[ CAS No. 18156-74-6 ] {[proInfo.proName]}

Name: 18156-74-6|1-(Trimethylsilyl)-1H-imidazole|98%
Brand: Ambeed
SKU: A292420
Price: 5.0 USD
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Quality Control of [ 18156-74-6 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 18156-74-6 ]

CAS No. :	18156-74-6	MDL No. :	MFCD00005280
Formula :	C₆H₁₂N₂Si	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YKFRUJSEPGHZFJ-UHFFFAOYSA-N
M.W :	140.26	Pubchem ID :	28925
Synonyms :

Calculated chemistry of [ 18156-74-6 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.97
TPSA :	17.82 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.99
Log Po/w (XLOGP3) :	1.54
Log Po/w (WLOGP) :	1.57
Log Po/w (MLOGP) :	0.32
Log Po/w (SILICOS-IT) :	-0.53
Consensus Log Po/w :	0.98

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.02
Solubility :	1.32 mg/ml ; 0.00944 mol/l
Class :	Soluble
Log S (Ali) :	-1.52
Solubility :	4.2 mg/ml ; 0.03 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.65
Solubility :	3.15 mg/ml ; 0.0225 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.23

Safety of [ 18156-74-6 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P210-P261-P305+P351+P338	UN#:	1993
Hazard Statements:	H225-H315-H319-H335	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 18156-74-6 ]

* 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 [ 18156-74-6 ]
Downstream synthetic route of [ 18156-74-6 ]

[ 18156-74-6 ] Synthesis Path-Upstream 1~21

1
[ 74731-19-4 ]
[ 18156-74-6 ]
[ 530-62-1 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 4, p. 705 - 711[2] Zhurnal Obshchei Khimii, 1980, vol. 50, # 4, p. 875 - 881

2
[ 75-44-5 ]
[ 18156-74-6 ]
[ 74731-19-4 ]
[ 530-62-1 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 4, p. 705 - 711[2] Zhurnal Obshchei Khimii, 1980, vol. 50, # 4, p. 875 - 881
[3] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 4, p. 705 - 711[4] Zhurnal Obshchei Khimii, 1980, vol. 50, # 4, p. 875 - 881

3
[ 67-66-3 ]
[ 18156-74-6 ]
[ 14508-49-7 ]
[ 17180-94-8 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430

4
[ 105-39-5 ]
[ 18156-74-6 ]
[ 22884-10-2 ]

Reference： [1] Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088
[2] Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088

5
[ 96-34-4 ]
[ 18156-74-6 ]
[ 22884-10-2 ]

Reference： [1] Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088
[2] Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088

6
[ 18293-71-5 ]
[ 18156-74-6 ]
[ 22884-10-2 ]

Reference： [1] Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088
[2] Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088

7
[ 18156-74-6 ]
[ 350-46-9 ]
[ 2301-25-9 ]
[ 420-56-4 ]

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154

8
[ 18156-74-6 ]
[ 460-00-4 ]
[ 420-56-4 ]
[ 10040-96-7 ]

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154

9
[ 1194-02-1 ]
[ 18156-74-6 ]
[ 25372-03-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: With cesium fluoride In N,N-dimethyl-formamide for 0.166667 h; Inert atmosphere Stage #2: at 60℃; for 20 h;	Under a nitrogen atmosphere 362 mg (2.38 mmol) of CsF, previously activated with NaOH, were suspended in 5 ml of DMF and stirred for 30 min. Then, 1.00 g (8.26 mmol) of 4-fluorobenzonitrile was added. After 10 min 1.20 ml (8.18 mmol) N-trimethylsilylimidazole were added and the mixture was stirred at 60° C. for 20 hr. For workup, most of the solvent was removed under vacuum (oil pump), and then 5 ml of water and 5 ml of CH₂Cl₂were added to the reaction mixture. The organic phase was separated, the aqueous phase was extracted with CH₂Cl₂, the organic phases were combined, washed several times with water and dried over MgSO₄. The solvent was removed under vacuum, and the resulting solid was rinsed twice with pentane.Yield: 1.07 g (6.31 mmol, 77percent), appearance: colorless solid. ¹H NMR (CDCl₃, 25° C., 400.13 MHz): δ=7.25 (s, 1H, ImH), 7.33 (s, 1H, ImH), 7.51-7.53 (m, 2H, PhH), 7.79-7.81 (m, 2H, PhH), 7.94 (s, 1H, ImH). ¹³C NMR (CDCl₃, 25° C., 100.61 MHz): δ=111.3 (C-1), 117.7 (C-9), 117.9 (-CN), 121.5 (C-3, C-5), 131.6 (C-8), 134.2 (C-2, C-6), 135.4 (C-7) 140.6 (C-4).

Reference： [1] Patent: US2012/142937, 2012, A1, . Location in patent: Page/Page column 5

10
[ 1194-02-1 ]
[ 18156-74-6 ]
[ 420-56-4 ]
[ 25372-03-6 ]

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154

11
[ 463-71-8 ]
[ 18156-74-6 ]
[ 6160-65-2 ]

Reference： [1] Pharmaceutical Chemistry Journal, 1992, vol. 26, # 3, p. 259 - 262[2] Khimiko-Farmatsevticheskii Zhurnal, 1992, vol. 26, # 3, p. 59 - 62
[3] Journal of the American Chemical Society, 1995, vol. 117, # 34, p. 8757 - 8768

12
[ 18156-74-6 ]
[ 7189-69-7 ]

Reference： [1] Pharmaceutical Chemistry Journal, 1992, vol. 26, # 3, p. 259 - 262[2] Khimiko-Farmatsevticheskii Zhurnal, 1992, vol. 26, # 3, p. 59 - 62

13
[ 18156-74-6 ]
[ 98-59-9 ]
[ 75-77-4 ]
[ 2232-08-8 ]

Reference： [1] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 321 - 326

14
[ 7515-73-3 ]
[ 18156-74-6 ]
[ 60628-96-8 ]

Reference： [1] Patent: US4118487, 1978, A,

15
[ 19273-05-3 ]
[ 18156-74-6 ]
[ 10294-56-1 ]
[ 18999-45-6 ]

Reference： [1] Patent: US5206253, 1993, A,

16
[ 6553-96-4 ]
[ 18156-74-6 ]
[ 50257-40-4 ]

Reference： [1] Phosphorus and Sulfur and the Related Elements, 1986, vol. 26, p. 321 - 326

17
[ 18156-74-6 ]
[ 13435-12-6 ]
[ 10416-59-8 ]

Reference： [1] Patent: US6335456, 2002, B1, . Location in patent: Example 3
[2] Patent: US6335456, 2002, B1, . Location in patent: Example 1
[3] Patent: US6335456, 2002, B1, . Location in patent: Example 4
[4] Patent: US6335456, 2002, B1, . Location in patent: Example 5
[5] Patent: US6335456, 2002, B1, . Location in patent: Example 2

18
[ 60-35-5 ]
[ 18156-74-6 ]
[ 10416-59-8 ]

Reference： [1] Patent: US6335456, 2002, B1, . Location in patent: Example 6
[2] Patent: US6335456, 2002, B1, . Location in patent: Example 7
[3] Patent: US6335456, 2002, B1, . Location in patent: Example 9B
[4] Patent: US6335456, 2002, B1, . Location in patent: Example 8

19
[ 403-33-8 ]
[ 18156-74-6 ]
[ 420-56-4 ]
[ 101184-08-1 ]

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154

20
[ 74-87-3 ]
[ 18156-74-6 ]
[ 79917-88-7 ]

Reference： [1] Synthesis, 1996, # 6, p. 697 - 698

21
[ 22348-32-9 ]
[ 18156-74-6 ]
[ 848821-58-9 ]

Reference： [1] Chemistry - A European Journal, 2005, vol. 11, # 3, p. 939 - 944

[ 18156-74-6 ] Synthesis Path-Downstream 1~88

1
[ 67-62-9 ]
[ 453-17-8 ]
[ 18156-74-6 ]
[ 56196-02-2 ]
[ 56196-02-2 ]

Reference： [1]Carbohydrate Research,1989,vol. 194,p. 1 - 19

2
[ 67-62-9 ]
[ 7512-17-6 ]
[ 18156-74-6 ]
[ 128613-39-8 ]

Reference： [1]Carbohydrate Research,1989,vol. 194,p. 1 - 19

3
[ 67-62-9 ]
[ 3615-17-6 ]
[ 18156-74-6 ]
[ 128613-40-1 ]
trimethylsilyl ether of N-acetylmannosamine-syn-O-methyloxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	1.) NMP, 75 deg C, 30 min, 2.) NMP, RT, 5-10 min; Multistep reaction;

Reference： [1]Andrews, Mark A. [Carbohydrate Research, 1989, vol. 194, # C, p. 1 - 19]

4
[ 67-62-9 ]
[ 134-61-2 ]
[ 18156-74-6 ]
[ 128613-42-3 ]
[ 128613-41-2 ]

Reference： [1]Carbohydrate Research,1989,vol. 194,p. 1 - 19

5
[ 68892-42-2 ]
[ 18156-74-6 ]
N-[6-Oxo-9-((2R,4S,5R)-4-trimethylsilanyloxy-5-trimethylsilanyloxymethyl-tetrahydro-furan-2-yl)-6,9-dihydro-1H-purin-2-yl]-isobutyramide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 755 - 758

6
[ 6553-96-4 ]
[ 18156-74-6 ]
[ 50257-40-4 ]

Reference： [1]Phosphorus and Sulfur and the Related Elements,1986,vol. 26,p. 321 - 326

7
[ 32328-03-3 ]
[ 18156-74-6 ]
[ 91424-41-8 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1858 - 1873
[2]Journal of Organic Chemistry,1984,vol. 49,p. 3657 - 3659

8
[ 453-17-8 ]
[ 622-33-3 ]
[ 18156-74-6 ]
[ 128613-30-9 ]

Reference： [1]Carbohydrate Research,1989,vol. 194,p. 1 - 19

9
[ 453-17-8 ]
[ 622-33-3 ]
[ 18156-74-6 ]
[ 128613-30-9 ]

Reference： [1]Carbohydrate Research,1989,vol. 194,p. 1 - 19

10
[ 67-66-3 ]
[ 18156-74-6 ]
[ 14508-49-7 ]
[ 17180-94-8 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1980,p. 1427 - 1430

11
[ 7397-62-8 ]
[ 18156-74-6 ]
[ 87826-84-4 ]

Reference： [1]Chemische Berichte,1983,vol. 116,p. 3413 - 3426

12
[ 26054-60-4 ]
[ 18156-74-6 ]
[ 147896-60-4 ]

Reference： [1]Tetrahedron Letters,1994,vol. 35,p. 7605 - 7608

13
[ 130451-27-3 ]
[ 18156-74-6 ]
[ 120240-10-0 ]
[ 1546-79-8 ]

Reference： [1]Tetrahedron Letters,1990,vol. 31,p. 4081 - 4084

14
[ 18156-74-6 ]
[ 98-59-9 ]
[ 75-77-4 ]
[ 2232-08-8 ]

Reference： [1]Phosphorus and Sulfur and the Related Elements,1986,vol. 26,p. 321 - 326

15
[ 18156-74-6 ]
[ 7189-69-7 ]

Reference： [1]Pharmaceutical Chemistry Journal,1992,vol. 26,p. 259 - 262
Khimiko-Farmatsevticheskii Zhurnal,1992,vol. 26,p. 59 - 62

16
[ 102490-05-1 ]
[ 18156-74-6 ]
(R)-(+)-2,2'-di-O-TMS-3,3'-diphenyl-1,1'-binaphthol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane for 1h;

Reference： [1]Chapuis, C.; Bauer, T.; Jezewski, A.; Jurczak, J. [Polish Journal of Chemistry, 1994, vol. 68, # 11, p. 2323 - 2332]

17
[ 111-11-5 ]
[ 18156-74-6 ]
1-Methoxy-1-(trimethylsiloxy)octane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 12h;

Reference： [1]Sames, Dalibor; Liu, Yunqi; DeYoung, Lynn; Polt, Robin [Journal of Organic Chemistry, 1995, vol. 60, # 7, p. 2153 - 2159]

18
[ 106-32-1 ]
[ 18156-74-6 ]
1-Ethoxy-1-(trimethylsiloxy)octane [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 2153 - 2159

19
[ 18156-74-6 ]
[ 141404-08-2 ]
[ 141404-09-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	In dichloromethane
99%	In dichloromethane at 0℃; for 2h;	4.14 To a solution of 19 (1.12 g, 2.99 mmol) in dry CH2Cl2 (10 mL) was added 1-(trimethylsilyl)imidazole (839 mg, 5.98 mmol) at 0° C. After being stirred for 2 h at the same temperature, water (1.5 mL) was add and the mixture was stirred for 30 min. The reaction mixture was extracted with CH2Cl2. The organic extract was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel (30 g) with 3% AcOEt hexane to afford 20 (1.32 g, 99%). [0121] 20: 1H NMR (CDCl3) δ: 0.05 (6H, s, Si-CH3), 0.06 and 0.07 (each 3H, s, Si-CH3), 0.16 (9H, s, Si-CH3), 0.86 and 0.89 (each 1H, s, Si-tBu), 2.17 (1H, dm), 2.36 (1H, dd, J=13.7, 4.4 Hz), 2.73 (2H, m), 3.80 (1H, m, 4-H), 4.03 (1H, m), 4.24 (1H, ddd, J=10.6, 4.5, 2.3 Hz). [0122] Mass m/z (%): 446 (no M+), 431 (7), 389 (100), 315 (4), 299 (99), 257 (57), 225 (22).
95%	In dichloromethane for 20h;

In hexane; dichloromethane; water; ethyl acetate

1.e EXAMPLE 1 (e) (3R,5R) [3,5-Bis (tert.-butyldimethylsilyloxy)-4-tri-methylsilyloxy]-1-cyclohexanone (4). N-(Trimethylsilyl)imidazole (2.52 mL, 26.67 mmol) was added to a solution of the ketoalcohol 3 (1.56 g, 4.167 mmol) in methylene chloride (38 mL). The solution was stirred for 20 h. Water (1 mL) was added and the solution stirred for 30 min. Brine and methylene chloride was added. The brine was extracted with methylene chloride. The combined methylene chloride fractions were dried with anh. MgSO4, filtered and concentrated. The residue was further purified by column chromatography on silica gel with 10% ethyl acetate in hexane to give 4 (1.76 g, 3.95 mmol) in 95% yield. 1 H NMR (CDCl3, 500 MHz) δ 4.25 (m, 1 H), 4.13 (m. 1 H), 4.04 (m, 1 H), 2.74 (ddd, 2 H), 2.38 (dd, 1 H), 2.19 (dd, 1 H), 0.90 (s, 9 H), 0.86 (s, 9 H), 0.16 (s, 9 H), 0.07 (bs, 12 H). MS m/e (relative intensity): 431 (5), 389 (100), 299 (45), 257 (28).

Reference： [1]Shimizu, Masato; Iwasaki, Yukiko; Shibamoto, Yoshinori; Sato, Miki; DeLuca; Yamada, Sachiko [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 5, p. 809 - 812]
[2]Current Patent Assignee: UNIVERSITY OF WISCONSIN SYSTEM; WARF (in: University of Wisconsin) - US2004/133026, 2004, A1 Location in patent: Page 11
[3]Sicinski; Perlman; DeLuca [Journal of Medicinal Chemistry, 1994, vol. 37, # 22, p. 3730 - 3738]
[4]Current Patent Assignee: WARF (in: University of Wisconsin); UNIVERSITY OF WISCONSIN SYSTEM - US5536713, 1996, A

20
[ 19356-17-3 ]
[ 18156-74-6 ]
[ 67804-03-9 ]

Reference： [1]Journal of Mass Spectrometry,1995,vol. 30,p. 348 - 356

21
[ 106-94-5 ]
[ 18156-74-6 ]
[ 179231-43-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	In tetrahydrofuran at 25℃; for 0.0833333h;	1 Example 1: The 50mmol trimethylsilyl imidazole dissolved in tetrahydrofuran, diluted to 50ml for the A phase; the 100mmol of bromopropane was dissolved in tetrahydrofuran, diluted to 50ml for the B phase.A phase B in accordance with the volume ratio of 1: 1 ratio pump nuanced reactor (sandwichreactorHC), reaction at 25 residence 5min; micro reactor discharges into separator through sedimentation, filtration, and dried to give N, N- disubstituted imidazole propane bromide, in 88% yield.
71%	In toluene for 10h; Reflux;	Preparation of [(1,3-Pr₂im)Br] ionic liquid 1,3-Dipropylimidazolium bromide ionic liquid was synthesized according to the procedure reported previously [24]. Briefly, N-Trimethylsilylimidazole (12.6 mL, 0.0858 mol), 1-bromopropane (21.7 mL, 0.239 mol) and toluene (28 mL) were refluxed for 10 h and the crystalline product was isolated by the filtration. [(1,3-Pr2im)Br] was dissolved in dry acetonitrile and admixtures were removed by hexane extraction. After acetonitrile removal the product was dried in vacuo for 5 h; yield was 14.2 g (71%), mp 135. 1H NMR (acetone-d6): d = 0:89 (t, 6H, CH3, J(HH) = 7.6 Hz), 1.95 (m,4H, CH2CH2CH3, J(HH) = 7.2 Hz), 4.49 (t, 4H, NCH2,J(HH) = 7.2 Hz), 8.15 (s, 2H, H4, 5(Imidazole)), 10.27 (s, 1H, H2(Imidazole)). Anal. Calcd for C9H17N2Br (232.9): C, 46.37%; H,7.29%; Br, 34.30%; N, 12.02%. Found: C, 44.09%; H, 7.25%; Br,30.29%; N, 11.90% [25].
34%	In toluene for 4h; Ambient temperature;

Reference： [1]Current Patent Assignee: NANJING TECH UNIVERSITY - CN105541722, 2016, A Location in patent: Paragraph 0029; 0030
[2]Azizi, Seyed Naser; Chaichi, Mohammad Javad; Shakeri, Parmis; Bekhradnia, Ahmadreza [Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2015, vol. 146, p. 277 - 285]
[3]Harlow, Karsten J.; Hill, Anthony F.; Welton, Tom [Synthesis, 1996, # 6, p. 697 - 698]

22
[ 74-87-3 ]
[ 18156-74-6 ]
[ 79917-88-7 ]

Reference： [1]Synthesis,1996,p. 697 - 698

23
[ 67-56-1 ]
[ 4973-29-9 ]
[ 3006-96-0 ]
[ 18156-74-6 ]
[ 6908-41-4 ]
4-[2-Imidazol-1-yl-1-(4-phenoxy-phenyl)-ethoxymethyl]-benzoic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 5687 - 5690

24
[ 57497-39-9 ]
[ 18156-74-6 ]
[ 82580-24-3 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 641 - 643

25
[ 50632-53-6 ]
[ 18156-74-6 ]
[ 219943-31-4 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 641 - 643

26
[ 18156-74-6 ]
[ 215257-77-5 ]
[ 215257-71-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	In dichloromethane at 20℃; for 4h;
91%	In dichloromethane; water at 20℃; for 4.5h;	2 To a stirred solution of 366.6 mg (1.0 mmol) of [lS-(lα,3aβ,7aα)]octahydro-l-[5-hydroxy-l-(4- hydroxy-4-me thylpentyl)-5-methylhexyl]-7a-methyl-4H-inden-4-one in 10.0 mL of dichloromethane was added 1.25 mL (8.5 mmol) of l-(trimethylsilyl) imidazole and the mixture was stirred under argon at room temperature for 4.25 hrs. It was diluted with 7.0 mL of water, stirred for a further 15 minutes, and poured into a mixture of 75 mL of ethyl acetate and 50 mL of 50% brine. The organic phase was collected and the aqueous phase was re-extracted with 3x50 mL of ethyl acetate. The combined organic extracts were washed with 3x75 mL of 50% brine, dried (Na2SO4), and evaporated to give a colorless oil, which was purified by flash chromatography on 65 g of silica gel (40-65 μm mesh, 3.5 cm diameter column) with 20% ethyl acetate in hexanes as eluent, taking 20-mL fractions. Fractions 5-7 were combined, concentrated to ca. 5 mL, filtered through a 0.45 μm filter (Millex-HV) and evaporated to give a colorless oil, which was kept under high vacuum for 18 hrs to give 469 mg (91%) of the titled compound: [CC]25D -3.21° (CHCl3, c=0.87); IR (CHCl3); 1706 cm"1 ; * H NMR (CDCl3) δ 0.01 (18H, s), 0.63 (3H, s), 1.20 (6H, s), 1.21 (6H, s),1.26-1.49 (14H, m), 1.50-2.10 (8H, m), 2.21-2.31 (2H, m), 2.46 (IH, dd, J=12,l 1 Hz); MS (EI) m/z 495 (M+ -15). Anal. Calcd for C29 H58O3 Si2 : C, 68.17;H, 11.44; Si, 10.99. Found: C, 68.19; H, 11.41; Si, 11.07.
91%	In tetrahydrofuran

91%

In dichloromethane at 20℃; for 4.25h;

2 To a stirred solution of 366.6 mg (1.0 mmol) of [lS-(lα,3aβ,7aα)]octahydro-l-[5-hydroxy-l-(4- hydroxy-4-me thylpentyl)-5-methylhexyl]-7a-methyl-4H-inden-4-one in 10.0 mL of dichloromethane was added 1.25 mL (8.5 mmol) of l-(trimethylsilyl) imidazole and the mixture was stirred under argon at room temperature for 4.25 hrs. It was diluted with 7.0 mL of water, stirred for a further 15 minutes, and poured into a mixture of 75 mL of ethyl acetate and 50 mL of 50% brine. The organic phase was collected and the aqueous phase was re-extracted with 3x50 mL of ethyl acetate. The combined organic extracts were washed with 3x75 mL of 50% brine, dried (Na2SO4), and evaporated to give a colorless oil, which was purified by flash chromatography on 65 g of silica gel (40-65 μm mesh, 3.5 cm diameter column) with 20% ethyl acetate in hexanes as eluent, taking 20-mL fractions. Fractions 5-7 were combined, concentrated to ca. 5 mL, filtered through a 0.45 μm filter (Millex-HV) and evaporated to give a colorless oil, which was kept under high vacuum for 18 hrs to give 469 mg (91%) of the titled compound: [CC]25D -3.21° (CHCl3, c=0.87); IR (CHCl3); 1706 cm"1 ; * H NMR (CDCl3) δ 0.01 (18H, s), 0.63 (3H, s), 1.20 (6H, s), 1.21 (6H, s),1.26-1.49 (14H, m), 1.50-2.10 (8H, m), 2.21-2.31 (2H, m), 2.46 (IH, dd, J=12,l 1 Hz); MS (EI) m/z 495 (M+ -15). Anal. Calcd for C29 H58O3 Si2 : C, 68.17;H, 11.44; Si, 10.99. Found: C, 68.19; H, 11.41; Si, 11.07.

Reference： [1]Norman, Anthony W.; Manchand, Percy S.; Uskokovic, Milan R.; Okamura, William H.; Takeuchi, Janet A.; Bishop, June E.; Hisatake, Jun-Iichi; Koeffler, H. Phillip; Peleg, Sara [Journal of Medicinal Chemistry, 2000, vol. 43, # 14, p. 2719 - 2730]
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 96-97
[3]Pazos, Gonzalo; Pérez, Manuel; Gándara, Zoila; Gómez, Generosa; Fall, Yagamare [RSC Advances, 2016, vol. 6, # 66, p. 61073 - 61076]
[4]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 96

27
[ 22348-32-9 ]
[ 18156-74-6 ]
[ 848821-58-9 ]

Reference： [1]Chemistry - A European Journal,2005,vol. 11,p. 939 - 944

28
[ 96-34-4 ]
[ 18156-74-6 ]
1,3-bis(2-methoxy-2-oxoethyl)-1H-imidazole-3-ium chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	at 60℃; for 24h;
99.7%	at 60℃; for 24h;	1 1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9) Example 1 1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9) Methyl chloroacetate (2; 29.8 mL, 338.6 mmol, 2.0 eq) was added drop-wise to 1-(trimethylsilyl)-1H-imidazole (8; 25.0 mL, 169.3 mmol). The mixture was heated at 60° C. for 24 hours. The mixture was cooled to room temperature, washed with Et2O (3*500 mL) and dried in vacuo yielding 9 (41.97 g, 168.8 mmol, 99.7%) as a white solid.
99.7%	at 60℃; for 24h;	1 1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9) 1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9) Methyl chloroacetate (2; 29.8 mL, 338.6 mmol, 2.0 eq) was added drop-wise to 1-(trimethylsilyl)-1H-imidazole (8; 25.0 mL, 169.3 mmol). The mixture was heated at 60° C. for 24 hours. The mixture was cooled to room temperature, washed with Et2O (3*500 mL) and dried in vacuo yielding 9 (41.97 g, 168.8 mmol, 99.7%) as a white solid.

99.7%	In neat liquid at 60℃; for 24h;	1 1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9) Example 1 1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-ium chloride (9) Methyl chloroacetate (2; 29.8 mL, 338.6 mmol, 2.0 eq) was added drop-wise to 1-(trimethylsilyl)-1H-imidazole (8; 25.0 mL, 169.3 mmol). The mixture was heated at 60° C. for 24 hours. The mixture was cooled to room temperature, washed with Et2O (3*500 mL) and dried in vacuo yielding 9 (41.97 g, 168.8 mmol, 99.7%) as a white solid.
97%	at 60℃; for 24h; Inert atmosphere;

Reference： [1]Fei, Zhaofu; Zhao, Dongbin; Geldbach, Tilmann J.; Scopelliti, Rosario; Dyson, Paul J. [Chemistry - A European Journal, 2004, vol. 10, # 19, p. 4886 - 4893]
[2]Current Patent Assignee: AXSOME THERAPEUTICS, INC; ANTECIP BIOVENTURES LI LLC - US8835650, 2014, B1 Location in patent: Page/Page column 10-11
[3]Current Patent Assignee: ANTECIP BIOVENTURES LI LLC - US8865757, 2014, B1 Location in patent: Page/Page column 17
[4]Current Patent Assignee: ANTECIP BIOVENTURES LI LLC - US8901161, 2014, B1 Location in patent: Page/Page column 18
[5]Farger, Pierre; Guillot, Rgis; Leroux, Fabrice; Parizel, Nathalie; Gallart, Mathieu; Gilliot, Pierre; Rogez, Guillaume; Delahaye, Emilie; Rabu, Pierre [European Journal of Inorganic Chemistry, 2015, vol. 2015, # 32, p. 5342 - 5350]

29
[ 3153-37-5 ]
[ 18156-74-6 ]
1,3-bis-(3-methoxycarbonyl-propyl)-3<i>H</i>-imidazol-1-ium; chloride [ No CAS ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 4886 - 4893

30
[ 562-74-3 ]
[ 18156-74-6 ]
(1-isopropyl-4-methyl-cyclohex-3-enyloxy)-trimethyl-silane [ No CAS ]

Reference： [1]Synthesis,2005,p. 2677 - 2682

31
[ 2077-19-2 ]
[ 18156-74-6 ]
[ 917024-62-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20℃;	N-trimethylsilylimidazole (80.6 mL, 0.552 mol) was added to a solution of the crude <strong>[2077-19-2]2-(4-bromo-phenyl)-propan-2-ol</strong> in tetrahydrofuran (500 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography (n-hexane:ethyl acetate = 40:1) to give the title compound as a colorless oil (125.6 g, 87% in two steps). 1H-NMR (chloroform-d): 0.10 (9H, s), 1.55 (6H, s), 7.30 (2H, d, J=8.6Hz), 7.42 (2H, d, J=8.6Hz).

Reference： [1]Patent: EP1894911,2008,A1 .Location in patent: Page/Page column 42

32
[ 105-39-5 ]
[ 18156-74-6 ]
[ 17450-34-9 ]
1,3-bis(2-ethoxy-2-oxoethyl)-1H-imidazol-3-ium chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 67 - 70℃;
	at 90 - 100℃;

Reference： [1]Lebedev; Sheludyakov; Lebedeva; Frolov; Shatunov; Ustinova; Kovaleva [Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088]
[2]Lebedev; Sheludyakov; Lebedeva; Frolov; Shatunov; Ustinova; Kovaleva [Russian Journal of General Chemistry, 2007, vol. 77, # 6, p. 1086 - 1088]

33
[ 105-39-5 ]
[ 18156-74-6 ]
1,3-bis(carboxymethyl)-1H-imidazol-3-ium chloride [ No CAS ]
[ 22884-10-2 ]

Reference： [1]Russian Journal of General Chemistry,2007,vol. 77,p. 1086 - 1088
[2]Russian Journal of General Chemistry,2007,vol. 77,p. 1086 - 1088

34
[ 96-34-4 ]
[ 18156-74-6 ]
1,3-bis(carboxymethyl)-1H-imidazol-3-ium chloride [ No CAS ]
[ 22884-10-2 ]

Reference： [1]Russian Journal of General Chemistry,2007,vol. 77,p. 1086 - 1088
[2]Russian Journal of General Chemistry,2007,vol. 77,p. 1086 - 1088

35
[ 18293-71-5 ]
[ 18156-74-6 ]
1,3-bis(carboxymethyl)-1H-imidazol-3-ium chloride [ No CAS ]
[ 22884-10-2 ]

Reference： [1]Russian Journal of General Chemistry,2007,vol. 77,p. 1086 - 1088
[2]Russian Journal of General Chemistry,2007,vol. 77,p. 1086 - 1088

36
[ 18156-74-6 ]
[ 13435-12-6 ]
[ 10416-59-8 ]

Yield	Reaction Conditions	Operation in experiment
79.3%	at 175℃; 30-theoretical-plates distillation column of Old-ershaw type;
198.6 g	at 150 - 180℃; 20-theoretical-plates distillation column of Old-ershaw type;
118.9 g	at 100 - 121℃; 30-theoretical-plates distillation column of Old-ershaw type;

154.2 g	at 130 - 162℃; 20-theoretical-plates distillation column of Old-ershaw type;
	at 175℃; 20-theoretical-plates distillation column of Old-ershaw type;

Reference： [1]Current Patent Assignee: TESSENDERLO GROUP NV/SA - US6335456, 2002, B1 Location in patent: Example 3
[2]Current Patent Assignee: TESSENDERLO GROUP NV/SA - US6335456, 2002, B1 Location in patent: Example 1
[3]Current Patent Assignee: TESSENDERLO GROUP NV/SA - US6335456, 2002, B1 Location in patent: Example 4
[4]Current Patent Assignee: TESSENDERLO GROUP NV/SA - US6335456, 2002, B1 Location in patent: Example 5
[5]Current Patent Assignee: TESSENDERLO GROUP NV/SA - US6335456, 2002, B1 Location in patent: Example 2

37
[ 848945-55-1 ]
[ 18156-74-6 ]
[ 848945-54-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	In dichloromethane at 20℃; for 1h;	4 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl- pentenyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (440 mg, 1.50 mmol) and Celite (2.0 g) in dichloromethane (10 niL) at room temperature wad added pyridinium dichromate (1.13 g, 3.0 mmol). The resulting mixture was stirred for 5 h filtered through silica gel (10 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)- 7a-Methyl-l-[l-(4-hydroxy-4-methyl-pentenyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro- 3H-inden-4-one (426 mg, 1.47 mmol, 98 %). To a stirred solution of (3aR,7aR)-7a- Methyl- 1 -[ 1 -(4-hydroxy-4-methyl-pentenyl)-cyclopropyl]-3 a,4,5,6,7,7a-hexahydro-3H- inden-4-one (424 mg, 1.47 mmol) in dichloromethane (10 mL) at room temperature was added trimethylsilyl-imidazole (0.44 mL, 3.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (460 mg, 1.27 mmol, 86 %). [α]29D= -9.9 c 0.55, CHCl3.1H NMR (CDCl3): 5.33 (IH, dd, J=3.2, 1.5 Hz), 2.81 (IH, dd, J= 10.7, 6.2 Hz), 2.44 (IH, ddd, J=15.6, 10.7, 1.5 Hz), 2.30-1.15 (13H, m) overlapping 2.03 ( ddd, J= 15.8, 6.4, 3.2 Hz), 1.18 (6H, s), 0.92 (3H, s), 0.66-0.28 (4H, m), 0.08 (9H, s); 13C NMR (CDCl3): 211.08 (0), 155.32(0), 124.77(1), 73.98(0), 64.32(1), 53.91(0), 44.70(2), 40.45(2), 38.12(2), 34.70(2), 29.86(3), 29.80(3), 26.80(2), 24.07(2), 22.28(2), 21.24(0), 18.35(3), 12.60(2), 10.64(2), 2.63 (3); MS HRES Calculated for C22H38O2Si M+ 362.2641. Observed M+ 362.2648.
86%	In dichloromethane at 20℃; for 1h;	23; 50 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pentenyl)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (440 mg, 1.50 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.13 g, 3.0 mmol). The resulting mixture was stirred for 5 h filtered through silica gel (10 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pentenyl)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (426 mg, 1.47 mmol, 98 %). To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pentenyl)-cyclopropyl]- 3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (424 mg, 1.47 mmol) in dichloromethane (10 mL) at room temperature was added trimethylsilyl- imidazole (0.44 mL, 3.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (460 mg, 1.27 mmol, 86 %). [α]29D= -9.9 c 0.55, CHCl3. 1H NMR (CDCl3): 5.33 (IH, dd, J=3.2, 1.5 Hz), 2.81 (IH, dd, J= 10.7, 6.2 Hz), 2.44 (IH, ddd, J=15.6, 10.7, 1.5 Hz), 2.30- 1.15 (13H, m) overlapping 2.03 ( ddd, J= 15.8, 6.4, 3.2 Hz), 1.18 (6H, s), 0.92 (3H, s), 0.66-0.28 (4H, m), 0.08 (9H, s); 13C NMR (CDCl3): 211.08 (0), 155.32(0), 124.77(1), 73.98(0), 64.32(1), 53.91(0), 44.70(2), 40.45(2), 38.12(2), 34.70(2), 29.86(3), 29.80(3), 26.80(2), 24.07(2), 22.28(2), 21.24(0), 18.35(3), 12.60(2), 10.64(2), 2.63 (3); MS HRES Calculated for C22H38O2Si M+ 362.2641. Observed M+ 362.2648
86%	In dichloromethane at 20℃; for 1h;	23 To a stirred solution of (3aR,7aR)-7a-Methyl-l -[I -(4-hydroxy-4-methyl-pentyl)-cyclopropyl]- 3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (424 rag, 1.47 mraol) in dichloromethane (10 mL) at room temperature was added trimethylsilyl-imidazole (0.44 mL, 3.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (460 mg, 1.27 mraol, 86 %). [α]29D= -9.9 c 0.55, CHCl3. 1H NMR (CDCl3): 5.33 (IH, dd, J=3.2, 1.5 Hz), 2.81 (IH, dd, J= 10.7, 6.2 Hz)3 2.44 (IH, ddd, JM15.6, 10.7, 1.5 Hz), 2.30- 1.15 (I 3H, m) overlapping 2.03 ( ddd, J= 15.8, 6.4, 3.2 Hz)5 1.18 (6H, s), 0.92 (3H3 s), 0.66-0.28 (4H, m). 0.08 (9H5 s); 13CNMR (CDCl3): 211.08 (0), 155.32(0), 124.77(1), 73.98(O)5 64.32(1), 53.91(0), 44.70(2), 40.45(2), 38.12(2), 34.70(2), 29.86(3), 29.80(3), 26.80(2), 24.07(2), 22.28(2), 21.24(0), 18.35(3), 12.60(2), 10.64(2), 2.63 (3); MS HRES Calculated for C22H38O2Si M+ 362.2641. Observed M+ 362.2648.

86%

In dichloromethane at 20℃; for 1h;

23; 46 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-1-[1-(4-hydroxy-4-methyl-pentenyl)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (440 mg, 1.50 mmol) and Celite (2.0 g) in dichloromethane (10 ml.) at room temperature wad added pyridinium dichromate (1.13 g, 3.0 mmol). The resulting mixture was stirred for 5 h filtered through silica gel (10 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-1-[1-(4-hydroxy-4-methyl-pentenyl)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (426 mg, 1.47 mmol, 98 %). To a stirred solution of (3aR,7aR)-7a-Methyl-1 -[1 -(4-hydroxy-4-methyl-pentenyl)-cyclopropyl]-3a,4,5,6,7,7a- EPO hexahydro-3H-inden-4-one (424 mg, 1.47 mmol) in dichloromethane (10 ml.) at room temperature was added trimethylsilyl-imidazole (0.44 ml_, 3.0 mmol). The resulting mixture was stirred for 1.O h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (460 mg, 1.27 mmol, 86 %). [α]29D= -9.9 c 0.55, CHCI3.1H NMR (CDCI3): 5.33 (1 H, dd, J=3.2, 1.5 Hz), 2.81 (1 H1 dd, J= 10.7, 6.2 Hz), 2.44 (1 H, ddd, J=15.6, 10.7, 1.5 Hz), 2.30-1.15 (13H, m) overlapping 2.03 ( ddd, J= 15.8, 6.4, 3.2 Hz), 1.18 (6H, s), 0.92 (3H, s), 0.66-0.28 (4H, m), 0.08 (9H, s); 13C NMR (CDCI3): 211.08 (0), 155.32(0), 124.77(1), 73.98(0), 64.32(1), 53.91(0), 44.70(2), 40.45(2), 38.12(2), 34.70(2), 29.86(3), 29.80(3), 26.80(2), 24.07(2), 22.28(2), 21.24(0), 18.35(3), 12.60(2), 10.64(2), 2.63 (3); MS HRES Calculated for C22H38O2Si M+ 362.2641. Observed M+ 362.2648.

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/36813, 2006, A2 Location in patent: Page/Page column 68-69
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/35075, 2006, A1 Location in patent: Page/Page column 65; 111
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/51106, 2006, A1 Location in patent: Page/Page column 67-68
[4]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/100285, 2006, A1 Location in patent: Page/Page column 67-68; 109-110

38
[ 848945-58-4 ]
[ 18156-74-6 ]
[ 848945-57-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	In dichloromethane at 20℃; for 0.5h;	5 To a stirred suspension of (3aR, 4S,7aR)-7a-Memyl-l-[l-(4-hydroxy-4-methyl- pent-2-ynyll)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (381 mg, 1.32 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.0 g, 2.65 mmol). The resulting mixture was stirred for 1.5 h EPO filtered through silica gel (10 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)- 7a-Methyl-l-[l-(4-hydroxy-4-methyl-pent-2-ynyll)-cyclopropyl]-3a,4,5,6,7,7a- hexahydro-3H-inden-4-one (360 mg, 1.26 mmol, 95 %). To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pent-2-ynyll)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (360 mg, 1.26 mmol) in dichloromethane (10 mL) at room temperature was added trimethylsilyl-imidazole (0.25 mL, 1.7 mmol). The resulting mixture was stirred for 0.5 h filtered through silica gel (10 g) and the silica gel pad was washed with 5% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (382 mg, 1.07 mmol, 81 %).
81%	In dichloromethane at 20℃; for 0.5h;	24; 52 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pent-2-ynyll)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (381 mg, 1.32 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.0 g, 2.65 mmol). The resulting mixture was stirred for 1.5 h filtered through silica gel (10 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pent-2-ynyll)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (360 mg, 1.26 mmol, 95 %). To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pent-2-ynyll)-cyclopropyl]- 3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (360 mg, 1.26 mmol) in dichloromethane (10 mL) at room temperature was added trimethylsilyl- imidazole (0.25 mL, 1.7 mmol). The resulting mixture was stirred for 0.5 h filtered through silica gel (10 g) and the silica gel pad was washed with 5% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (382 mg, 1.07 mmol, 81 %)
81%	In dichloromethane at 20℃; for 0.5h;	24 To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l-(4-hydroxy-4-methyl-pent-2-ynyl)-cyc]opropyl]- 3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (360 mg, 1.26 mmol) in dichloromethane (10 mL) at room temperature was added trimethylsilyl-imidazole (0.25 mL, 1.7 mmol). The resulting mixture was stirred for 0.5 h filtered through silica gel (1 0 g) and the silica gel pad was washed with 5% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (382 mg, 1.07 mmol, 81 %).

81%

In dichloromethane at 20℃; for 0.5h;

24 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-1-[1-(4-hydroxy-4-methyl-pent-2-ynyll)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (381 mg, 1.32 mmol) and Celite (2.0 g) in dichloromethane (10 ml.) at room temperature wad added pyridinium dichromate (1.0 g, 2.65 mmol). The resulting mixture was stirred for 1.5 h filtered through silica gel (10 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-1-[1-(4-hydroxy-4-methyl-pent-2-ynyll)- cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (360 mg, 1.26 mmol, 95 %). To a stirred solution of (3aR,7aR)-7a-Methyl-1 -[1 -(4-hydroxy-4-methyl-pent-2-ynyll)-cyclopropyl]- 3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (360 mg, 1.26 mmol) in dichloromethane (10 ml.) at room temperature was added trimethylsilyl-imidazole (0.25 ml_, 1.7 mmol). The resulting mixture was stirred for 0.5 h filtered through silica gel (10 g) and the silica gel pad was washed with 5% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (382 mg, 1.07 mmol, 81 %).

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/36813, 2006, A2 Location in patent: Page/Page column 69-70
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/35075, 2006, A1 Location in patent: Page/Page column 65-66; 113-114
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/51106, 2006, A1 Location in patent: Page/Page column 68
[4]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/100285, 2006, A1 Location in patent: Page/Page column 68

39
[ 848945-70-0 ]
[ 18156-74-6 ]
[ 848945-69-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane at 20℃; for 1h;	2; 13 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoro-4- hydroxy-4-txifluoromethyl-pent-2E-enyl)-cyclopropyl]-3a,4,5,6,7,7a-liexahydro-3H- inden-4-ol (600 mg, 1.51 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.13 g, 3.0 mmol). The resulting mixture was stirred for 3.5 h filtered through silica gel (10 g), and then silica gel pad was washed with 25% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoiO-4-hydroxy-4-trifluoromethyl- pent-2E-enyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (550 mg, 1.39 mmol, 92 %). To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoro-4- hydroxy^-trifluoromethyl-pent^E-eny^-cyclopropylJ-Sa^jSjβJ^a-hexahydro-SH- inden-4-one (550 mg, 1.39 mmol) in dichloromethane (15 mL) at room temperature was added trimethylsilyl-imidazole (1.76 mL, 12.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (623 mg, 1.33 mmol, 88 %). [α]28D= -1.6 c 0.51, CHCl3. 1H NMR (CDCl3): 6.14 (IH, dt, J=15.5, 6.7 Hz), 5.55 (IH, d, J=I 5.5 Hz), 5.35 (IH, m), 2.80 (IH, dd, J= 10.7, 6.4 Hz), 2.47-1.74 (1OH, m), 0.90 (3H, s), 0.76-0.40 (4H, m), O.2 (9H, s); 13C NMR (CDCl3): 210.99 (0), 154.28(0), 137.41(1), 126.26(1), 122.59(O, q, J=289 Hz), 120.89 (1), 64.31(1), 53.96(0), 40.60(2), 40.13(2), 35.00(2), 27.03(2), 24.21(2), 20.57(0), 18.53(3), 12.41(2), 10.79(2), 1.65 (3); MS HRES Calculated for C22H30O2F6Si M+H 469.1992. Observed M+ H 469.1995.
88%	In dichloromethane at 20℃; for 1h;	32 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoro-4-hydroxy-4- trifluoromethyl-pent-2E-enyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (600 mg, 1.51 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.13 g, 3.0 mmol). The resulting mixture was stirred for 3.5 h filtered through silica gel (10 g), and then silica gel pad was washed with 25% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-l-[l- (5,5,5-trifluoro-4-hydroxy-4-trifluoromethyl-pent-2E-enyl)-cyclopropyl]-3a,4,5,6,7,7a- hexahydro-3H-inden-4-one (550 mg, 1.39 mmol, 92 %). To a stirred solution of (3aR,7aR)-7a- Methyl-l-[l-(5,5,5-trifluoro-4-hydroxy-4-trifluoromethyl-pent-2E-enyl)-cyclopropyl]- 3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (550 mg, 1.39 mmol) in dichloromethane (15 mL) at room temperature was added trimethylsilyl- imidazole (1.76 mL, 12.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (623 mg, 1.33 mmol, 88 %). [α]28D= -1.6 c 0.51, CHCl3. 1H NMR (CDCl3): 6.14 (IH, dt, J=15.5, 6.7 Hz), 5.55 (IH, d, J=15.5 Hz), 5.35 (IH, m), 2.80 (IH, dd, J= 10.7, 6.4 Hz), 2.47-1.74 (1OH, m), 0.90 (3H, s), 0.76-0.40 (4H, m), 0.2 (9H, s); 13C NMR (CDCl3): 210.99 (0), EPO 154.28(0), 137.41(1), 126.26(1), 122.59(0, q, J=289 Hz), 120.89 (1), 64.31(1), 53.96(0), 40.60(2), 40.13(2), 35.00(2), 27.03(2), 24.21(2), 20.57(0), 18.53(3), 12.41(2), 10.79(2), 1.65 (3); MS HRES Calculated for C22H30O2F6Si M+H 469.1992. Observed M+ H 469.1995.
88%	In dichloromethane at 20℃; for 1h;	32 To a stirred solution of (3aR,7aR)-7a- Methyl- 1 -[I -(5,5,5-trifluoro-4-hydroxy-4-trifluoromethyl-pent-2E-enyl)-cyclopropyl]- 3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (550 mg, 1.39 mmol) in dichloromethane (15 mL) at room temperature was added trimethylsilyl-imidazole (1.76 m.L, 12.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (623 mg, 1.33 mmol, 88 %). [α]28D= -1.6 c 0.51, CHCl3. 1H NMR (CDCl3): 6.14 (IH, dt, JM15.5, 6.7 Hz), 5.55 (IH, d, J=15.5 Hz), 5.35 (IH, m), 2.80 (IH, dd, J= 10.7, 6.4 Hz), 2.47-1.74 (10H5 m), 0.90 (3H, s), 0.76-0.40 (4H, m), 0.2 (9H, s); 13CNMR (CDCl3): 210.99 (O)5 154.28(0), 137.41(1), 126.26(1), 122.59(0, q, J=289 Hz), 120.89 (1), 64.31(1), 53.96(0), 40.60(2), 40.13(2), 35.00(2), 27.03(2), 24.21(2), 20.57(0), 18.53(3), 12.41(2), 10.79(2), 1.65 (3); MS HRES Calculated for C22H30O2F6Si M+H 469.1992. Observed M+ H 469.1995.

88%

In dichloromethane at 20℃; for 1h;

32 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-1-[1-(5,5,5-trifluoro-4-hydroxy-4- trifluoromethyl-pent^E-enyO-cyclopropyll-Sa^.S.βyya-hexahydro-SH-inden-4-ol (600 mg, 1.51 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.13 g, 3.0 mmol). The resulting mixture was stirred for 3.5 h filtered through silica gel (10 g), and then silica gel pad was washed with 25% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-1-[1-(5,5,5-trifluoro-4- hydroxy-4-trifluoromethyl-pent^E-enylJ-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-SH-inden-4-one (550 mg, 1.39 mmol, 92 %). To a stirred solution of (3aR,7aR)-7a-Methyl-1-[1-(5,5,5-trifluoro-4- hydroxy-4-trifluoromethyl-pent^E-enylJ-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-SH-inden-4-one EPO (550 mg, 1.39 mmol) in dichloromethane (15 ml.) at room temperature was added trimethylsilyl- imidazole (1.76 ml_, 12.0 mmol). The resulting mixture was stirred for 1.O h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (623 mg, 1.33 mmol, 88 %). [α]28D= -1.6 c 0.51 , CHCI3 1H NMR (CDCI3): 6.14 (1 H, dt, J=15.5, 6.7 Hz), 5.55 (1 H, d, J=15.5 Hz), 5.35 (1H, m), 2.80 (1 H, dd, J= 10.7, 6.4 Hz), 2.47-1.74 (1OH, m), 0.90 (3H, s), 0.76-0.40 (4H, m), 0.2 (9H, s); 13C NMR (CDCI3): 210.99 (0), 154.28(0), 137.41(1), 126.26(1), 122.59(0, q, J=289 Hz), 120.89 (1), 64.31(1), 53.96(0), 40.60(2), 40.13(2), 35.00(2), 27.03(2), 24.21(2), 20.57(0), 18.53(3), 12.41(2), 10.79(2), 1.65 (3); MS HRES Calculated for C22H30O2F6Si M+H 469.1992. Observed M+ H 469.1995.

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/36813, 2006, A2 Location in patent: Page/Page column 76-77
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/35075, 2006, A1 Location in patent: Page/Page column 72-73
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/51106, 2006, A1 Location in patent: Page/Page column 75
[4]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/100285, 2006, A1 Location in patent: Page/Page column 74-75

40
[ 848945-80-2 ]
[ 18156-74-6 ]
[ 848945-72-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane at 20℃; for 1h;	2; 17 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoro-4- hydroxy-4-trifluoromethyl-pent-2Z-enyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H- inden-4-ol (617 mg, 1.55 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.17 g, 3.1 mmol). The resulting mixture was stirred for 2.5 h filtered through silica gel (5 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoro-4-hydroxy-4-trifluoromethyl- pentenyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (600 mg, 1.51 mmol, 98 %). To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoro-4-hydroxy-4- trifluoromethyl-pent-2Z-enyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (600 mg, 1.51 mmol) in dichloromethane (15 mL) at room temperature was added trimethylsilyl-imidazole (1.76 mL, 12.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (640 mg, 1.37 mmol, 88 %). [α]28D= -0.2 c 0.55, CHCl3. 1H NMR (CDCl3): 5.97 (IH, dt, J=12.2, 6.2 Hz), 5.40 (IH, m), 5.38 (IH, d, J=I 2.2Hz), 2.82 (IH, dd, J= 10.7, 6.6 Hz), 2.60-1.74 (1OH, m), 0.89 (3H, s), 0.75-0.36 (4H, m), 0.21 (9H, s); 13C NMR (CDCl3): 210.56 (0), 154.30(0), 139.28(1), 125.81(1), 122.52(0, q, J=289 Hz), 118.17 (1), 64.11(1), 53.69(0), 40.43(2), 35.51(2), 34.85(2), 26.94(2), 24.07(2), 20.89(0), 18.39(3), 12.26(2), 10.61(2), 1.43 (3); MS HRES Calculated for C22H30O2F6Si M+H 469.1992. Observed M+ H 469.1992.
88%	In dichloromethane at 20℃; for 1h;	36 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-l-[l-(5,5,5-trifluoro-4-hydroxy-4- trifluoromethyl-pent-2Z-enyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (617 mg, 1.55 mmol) and Celite (2.0 g) in dichloromethane (10 mL) at room temperature wad added pyridinium dichromate (1.17 g, 3.1 mmol). The resulting mixture was stirred for 2.5 h filtered through silica gel (5 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-l-[l- (5,5,5-trifluoro-4-hydroxy-4-trifluoromethyl-pentenyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro- 3H-inden-4-one (600 mg, 1.51 mmol, 98 %). To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l- (5,5,5-trifluoro-4-hydroxy-4-trifluoromethyl-pent-2Z-enyl)-cyclopropyl]-3a,4,5,6,7,7a- hexahydro-3H-inden-4-one (600 mg, 1.51 mmol) in dichloromethane (15 mL) at room temperature was added trimethylsilyl-imidazole (1.76 mL, 12.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (640 mg, 1.37 mmol, 88 %). [α]28D= -0.2 c 0.55, CHCl3. 1H NMR (CDCl3): 5.97 (IH, dt, J=12.2, 6.2 Hz), 5.40 (IH, m), 5.38 (IH, d, J=12.2Hz), 2.82 (IH, dd, J= 10.7, 6.6 Hz), 2.60-1.74 (1OH, m), 0.89 (3H, s), 0.75-0.36 (4H, m), 0.21 (9H, s); 13C NMR (CDCl3): 210.56 (0), 154.30(0), 139.28(1), 125.81(1), 122.52(0, q, J=289 Hz), 118.17 (1), 64.11(1), 53.69(0), 40.43(2), 35.51(2), 34.85(2), 26.94(2), 24.07(2), 20.89(0), 18.39(3), 12.26(2), 10.61(2), 1.43 (3); MS HRES Calculated for C22H30O2F6Si M+H 469.1992. Observed M+ H 469.1992.
88%	In dichloromethane at 20℃; for 1h;	36 To a stirred solution of (3aR,7aR)-7a-Methyl-l-[l- (5,5,5-trifluoro-4-hydroxy-4-trifluoromethyl-pent-2Z-enyl)-cyclopropy]]-3a,4,5,6,7,7a- hexahydro-3H-inden-4-one (600 mg, 1.51 minol) in dichloromethane (15 mL) at room temperature was added trimethylsilyl-imidazole (1.76 mL, 12.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (640 mg, 1.37 mmol, 88 %). [α]28D= -0.2 c 0.55, CHCl3. 1H NMR (CDCl3): 5.97 (IH, dt, J=12.2, 6.2 Hz), 5.40 (IH, m), 5.38 (IH, d, J=12.2Hz), 2.82 (IH, dd, J= 10.7, 6.6 Hz)3 2.60-1.74 (10H3 m), 0.89 (3H5 s), 0.75-0.36 (4H, m), 0.21 (9H, s); 13C NMR (CDCl3): 210.56 (0), 154.30(0), 139.28(1), 125.81(1), 122.52(0, q3 .1=289 Hz), 118.17 (1), 64.11(I)3 53.69(0), 40.43(2), 35.51(2), 34.85(2), 26.94(2), 24.07(2), 20.89(0), 18.39(3), 12.26(2), 10.61(2), 1.43 (3); MS HRES Calculated for C22H30O2F6Si M+H 469. J 992. Observed M+ H 469.1992.

88%

In dichloromethane at 20℃; for 1h;

36 To a stirred suspension of (3aR, 4S,7aR)-7a-Methyl-1-[1-(5,5,5-trifluoro-4-hydroxy-4- trifluoromethyl-pent-2Z-enyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-ol (617 mg, 1.55 mmol) and Celite (2.0 g) in dichloromethane (10 ml.) at room temperature wad added pyridinium dichromate (1.17 g, 3.1 mmol). The resulting mixture was stirred for 2.5 h filtered through silica gel (5 g), and then silica gel pad was washed with 20% AcOEt in hexane. The combined filtrate and washes were evaporated, to give a crude (3aR,7aR)-7a-Methyl-1-[1-(5,5,5-trifluoro-4- hydroxy-4-trifluoromethyl-pentenyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden -4-one (600 mg, 1.51 mmol, 98 %). To a stirred solution of (3aR,7aR)-7a-Methyl-1-[1-(5,5,5-trifluoro-4- hydroxy-4-trifluoromethyl-pent-2Z-enyl)-cyclopropyl]-3a,4,5,6,7,7a-hexahydro-3H-inden-4-one (600 mg, 1.51 mmol) in dichloromethane (15 ml.) at room temperature was added trimethylsilyl- imidazole (1.76 ml_, 12.0 mmol). The resulting mixture was stirred for 1.0 h filtered through silica gel (10 g) and the silica gel pad was washed with 10% AcOEt in hexane. Combined filtered and washes were evaporated to give the titled compound (640 mg, 1.37 mmol, 88 %). [α]28D= -0.2 c 0.55, CHCI3 1H NMR (CDCI3): 5.97 (1 H, dt, J=12.2, 6.2 Hz), 5.40 (1 H, m), 5.38 (1H, d, J=12.2Hz), 2.82 (1 H, dd, J= 10.7, 6.6 Hz), 2.60-1.74 (10H, m), 0.89 (3H, s), 0.75-0.36 (4H, m), 0.21 (9H, s); 13C NMR (CDCI3): 210.56 (0), 154.30(0), 139.28(1), 125.81(1), 122.52(0, q, J=289 Hz), 118.17 (1), 64.11(1), 53.69(0), 40.43(2), 35.51(2), 34.85(2), 26.94(2), 24.07(2), 20.89(0), 18.39(3), 12.26(2), 10.61(2), 1.43 (3); MS HRES Calculated for C22H30O2F6Si M+H 469.1992. Observed M+ H 469.1992.

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/36813, 2006, A2 Location in patent: Page/Page column 81
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/35075, 2006, A1 Location in patent: Page/Page column 75-76
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/51106, 2006, A1 Location in patent: Page/Page column 78-79
[4]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/100285, 2006, A1 Location in patent: Page/Page column 77-78

41
[ 18156-74-6 ]
[ 713521-57-4 ]
[ 910623-46-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	In dichloromethane; water at 20℃; for 2.16667h;	3 A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.78 g (4.510 mmol) of 6-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl- silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2-methyl-hept-6-en-2-ol and 15 ml of dichloromethane. A 1.98 ml (13.53 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 2h. A 15 ml of water was added and the mixture was stirred for 10 min. The resulting mixture was dissolved by the addition of 100 ml of water. The aqueous layer was extracted three times with 50 ml of dichloromethane. The combined organic layers were washed with 30 ml of brine dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm ) using hexane: ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 2.037 g (96%) of product as colorless oil.
96%	In dichloromethane at 20℃; for 2h;	1 (IR, 3aR, 4S, 7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-l-(5-methyl-l- metkylene-5-trimethylsilanyloxy-hexyl)-octahydro-mdene (41)A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.78 g (4.510 mmol) of 6-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl- dimethyl-silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2-methyl-hept-6-en-2-ol (40) and 15 ml of dichloromethane. A 1.98 ml (13.53 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 2h. A 15 ml of water was added and the mixture was stirred for 10 min. The resulting mixture was dissolved by the addition of 100 ml of water. The aqueous layer was extracted three times with 50 ml of dichloromethane. The combined organic layers were washed with 30 ml of brine dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane:ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 2.037 g (96%) of product 41 as colorless oil.
96%	In dichloromethane at 20℃; for 2h;	3 A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.78 g (4.510 mmol) of 6-[(1R, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl- silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2-methyl-hept-6-en-2-ol and 15 ml of dichloromethane. A 1.98 ml (13.53 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 2h. A 15 ml of water was added and the mixture was stirred for 10 min. The resulting mixture was dissolved by the addition of 100 ml of water. The aqueous layer was extracted three times with 50 ml of dichloromethane. The combined organic layers were washed with 30 ml of brine dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane: ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 2.037 g (96%) of product as colorless oil.

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 98
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 60; 81
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 97-98

42
[ 910623-67-5 ]
[ 18156-74-6 ]
[ 910623-68-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	In dichloromethane at 20℃; for 1h;	6 A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.300 g (2.990 mmol) of (6S)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl- dimethyl-silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2,6-dimethyl-non-8-yn-2-ol and 25 ml of dichloromethane. A 2.00 ml (13.63 mmol) of l-(trimethylsilyl) imidasole was added dropwise. The mixture was stirred at room temperature for Ih.A 100 ml of water was added and the mixture was extracted three times with 80 ml of hexane, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm ) using hexane:ethyl acetate (25:1) as mobile phase. Fractions containing product were pooled and evaporated to give 1.409 g (93%) of product as colorless oil.1H NMR (CDCl3): 3.98(1H, br s), 2.27(2H, d, J=2.9 Hz), 1.97-1.91(2H, m), 1.82-1.75(1H, m), 1.69-1.62(lH, m), 1.59-1.50(2H, m), 1.42-1.20(12H, m), 1.20(6H, s), 1.05(3H, s), 1.00(3H, s), 0.93-0.85(1H, m), 0.88(9H, s), 0.10(9H, s), 0.00(3H, s), -0.01(3H, s)
93%	In dichloromethane at 20℃; for 1h;	4 (IR, 3aR, 4S, 7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-l-[(lS)-l,5-dimethyl-l-prop- 2-ynyl-5-trimethylsilanyloxy-hexyl]-7a-methyl-octahydro-indene (67)A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.300 g (2.990 mmol) of (6S)-6-[(lR, 3aR, 4S, 7aR)-4-(tert- butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2,6-dimethyl-non-8-yn-2- ol (66) and 25 ml of dichloromethane. A 2.00 ml (13.63 mmol) of l-(trimethylsilyl) imidasole was added dropwise. The mixture was stirred at room temperature for Ih. A 100 ml of water was added and the mixture was extracted three times with 80 ml of hexane, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm ) using hexane:ethyl acetate (25:1) as mobile phase. Fractions containing product were pooled and evaporated to give 1.409 g (93%) of product 61 as colorless oil.1EE NMR (CDCl3): 3.98(1H, br s), 2.27(2H, d, J=2.9 Hz), 1.97-1.91(2H, m), 1.82- 1.75(1H, m), 1.69-1.62(1H, m), 1.59-1.50(2H, m), 1.42-1.20(12H, m), 1.20(6H, s), 1.05(3H, s), 1.00(3H, s), 0.93-0.85(1H, m), 0.88(9H, s), 0.10(9H5 s), 0.00(3H, s), - 0.01(3H, s)
93%	In dichloromethane at 20℃; for 1h;	6 A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.300 g (2.990 mmol) of (6S)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl- dimethyl-silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2,6-dimethyl-non-8-yn-2-ol and 25 ml of dichloromethane. A 2.00 ml (13.63 mmol) of l-(trimethylsilyl) imidasole was added dropwise. The mixture was stirred at room temperature for Ih.A 100 ml of water was added and the mixture was extracted three times with 80 ml of hexane, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane:ethyl acetate (25:1) as mobile phase. Fractions containing product were pooled and evaporated to give 1.409 g (93%) of product as colorless oil.1H NMR (CDCl3): 3.98(1H, br s), 2.27(2H, d, J=2.9 Hz), 1.97-1.91(2H, m), 1.82-1.75(1H, m), 1.69-1.62(lH, m), 1.59-1.50(2H, m), 1.42-1.20(12H, m), 1.20(6H, s), 1.05(3H, s), 1.00(3H, s), 0.93-0.85(1H, m), 0.88(9H, s), 0.10(9H, s), 0.00(3H, s), -0.01(3H, s)

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 114
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 63; 100
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 113

43
[ 910623-71-1 ]
[ 18156-74-6 ]
[ 910623-76-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	In dichloromethane at 20℃; for 3h;	7 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 585 mg (1.207 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lS)-6,6,6- trifluoro-5 -hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-5 -trifluoromethyl-hex-3 -ynyl] - octahydro-inden-4-one and 10 ml of dichloromethane. A 1.5 ml (10.2 mmol) of 1- (trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 3h. A 150 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated.The oil residue was chromatographed on column (50 cm3) using hexane: ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 660 mg (87%) of product as colorless oil.1H NMR (CDCl3): 2.44-2.39(3H, m), 2.32-2.16(2H, m), 2.10-1.99(2H, m), 1.95-1.84(2H, m), 1.77-1.56(4H, m), 1.38-1.19(7H, m), 1.20(6H, s), 1.03(3H, s), 0.74(3H, s), 0.28(9H, s), 0.10(9H, s)
87%	In dichloromethane at 20℃; for 3h;	5 (IR, 3aR, 4S, 7aR)-7a-Methyl-l-[(lS)-6,6,6-trifluoro-l-methyI-l-(4-methyl-4- trimethylsilanyloxy-pentyl)-5-trifluoromethyl-5-trimethylsilanyIoxy-hex-3-ynyl] - octahydro-inden-4-one (75)A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 585 mg (1.207 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l- [( 1 S)-6,6,6-trifluoro-5-hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-5- trifluoromethyl-hex-3-ynyl]-octahydro-inden-4-one (70) and 10 ml of dichloromethane. A 1.5 ml (10.2 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 3h. A 150 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (50 cm3) using hexane:ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 660 mg (87%) of product 75 as colorless oil.1H NMR (CDCl3): 2.44-2.39(3H, m), 2.32-2.16(2H, m), 2.10-1.99(2H, m), 1.95- 1.84(2H, m), 1.77-1.56(4H, m), 1.38-1.19(7H, m), 1.20(6H, s), 1.03(3H, s), 0.74(3H, s), 0.28(9H, s), 0.10(9H, s) EPO
87%	In dichloromethane at 20℃; for 3h;	7 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 585 mg (1.207 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lS)-6,6,6- trifluoro-5 -hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-5 -trifluoromethyl-hex-3 -ynyl] - octahydro-inden-4-one and 10 ml of dichloromethane. A 1.5 ml (10.2 mmol) of 1- (trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 3h. A 150 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated.The oil residue was chromatographed on column (50 cm3) using hexane: ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 660 mg (87%) of product as colorless oil.1H NMR (CDCl3): 2.44-2.39(3H, m), 2.32-2.16(2H, m), 2.10-1.99(2H, m), 1.95-1.84(2H, m), 1.77-1.56(4H, m), 1.38-1.19(7H, m), 1.20(6H, s), 1.03(3H, s), 0.74(3H, s), 0.28(9H, s), 0.10(9H, s)

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 118
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 65; 104
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 117

44
[ 910623-75-5 ]
[ 18156-74-6 ]
[ 910623-78-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane at 20℃; for 5.5h;	13 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 577 mg (1.186 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lS,3E)- 6,6,6-trifluoro-5-hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-S-trifluoromethyl-hex-S- enyl]-octahydro-inden-4-one and 20 ml of dichloromethane. A 1.5 ml (10.2 mmol) of 1- (trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 5h 30min. A 150 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane:ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 710 mg (95%) of product as colorless oil.1H NMR (CDCl3): 6.21(1H, dt, J=15.1, 7.2 Hz), 5.56(1H, d, J=15.4 Hz), 1.22-1.19(1H, m), 2.32-1.06(2H, m), 2.27(2H, d, J=7.0 Hz), 2.06-1.52(9H, m), 1.34-1.08(6H, m), 1.20(3H, s), 1.19(3H, s), 0.96(3H, s), 0.73(3H, s), 0.22(9H, s), 0.10(9H, s)
95%	In dichloromethane at 20℃; for 5.5h;	11 (IR, 3aR, 4S, 7aR)-7a-MethyI-l-[(lS,3E)-6,6,6-trifluoro-l-methyl-l-(4-methyl-4- trimethylsilanyloxy-pentyl)-5-trifluoromethyl-5-trimethylsilanyloxy-hex-3-enyl]- octahydro-inden-4-one (77)A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 577 mg (1.186 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l- [(lS,3E)-6,6,6-trifluoro-5-hydroxy-l-(4-hydroxy-4-methyl-pentyl)-l-methyl-5- trifluoromethyl-hex-3-enyl]-octahydro-inden-4-one (74) and 20 ml of dichloromethane. A 1.5 ml (10.2 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 5h 30min. A 150 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane:ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 710 mg (95%) of product 77 as colorless oil.1H NMR (CDCl3): 6.21(1H, dt, J=15.1, 7.2 Hz), 5.56(1H, d, J=15.4 Hz), 1.22-1.19(1H, m), 2.32-1.06(2H, m), 2.27(2H, d, J=7.0 Hz), 2.06-1.52(9H, m), 1.34-1.08(6H, m), 1.20(3H, s), 1.19(3H, s), 0.96(3H, s), 0.73(3H, s), 0.22(9H, s), 0.10(9H, s)
95%	In dichloromethane at 20℃; for 5.5h;	13 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 577 mg (1.186 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lS,3E)- 6,6,6-trifluoro-5-hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-S-trifluoromethyl-hex-S- enyl]-octahydro-inden-4-one and 20 ml of dichloromethane. A 1.5 ml (10.2 mmol) of 1- (trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 5h 30min. A 150 ml of ethyl acetate was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane:ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 710 mg (95%) of product as colorless oil.1H NMR (CDCl3): 6.21(1H, dt, J=15.1, 7.2 Hz), 5.56(1H, d, J=15.4 Hz), 1.22-1.19(1H, m), 2.32-1.06(2H, m), 2.27(2H, d, J=7.0 Hz), 2.06-1.52(9H, m), 1.34-1.08(6H, m), 1.20(3H, s), 1.19(3H, s), 0.96(3H, s), 0.73(3H, s), 0.22(9H, s), 0.10(9H, s)

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 129
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 67; 116-117
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 128

45
[ 910623-80-2 ]
[ 18156-74-6 ]
[ 910623-81-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	In dichloromethane at 20℃; for 1h;	15 A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.151 g (2.647 mmol) of (6R)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl- dimethyl-silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2,6-dimethyl-non-8-yn-2-ol and 20 ml of dichloromethane. A 2.0 ml (13.63 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for Ih. A 100 ml of water was added and the mixture was extracted three times with 50 ml of ethyl acetate, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane: ethyl acetate (25:1) as mobile phase. Fractions containing product were pooled and evaporated to give 1.260 g (94%) of product as colorless oil.[α] D = +18.5° c=0.46, CHCl3 1H NMR (CDCl3): 3.98(1H, br s), 2.12-2.08(2H, m), 20.5-1.95(2H, m), 1.92-1.9O(1H, m), 1.83-1.21(16H, m), 1.21(6H, s), 1.04(3H, s), 0.98(3H, s), 0.88(9H, s), 0.11(9H, s), 0.00(3H, s), -0.01(3H, s)13C NMR (CDCl3): 83.00, 74.07, 69.70, 69.50, 56.63, 53.03, 45.66, 43.74, 41.35, 39.59, 5 39.45, 34.38, 29.99, 29.60, 25.85, 22.81, 22.43, 22.06, 18.56, 18.05, 17.76, 16.49, 2.65, -4.77, - 5.13MS HRES Calculated for: C30H58O2Si2 [M+Na]+ 529.3867Observed: [M+Na]+ 529.3868
94%	In dichloromethane at 20℃; for 1h;	13 (IR, 3aR, 4S, 7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-l-[(lR)-l,5-dimethyl-l-prop- 2-ynyl-5-trimethylsilanyloxy-hexyI]-7a-methyl-octahydro-indene (80) A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.151 g (2.647 mmol) of (6R)-6-[(lR, 3aR, 4S, 7aR)-4-(tert- butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2,6-dimethyl-non-8-yn-2- ol and 20 ml of dichloromethane. A 2.0 ml (13.63 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for Ih. A 100 ml of water was added and the mixture was extracted three times with 50 ml of ethyl acetate, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane:ethyl acetate (25:1) as mobile phase. Fractions containing product were pooled and evaporated to give 1.260 g (94%) of product as colorless oil.[α] D = +18.5° c=0.46, CHCl31H NMR (CDCl3): 3.98(1H, br s), 2.12-2.08(2H, m), 20.5-1.95(2H, m), 1.92-1.90(1H, m), 1.83-1.21(16H, m), 1.21(6H, s), 1.04(3H, s), 0.98(3H, s), 0.88(9H, s), 0.11(9H, s),0.00(3H, s), -0.01(3H, s)13C NMR (CDCl3): 83.00, 74.07, 69.70, 69.50, 56.63, 53.03, 45.66, 43.74, 41.35, 39.59, 39.45, 34.38, 29.99, 29.60, 25.85, 22.81, 22.43, 22.06, 18.56, 18.05, 17.76, 16.49, 2.65, -4.77, -5.13MS HRES Calculated for: C30H58O2Si2 [M+Naf 529.3867Observed: [M+Naf 529.3868
94%	In dichloromethane at 20℃; for 1h;	15 A 50 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.151 g (2.647 mmol) of (6R)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl- dimethyl-silanyloxy)-7a-methyl-octahydro-inden-l-yl]-2,6-dimethyl-non-8-yn-2-ol and 20 ml of dichloromethane. A 2.0 ml (13.63 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for Ih. A 100 ml of water was added and the mixture was extracted three times with 50 ml of ethyl acetate, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (75 cm3) using hexane: ethyl acetate (25:1) as mobile phase. Fractions containing product were pooled and evaporated to give 1.260 g (94%) of product as colorless oil.[α] D = +18.5° c=0.46, CHCl3 1H NMR (CDCl3): 3.98(1H, br s), 2.12-2.08(2H, m), 20.5-1.95(2H, m), 1.92-1.9O(1H, m), 1.83-1.21(16H, m), 1.21(6H, s), 1.04(3H, s), 0.98(3H, s), 0.88(9H, s), 0.11(9H, s), 0.00(3H, s), -0.01(3H, s)13C NMR (CDCl3): 83.00, 74.07, 69.70, 69.50, 56.63, 53.03, 45.66, 43.74, 41.35, 39.59, 5 39.45, 34.38, 29.99, 29.60, 25.85, 22.81, 22.43, 22.06, 18.56, 18.05, 17.76, 16.49, 2.65, -4.77, - 5.13MS HRES Calculated for: C30H58O2Si2 [M+Na]+ 529.3867Observed: [M+Na]+ 529.3868

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 133-134
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 67-68; 122
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 132-133

46
[ 910623-84-6 ]
[ 18156-74-6 ]
[ 910623-89-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane at 20℃; for 4h;	16 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 399 mg (0.823 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lR)-6,6,6- trifluoro-5 -hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-5 -trifluoromethyl-hex-3 -ynyl] - octahydro-inden-4-one and 8.0 ml of dichloromethane. A 0.9 ml (6.2 mmol) of 1- (trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 4h. A 150 ml of hexane was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (50 cm3) using hexane:ethyl acetate (5:1) as mobile phase. Fractions containing product were pooled and evaporated to give 492 mg (95%) of product as oil.
95%	In dichloromethane at 20℃; for 4h;	14 (IR, 3aR, 4S, 7aR)-7a-Methyl-l-[(lR)-6,6,6-trifluoro-l-methyl-l-(4-methyl-4- trimethylsilanyloxy-pentyl)-5-trifluoromethyl-5-trimethyIsilanyloxy-hex-3-ynyl]- octahydro-inden-4-one (88)A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 399 mg (0.823 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l- [( 1 R)-6,6,6-trifluoro-5-hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-5- trifluoromethyl-hex-3-ynyl]-octahydro-inden-4-one and 8.0 ml of dichloromethane. A 0.9 ml (6.2 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 4h. A 150 ml of hexane was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (50 cm3) using hexane:ethyl acetate (5:1) as mobile phase. Fractions containing product were pooled and evaporated to give 492 mg (95%) of product as oil.
95%	In dichloromethane at 20℃; for 4h;	16 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 399 mg (0.823 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lR)-6,6,6- trifluoro-5 -hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-5 -trifluoromethyl-hex-3 -ynyl] - octahydro-inden-4-one and 8.0 ml of dichloromethane. A 0.9 ml (6.2 mmol) of 1- (trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 4h. A 150 ml of hexane was added and the mixture was washed three times with 50 ml of water, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (50 cm3) using hexane:ethyl acetate (5:1) as mobile phase. Fractions containing product were pooled and evaporated to give 492 mg (95%) of product as oil.

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 137
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 69; 126
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 136

47
[ 910623-86-8 ]
[ 18156-74-6 ]
[ 910623-90-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane at 20℃; for 3h;	18 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 295 mg (0.606 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lR,3Z)- 6,6,6-trifluoro-5-hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-S-trifluoromethyl-hex-S- enyl]-octahydro-inden-4-one and 8.0 ml of dichloromethane. A 0.7 ml (4.8 mmol) of 1-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 3h. A 100 ml of water was added and the mixture was extracted three times with 50 ml of ethyl acetate, dried over Na2SO4 and evaporated.The oil residue was chromatographed on column (50 cm3) using hexane: ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 362 mg (95%) of product as colorless oil.1H NMR (CDCl3): 6.02-5.94(1H, m), 5.42(1H, d, J=I LO Hz), 2.50-2.40(2H, m), 2.35- 2.14(4H, m), 2.06-1.55(7H, m), 1.43-1.14(7H, m), 1.21(6H, s), 0.96(3H, s), 0.74(3H, s), 0.24(9H, s), 0.10(9H, s)
95%	In dichloromethane at 20℃; for 3h;	16 (IR, 3aR, 4S, 7aR)-7a-Methyl-l-[(lR,3Z)-6,6,6-trifluoro-l-methyl-l-(4-methyl-4- trimethylsilanyloxy-pentyl)-5-trifluoromethyl-5-trimethylsilanyloxy-hex-3-enyl]- octahydro-inden-4-one (89)A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 295 mg (0.606 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l- [(lR,3Z)-6,6,6-trifluoro-5-hydroxy-l-(4-hydroxy-4-methyl-pentyl)-l-methyl-5- trifluoromethyl-hex-3-enyl]-octahydro-inden-4-one and 8.0 ml of dichloromethane. A 0.7 ml (4.8 mmol) of l-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 3h. A 100 ml of water was added and the mixture was extracted three times with 50 ml of ethyl acetate, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (50 cm3) using hexane:ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 362 mg (95%) of product as colorless oil.1KE NMR (CDCl3): 6.02-5.94(1H, m), 5.42(1H, d, J=ILO Hz), 2.50-2.40(2H, m), 2.35- 2.14(4H, m), 2.06-1.55(7H, m), 1.43-1.14(7H, m), 1.21(6H, s), 0.96(3H, s), 0.74(3H, s), 0.24(9H, s), 0.10(9H, s)
95%	In dichloromethane at 20℃; for 3h;	18 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 295 mg (0.606 mmol) of (IR, 3aR, 4S, 7aR)-7a-methyl-l-[(lR,3Z)- 6,6,6-trifluoro-5-hydroxy- 1 -(4-hydroxy-4-methyl-pentyl)- 1 -methyl-S-trifluoromethyl-hex-S- enyl]-octahydro-inden-4-one and 8.0 ml of dichloromethane. A 0.7 ml (4.8 mmol) of 1-(trimethylsilyl)imidazole was added dropwise. The mixture was stirred at room temperature for 3h. A 100 ml of water was added and the mixture was extracted three times with 50 ml of ethyl acetate, dried over Na2SO4 and evaporated.The oil residue was chromatographed on column (50 cm3) using hexane: ethyl acetate (10:1) as mobile phase. Fractions containing product were pooled and evaporated to give 362 mg (95%) of product as colorless oil.1H NMR (CDCl3): 6.02-5.94(1H, m), 5.42(1H, d, J=I LO Hz), 2.50-2.40(2H, m), 2.35- 2.14(4H, m), 2.06-1.55(7H, m), 1.43-1.14(7H, m), 1.21(6H, s), 0.96(3H, s), 0.74(3H, s), 0.24(9H, s), 0.10(9H, s)

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 141-142
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 69; 131
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 140-141

48
[ 910623-96-0 ]
[ 18156-74-6 ]
[ 910623-97-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	In dichloromethane at 20℃; for 1.75h;	24 A 100ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (6S)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a- methyl-octahydro-inden- 1 -yl]- 1 ,1,1 -trideutero-6-methyl-2-trideuteromethyl-non-8-yn-2-ol (3.100 g, 7.033 mmol) and dichloromethane (30 ml). l-(trimethylsilyl)imidazole (3.0 ml, 20.45 mmol) was added dropwise. The mixture was stirred at room temperature for Ih 45min. Water (100ml) was added and the mixture was extracted with ethyl acetate (3x100ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (125cm3) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (3.36g, 93%).[α]2D6= +15.4 (c=0.52, CHCl3)1H NMR (CDCl3): 3.99(1H, br s), 2.27(2H, br s), 2.00-1.93(2H, m), 1.84-1.73(1H, m), 1.65(1H, d, J=14.3 Hz), 1.59-1.49(3H, m), 1.42-1.20(12H, m), 1.05(3H, s), 1.00(3H, s), 0.88(9H, s), 0.10(9H, s), 0.00(3H, s), -0.01(3H, s)13C NMR (CDCl3): 83.18, 76.66(sep, J=28.8 Hz), 69.74, 69.58, 56.62, 52.91, 45.38, 43.67, 41.27, 40.07, 39.28, 34.34, 28.77, 25.88, 22.76, 22.16, 18.13, 18.11, 17.77, 16.76, 2.74, - 4.69, -5.05MS HRES Calculated for: C30H52D6O2Si2 [M+Na]+ 535.4244Observed: [M+Na]+ 535.4246
93%	In dichloromethane at 20℃; for 1.75h;	22 (IR, 3aR, 4S, 7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-l-[(lS)-6,6,6- trideutero-l-methyl-l-(prop-2-ynyl)-5-trideuteromethyl-5-trimethylsilanyloxy- hexyl]-octahydro-indene (96)A 100ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (6S)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl-silanyloxy)- 7a-methyl-octahydro-inden-l-yl]-l,l,l-trideutero-6-methyl-2-trideuteromethyl-non-8- yn-2-ol (3.100 g, 7.033 mmol) and dichloromethane (30 ml). l-(trimethylsilyl)imidazole (3.0 ml, 20.45 mmol) was added dropwise. The mixture was stirred at room temperature for Ih 45min. Water (100ml) was added and the mixture was extracted with ethyl acetate (3x100ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (125cm3) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (3.36g, 93%). EPO 1H NMR (CDCl3): 3.99(1H, br s), 2.27(2H, br s), 2.00-1.93(2H, m), 1.84-1.73(1H, m), 1.65(1H, d, J=14.3 Hz), 1.59-1.49(3H, m), 1.42-1.20(12H, m), 1.05(3H, s), 1.00(3H, s), 0.88(9H, s), 0.10(9H, s), 0.00(3H, s), -0.01(3H, s)13C NMR (CDCl3): 83.18, 76.66(sep, J=28.8 Hz), 69.74, 69.58, 56.62, 52.91, 45.38, 43.67, 41.27, 40.07, 39.28, 34.34, 28.77, 25.88, 22.76, 22.16, 18.13, 18.11, 17.77, 16.76, 2.74, -4.69, -5.05MS HRES Calculated for: C30H52D6O2Si2 [M+Na]+ 535.4244Observed: [M+Naf 535.4246
93%	In dichloromethane at 20℃; for 1.75h;	24 A 100ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (6S)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a- methyl-octahydro-inden- 1 -yl]- 1 ,1,1 -trideutero-6-methyl-2-trideuteromethyl-non-8-yn-2-ol (3.100 g, 7.033 mmol) and dichloromethane (30 ml). l-(trimethylsilyl)imidazole (3.0 ml, 20.45 mmol) was added dropwise. The mixture was stirred at room temperature for Ih 45min. Water (100ml) was added and the mixture was extracted with ethyl acetate (3x100ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (125cm3) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (3.36g, 93%).[α]2D6= +15.4 (c=0.52, CHCl3)1H NMR (CDCl3): 3.99(1H, br s), 2.27(2H, br s), 2.00-1.93(2H, m), 1.84-1.73(1H, m), 1.65(1H, d, J=14.3 Hz), 1.59-1.49(3H, m), 1.42-1.20(12H, m), 1.05(3H, s), 1.00(3H, s), 0.88(9H, s), 0.10(9H, s), 0.00(3H, s), -0.01(3H, s)13C NMR (CDCl3): 83.18, 76.66(sep, J=28.8 Hz), 69.74, 69.58, 56.62, 52.91, 45.38, 43.67, 41.27, 40.07, 39.28, 34.34, 28.77, 25.88, 22.76, 22.16, 18.13, 18.11, 17.77, 16.76, 2.74, - 4.69, -5.05MS HRES Calculated for: C30H52D6O2Si2 [M+Na]+ 535.4244Observed: [M+Na]+ 535.4246

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 155
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 72; 146-147
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 154

49
[ 910624-02-1 ]
[ 18156-74-6 ]
[ 910624-06-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	In dichloromethane at 20℃; for 1.5h;	27 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lS, 3Z)-6,6,6-trifluororo-5-hydroxy-l- methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5-trifluoromethyl-hex-3-enyl]- octahydro-inden-4-one (690 mg, 1.401 mmol) and dichloromethane (8 ml). 1- (Trimethylsilyl)imidazole (1.8 ml, 12.3 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5h. Ethyl acetate (150ml) was added and the mixture was washed three times with water (50ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (50cm3) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (854 mg, 96%).
96%	In dichloromethane at 20℃; for 1.5h;	25 (IR53aR, 7aR)-7a-Methyl-l-[(lS, 3Z)6,6,6-trifluoro-l-methyl-l-(5,5,5-trideutero-4- trideuteromethyl-4-trimethylsilanyloxy-pentyl)-5-trifluoromethyl-5- trimethylsilanyloxy-hex-3-enyl]-octahydro-inden-4-one (105)A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lS, 3Z)-6,6,6-trifluororo-5- hydroxy- 1 -methyl- 1 -(5 ,5 , 5 -trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5- trifluoromethyl-hex-3-enyl]-octahydro-inden-4-one (690 mg, 1.401 mmol) and dichloromethane (8 ml). l-(Trimethylsilyl)imidazole (1.8 ml, 12.3 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5h. Ethyl acetate (150ml) was added and the mixture was washed three times with water (50ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (50cm ) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (854 mg, 96%).
96%	In dichloromethane at 20℃; for 1.5h;	27 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lS, 3Z)-6,6,6-trifluororo-5-hydroxy-l- methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5-trifluoromethyl-hex-3-enyl]- octahydro-inden-4-one (690 mg, 1.401 mmol) and dichloromethane (8 ml). 1- (Trimethylsilyl)imidazole (1.8 ml, 12.3 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5h. Ethyl acetate (150ml) was added and the mixture was washed three times with water (50ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (50cm3) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (854 mg, 96%).

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 164
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 75; 156
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 163

50
[ 910624-04-3 ]
[ 18156-74-6 ]
[ 910624-07-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	In dichloromethane at 20℃; for 2h;	30 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lS, 3E)-6,6,6-trifluoro-5-hydroxy-l- methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5-trifluoromethyl-hex-3-enyl]- octahydro-inden-4-one (698 mg, 1.417 mmol) and dichloromethane (8 ml). 1- (trimethylsilyl)imidazole (1.8 ml, 12.3 mmol) was added dropwise. The mixture was stirred at room temperature for 2h. Ethyl acetate (150ml) was added and the mixture was washed with water (4x50ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (60cm3) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (871 mg, 96%).
96%	In dichloromethane at 20℃; for 2h;	28 (IR, 3aR, 7aR)-7a-Methyl-l-[(lS, 3E)-6,6,6-trifluoro-l-methyl-l-(5,5,5-trideutero-4-trideuteromethyl-4-trimethylsilanyloxy-pentyl)-5-trifluoromethyl-5- trimethylsilanyloxy-hex-3-enyl]-octahydro-inden-4-one (106) EPO A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lS, 3E)-6,6,6-trifluoro-5- hydroxy-l-methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5- trifluoromethyl-hex-3-enyl]-octahydro-inden-4-one (698 mg, 1.417 mmol) and dichloromethane (8 ml). l-(trimethylsilyl)imidazole (1.8 ml, 12.3 mmol) was added dropwise. The mixture was stirred at room temperature for 2h. Ethyl acetate (150ml) was added and the mixture was washed with water (4x50ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (60cm ) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (871 mg, 96%).
96%	In dichloromethane at 20℃; for 2h;	30 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lS, 3E)-6,6,6-trifluoro-5-hydroxy-l- methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5-trifluoromethyl-hex-3-enyl]- octahydro-inden-4-one (698 mg, 1.417 mmol) and dichloromethane (8 ml). 1-(trimethylsilyl)imidazole (1.8 ml, 12.3 mmol) was added dropwise. The mixture was stirred at room temperature for 2h. Ethyl acetate (150ml) was added and the mixture was washed with water (4x50ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (60cm ) using hexane:ethyl acetate - 10:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (871 mg, 96%).

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 170
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 76; 162-163
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 169

51
[ 910624-09-8 ]
[ 18156-74-6 ]
[ 910624-10-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	In dichloromethane at 20℃; for 1.58333h;	33 A 100ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (6R)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a- methyl-octahydro-inden- 1 -yl]- 1 ,1,1 -trideutero-6-methyl-2-trideuteromethyl-non-8-yn-2-ol (3.80 g, 8.62 mmol) and dichloromethane (30 ml). l-(trimethylsilyl)imidazole (3.7 ml, 25.22 mmol) was added dropwise. The mixture was stirred at room temperature for Ih 35min. Water (100ml) was added and the mixture was extracted with hexane (3x70ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (250 cm ) using hexane: ethyl acetate - 20:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (4.09 g, 93%).
93%	In dichloromethane at 20℃; for 1.58333h;	31 (IR, 3aR, 4S, 7aR)-4-(tert-Butyl-dimethyl-silanyloxy)-7a-methyl-l-[(lR)-6,6,6- trideutero-l-methyl-l-(prop-2-ynyl)-5-trideuteromethyl-5-trimethylsilanyloxy- hexyl]-octahydro-indene (109)A 100ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (6R)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl-silanyloxy)- 7a-methyl~octahydro-inden-l -yl]-l , 1 , 1 -trideutero-δ-methyl^-trideuteromethyl-non-δ- yn-2-ol (3.80 g, 8.62 mmol) and dichloromethane (30 ml). l-(trimethylsilyl)imidazole (3.7 ml, 25.22 mmol) was added dropwise. The mixture was stirred at room temperature for Ih 35min. Water (100ml) was added and the mixture was extracted with hexane (3x70ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (250 cm3) using hexane:ethyl acetate - 20:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (4.09 g, 93%). EPO
93%	In dