25 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 804.34, 806.34 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 68; 70
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

22
[ 852821-06-8 ]
[ 1254367-73-1 ]
[ 1254367-74-2 ]

Yield	Reaction Conditions	Operation in experiment
26%		Synthesis ofS9-3~l.A solution of intermediate S9-2-1 (54 mg, 0.090 mmol) in THF (0.5 mL) was added drop wise to a -78 C solution of lithium diisopropylamide (2.0 M solution in THF, 0.1 12 mL, 0.224 mmol) and TMEDA (0.081 mL, 0.54 mmol) in THF (2 mL), resulting in an orange colored solution. After 10 min, a solution of S3- 1 (43 mg, 0.090 mmol) in THF (0.5 mL) was added drop wise over -30 seconds. After complete addition, the reaction mixture was allowed to warm to -10 C over 1 h. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution), was diluted with water, and was extracted with EtOAc (2 x). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 20-?100% B; mass-directed fraction collection], yielding 22.9 mg (26%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.55 (br s, 1 H), 7.52-7.20 (m, 15 H), 5.36 (s, 2 H), 5.20-5.00 (m, 2 H), 4.80 (s, 2 H), 3.90 (d, J = 1 1.0 Hz, 1 H), 3.19-3.05 (m, 2 H), 2.62-2.57 (m, 1 H), 2.56-2.12 (m, 19 H), 0.94- 0.74 (m, 15 H), 0.26 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 988.59 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 72-73
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

23
[ 852821-06-8 ]
[ 1254367-78-6 ]
[ 1254367-79-7 ]

Yield	Reaction Conditions	Operation in experiment
53%		Synthesis of Sl 1-3-1.Lithium diisopropylamide was prepared at -40 0C by the addition of H-BuLi (1.84 M solution in hexane, 0.458 mL, 0.843 mmol) to a solution of diisopropylamine (0.1 19 mL, 0.843 mmol) in THF (7 mL). TMEDA (0.507 mL,3.37 mmol) was added, and the reaction mixture was cooled to -78 C. A solution of intermediate Sl 1-2-1 (422 mg, 0.731 mmol) in THF (1.5 mL) was added drop wise, giving a reddish orange colored solution. After 5 min, a solution of S3-1 (271 mg, 0.562 mmol) in THF (1.5 mL) was added. The reaction mixture was allowed to warm to -10 C over -30 min. The reaction mixture was quenched by the addition of NH4Cl (saturated, aqueous solution) and was extracted with EtOAc (2 x). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1%HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 90?100% B; mass-directed fraction collection], yielding 288 mg (53%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.50 (s, 1 H),7.52-7.24 (m, 10 H), 5.36 (s, 2 H), 4.85 (q, J= 86.1 Hz, J= 9.76 Hz, 2 H), 4.02 (d, J = 10.4 Hz, 1 H), 3.08-3.00 (m, 1 H), 3.00-2.82 (m, 1 H), 2.77 (s, 6 H), 2.62-2.38 (m, 9 H), 2.20-2.12 (m, 1 H), 1.35, (br s, 18 H), 0.79 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 966.59 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 79-81
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

24
[ 852821-06-8 ]
[ 1254367-87-7 ]
[ 1254367-88-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - -10℃; for 2h;	Synthesis ofSU-3-2.LHMDS solution (1.0 M, 2.6 mL, 2.6 mmol) was added over ~1 min to a -780C solution of intermediate Sl 1-2-2 (480 mg, 0.868 mmol) and S3-1 (418 mg, 0.867 mmol) in THF (8 mL). After 1 h, the reaction mixture was allowed to slowly warm to -10 C over 1 hr. The reaction mixture was quenched by the addition OfNH4Cl (saturated, aqueous solution, 15 mL) and was extracted with EtOAc (20 mL). The extracts were washed with water (15 mL) and were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1%HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 80?100% B; mass-directed fraction collection], yielding 459 mg (56%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.59 (s, 1 H), 7.56-7.24 (m, 10 H), 5.36 (s, 2 H), 4.92 (q, J= 67.8 Hz, J= 9.16 Hz, 2 H), 3.91 (d, J= 1 1.0 Hz, 1 H), 3.20-3.02 (m, 2 H), 2.62-2.45 (m, 9 H), 2.19-2.12 (m, 1 H), 1.37, (s, 18 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 941.59 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 79; 88
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

25
[ 852821-06-8 ]
[ 1254368-03-0 ]
[ 1254368-04-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With N,N,N,N,-tetramethylethylenediamine; lithium diisopropyl amide; In tetrahydrofuran; hexanes; at -78 - 0℃;	Synthesis of S 17-4.Lithium diisopropylamide (10 wt% suspension in hexanes, 0.60 mL, 0.40 mmol) was added in -0.020 mL portions to a -78 0C solution of intermediate S17-3 (76.2 mg, 0.124 mmol), TMEDA (0.070 mL, 0.58 mmol) and S3-1 (35 mg, 0.072 mmol) in THF (2 mL). At this point, a reddish colored solution persisted, and the reaction mixture was allowed to warm to 0 C. The reaction mixture was quenched by the addition of ammonium chloride (saturated, aqueous solution) and was extracted with EtOAc (2 x). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 80-?100% B; mass-directed fraction collection], yielding 40 mg (55%) of the desired product as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.46 (s, 1 H), 7.56-7.24 (m, 10 H), 5.36 (s, 2 H), 4.93 (dd, J = 36.0 Hz, J= 9.8 Hz, 2 H), 3.90 (d, J= 1 1.0 Hz, 1 H), 3.28 (dd, J= 16.5 Hz, J= 5.48 Hz, 1 H), 3.14-3.05 (m, 1 H), 2.65-2.42 (m, 9 H), 2.17 (d, J= 14.6 Hz, 1 H), 1.40 (s, 18 H), 0.81 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 1001.86, 1003.86 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 110; 113

26
[ 852821-06-8 ]
[ 1254367-39-9 ]
[ 1254367-52-6 ]

Yield	Reaction Conditions	Operation in experiment
50%		Synthesis ofS3-2-2.S3-2-2A solution of intermediate S3-1-6 (412 mg, 1.14 mmol) in THF (1 mL) was added drop wise to a -78 C solution of lithium diisopropylamide (10 wt% suspension in hexanes, 2.55 mL, 1.70 mmol) and TMEDA (0.684 mL, 4.54 mmol) in THF (10 mL), resulting in a reddish orange colored solution. After 10 min, a solution of S3-1 (274 mg, 0.568 mmol) in THF (1 mL) was added drop wise. The color gradually lightened to orange. After complete addition, the reaction mixture was allowed to warm to 0 0C over 1 h. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution), was diluted with water, and was extracted with EtOAc (3 x). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep C 18 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 80-?100% B; mass-directed fraction collection], yielding 21 1 mg (50%) of the desired product S3-2-2 as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.65 (s, 1 H), 8.01 (s, 1 H), 7.52-7.22 (m, 10 H), 5.36 (s, 2 H), 5.17 (q, J= 1 1.0 Hz, 2 H), 4.02 (d, J= 1 1.0 Hz, 1 H), 3.05 (dd, J = 17.2 Hz, J= 1 1.6 Hz, 1 H), 2.98-2.86 (m, 1 H), 2.73 (s, 6 H), 2.62-2.38 (m, 9 H), 2.12 (d, J= 13.4 Hz, 1 H), 0.81 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 751.79 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 43; 45
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

27
[ 852821-06-8 ]
[ 1254367-42-4 ]
[ 1254367-57-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 0℃; for 1.16667h;Inert atmosphere;	Synthesis ofS5-l.Intermediate Sl-9 (793 mg, 1.84 mmol) and S3-1 (885 mg, 1.84 mmol, 1.0 eq) were dissolved in THF (anhydrous, 16 mL) under a nitrogen atmosphere in a flame-dried Schlenck flask. The resulting solution was cooled to -78 C in a dry ice/acetone bath. LHMDS solution (1.0 M, 5.51 mL, 3.0 equiv) was added slowly via syringe. After 10 min, LC/MS indicated that the starting material was consumed and the product present. The reaction mixture was allowed to slowly warm to 0 C over 1 hr. A phosphate buffer solution (pH 7.0, 20 mL) was added, followed by the addition of ammonium chloride (saturated, aqueous solution, 50 mL). The resulting mixture was extracted with methylene chloride (3 x 50 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown solid was washed with cold methanol (3 x 5 mL) to afford the desired product S5-1 as a yellow-brown powder (1.11 g, 74 %). The organics were concentrated under reduced pressure and purified by column chromatography (Biotage 20 g column, 5 to 20% EtOAc in hexanes gradient), yielding another 150 mg (10%) of intermediate S5-1. 1H NMR (400 MHz, CDCl3) delta 15.45 (br, 1 H), 7.54- 7.48 (m, 4 H), 7.40-7.30 (m, 6 H), 5.36 (s, 2 H), 5.03 (abq, J= 10.4 Hz, 2 H), 3.87 (d, J= 11.0 Hz, 1 H), 3.27-3.23 (m, 1 H), 3.10-3.00 (m, 1 H), 2.65-2.57 (m, 1 H), 2.57-2.43 (m, 8 H), 2.16 (d, J= 1 1.0 Hz, 1 H), 0.81 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 820.37, 822.37 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 52-53
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

28
[ 852821-06-8 ]
[ 1254367-50-4 ]
[ 1254367-53-7 ]

Yield	Reaction Conditions	Operation in experiment
27%		Synthesis of S3-2-3.A solution of intermediate S2-5 (20.3 mg, 0.058 mmol) in THF (1 mL) was added drop wise to a -78 C solution of lithium diisopropylamide (1.8 M solution in hexanes, 0.050 mL, 0.090 mmol) and TMEDA (0.022 mL, 0.15 mmol) in THF (2 mL). After 10 min, a solution of S3-1 (14 mg, 0.029 mmol) in THF (0.5 mL) was added. After complete addition, the reaction mixture was allowed to warm to 0 C over 1 h. LC/MS indicated a lot of S2-5 and S3-1 remained. The reaction mixture was again cooled to -78 C, and additional lithium diisopropylamide (1.8 M solution in hexanes, 0.050 mL, 0.090 mmol) was added. This was allowed to warm to 0 C over 30 min. The reaction was quenched by the addition of ammonium chloride(saturated, aqueous solution, 20 mL), was diluted with water, and was extracted with EtOAc (3 x 20 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 80?100% B; mass-directed fraction collection], yielding 5.9 mg (27%) of the desired product S3-2-3 as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 15.70 (s, 1 H), 7.83 (s, 1 H), 7.55-7.24 (m, 10 H), 5.36 (s, 2 H), 5.17 (q, J= 13.4 Hz, 2 H), 3.98 (d, J= 1 1.0 Hz, 1 H), 3.72 (s, 3 H), 3.18 (d, J= 16.5 Hz, 1 H), 3.04 -2.96 (m, 1 H), 2.60-2.30 (m, 9 H), 2.15 (d, J= 14 Hz, 1 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 738.66 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 43; 46-47
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

29
[ 852821-06-8 ]
[ 1254367-60-6 ]
[ 1254367-93-5 ]

Yield	Reaction Conditions	Operation in experiment
54%		Synthesis ofS14-l.Lithium diisopropylamide was prepared at -40 C by the addition of «-BuLi (2.5 M solution in hexane, 0.60 mL, 0.1.5 mmol) to a solution of diisopropylamine (0.213 mL, 0.1.51 mmol) in THF (10 mL). The reaction mixture was cooled to -78 C and TMEDA (0.542 mL, 3.62 mmol) was added. A solution of intermediate S6-1 (266 mg, 0.603 mmol) in THF (4 mL) was added drop wise, giving a dark red colored solution. After 5 min, a solution of S3-1 (242 mg, 0.502 mmol) in THF (2 mL) was added. The reaction mixture was allowed to warm to -20 C over ~45 min. The reaction mixture was quenched by the addition OfNH4Cl (saturated, aqueous solution) and was extracted with EtOAc (2 x). The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on a Waters Autopurification system equipped with a Sunfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1%HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 90?100% B; mass-directed fraction collection], yielding 225 mg (54%) of the desired product as a yellow solid. MS (ESI) m/z 829.49, 831.48 (M+H).

Reference： [1]Patent: WO2010/129055,2010,A1 .Location in patent: Page/Page column 99-100
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 1511 - 1528

30
[ 852821-06-8 ]
[ 1254949-80-8 ]
[ 1254949-83-1 ]

Yield	Reaction Conditions	Operation in experiment
87%		A solution of lithium diisopropylamide (1.8 M, 1.10 mL, 1.97 mmol, 3.0 eq) in heptane/ethylbezene/THF was added drop wise via syringe to a solution of ester S5-7 (772 mg, 1.32 mol, 2.0 eq), enone (318 mg, 0.658 mol, 1.0 eq) and TMEDA (592 muL, 3.95 mmol, 6.0 eq) in tetrahydrofuran (30 mL) at -78 C. The resulting orange mixture was allowed to warm slowly to -25 C over 5.5 h, then was poured into a mixture of saturated ammonium chloride (30 mL) and pH=7 potassium phosphate buffer solution (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep Cl 8 OBD column [5 mum, 19x50 mm; flow rate, 20 mL/min; Solvent A: H2O; Solvent B: MeOH; injection volume: 3.0 mL (CH3CN); gradient: 85?100% B over 8 min, then 100% B for 7 min; mass-directed fraction collection]. Fractions with the desired MW, were collected and concentrated on a RotaVap at rt to afford the desired product S5-8-3 (560 mg, 87%, a mixture of rotamers) as a yellow solid. 1H NMR of the major rotamer (400 MHz, CDCl3) delta 15.82 (br s, 1 H), 8.29 (br s, 1 H), 7,74 (dd, J= 1.8, 8.5 Hz, 1 H), 7.64 (dd, J = 8.5 Hz, 1 H), 7.55-7.51 (m, 2 H), 7.42-7.35 (m, 3 H), 5.36, 5.39 (ABq, J= 12.2 Hz, 2 H), 3.93 (d, J= 10.7 Hz, 1 H), 3.15 (s, 3 H), 3.12- 3.09 (m, 1 H), 3.04-2.98 (m, 1 H), 2.62-2.46 (m, 9 H), 2.19-2.15 (m, 1 H), 1.61 (s, 9 H), 1.27 (s, 9 H), 0.82 (s, 9 H), 0.28 (s, 3 H), 0.15 (s, 3 H); MS (ESI) m/z 974.62, 976.62 (M+H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 97; 103

31
[ 852821-06-8 ]
[ 1254949-88-6 ]
[ 1254949-89-7 ]

Yield	Reaction Conditions	Operation in experiment
45%		A suspension of LDA in hexanes (10 wt%, 7.96 mL, 5.32 mmol, 2.5 eq) was added slowly over 20 min to a solution of phenyl ester S6-2 (1.56 g, 3.20 mmol, 1.5 eq), enone (1.03 g, 2.13 mmol, 1.0 eq) and TMEDA (1.60 mL, 10.65 mmol, 5.0 eq) in tetrahydrofuran (50 mL) at -78 C. The resulting dark red solution was allowed to warm slowly to -40 C over 3 h. The reaction mixture was then partitioned between saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase was further extracted with ethyl acetate (100 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (2-20% ethyl acetate-hexanes) to afford the Michael-Dieckmann product S6-3 as a yellow solid (829 mg, 45%). 1H NMR (400 MHz, CDCl3) delta 15.94 (br s, 1 H), 8.23 (br s, 1 H), 7.94 (d, J= 8.5 Hz, 1 H), 7.67 (dd, J= 2.4, 8.5 Hz, 1 H), 7.50-7.48 (m, 2 H), 7.39-7.32 (m, 3 H), 5.37, 5.33 (ABq, J= 12.2 Hz, 2 H), 3.98 (d, J= 1 1.0 Hz, 1 H), 3.85 (s, 3 H), 3.48 (dd, J= 4.9, 15.3 Hz, 1 H), 3.06-2.98 (m, 1 H), 2.62-2.44 (m, 9 H), 2.20 (d, J= 14.0 Hz, 1 H), 1.58 (s, 9 H), 0.82 (s, 9 H), 0.27 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 875.55, 877.52 (M+H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 108-110

32
[ 852821-06-8 ]
[ 1254949-94-4 ]
[ 1254949-95-5 ]

Yield	Reaction Conditions	Operation in experiment
47%		A suspension of LDA in hexanes (1.8 M, 269 muL, 0.485 mmol, 2.5 eq) was added slowly to a solution of phenyl ester S7-2 (149.6 g, 0.291 mmol, 1.5 eq), enone (94 mg, 0.194 mmol, 1.0 eq) and TMEDA (145 muL, 0.97 mmol, 5.0 eq) in tetrahydrofuran (7 mL) at -78 C. The resulting dark red brownish solution was allowed to warm slowly to -10 C over 1 h. The reaction mixture was diluted with saturated aqueous ammonium chloride solution and pH=7 phosphate buffer solution. The resulting mixture was extracted with methylene chloride (3 x 15 mL), The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (1-10% ethyl acetate-hexanes) to afford the Michael-Dieckmann product S7-3 as a yellow solid (83 mg, 47%). 1H NMR (400 MHz, CDCl3) delta 15.93 (br s, 1 H), 8.23 (br s, 1 H), 7.92 (d, J= 9.2 Hz, 1 H), 7.67 (dd, J= 1.8, 9.2 Hz, 1 H), 7.50-7.48 (m, 2 H), 7.39-7.30 (m, 3 H), 6.20-6.10 (m, 1 H), 5.45 (dd, J= 1.2, 15.1 Hz, 1 H), 5.38-5.32 (m, 3 H), 4.47-4.38 (m, 2 H), 3.96 (d, J= 1 1.0 Hz, 1 H), 3.49 (dd, J= 4.3, 15.3 Hz, 1 H), 3.03-2.98 (m, 1 H), 2.60-2.44 (m, 9 H), 2.17 (d, J= 14.6 Hz, 1 H), 1.58 (s, 9 H), 0.81 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 901.77, 903.78 (M+H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 117; 119

33
[ 852821-06-8 ]
[ 1254950-09-8 ]
[ 1254950-10-1 ]

Yield	Reaction Conditions	Operation in experiment
61%		A suspension of LDA in hexanes (10 wt%, 5.4 mL, 3.6 mmol, 2.5 eq) was added slowly to a solution of phenyl ester Sll-2 (1.06 g, 2.16 mmol, 1.5 eq), enone (694 mg, 1.44 mmol, 1.0 eq) and TMEDA (1.08 mL, 7.2 mmol, 5.0 eq) in tetrahydrofuran (70 mL) at -78 C. The resulting orange mixture was allowed to warm slowly to -30 C over 2 h. The reaction mixture was then partitioned between saturated aqueous ammonium chloride solution (120 mL) and ethyl acetate (200 mL). The phases were separated and the aqueous phase was further extracted with ethyl acetate (50 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (1-5% ethyl acetate-hexanes) to afford the Michael-Dieckmann product Sll-3 as a yellow solid (773 mg, 61%). 1H NMR (400 MHz, CDCl3) delta 15.74 (br s, 1 H), 8.19 (br s, 1 H), 8.04 (d, J= 9.2 Hz, 1 H), 7.66 (dd, J= 1.8, 9.2 Hz, 1 H), 7.43-7.41 (m, 2 H), 7.31-7.24 (m, 3 H), 5.30, 5.26 (ABq, J= 12.2 Hz, 2 H), 3.87 (d, J= 10.4 Hz, 1 H), 3.59 (dd, J= 4.3, 15.9 Hz, 1 H), 3.04-2.98 (m, 1 H), 2.60 (t, J= 15.3 Hz, 1 H), 2.54-2.39 (m, 8 H), 2.14 (d, J= 14.0 Hz, I H), 1.50 (s, 9 H), 0.75 (s, 9 H), 0.20 (s, 3 H), 0.06 (s, 3 H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 134-136

34
[ 852821-06-8 ]
[ 1254950-15-6 ]
[ 1254950-16-7 ]

Yield	Reaction Conditions	Operation in experiment
56%		A suspension of LDA in hexanes (10 wt%, 8.07 mL, 5.40 mmol, 2.5 eq) was added slowly to a solution of phenyl ester S12-2 (1.23 g, 2.59 mmol, 1.2 eq), enone (1.04 g, 2.16 mmol, 1.0 eq) and TMEDA (1.62 mL, 10.8 mmol, 5.0 eq) in tetrahydrofuran (60 mL) at -78 C. The resulting orange mixture was allowed to warm slowly to -30 C over 2.5 h. The reaction mixture was then partitioned between saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase was further extracted with ethyl acetate (30 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (0-5% ethyl acetate-hexanes to elute the remaining ester starting material S12-2 and PhOH, then 10% ethyl acetate-hexanes to elute the desired product S12-3 and remaining enone) to afford the Michael-Dieckmann product S12-3 as a yellow solid (1.05 g, 56%) [481 mg of ester SM S12-2 and 262 mg enone SM were recovered]. 1H NMR (400 MHz, CDCl3) delta 15.96 (s, 1 H), 8.24 (s, 1 H), 7.89 (d, J= 8.5 Hz, 1 H), 7.70 (dd, J= 1.8, 8.5 Hz, 1 H), 7.51-7.50 (m, 2 H), 7.39-7.31 (m, 3 H), 5.39, 5.35 (ABq, J= 12.2 Hz, 2 H), 3.97 (d, J= 10.4 Hz, 1 H), 3.48 (dd, J- 4.3, 15.3 Hz, 1 H), 3.14-3.07 (m, 1 H), 2.64-2.48 (m, 9 H), 2.23 (d, J= 14.0 Hz, 1 H), 1.61 (s, 9 H), 0.85 (s, 9 H), 0.30 (s, 3 H), 0.17 (s, 3 H); MS (ESI) m/z 863.43, 865.42 (M+H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 139; 141-142

35
[ 852821-06-8 ]
[ 1254949-52-4 ]
[ 1095277-54-5 ]

Yield	Reaction Conditions	Operation in experiment
47%		Michael-Dieckmann Cyclization. General Procedure A. A solution of lithium diisopropylamide (1.8 M, 4.30 mL, 7.74 mmol, 3.0 eq) in heptane/ethylbezene/THF was added drop wise via syringe to a solution of ester Sl- 6 (2.36 g, 5.16 mol, 2.0 eq), enone (1.24 g, 2.58 mol, 1.0 eq) and TMEDA (2.32 mL, 15.48 mmol, 6.0 eq) in tetrahydrofuran (100 mL) at -78 C. The resulting red orange reaction mixture was allowed to warm to -10 C over 2 h, then was diluted with aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 50 mL) and saturated ammonium chloride. The resulting mixture was extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, affording a red oil. The product was purified by flash-column chromatography (5- 10% ethyl acetate-hexanes) to afford the Michael-Dieckmann cyclization product Sl-7 as an orange solid (1.02 g, 47%). 1H NMR (500 MHz, CDCl3) delta 15.98 (br s, 1 H ), 8.24 (br s, 1 H), 7.64 (s, 2 H), 7.51-7.49 (m, 3 H), 7.39- 7.33 (m, 3 H), 5.37 (d, J- 12.0 Hz, 1 H), 5.34 (d, J= 12.0 Hz, 1 H), 3.96 (d, J = 10.5 Hz, 1 H), 3.1 1-3.06 (m, 2 H), 2.93 (t, J= 15.5 Hz, 1 H), 2.56 (dd, J= 11.0, 5.0 Hz, 1 H), 2.49 (s, 6 H), 2.49-2.46 (m, 1 H), 2.14 (d, J= 14.0 Hz, 1 H), 1.59 (s, 9 H), 0.82 (s, 9 H), 0.27 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 845.70, 847.69 (M+H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 50; 54

36
[ 852821-06-8 ]
[ 1254950-32-7 ]
[ 1254950-33-8 ]

Yield	Reaction Conditions	Operation in experiment
61%		A solution of n-BuLi in hexane (2.5 M, 0.10 mL, 0.25 mmol, 4.0 eq.) was added drop wise to a solution of S15-6 (100 mg, 0.21 mmol, 3.3 eq.) and enone (30 mg, 0.062 mmol, 1.0 eq.) in dry THF (2.5 mL), which had been cooled to -1000C using a liquid N2/EtOH bath. After addition, the resulting mixture was allowed to warm to 0 C gradually over 1 h. The reaction was then quenched with brine (20 mL) and extracted with EtOAc (20 mL>;<;3). The combined organic layers was dried, filtered and then concentrated. The residue was purified with flash chromatography (200 ~ 300 mesh, petroleum ether/EtOAc = 40: 1 ~ 20: 1) to give the desired product S15-7 (30 mg, 61%) as a yellow solid: 1H NMR (400 MHz, CDCl3): 67.93 (s, 1 H), 7.62 (d, J= 8.4 Hz, 1 H), 7.46-7.44 (m, 2 H), 7.40-7.28 (m, 5 H), 6.87 (d, J= 6.8 Hz, 1 H), 5.31 (s, 2 H), 3.95 (s, 3 H), 3.11-3.03 (m, 2 H), 2.92 (d, J = 10.4 Hz, 1 H), 2.51-2.38 (m, 9 H), 2.11-2.05 (m, 1 H), 1.73-1.65 (m, 1 H), 1.53 (s, 9H), 0.80 (s, 9 H), 0.22 (s, 3 H), 0.09 (s, 3 H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 159; 163-164

37
[ 852821-06-8 ]
[ 1254950-45-2 ]
[ 1254950-46-3 ]

Yield	Reaction Conditions	Operation in experiment
53%		A solution of n-BuLi in hexane (2.5 M, 0.30 mL, 0.75 mmol, 3.2 eq.) was added drop wise to a solution of S16-3 (504 mg, 0.75 mmol, 3.2 eq.) and enone (1 13 mg, 0.23 mmol, 1.0 eq.) in dry THF (10 mL), which had been cooled to -100 0C using a liquid N2ZEtOH bath. After addition, the resulting mixture was stirred at -100 C for 30 min and then allowed to warm to 0 C gradually. The reaction was then quenched with brine (20 mL) and extracted with EtOAc (20 mL>;<;3). The combined organic layers was dried, filtered and then concentrated. The residue was purified with flash chromatography (200 - 300 mesh, petroleum ether/EtOAc = 30:1 - 20:1 ~ 10:1) to give the desired product S 16-4 (123 mg, 53 %) as a yellow gum: 1H NMR (400 MHz, CDCl3): 58.33 (d, J = 8.4 Hz, 1 H), 7.77-7.71 (m, 5 H), 7.66-7.48 (m, 6 H), 7.35 (d, J = 8.8 Hz, 2 H), 5.59 (s, 2 H), 4.27-4.18 (m, 1 H), 3.40-3.29 (m, 2 H), 3.20 (d, J= 10.4 Hz, 1 H), 2.90-2.68 (m, 9 H), 2.28-2.18 (m, 1 H), 1.56 (s, 9 H), 1.50 (s, 18 H), 1.08 (s, 9 H), 0.50 (s, 3 H), 0.37 (s, 3 H).

Reference： [1]Patent: WO2010/132670,2010,A2 .Location in patent: Page/Page column 165; 167

38
[ 852821-06-8 ]
[ 1268463-51-9 ]
[ 1268463-52-0 ]

Yield	Reaction Conditions	Operation in experiment
67%		(4 aS}llaR, J2aS, 13S)-3-(benzyloxy) -4 a- (tert-b utyldimethylsilyloxy) -13- (dimethylamino)-5~hydroxy-10-methoxy-4,6-dioxo-4,4a,6,ll,lla,12,12a,13- octahydrotetraceno[2,3-d]isoxazol-7-yl tert-butyl carbonate (1-7), A THF solution (8 mL) of 1-5 (520 mg, 1 ,45 mmol, 2,5 equiv) was added to a THF solution (8 mL) of LDA (6,50 mL, 10% Wt5 4.36 mmol, 7.5 equiv) and TMEDA (1.0 mL, 7.3 mmol, 12.5 equiv) at -78 0C. The reaction was stirred at -78 0C for 5 min. A THF solution (8 mL) of enone 1-6 (280 mg, 0.58 mmol, 1.0 equiv) was added to the reaction mixture dropwise. The enone 1-6 was prepared as described in PCT publication WO 2005/1 12945 and WO 2007/117639. The reaction was stirred from -78 0C to 25 0C for 1 h, quenched with saturated NH4Cl, and extracted with EtOAc, The combined EtOAc extracts were dried (Na2SO4) and concentrated to yield the crude product. Preparative reverse phase HPLC purification on a Waters Autopurification system using a Suirfire Prep Cl 8 OBD column [5 mum, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B : CH3CN with 0.1 %HCO2H; injection volume: 4.0 ml (CH3CN); gradient: 80?100% B over 15 min; mass-directed fraction collection]. Fractions with the desired MW were collected and concentrated on a RotaVap at 25 0C to remove most of the acetonitrile. The resulting mostly aqueous solution was extracted with EtOAc. The combined EtOAc extracts were dried (Na2SO4) and concentrated to give 290 mg of pure 1-7 (67%).

Reference： [1]Patent: WO2011/25982,2011,A2 .Location in patent: Page/Page column 65-66

39
[ 852821-06-8 ]
[ 1268463-89-3 ]
[ 1268463-90-6 ]
[ 1268463-91-7 ]

Yield	Reaction Conditions	Operation in experiment
56%		(4aS,llaR,12aS,13S)-3-(benzyloxy)-4a-(tert-butyldimethylsilyloxy)-13- (dimethylamino)-5-hydroxy-4,6-dioxo-10-(trifluoromethoxy)- 4,4a,6,ll,lla,12t12a,13-octahydrotetraceno[2,3-d]isoxazol-7-yl tert-butyl carbonate (10-6), To diisopropylamine (0.062 mL, 0.44 mmol, 2.2 equiv) in THF (5 mL) at -78 0C was added with nBuLi dropwise (0.27 mL, 1.6 M/hexane, 0.44 mmol, 2,2 equiv). The pale solution was brought to 0 0C, stirred at that temperature for 10 min, and cooled to -78 0C. TMEDA (0.075 mL, 0.50 mmol, 2,5 equiv) was added, followed by dropwise addition of compound 10-5 (91 mg, 0.22 mmol, 1 ,1 equiv, in 5 mL THF) over a period of 10 min. The resulting deep-red solution was stirred at -78 0C for 15 min. Enone 1-6 (97 mg, 0.20 mmol, 1 equiv, in 5 mL THF) was added dropwise over a period of 2 min. The resulting yellow solution was stirred from -78 0C to -10 0C over a period of 1 hr, quenched with aqueous saturated ammonium chloride (50 mL), and extracted with EtOAc (50 mL x 3). The extracts were combined, dried over sodium sulfate, and concentrated in vacuo. Preparative HPLC purification on a C-18 column (mobile phase: A-0.1% formic acid/water, B- 0.1% formic acid/acetonitrile; gradient: 80% B to 100% B over 10 min) yielded the desired product 10-6-1 as a yellow solid (90 mg, 56%); Rf 0.40 (10%EtOAc/hexane); 1H NMR (400 MHz, CDCl3) delta 15.48 (s, 1 H), 7.36 (d, J= 7.2 Hz, 2 H)3 7.29-7.20 (m, 4 H), 6.94 (d, J= 7.2 Hz, 1 H), 5.22 (s, 2 H)1 3.81 (d, J= 10.8 Hz, 1 H), 3.15 (dd, J= 16.0, 4.8 Hz, 1 H), 2.94-2.85 (m, 1 H), 2.44-2.31 (m, 9 H)3 2.03 (d, J= 14.4 Hz, 1 H), 1.42 (s, 9 H), 0.78(s, 9 H), 0.15(s, 3 H)3 0.08(s, 3 H); MS (ESI) m/z 801.3 (M+H).(4aS,llaR,12aS,13Sytert-butyl 3-(benzyloxy)-4a-(tert-butyldimethylsilyloxy)-13- (dimethylamino)-5,7-dihydroxy-4,6-dioxo-10-(trifluoromethoxy)- 4,4a,6,ll,lla,12,12a,13-octahydrotetraceno[2,3-d]isoxazole-8-carboxylate (10-6- 2). The title compound (10-6-2) was also isolated from the preparation of 10-6-1: MS (ESI) m/z 801.3 (M+H).

Reference： [1]Patent: WO2011/25982,2011,A2 .Location in patent: Page/Page column 130

40
[ 852821-06-8 ]
[ 1335556-90-5 ]
[ 1335557-58-8 ]

Yield	Reaction Conditions	Operation in experiment
55%		Synthesis of Sll-5-1To a solution of lithium diisopropylamide (1.8 M in hexanes, 73 mu,, 0.132 mmol, 2.4 eq) and TMEDA (41 mu, 0.275 mmol, 6 eq) in THF (2 mL) at -78 C was added a solution of compound Sll-4-1 (29 mg, 0.065 mmol, 1.1 eq) in THF (400 mu) by dropwise addition. This resulted in a dark red colored solution. After 10 min, a solution of enone S7-1 (27 mg, 0.055 mmol, 1 eq) in THF (400 muKappa) was added. After complete addition, the reaction mixture was allowed to warm to -20 C over 1 h. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution, 800 mu,) and was extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated under reduced pressure. Purification of the resulting oil via flash column chromatography on silica gel (Biotage, 10 g, 5 to 40% EtOAc in hexanes gradient) provided 25 mg of Sll-5-1 (55%): 1H NMR (400 MHz, CDC13) delta 7.51-7.46 (m, 2 H), 7.46-7.41 (m, 2 H), 7.40-7.29 (m, 6 H), 5.35 (s, 2 H), 4.90-4.75 (m, 2 H), 3.96 (d, J= 11.0 Hz, 1 H), 3.80-3.42 (m, 2 H), 3.26-3.16 (m, 1 H), 3.02-2.64 (m, 3 H), 2.62-2.40 (m, 10 H), 2.14 (d, J= 14.0 Hz, 1 H), 0.97-0.92 (3 H), 0.89-0.77 (m, 10 H), 0.27 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 820.71 (M-H).

Reference： [1]Patent: WO2011/123536,2011,A1 .Location in patent: Page/Page column 128

41
[ 852821-06-8 ]
[ 1335557-69-1 ]
[ 1335557-70-4 ]

Yield	Reaction Conditions	Operation in experiment
74%		Synthesis ofSlS- -1.To diisopropylamine (44 ^L, 0.31 mmol, 2.2 eq) in anhydrous THF (1 mL) at -78 C was added rcBuLi (0.20 mL, 1.6 M/hexanes, 0.32 mmol, 2.2 eq) dropwise. The reaction solution was stirred at 0 C for 10 min and re-cooled to -78 C.TMEDA (53 mu, 0.35 mmol, 2.5 eq) was added, followed by dropwise addition of compound S13-9-1 (85 mg, 0.14 mmol, 1 eq) in anhydrous THF (2 mL) over a period of 3 min. The resulting deep red solution was stirred at -78 C for 30 min. Enone S7-1 (68 mg, 0.14 mmol) in anhydrous THF (2 mL) was added dropwise. The resulting light brown solution was gradually warmed up with stirring from -78 C to -20 C over a period of 1 h. Acetic acid (0.1 mL) was added. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. Flash column chromatography on silica gel (0% -> 20% ethyl acetate/hexanes) yielded the desired product S13-10-1 as a yellow oil (103 mg, 74%): Rf 0.20 (10% ethyl acetate/hexane); 1H NMR (400 MHz, CDC13) mixture of tautomers, complex; MS (electrospray) m/z 991.8 (M+H), calcd for C56H72FN409Si 991.5.

Reference： [1]Patent: WO2011/123536,2011,A1 .Location in patent: Page/Page column 148-149

42
[ 852821-06-8 ]
[ 1335556-07-4 ]
[ 1335557-49-7 ]

Yield	Reaction Conditions	Operation in experiment
71%		Synthesis of S8-1.To a solution of lithium diisopropylamide (1.8 M in hexanes, 446 Epsilon, 0.804 mmol, 2.2 eq) and TMEDA (328 mu, 2.19 mmol, 6 eq) in THF (8 mL) at -78 C was added a solution of compound Sl-11-21 (168 mg, 0.402 mmol, 1.1 eq) in THF (1 mL) by dropwise addition. This resulted in a dark red colored solution. After 30 min, a solution of enone S7-1 (175 mg, 0.362 mmol, 1 eq) in THF (1.2 mL) was added. After complete addition, the reaction mixture was allowed to warm to -15 C over 1 h. The reaction was quenched by the addition of ammonium chloride (saturated, aqueous solution, 15 mL) and was extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated under reduced pressure. Purification of the resulting oil via flash columnchromatography on silica gel (Silicycle, 25 g, 10 to 25% EtOAc in hexanes gradient) provided 208 mg of S8-1 (71%) as a white solid: 1H NMR (400 MHz, CDC13) delta 16.05 (s, 1 H), 7.53-7.43 (m, 2 H), 7.42-7.28 (m, 8 H), 5.95-5.79 (m, 1H), 5.35 (s, 2 H), 5.27-5.12 (m, 2 H), 4.90 (q, J= 10.4 Hz, 2 H), 4.01-3.74 (m, 4 H), 3.29 (d, J= 6.1 Hz, 1 H), 3.25-3.18 (m, 1 H), 3.03-2.92 (m, 1 H), 2.58-2.34 (m, 9 H), 2.13 (d, J = 14.7 Hz, 1 H), 0.82 (s, 9 H), 0.27 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 806.38 (M+H).

Reference： [1]Patent: WO2011/123536,2011,A1 .Location in patent: Page/Page column 112-113

43
[ 852821-06-8 ]
[ 75-77-4 ]
[ 5418-86-0 ]
C₃₃H₅₂N₂O₅S₃Si₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		A solution of n-butyllithium in hexanes (2.5 M, 518 muL, 1.30 mmol, 1.25 equiv) was added dropwise via syringe to a solution of tris(methylthio)methane (176 muL, 1.30 mmol, 1.25 equiv) in tetrahydrofuran (11 mL) at -78 C. The resulting colorless solution was stirred at this temperature for 20 min, whereupon a solution of the AB enone 1 (500 mg, 1.04 equiv, 1 equiv) in tetrahydrofuran (3.0 mL) was added dropwise via syringe, forming a bright orange-yellow solution. The reaction solution was allowed to warm slowly to -45 C over 60 min, then chlorotrimethylsilane (199 muL, 1.55 mmol, 1.5 equiv) was added. The (yellow) reaction mixture was stirred at -45 C for 30 min, then was partitioned between aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 20 mL) and dichloromethane (30 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (20 mL). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, affording an orange-yellow oil. The crude product was purified by flash-column chromatography (6% ethyl acetate/hexanes), providing beta-tris(methylthio)methyl trimethylsilyl enol ether 4 as a pale yellow foam (654 mg, 89%). Rf=0.69 (20% ethyl acetate/hexanes); 1H NMR (500 MHz, CDCl3) delta 7.49-7.47 (m, 2H), 7.37-7.32 (m, 3H), 5.37 (AB quartet, 2H), 5.36 (d, 1H, J=2.0 Hz), 4.00 (d, 1H, J=9.3 Hz), 3.15-3.12 (m, 1H), 2.52 (dd, 1H, J=14.4, 4.2 Hz), 2.45 (s, 6H), 2.42-2.39 (m, 1H), 2.18 (s, 9H), 2.14-2.06 (m, 1H), 0.86 (s, 9H), 0.22 (s, 3H), 0.12 (s, 3H), -0.01 (s, 9H); 13C NMR (125 MHz, CDCl3) delta 189.6, 181.6, 167.2, 150.5, 135.2, 128.6, 128.5, 128.4, 108.7, 103.8, 81.6, 75.1, 72.2, 61.7, 46.6, 42.1, 41.7, 26.1, 21.2, 19.0, 14.1, -0.3, -2.6, -3.3; FTIR (neat film), 1722 (m), 1651 (w), 1614 (w), 1510 (m), 1472 (w), 1254 (m), 1206 (w), 903 (m), 839 (s) cm-1; HRMS-ESI (m/z): [M+H]+ calcd for C33H53N2O5S3Si2, 709.2650; found, 709.2617.

Reference： [1]Tetrahedron,2011,vol. 67,p. 9853 - 9869

44
[ 852821-06-8 ]
[ 75-77-4 ]
[ 917-54-4 ]
[ 1352457-37-4 ]

Yield	Reaction Conditions	Operation in experiment
85%		A round-bottomed flask charged with copper (I) iodide (1.89 g, 9.95 mmol, 1.6 equiv) was flame-dried under high vacuum. After cooling to room temperature, the flask was blanketed with dry argon. Tetrahydrofuran (50 mL) was added and the resulting suspension was cooled to 0 C. A solution of methyllithium in ethyl ether (1.6 M, 12.2 mL, 19.6 mmol, 3.15 equiv) was added dropwise via syringe over 5 min. The resulting solution was stirred at 0 C for 20 min, then was cooled to -78 C. A solution of the AB enone 1 (3.0 g, 6.22 mmol, 1 equiv) and chlorotrimethylsilane (1.25 mL, 9.95 mmol, 1.6 equiv) in tetrahydrofuran (10 mL) was added to the cuprate solution dropwise via syringe at -78 C. After stirring at -78 C for 90 min, the cooling bath was removed and the product solution was diluted with ethyl acetate (100 mL) and hexanes (100 mL). A mixture of saturated aqueous ammonium chloride solution and saturated aqueous ammonium hydroxide solution (19:1, 100 mL) was then added carefully. The phases were separated and the organic phase was washed sequentially with saturated aqueous ammonium chloride solution (100 mL) and saturated aqueous sodium chloride solution (2×100 mL). The organic phase was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The product was purified by flash-column chromatography (7% ethyl acetate/hexanes), providing beta-methyl-substituted trimethylsilyl enol ether 2 as a white solid (3.01 g, 85%). Rf=0.57 (15% ethyl acetate/hexanes); 1H NMR (500 MHz, CDCl3) delta 7.48 (dd, 2H, J=8.0, 1.5 Hz), 7.36-7.31 (m, 3H), 5.36 (AB quartet, 2H), 4.69 (d, 1H, J=3.0 Hz), 3.76 (d, 1H, J=10.0 Hz), 2.55-2.52 (m, 1H), 2.44 (s, 6H), 2.32-2.25 (m, 2H), 1.84 (d, 1H, J=13.5 Hz), 1.18 (d, 3H, J=7.5 Hz), 0.87 (s, 9H), 0.22 (s, 3H), 0.11 (s, 3H), -0.04 (s, 9H); 13C NMR (125 MHz, CDCl3) delta 189.7, 181.5, 167.4, 147.2, 135.2, 128.6, 128.5, 128.4, 110.7, 108.3, 80.7, 72.2, 61.1, 46.3, 41.9, 26.2, 26.0, 25.1, 24.0, 18.8, -0.5, -2.8, -3.6; FTIR (neat film), 2955 (w), 1721 (m), 1653 (w), 1614 (w), 1510 (m), 1471 (w), 1250 (m), 1198 (m), 1148 (m), 936 (m), 833 (s) cm-1; HRMS-ESI (m/z): [M+H]+ calcd for C30H47N2O5Si2, 571.3018; found, 571.3041.

Reference： [1]Tetrahedron,2011,vol. 67,p. 9853 - 9869

45
[ 852821-06-8 ]
[ 75-77-4 ]
[ 100045-83-8 ]
[ 1352457-44-3 ]

Yield	Reaction Conditions	Operation in experiment
55%		A solution of n-butyllithium in hexanes (2.5 M, 374 muL, 0.936 mmol, 2.1 equiv) was added to a solution of tri-n-butyl[(methoxymethoxy)methyl]stannanerefPreviewPlaceHolder19 (326 mg, 0.893 mmol, 2.0 equiv) in tetrahydrofuran (4.0 mL) at -78 C. The resulting solution was stirred at this temperature for 15 min, at which point hexamethylphosphoramide (313 muL, 1.78 mmol, 4.0 equiv) was added dropwise. After stirring at -78 C for a further 1 min, a solution of the AB enone 1 (215 mg, 0.446 mmol, 1 equiv) in tetrahydrofuran (1.0 mL) was added to the reaction solution dropwise via syringe. The reaction mixture was stirred at -78 C for 30 min whereupon chlorotrimethylsilane (170 muL, 1.34 mmol, 3.0 equiv) was added. After stirring at -78 C for 30 min, aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 10 mL) was added to the reaction solution. The resulting mixture was allowed to warm to 23 C, then was extracted with ethyl acetate (3×20 mL). The organic extracts were combined and the combined solution was dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The product was purified by flash-column chromatography (10% ethyl acetate/hexanes), affording beta-methoxymethoxymethyl trimethylsilyl enol ether 11 as a pale yellow solid (156 mg, 55%). Rf=0.43 (20% ethyl acetate/hexanes); 1H NMR (500 MHz, CDCl3) delta 7.49-7.46 (m, 2H), 7.36-7.30 (m, 3H), 5.36 (AB quartet, 2H), 4.78 (d, 1H, J=2.4 Hz), 4.67 (s, 2H), 3.82 (d, 1H, J=9.8 Hz), 3.54-3.45 (m, 2H), 3.38 (s, 3H), 2.71-2.66 (m, 1H), 2.42 (s, 6H), 2.30-2.22 (m, 2H), 2.01 (d, 1H, J=13.7 Hz), 0.86 (s, 9H), 0.23 (s, 3H), 0.12 (s, 3H), -0.05 (s, 9H); 13C NMR (125 MHz, CDCl3) delta 189.6, 181.6, 167.4, 148.9, 135.1, 128.7, 128.5, 128.4, 108.3, 105.8, 96.5, 81.1, 73.0, 72.2, 61.0, 55.2, 46.1, 41.9, 32.4, 26.0, 20.1, 18.9, -0.5, -2.8, -3.6; HRMS-ESI (m/z): [M+Na]+ calcd for C32H50N2O7Si2Na, 653.3049; found, 653.3056.

Reference： [1]Tetrahedron,2011,vol. 67,p. 9853 - 9869

46
[ 852821-06-8 ]
[ 1359022-03-9 ]
[ 1359022-04-0 ]

Yield	Reaction Conditions	Operation in experiment
55%		Synthesis ofS5-2. ; S5"2 A solution of n-BuLi in hexanes (0.48 mL, 2.5 M, 1.20 mmol, 3.3 eq) was added drop wise to a solution of z'-Pr2NH (0.17 mL, 1.20 mmol, 3.3 eq) in dry THF (7 mL) at -78 C under a N2 atmosphere. The reaction solution was stirred at -78 C for 20 min and 0 C for 30 min, and re-cooled to -78 C. TMEDA (0.10 mL, 0.48 mmol, 1.3 eq) was added, followed by the drop wise addition of S5-1 (0.20 g, 0.37 mmol, 1 eq) in dry THF (1 mL) via a cannula. After complete addition, the resulting dark-red mixture was stirred for 1 h at -78 C and cooled to -100 C. A solution of enone S2-1 (0.18 g, 0.37 mmol, 1 eq) in THF (lmL) was added drop wise via a cannula. The resulting red mixture was slowly warmed to -78 C. LHMDS (0.44 mL, 1.0 M/THF, 0.44 mmol, 1.2 eq) was added and the reaction was slowly warmed to -5 C. Saturated aqueous NH4C1 was added. The mixture was extracted three times with EtOAc. The combined EtOAc extracts were washed with brine, dried over sodium sulfate, and concentrated. Purification of the residue by flash chromatography gave compound S5-2 (0.19 g, 55%) as a light yellow foam, which was used in the next step without further purification.

Reference： [1]Patent: WO2012/21712,2012,A1 .Location in patent: Page/Page column 96-97

47
[ 852821-06-8 ]
[ 1359023-03-2 ]
[ 1359023-04-3 ]

Yield	Reaction Conditions	Operation in experiment
84%		added TMEDA (185 mu, 1.23 mmol, 1.3 eq). After stirring for 5 min, a solution of compound S14-4-1 (445 mg, 0.95 mmol, 1 eq) in THF (5 mL) was added drop wise. The resulting red solution was stirred at -78 C for 30 min. Enone S2-1 (456 mg, 0.95 mmol, in 5 ml THF, 1 eq) was added. The reaction was gradually warmed to - 50 C. LHMDS (1.00 mL, 1.0 M/THF, 1.00 mmol, 1.05 eq) was added. The reaction was gradually warmed to -5 C. Saturated aqueous NH4C1 was added. The mixture was extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography on silica gel using 0%-20% EtOAc/hexanes yielded the desired product S14-5-1 as a light yellow solid (685 mg, 84%>): MS (electrospray) m/z 857.9 (M+H).

Reference： [1]Patent: WO2012/21712,2012,A1 .Location in patent: Page/Page column 155
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 2498 - 2512

48
[ 852821-06-8 ]
[ 1359024-14-8 ]
[ 1359024-16-0 ]

Yield	Reaction Conditions	Operation in experiment
78%		Synthesis of SI 7-9; ft-BuLi (68 mu, 1.6 M/hexanes, 0.109 mmol, 1.3 eq) was added drop wise to a solution of diisopropylamine (17 mu, 0.118 mmol, 1.4 eq) in THF (1 mL) at - 70 C. The reaction mixture was warmed up to -20 C and re-cooled to -78 C. TMEDA (18 mu,, 0.118 mmol, 1.4 eq) was added. The reaction solution was stirred at -78 C for 5 min. A solution of compound S17-8 (47 mg, 0.084 mmol, 1 eq) in THF (0.5 mL) was added dropwise via a cannula at below -70 C. The resulting red orange solution was stirred at -78 C for 40 min, and cooled to -100 C using a EtOH/liquid N2 bath. A solution of enone S2-1 (40 mg, 0.084 mmol, 1 eq) in THF (0.5 mL) was added to the reaction mixture. The reaction mixture was allowed to gradually warm up to -90 C and then LHMDS (84 mu, 1.0 M/THF, 0.084 mmol, 1 eq) was added. The reaction mixture was gradually warmed up to -10 C. A saturated aqueous NH4C1 (20 mL) solution was added to the reaction. The reaction mixture was extracted with EtOAc (30 mL). The organic phase was washed with brine (100 mL), dried over Na2S04, and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC on a WatersAutopurification system using a Sunfire Prep CI 8 OBD column [5 muiotaeta, 19x50mm; flow rate, 20 mL/min; Solvent A: H20 with 0.1% HC02H; Solvent B: CH3CN with 0.1% HC02H; injection volume: 3.0 mL (CH3CN); gradient: 800?100% B in A over 10 min; mass-directed fraction collection]. Fractions containing the desired product were collected and concentrated to give the desired product SI 7-9 as a yellow solid (-1 : 1 mixture of diastereomers, 62 mg, 78%): lU NMR (400 MHz, CDC13) delta 15.69 (s, 0.5 H), 15.64 (s, 0.5 H), 7.86 (s, 0.5 H), 7.82 (s, 0.5 H), 7.50-7.48 (m, 4 H), 7.40-7.32 (m, 5 H), 7.31-7.25 (m, 4 H), 7.19-7.14 (m, 2 H), 5.38-5.27 (m, 4 H), 4.03-3.97 (m, 1.5 H), 3.88-3.83 (m, 1 H), 3.76 (d, J= 14.0 Hz, 0.5 H), 3.34- 3.19 (m, 3 H), 2.93-2.71 (m, 2 H), 2.58-2.45 (m, 8 H), 2.32-2.22 (m, 1 H), 2.13 (d, J = 14.0 Hz, 1 H), 1.94-1.58 (m, 5 H), 1.44-1.38 (m 1 H), 0.84 (s, 4.5 H), 0.83 (s, 4.5 H), 0.274 (s, 1.5 H), 0.268 (s, 1.5 H), 0.16 (s, 1.5 H), 0.15 (s, 1.5 H); MS (ESI) m/z 948.41 (M+H).

Reference： [1]Patent: WO2012/21712,2012,A1 .Location in patent: Page/Page column 196-197

49
[ 852821-06-8 ]
[ 1359021-42-3 ]
[ 1359021-46-7 ]
[ 1359021-48-9 ]

Yield	Reaction Conditions	Operation in experiment
43%		n-BuLi (10.0 ml, 2.4 M/hexanes, 24.08 mmol, 1.4 eq) was added dropwise to asolution of diisopropylamine (3.4 ml, 24.08 mmol, 1.4 eq) in THF (150 ml) at -72 C. The reaction mixture was warmed up to 0 C and re-cooled to -74 C. N,N,N?,N?-tetramethylethylenediamine (3.61 ml, 24.08 mmol, 1.4 eq) was added. The reaction solution was stirred at -78 C for 10 min. A solution of crude 6 (17.2 mmol) in THF (50 ml) was added dropwise via a cannula between -73?-74 C over 25 min. The resulting red orange solution wasstirred at -74 C for 45 min, and cooled to -98 C using a EtOH/liquid N2 bath.A pre-cooled (-78 C) solution of enone 7 (8.30 g, 17.2 mmol, 1 eq) in THF(50 ml) was added to the reaction mixture via a cannula at -97?-98 C. The reaction mixture was allowed to gradually warm up to -83 C over 1 h. Lithiumhexamethyldisilazide (17.20 ml, 1.0 M/THF, 17.20 mmol, 1 eq) was added. The reaction mixture was gradually warmed up to -15 C over 105 min. Aqueous HCl (1 N, 85 ml), phosphate buffer (pH=7, 200 ml) and saturated aqueous NH4Cl (200 ml) were added to the reaction. The reaction mixture was extracted with EtOAc (200 ml). The organic extract was washed with brine(100 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C18 OBD column (5 mum,19× 50 mm; flow rate, 20 ml min- 1; Solvent A: H2O with 0.1% HCO2H;Solvent B: CH3CN with 0.1% HCO2H; injection volume: 4.0 ml (CH3CN);gradient: 95?100% B in A over 7 min; UV (350 nm) directed fraction collection). The first 350 nm UV peak was collected and concentrated to give compound 8 diastereomer A (8A) as an orange solid (7.81 g, 43% over three steps) and the second 350 nm UV peak was collected and concentrated to give compound 8 diastereomer B (8B) as an orange solid. A crude sample was also purified by flash column chromatography (5-10% ethyl acetate-hexanes) to give the desired product 8 as a 1:1 mixture of the two diastereomers (pale yellow solid): 1H NMR (400 MHz, CDCl3) delta 15.784, 15.776 (s, 1 H), 7.66(s, 0.5 H), 7.60 (s, 0.5 H), 7.48-7.57 (m, 8 H), 7.30-7.38 (m, 3 H), 7.09-7.21(m, 9 H), 5.31-5.39 (m, 2 H), 4.68-4.72 (m, 1 H), 4.05 (d, J=10.4 Hz, 0.5 H),3.94 (d, J=10.4 Hz, 0.5 H), 3.42-3.50 (m, 1 H), 3.28 (s, 1.5 H), 3.20 (dd,J=4.9, 15.3 Hz, 0.5 H), 2.90-3.07 (m, 4 H), 2.38-2.52 (m, 9 H), 2.10(d, J=14.0 Hz, 1 H), 1.81-1.91 (m, 1 H), 1.75-1.67 (m, 1 H), 1.60 (s, 4.5 H),1.59 (s, 4.5 H), 1.43-1.54 (m, 2 H), 0.87 (s, 4.5 H), 0.83 (s, 4.5 H), 0.28 (s, 1.5H), 0.27 (s, 1.5 H), 0.17 (s, 1.5 H), 0.13 (s, 1.5 H); MS (ESI) m/z 1058.84(M+H).
		ft-BuLi (10.0 mL, 2.4 M/hexanes, 24.08 mmol, 1.4 eq) was added drop wise to a solution of diisopropylamine (3.4 mL, 24.08 mmol, 1.4 eq) in THF (150 mL) at -72 C. The reaction mixture was warmed up to 0 C and re-cooled to -74 C. TMEDA (3.61 mL, 24.08 mmol, 1.4 eq) was added. The reaction solution was stirred at -78 C for 10 min. A solution of crude Sl-13 in THF (50 mL) was added drop wise via a cannula between -73?- 74 C over 25 min. The resulting red orange solution was stirred at -74 C for 45 min, and cooled to -98 C using a EtOH/liquid N2 bath. A pre-cooled (-78 C) solution of enone S2-1 (8.30 g, 17.2 mmol, 1 eq) in THF (50 mL) was added to the reaction mixture via a cannula at -97?-98 C. The reaction mixture was allowed to gradually warm up to -83 C over 1 h. LHMDS (17.20 mL, 1.0 M/THF, 17.20 mmol, 1 eq) was added. The reaction mixture was gradually warmed up to -15 C over 105 min. Aqueous HC1 (1 N, 85 mL), phosphate buffer (pH = 7, 200 mL) and saturated aqueous NH4C1 (200 mL) were added to the reaction. The reaction mixture was extracted with EtOAc (200 mL). The organic extract was washed with brine (100 mL), dried over Na2S04, and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C 18 OBD column [5 mutaueta, 19 x 50 mm; flow rate, 20 mL/min; Solvent A: H20 with 0.1% HC02H; Solvent B: CH3CN with 0.1% HC02H; injection volume: 4.0 mL(CH3CN); gradient: 95?100% B in A over 7 min; UV (350 nm) directed fraction collection]. The first 350 nm UV peak was collected and concentrated to give diastereomer A S2-2-A as an orange solid (7.81 g, 43% over 3 steps), and the second 350 nm UV peak was collected and concentrated to give diastereomer B S2-2-B as an orange solid.A crude sample was also purified by flash-column chromatography (5-10% ethyl acetate-hexanes) to give the desired product S2-2 as a 1 : 1 mixture of the two diastereomers (pale yellow solid): 1H NMR (400 MHz, CDC13) delta 15.784, 15.776 (s,1 H), 7.66 (s, 0.5 H), 7.60 (s, 0.5 H), 7.48-7.57 (m, 8 H), 7.30-7.38 (m, 3 H), 7.09- 7.21 (m, 9 H), 5.31-5.39 (m, 2 H), 4.68-4.72 (m, 1 H), 4.05 (d, J= 10.4 Hz, 0.5 H), 3.94 (d, J= 10.4 Hz, 0.5 H), 3.42-3.50 (m, 1 H), 3.28 (s, 1.5 H), 3.20 (dd, J= 4.9, 15.3 Hz, 0.5 H), 2.90-3.07 (m, 4 H), 2.38-2.52 (m, 9 H), 2.10 (d, J= 14.0 Hz, 1 H), 1.81-1.91 (m, 1 H), 1.75-1.67 (m, 1 H), 1.60 (s, 4.5 H), 1.59 (s, 4.5 H), 1.43-1.54 (m,2 H), 0.87 (s, 4.5 H), 0.83 (s, 4.5 H), 0.28 (s, 1.5 H), 0.27 (s, 1.5 H), 0.17 (s, 1.5 H), 0.13 (s, 1.5 H); MS (ESI) m/z 1058.84 (M+H).

Reference： [1]Journal of Antibiotics,2018,vol. 71,p. 287 - 297
[2]Patent: WO2012/21712,2012,A1 .Location in patent: Page/Page column 71-72

50
[ 852821-06-8 ]
[ 1359025-17-4 ]
[ 1359025-18-5 ]

Yield	Reaction Conditions	Operation in experiment
63%		Synthesis of Compound S22-5.; To a solution of diisopropylamine (1.70 mL, 12 mmol) in THF (5 mL) at -78 C was added nBuLi (4.8 mL, 12 mmol, 2.5 M solution in hexane) dropwise. The reaction was stirred at -78 C for 30 min. TMEDA (3.5 mL, 24 mmol, 2 equiv) was added to the solution. The above LDA solution (2.5 mL) was added dropwise to a mixture of S22-4 (550 mg, 1.05 mmol, 1.0 equiv) in THF (2.0 mL) at -78 C to give a deep red solution. The mixture was stirred at -78 C for 10 min. Enone S2-1 (507 mg, 1.05 mmol, 1.0 equiv) in THF (2.0 mL) was added to the solution at -78 C dropwise. The color of the reaction turned yellow. The yellow solution was gradually warmed with stirring from -78 C to 0 C over a period of 1 h. The reaction was quenched with aqueous saturated ammonium chloride (20 mL) and was extracted with CH2C12 (4 x 20 mL). The extracts were concentrated and purified by preparative TLC to give S22-5 (600 mg, 63%): MS (ESI) m/z 457.8 (M/2+H).

Reference： [1]Patent: WO2012/21712,2012,A1 .Location in patent: Page/Page column 248

51
[ 852821-06-8 ]
[ 1359021-70-7 ]
[ 1359021-71-8 ]

Yield	Reaction Conditions	Operation in experiment
47%		Synthesis ofS3-4; . S3"4 A solution of n-BuLi in hexanes (0.48 mL, 2.5 M, 1.2 mmol, 3.3 eq) was added drop wise to a solution of z'-Pr2NH (0.17 mL, 1.2 mmol, 3.3equiv) in dry THF (7 mL) at -78 C under a N2 atmosphere. The solution was stirred at -78 C for 20 min and 0 C for 30 min, and then re-cooled to -78 C. TMEDA (0.1 mL, 0.48 mmol, 1.3 eq) was added, followed by the drop wise addition of S3-3 (0.21 g, 0.37 mmol, 1 eq) in dry THF (lmL) via a cannula. After complete addition, the resulting dark-red mixture was stirred for another hour at -78 C and then cooled to -100 C. A solution of enone S2-1 (0.18 g, 0.37 mmol, 1 eq) in THF (lmL) was added drop wise via a cannula. The resulting red mixture was slowly warmed to -78 C.LHMDS (0.44 mL, 1.0 M/THF, 0.44 mmol, 1.2 eq) was then added and the reaction was slowly warmed to -5 C. Saturated aqueous NH4C1 was added. The mixture was extracted three times with EtOAc. The combined EtOAc extracts were washed with brine, dried over sodium sulfate, and concentrated. Purification of the residue by flash chromatography gave compound S3-4 (0.17 g, 47 %) as a light yellow foam: MS (ESI) m/z 930

Reference： [1]Patent: WO2012/21712,2012,A1 .Location in patent: Page/Page column 83-84

52
[ 852821-06-8 ]
phenyl 6-(benzyloxy)-3-chloro-4-(dimethoxymethyl)-2-methylbenzoate [ No CAS ]
(1R,3S,4S,11S )-8,16-bis(benzyloxy)-11-[(tert-butyldimethylsilyl)oxy]-19-chloro-18-(dimethoxymethyl)-4-(dimethylamino)-12-hydroxy-6-oxa-7-azapentacyclo-[11.8.0.0^3,11.0^5,9.0^15,20]henicosa-5⁽⁹⁾,7,12,15⁽²⁰⁾,16,18-hexaene-10,14-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		A solution of n-BuLi in hexanes (2.37 mL, 2.2 M, 5.23 mmol, 1.2 equiv) was added dropwise to a solution of i-Pr2NH (0.77 mL, 5.45 mmol, 1.25 equiv) in THF (27 mL) at -78 C. under a N2 atmosphere. The resulting solution was stirred at -78 C. for 20 min and 0 C. for 5 min, and then re-cooled to -78 C. N,N,N?,N?-Tetramethylethylenediamine (TMEDA, 0.85 mL, 5.67 mmol, 1.30 equiv) was added, followed by the dropwise addition of S15-9 (2.05 g, 4.80 mmol, 1.1 equiv) in THF (30 mL) via a cannula. After complete addition, the resulting dark-red mixture was stirred for another hour at -78 C. and then cooled to -100 C. A solution of enone S1-9 (2.10 g, 4.36 mmol, 1.0 equiv) in THF (30 mL) was added dropwise via a cannula. The resulting red mixture was slowly warmed to -78 C. LHMDS (4.36 mL, 1.0 M/THF, 4.36 mmol, 1.0 equiv) was then added and the reaction was slowly warmed to -5 C. Saturated aqueous NH4Cl was added. The resulting mixture was extracted three times with EtOAc. The combined EtOAc extracts were washed with brine, dried (sodium sulfate), and concentrated. Purification of the residue by flash chromatography gave compound S15-10 (3.20 g, 90%) as a light yellow foam: 1H NMR (400 MHz, CDCl3) delta 0.16 (s, 3 H), 7.22-7.52 (m, 11 H), 5.55 (s, 1 H), 5.38 (s, 2 H), 5.29 (d, J=11.4 Hz, 1 H), 5.24 (d, J=11.4 Hz, 1 H), 3.97 (d, J=10.4 Hz, 1 H), 3.46 (dd, J=4.9, 15.9 Hz, 1 H), 3.38 (s, 3 H), 3.29 (s, 3 H), 2.96-3.04 (m, 1 H), 2.45-2.58 (m, 9 H), 2.15 (d, J=14.6 Hz, 1 H), 0.84 (s, 9 H), 0.28 (s, 3 H); MS (ESI) m/z 815.30 (M+H), calcd for C44H52ClN2O9Si 815.31.

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 8112 - 8138
[2]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 181; 182; 187

53
[ 852821-06-8 ]
phenyl 6-[(tert-butoxy)carbonyl]oxy}-4-(dimethoxymethyl)-3-methoxy-2-methylbenzoate [ No CAS ]
(1R,3S,4S,11S)-8-(benzyloxy)-11-[(tert-butyldimethylsilyl)-oxy]-18-(dimethoxymethyl)-4-(dimethylamino)-12-hydroxy-19-methoxy-10,14-dioxo-6-oxa-7-azapentacyclo-[11.8.0.0^3,11.0^5,9.0^15,20]henicosa-5⁽⁹⁾,7,12,15,17,19-hexaen-16-yl tert-butyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		nBuLi solution (2.5 M in hexanes, 138 muL, 0.345 mmol, 1.2 equiv) was added dropwise to a solution of diisopropylamine (49 muL, 0.345 mmol, 1.2 equiv) and TMEDA (103 muL, 0.689 mmol, 2.4 equiv) in THF (2.5 mL) at -78 C. The resulting reaction solution was stirred at -78 C. for 30 min. A solution of ester S24-5 (124.2 mg, 0.287 mmol, 1.0 equiv) in THF (1.5 mL) was added via cannula. The resulting dark red solution was then stirred at -78 C. for 30 min, and cooled to -100 C. using a EtOH/liquid N2 bath. A solution of enone (125 mg, 0.258 mmol, 0.9 equiv) in THF (1.5 mL) was added to the reaction mixture via cannula. The resulting reaction mixture was allowed to warm up to -78 C. over 30 min. LHMDS solution (1.0 M, 287 muL, 0.287 mmol, 1.0 equiv) was added. Then the reaction mixture was warmed up to -10 C. naturally over 40 min, quenched with saturated NH4Cl and pH=7 buffer (1:1, 30 mL), and extracted with EtOAc (40 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by flash-column chromatography (5-30% ethyl acetate-hexanes) to afford the desired product S24-6 as a pale yellow solid (201.6 mg, 95%). 1H NMR (400 MHz, CDCl3) delta 15.67 (s, 1 H), 7.49-7.46 (m, 2 H), 7.38-7.29 (m, 3 H), 5.59 (s, 1 H), 5.35, 5.32 (ABq, J=12.2 Hz, 2 H), 3.97 (d, J=10.4 Hz, 1 H), 3.73 (s, 3 H), 3.37 (s, 3 H), 3.31 (s, 3 H), 3.28 (dd, J=4.9, 15.9 Hz, 1 H), 3.02-2.95 (m, 1 H), 2.55-2.42 (m, 9 H), 2.13 (d, J=12.0 Hz, 1 H), 1.51 (s, 9 H), 0.82 (s, 9 H), 0.25 (s, 3 H), 0.11 (s, 3 H); MS (ESI) m/z 821.51 (M+H).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 8112 - 8138
[2]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 365; 366; 369

54
[ 852821-06-8 ]
phenyl 2-(benzyloxy)-4-(dimethoxymethyl)-6-methyl-3-(trifluoromethyl)benzoate [ No CAS ]
(1R,3S,4S,11S)-8,16-bis(benzyloxy)-11-[(ert-butyldimethylsilyl)oxy]-18-(dimethoxymethyl)-4-(dimethylamino)-12-hydroxy-19-(trifluoromethyl)-6-oxa-7-azapentacyclo[11.8.0.0^3,11.0^5,9.0^15,20]henicosa-5-⁽⁹⁾,7,12,15,17,19-hexaene-10,14-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		To diisopropylamine (0.414 mL, 2.5 mmol, 5.0 equiv) in THF at -78 C. was added nBuLi (1.04 mL, 2.50 M/hexane, 2.5 mmol, 5.0 equiv) and TMEDA (1.04 mL, 2.5 mmol, 5.0 equiv) at -78 C. dropwise. The reaction was stirred at -78 C. for 30 min. Compound S25-7 (460 mg, 1.25 mmol, 2.5 equiv) in THF was added to the reaction mixture dropwise at -78 C. The resulting deep-red solution was stirred at -78 C. 15 min and added with the enone (240 mg 0.50 mmol, 1.0 equiv) in THF. The deep-red solution was gradually warmed up with stirring from -78 C. to 0 C. over a period of 30 min. and quenched with aqueous saturated ammonium chloride (100 mL). The yellow-green mixture was extracted with EtOAc two times. The combined EtOAc extracts were dried (Na2SO4) and concentrated to yield the crude product. Flash column chromatography on silica gel with 0%, 5%, 10%, and 20% EtOAc/hexane sequentially yielded the desired product S25-8 as a light-yellow solid (380 mg, 89%). 1 H NMR (400 MHz, CDCl3) delta 15.65 (s, 1 H), 7.46-7.22 (m, 11 H), 5.49 (s, 1 H), 5.30 (s, 2 H), 5.25 (s, 2 H), 3.91 (d, J=10.8 Hz, 1 H), 3.29 (s, 3 H), 3.20 (s, 3 H), 2.85-2.62 (m, 2 H), 2.53-2.35 (m, 9 H), 2.10-2.04 (m, 1 H), 0.88 (s, 9 H), 0.20 (s, 3 H), 0.09 (s, 3 H); MS (ESI) m/z 849.1 (M+H).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 8112 - 8138
[2]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 423; 425; 426; 427; 428; 431

55
[ 852821-06-8 ]
[ 1254343-67-3 ]
(1R,3S,4S,11S)-8,16-bis(benzyloxy)-18-bromo-11-[(tertbutyldimethylsilyl)oxy]-4,19-bis(dimethylamino)-12-hydroxy-6-oxa-7-azapentacyclo[11.8.0.0^3,11.0^5,9.0^15,20]henicosa-5-⁽⁹⁾,7,12,15,17,19-hexaene-10,14-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		n-BuLi (1.46 mL, 2.17 M/hexanes, 3.16 mmol, 1.10 equiv) was added dropwise to a solution of diisopropylamine (0.45 mL, 3.16 mmol, 1.10 equiv) in THF (6 mL) at -78 C. The reaction solution was warmed to -20 C. and then re-cooled to -78 C. TMEDA (0.47 mL, 3.16 mmol, 1.10 equiv) was added and the reaction mixture was stirred at -78 C. for 15 min. A solution of ester S16-5 (1.27 g, 2.88 mmol, 1.05 equiv) in THF (3 mL) was added via a cannula. The resulting deep red solution was stirred at -78 C. for 55 min and was then cooled to -100 C. A solution of enone S1-9 (1.33 g, 2.75 mmol, 1.0 equiv) in THF (3 mL) was added to the reaction mixture via a cannula. The reaction mixture was allowed to warm to -70 C. over 30 min. LHMDS (3.02 mL, 1.0 M/THF, 3.02 mmol, 1.1 equiv) was added. The reaction mixture was warmed to -5 C. slowly over 1 h 20 min, quenched by a mixture of saturated aqueous NH4Cl and pH 7 phosphate buffer (100 mL, 1:1, v/v), and extracted with EtOAc (75 mL, then 25 mL). The combined EtOAc extracts were dried (sodium sulfate), filtered and concentrated. The residue was purified by a preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C18 OBD column [5 mum, 19×50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; injection volume: 4.0 mL (CH3CN); gradient: 80?100% B in A over 10 min; mass-directed fraction collection]. Fractions containing the desired product, eluting at 7.6-11 min, were collected and concentrated at rt to remove most of the acetonitrile. The resulting mostly aqueous solution was freeze-dried to yield the desired product S16-6 (1.71 g, 75%): 1H NMR (400 MHz, CDCl3) delta 16.00 (br s, 1 H), 7.50-7.46 (m, 4 H), 7.39-7.27 (m, 6 H), 7.10 (s, 1 H), 5.36 (s, 2 H), 5.18, 5.12 (ABq, J=12.8 Hz, 2 H), 4.10 (d, J=10.4 Hz, 1 H), 3.37 (dd, J=4.3, 15.9 Hz, 1 H), 2.88-2.74 (m, 7 H), 2.55-2.40 (m, 9 H), 2.12 (d, J=14.0 Hz, 1 H), 0.84 (s, 9 H), 0.28 (s, 3 H), 0.14 (s, 3 H); MS (ESI) m/z 828.27, 830.30 (M+H).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 8112 - 8138
[2]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 257; 258; 261

56
[ 852821-06-8 ]
[ 1254336-22-5 ]
(1R,3S,4S,11S)-8,16-bis(benzyloxy)-17-bromo-11-[(tertbutyldimethylsilyl)oxy]-18-(dimethoxymethyl)-4-(dimethylamino)-19-fluoro-12-hydroxy-6-oxa-7-azapentacyclo-[11.8.0.0^3,11.05,9.0^15,20]henicosa-5⁽⁹⁾,7,12,15,17,19-hexaene-10,14-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; diisopropylamine; In tetrahydrofuran; hexane; at -78 - -10℃; for 0.5h;Inert atmosphere;	Compound S1-8 (1.37 g, 2.80 mmol, 3.0 equiv) and enone S1-9 (0.45 g, 0.93 mmol, 1.0 equiv) were dissolved in dry THF (5 mL) under N2. Freshly prepared LDA/TMEDA/THF (0.71 M/THF, 7.9 mL, 5.60 mmol, 2.0 equiv) was added to the solution at -78 C. The solution was stirred at -78 C. for about 10 min, and then the temperature was slowly increased from -78 C. to -10 C. over 20 min. The reaction mixture was quenched by saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 ml×3). The organic phase was dried over sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether:EtOAc: from 50:1 to 15:1) to give the desired compound S1-10 (0.60 g, 0.68 mmol, 74%): 1H NMR (400 MHz, CD3OD) delta 15.97 (s, 1 H), 7.61-7.59 (m, 2 H), 7.55-7.53 (m, 2 H)?7.42-7.40 (m, 6 H), 5.83 (s, 1 H), 5.40 (s, 2 H), 5.02-4.97 (m, 2 H)?3.96 (d, J=10.8 Hz, 1 H), 3.57 (s, 6 H), 3.35-3.26 (m, 1 H), 3.09-2.95 (m, 1 H), 2.67-2.58 (m, 1 H), 2.53 (s, 6 H), 2.50-2.39 (m, 1 H), 2.21-2.10 (m, 1 H), 1.58 (s, 9 H), 0.31 (s, 3 H), 0.16 (s, 3 H); MS (ESI) m/z 877.3 (M+H). (0650) Preparation of LDA/TMEDA/THF: To diisopropylamine (1.1 g, 10.90 mmol, 1.0 equiv) and TMEDA (5 mL) in dry THF (5 mL) at -78 C. was added n-BuLi (4.8 mL, 2.5 M/hexanes, 12.00 mmol, 1.1 equiv) dropwise under N2. The solution was stirred at -78 C. for 1 h. The prepared LDA/TMEDA/THF solution was about 0.71 M and was used immediately.

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 8112 - 8138
[2]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 45; 46; 47; 50; 51

57
[ 852821-06-8 ]
phenyl 2-(benzyloxy)-3-bromo-4-[(2,2-dimethylpropyl)amino]methyl}-5-fluoro-6-methylbenzoate [ No CAS ]
(1R,3S,4S,11S)-8,16-bis(benzyloxy)-17-bromo-11-[(tertbutyldimethylsilyl)oxy]-4-(dimethylamino)-18-[(2,2-dimethylpropyl)amino]methyl}-19-fluoro-12-hydroxy-6-oxa-7-azapentacyclo[11.8.0.0^3,11.0^5,9.0^15,20]henicosa-5⁽⁹⁾,7,12,15-⁽²⁰⁾,16,18-hexaene-10,14-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		LDA/THF was prepared by adding n-BuLi (0.29 mL, 1.6 M/hexanes, 0.46 mmol, 3.0 equiv) to diisopropylamine (65 muL, 0.46 mmol, 3.0 equiv) in 3 mL dry THF under a nitrogen atmosphere in a flame dried schenck flask at -78 C. The resulting solution was warmed to -20 C. and stirred for another 15 min. After the LDA solution was cooled down to -78 C., TMEDA (69 muL, 0.46 mmol, 3.0 equiv) was added slowly via a syringe. Compound S2-1-1 (0.10 g, 0.20 mmol, 1.3 equiv) was dissolved in 1 mL dry THF and added into the LDA solution slowly via a syringe. A dark-red color appeared as soon as addition started. After stirring for 10 min, enone S1-9 (74 mg, 0.15 mmol, 1.0 equiv) in 1 mL dry THF was added slowly a via syringe. After 10 min, LC/MS indicated that the enone was consumed and the product present. The reaction mixture was allowed to slowly warm to -20 C. in 1 h. A phosphate buffer solution (pH 7, 10 mL) was added, followed by the addition of 20 mL saturated aqueous ammonium chloride. The resulting mixture was extracted with dichloromethane (3×15 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting orange-red oil was purified by column chromatography (Biotage 10 g column, 10% to 30% EtOAc in hexanes gradient) to yield the desired compound S2-2-1 (90 mg, 65%).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 95; 96
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 8112 - 8138

58
[ 852821-06-8 ]
[ 1253799-29-9 ]
C₅₅H₅₈FN₃O₇Si [ No CAS ]

Reference： [1]Organic Process Research and Development,2013,vol. 17,p. 838 - 845

59
[ 852821-06-8 ]
[ 1253799-49-3 ]
C₄₂H₄₆BrFN₂O₈Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		LDA was freshly prepared by adding n-BuLi (1.6 M/hexanes, 1.59 mmol, 3.0 equiv) to diisopropylamine (0.22 mL, 1.59 mmol, 3.0 equiv) in 10 mL dry THF under a nitrogen atmosphere in a flame dried schenck flask at -78 C. The pale solution was warmed to -20 C. and stirred for 15 min. After the LDA solution was cooled down to -78 C. with a dry ice/acetone bath, TMEDA (0.24 mL, 1.59 mmol, 3.0 equiv) was added slowly via a syringe. Compound S3-1 (0.28 g, 0.64 mmol, 1.2 equiv) in 2 mL dry THF was added to slowly via a syringe. A dark-red color appeared as soon as the addition started. After stirring at -78 C. for 10 min, enone S1-9 (0.26 g, 0.53 mmol, 1.0 equiv) 2 mL dry THF was added slowly via a syringe. After 10 min, LC/MS indicated that the enone was consumed and the product present. The reaction mixture was allowed to slowly warm to -20 C. in 1 h. Phosphate buffer (pH 7, 10 mL) was added, followed by the addition of 20 mL saturated aqueous ammonium chloride. The resulting mixture was extract with dichloromethane (3×15 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting orange-red oil was purified by column chromatography (Biotage 24 g column, 10% to 30% EtOAc in hexanes gradient) yielding 0.22 g of compound S3-2 (50%): 1H NMR (400 MHz, CDCl3) delta 16.1 (br, s, 1 H), 7.58-7.54 (m, 2 H), 7.51-7.47 (m, 2 H), 7.41-7.32 (m, 6 H), 5.36 (s, 2 H), 4.95 (dd, J=26.6, 9.6 Hz, 2 H), 4.89 (d, J=7.8 Hz, 2 H), 3.92 (d, J=10.6 Hz, 1 H), 3.25 (dd, J=15.6, 4.1 Hz, 1 H), 3.04-2.94 (m, 1 H), 2.59-2.53 (m, 1 H), 2.49 (s, 6 H), 2.40 (t, J=15.6 Hz, 1 H), 2.20-2.10 (m, 2 H), 0.81 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 119; 120; 121; 122

60
[ 852821-06-8 ]
C₂₇H₂₉BrFNO₃ [ No CAS ]
C₄₇H₅₇BrFN₃O₇Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		A solution of S8-2-1 (20 mg, 0.038 mmol, 1.2 equiv) in THF (1 mL) was added to a solution of LDA (1.2 M/THF/heptane/ethylbenzene, 0.058 mL, 0.070 mmol, 2.2 equiv) and TMEDA (0.028 mL, 0.19 mmol, 6.0 equiv) in THF (2 mL) at -78 C., giving a red colored solution. The reaction was stirred at -78 C. for 5 min. A solution of enone S1-9 (15 mg, 0.032 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise to the reaction mixture. The reaction was stirred from -78 C. to -20 C. for 1 h, quenched by saturated aqueous NH4Cl, and extracted with EtOAc (2 times). The combined EtOAc extracts were dried (sodium sulfate) and concentrated to yield the crude product. The crude product was purified by preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C18 OBD column [5 mum, 19×50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; gradient: 20?100% B over 15 min; mass-directed fraction collection]. Fractions containing the desired product, eluting at 7.0-8.0 min, were collected and freeze-dried to give 18 mg of pure compound S8-3-1 (62%): 1H NMR (400 MHz, CDCl3) delta 7.58-7.45 (m, 4 H), 7.40-7.28 (m, 6 H), 5.35 (s, 2 H), 5.00-4.87 (m, 2 H), 3.91 (d, J=10.4 Hz, 1 H), 3.54-3.15 (m, 3 H), 3.02-2.88 (m, 3 H), 2.58-2.32 (m, 9 H), 2.17-2.08 (m, 1 H), 1.48-1.20 (br s, 9 H), 0.80 (s, 9 H), 0.26 (s, 3 H), 0.11 (s, 3 H); MS (ESI) m/z 902.48, 904.45 (M+H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 145; 146; 147; 148

61
[ 852821-06-8 ]
C₂₉H₃₃FN₂O₅ [ No CAS ]
C₄₉H₆₁FN₄O₉Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		To a solution of i-Pr2NH (0.27 mL, 1.93 mmol, 3.0 equiv) in THF (7 mL) was added a solution of n-BuLi (0.89 mL, 2.17 M/hexanes, 1.93 mmol, 3.0 equiv) dropwise at -78 C. The reaction was allowed to warm to 0 C., stirred at 0 C. for 25 min, and then cooled to -78 C. TMEDA (0.29 mL, 1.93 mmol, 3.0 equiv) was added, and the mixture was stirred at -78 C. for 5 min. A solution of compound S10-6 (0.51 g, 0.83 mmol, 1.3 equiv) in THF (0.5 mL) was added dropwise to the LDA solution over 5 min. Once addition was complete, the reaction mixture was stirred at -78 C. for 30 min. A solution of enone S1-9 (0.31 g, 0.64 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise over 2 min. The mixture was slowly warmed to -20 C. over 40 min and quenched by phosphate buffer (pH 7, 10 mL). The aqueous layer was extracted with EtOAc (20 mL×3). All organic layers were combined, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexanes/EtOAc (20:1 to 3:1) to afford 0.56 g of compound S10-7 (87%): 1H NMR (400 MHz, CDCl3) delta 15.96 (s, 1 H), 7.50-7.24 (comp, 10 H), 5.35 (s, 2 H), 4.93 (d, J=9.8 Hz, 1 H), 4.83 (d, J=9.8 Hz, 1 H), 3.94 (d, J=12.2 Hz, 1 H), 3.35 (s, 2 H), 3.31-3.23 (m, 1 H), 3.05-2.94 (m, 1 H), 2.49 (s, 6 H), 2.59-2.36 (comp, 3 H), 2.21 (s, 6 H), 2.20-2.10 (m, 1 H), 1.37 (s, 9 H), 1.32 (s, 9 H), 0.81 (s, 9 H), 0.27 (s, 3 H), 0.12 (s, 3 H); MS (ESI) m/z 997.42 (M+H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 153; 154; 157; 158

62
[ 852821-06-8 ]
C₂₂H₁₈BrFO₄ [ No CAS ]
C₄₂H₄₆BrFN₂O₈Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%		A solution of n-butyllithium in hexanes (1.36 mL, 1.6 M, 2.18 mmol, 2.2 equiv) was added to a solution of diisopropylamine (0.31 mL, 2.18 mmol, 2.2 equiv) and TMEDA (0.33 mL, 2.18 mmol, 2.2 equiv) in THF (20 mL) at -78 C. After stirring at -78 C. for 30 min, a solution of compound S20-5 (0.44 g, 0.99 mmol, 1.0 equiv) in THF (4 mL) was added dropwise via a cannula. The resulting red reaction mixture was then stirred at -78 C. for 10 min, and cooled to -100 C. A solution of enone S1-9 (0.38 g, 0.79 mmol, 0.8 equiv) in THF (4 mL) was added to the reaction mixture via a cannula. The resulting reaction mixture was allowed to warm to -30 C. over 1.5 hrs, quenched by saturated aqueous NH4Cl (40 mL), and extracted with EtOAc (100 mL). The organic phase were dried (sodium sulfate), filtered and concentrated. The residue was purified by a preparative reverse phase HPLC on a Waters Autopurification system using a Sunfire Prep C18 OBD column [5 mum, 19×50 mm; flow rate, 20 mL/min; Solvent A: H2O with 0.1% HCO2H; Solvent B: CH3CN with 0.1% HCO2H; injection volume: 3.0 mL (CH3CN); gradient: 80?100% B in A over 10 min; mass-directed fraction collection]. Fractions containing the desired product were collected and concentrated to yield compound S20-6 (0.36 g, 54%): 1H NMR (400 MHz, CDCl3) delta 15.79 (br s, 1 H), 7.51-7.48 (m, 2 H), 7.40-7.33 (m, 8 H), 5.36 (s, 2 H), 5.13 (d, J=11.0 Hz, 1 H), 4.18 (d, J=10.4 Hz, 1 H), 4.64 (dd, J=1.2, 12.2 Hz, 1 H), 4.53 (dd, J=1.2, 12.2 Hz, 1 H), 3.93 (d, J=10.4 Hz, 1 H), 3.40 (dd, J=10.7, 16.5 Hz, 1 H), 3.06-2.99 (m, 1 H), 2.61-2.57 (m, 1 H), 2.54-2.47 (m, 2 H), 2.50 (s, 6 H), 2.19 (d, J=14.6 Hz, 1 H), 1.86 (br s, 1 H), 0.83 (s, 9 H), 0.29 (s, 3 H), 0.14 (s, 3 H); MS (ESI) m/z 833.41, 835.38 (M+H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 335; 336; 339; 340

63
[ 852821-06-8 ]
C₂₉H₃₇NO₉ [ No CAS ]
C₄₉H₆₅N₃O₁₃Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		To diisopropylamine (28 muL, 0.20 mmol, 2.0 equiv) in anhydrous THF (4 mL) at -78 C. was added n-BuLi (0.13 mL, 1.6 M/hexanes, 0.20 mmol, 2.0 equiv). The solution was stirred at 0 C. for 10 min and cooled to -78 C. TMEDA (33 muL, 0.22 mmol, 2.2 equiv) was added, followed by dropwise addition of compound S21-7 (0.11 g, 0.20 mmol, 2.0 equiv) in anhydrous THF (4 mL) over a period of 5 min. Additional LDA (0.17 mL, 1.2 M/heptane/THF/ethylbenzene, 0.20 mmol, 2.0 equiv) was added. The resulting deep-red solution was stirred at -78 C. for 15 min. Enone (48 mg, 0.10 mmol, 1.0 equiv) in anhydrous THF (4 mL) was added. The resulting red-brown solution was slowly warmed to -10 C. over a period of 1 hr, quenched by pH 7 phosphate buffer (40 mL), and extracted with EtOAc (20 mL×3). The EtOAc extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. Flash column chromatography on silica gel with 0%-10% EtOAc/hexanes yielded the desired product S21-8 as a yellow foam (85 mg, 91%): Rf 0.45 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) delta 15.72 (s, 1 H), 7.30-7.50 (m, 5 H), 6.94 (d, J=1.8 Hz, 1 H), 6.86 (d, J=1.8 Hz, 1 H), 5.34 (s. 2 H), 3.94 (d, J=10.4 Hz, 1 H), 2.80-3.20 (m, 2 H), 2.45-2.55 (m, 10 H), 1.52 (s, 9 H), 1.43 (s, 18 H), 0.82 (s, 9 H), 0.25 (s, 3 H), 0.11 (s, 3 H); MS (ESI) m/z 932.3 (M+H), calcd for C49H65N3O13Si 931.4.

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 347; 348; 350; 351

64
[ 852821-06-8 ]
C₂₆H₂₉NO₄ [ No CAS ]
C₄₆H₅₇N₃O₈Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		n-Butyllithium (2.5 M/hexanes, 0.876 mL, 0.219 mmol) was added to diisopropylamine (0.310 mL, 0.219 mmol) in THF (3 mL) at -40 C. The reaction mixture was cooled to -78 C., and TMEDA (0.048 mL, 0.32 mmol) was added. A solution of compound S28-6-1 (36.8 mg, 0.0877 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred at -78 C. for 15 min. A solution of enone S1-9 (38.5 mg, 0.0800 mmol) in THF (0.5 mL) was added dropwise to the reaction mixture. The reaction was stirred from -78 C. to -20 C. for 1 h, quenched by saturated aqueous NH4Cl, and extracted with EtOAc (1 time). The combined EtOAc extracts were washed with water (2 times) and brine (1 time), dried (sodium sulfate) and concentrated. The material was purified by column chromatography (Biotage 10 g column, 0 to 10% MeOH in CH2Cl2 gradient). This gave 31.4 mg (49%) of product S28-7-1 as a yellow solid: 1H NMR (400 MHz, CDCl3) delta 16.2 (s, 1 H), 7.53-7.45 (m, 4 H), 7.40-7.28 (m, 5 H), 7.27-7.22 (m, 1 H), 7.09 (s, 1 H), 5.35 (s, 2 H), 5.19 (q, J=12.8 Hz, 2 H), 4.02 (d, J=10.4 Hz, 1 H), 3.66 (s, 3 H), 3.52-3.46 (m, 1 H), 3.26 (dd, J=15.9, 4.9 Hz, 1 H), 2.99-2.89 (m, 1 H), 2.55-2.42 (m, 9 H), 2.22-2.10 (m, 7 H), 1.34-1.20 (m, 3 H), 0.83 (s, 9 H), 0.27 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 808.55 (M+H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 501; 502; 503; 504; 506

65
[ 852821-06-8 ]
C₂₅H₂₆BrNO₃ [ No CAS ]
C₄₅H₅₄BrN₃O₇Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		A solution of n-BuLi in hexanes (1.05 mL, 1.6 M, 1.68 mmol, 1.4 equiv) was added dropwise to a solution of i-Pr2NH (0.235 mL, 1.68 mmol, 1.4 equiv) in THF (5 mL) at -78 C. under a N2 atmosphere. The resulting solution was stirred at -78 C. for 20 min and -20 C. for 5 min, and then re-cooled to -78 C. N,N,N?,N?-Tetramethylethylenediamine (TMEDA, 0.252 mL, 1.68 mmol, 1.4 equiv) was added, followed by dropwise addition of compound S32-1-1 (620 mg, 1.32 mmol, 1.1 equiv) in THF (3 mL) via syringe. After complete addition, the resulting dark-red mixture was stirred for another 15 min at -78 C. A solution of enone S1-9 (580 mg, 1.20 mmol, 1.0 equiv) in THF (2 mL) was added dropwise via syringe. LHMDS (1.44 mL, 1.0 M/THF, 1.44 mmol, 1.2 equiv) was then added and the reaction was slowly warmed to -20 C. Saturated aqueous NH4Cl was added. The resulting mixture was extracted three times with EtOAc. The combined EtOAc extracts were washed with brine, dried (sodium sulfate), and concentrated. Purification of the residue by flash chromatography gave compound S32-2-1 (627 mg, 62%) as light yellow foam: 1H NMR (400 MHz, CDCl3) delta 16.0 (s, 1 H), 7.52-7.45 (m, 4 H), 7.42-7.27 (m, 6 H), 7.12 (s, 1 H), 5.35 (s, 2 H), 5.22-5.09 (m, 2 H), 4.00 (d, J=9.8 Hz, 1 H), 3.62-3.52 (m, 1 H), 3.30-3.09 (m, 3 H), 3.04-2.93 (m, 1 H), 2.87-2.75 (m, 1 H), 2.58-2.30 (m, 9 H), 2.10 (d, J=14.0 Hz, 1 H), 1.03 (t, J=7.1 Hz, 3 H), 0.91 (t, J=7.1 Hz, 3 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 856.50 (M+H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 519; 520; 522

66
[ 852821-06-8 ]
C₂₄H₂₂ClFO₅ [ No CAS ]
C₄₄H₅₀ClFN₂O₉Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		A solution of n-BuLi in hexanes (196 muL, 1.6 M, 0.313 mmol, 1.5 equiv) was added dropwise to a solution of i-Pr2NH (43.9 muL, 0.313 mmol, 1.5 equiv) in THF (2 mL) at -78 C. under a N2 atmosphere. The resulting solution was stirred at -78 C. for 20 min and -20 C. for 5 min, and then re-cooled to -78 C. N,N,N?,N?-Tetramethylethylenediamine (TMEDA, 62.7 muL, 0.418 mmol, 2.0 equiv) was added, followed by dropwise addition of S33-5 (93 mg, 0.209 mmol, 1.0 equiv) in THF (1 mL) via syringe. After complete addition, the resulting dark-red mixture was stirred for another hour at -78 C. and then cooled to -100 C. A solution of enone S1-9 (100.9 mg, 0.209 mmol, 1.0 equiv) in THF (1 mL) was added dropwise via syringe. The resulting red mixture was slowly warmed to -78 C. LHMDS (0.313 mL, 1.0 M/THF, 0.313 mmol, 1.5 equiv) was then added and the reaction was slowly warmed to -20 C. Saturated aqueous NH4Cl was added. The resulting mixture was extracted three times with EtOAc. The combined EtOAc extracts were washed with brine, dried (sodium sulfate), and concentrated. Purification of the residue by flash chromatography gave the desired product (120 mg, 69%) as light yellow foam: MS (ESI) m/z 833.47 (M+H). (3468) To a solution of the above product (120 mg, 0.144 mmol, 1.0 equiv) in THF (10 mL) was added 6 N HCl (1.5 mL) at rt. The resulting mixture was stirred at rt for 2 hrs, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over sodium sulfate, and concentrated. Purification of the residue by flash chromatography gave crude aldehyde S33-6 as a light yellow foam: MS (ESI) m/z 819.40 [(M+MeOH)+H].

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 527; 528; 531

67
[ 852821-06-8 ]
[ 852821-20-6 ]
C₄₁H₄₇N₃O₇Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		(0232) (0233) A solution of n-butyllithium in hexanes (1.67 M, 80 muL, 0.13 mmol, 4.2 equiv) was added to a solution of diisopropylamine (20 muL, 0.14 mmol, 4.5 equiv) in tetrahydrofuran (2.5 mL) at -78 C. The resulting solution was allowed to warm to 0 C over 15 min. N,N'-dimethylpropyleneurea (17 muL, 0.14 mmol, 4.5 equiv) was added to the mixture prepared above at 0 C, whereupon the mixture was cooled to -78 C. A solution of the ester CDL-II-464 (31 mg, 0.093 mmol, 3.0 equiv) in tetrahydrofuran (250 muL) was then added at -78 C. The resulting yellow solution was stirred for 5 min at -78 C, then a solution of the enone DRS6 (15 mg, 0.031 mmol, 1.0 equiv) in tetrahydrofuran (250 muL) was added at -78 C. The resulting deep red mixture was allowed to warm to 0 C over 4 h. Acetic acid (40 muL) was added at to the deep red mixture at 0 C, followed by an aqueous potassium phosphate buffer solution (pH 7.0, 0.2 M, 15 mL). The resulting yellow mixture was extracted with dichloromethane (3 × 15 mL). The organic extracts were combined and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, providing a yellow oil. The product was purified by preparatory HPLC on a Coulter Ultrasphere ODS column (5 mum, 250 × 10 mm, flow rate 3.5 mL/min, Solvent A: water, Solvent B: methanol, UV detection at 350 nm) using an injection volume of 500 muL DMSO and a gradient elution of 92-100% B over 30 min. The peak eluting at 21-29 min was collected and concentrated to give enol CDL-II-466 as a light yellow solid (15.0 mg, 67%). Rf 0.55 (3:7 ethyl acetate-hexanes); 1H NMR (600 MHz, CD2Cl2) delta 16.05 (s, 1H, enol-OH), 7.52-7.26 (m, 10H, ArH), 6.66 (s, 1H, pyr-H), 5.57 (d, 1H, J = 12.7 Hz, OCHH'Ph), 5.43 (d, J = 12.7 Hz, 1H, OCHH'Ph), 5.33-5.28 (m, 2H, OCH2Ph), 3.99 (d, 2H, J = 10.5 Hz, CHN(CH3)2), 3.04-3.00 (m, 1H, CHCH2CHCHN(CH3)2), 2.84 (dd, 1H, J = 16.1, 4.9 Hz, CHH'CHCH2CHCHN(CH3)2), 2.74 (dd, 1H, J = 16.1, 16.1 Hz, CHH'CHCH2CHCHN(CH3)2), 2.53 (dd, 1H, J = 10.5, 3.9 Hz, CHCHN(CH3)2), 2.51-2.43 (m, 10H, N(CH3)2, Ar-CH3, CHH'CHCHN(CH3)2), 2.07 (d, 1H, J = 14.2 Hz, CHH'CHCHN(CH3)2), 0.82 (s, 9H, TBS), 0.22 (s, 3H, TBS), 0.10 (s, 3H, TBS); 13C NMR (100 MHz, CD2Cl2) delta 187.9, 185.2, 182.5, 178.8, 167.9, 161.9, 161.8, 154.8, 137.9, 135.6, 129.1, 129.0, 129.0, 128.7, 127.9, 127.9, 116.4, 111.6, 108.6, 107.5, 82.0, 73.0, 68.1, 61.7, 46.9, 42.0, 39.2, 28.6, 26.1, 24.6, 23.0, 19.3, -2.4, -3.5; FTIR (neat film), cm-1 2939 (m), 2857 (w), 1720 (s, C=O), 1593 (s), 1510 (s), 1469 (m), 1449 (m), 1326 (s), 1254 (m), 1187 (w), 1157 (m), 1090 (m), 1064 (m), 1007 (m); HRMS (ES) m/z calcd for (C41H47N3O7Si+H)+ 722.3262, found 722.3261.

Reference： [1]Patent: EP2016044,2020,B1 .Location in patent: Paragraph 0058; 0232-0233; 0251; 0265-0266

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 852821-06-8 ] {[proInfo.proName]}

Quality Control of [ 852821-06-8 ]

Related Doc. of [ 852821-06-8 ]

Product Details of [ 852821-06-8 ]

Calculated chemistry of [ 852821-06-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 852821-06-8 ]

Application In Synthesis of [ 852821-06-8 ]

[ 852821-06-8 ] Synthesis Path-Upstream 1~7

[ 852821-06-8 ] Synthesis Path-Downstream 1~67

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry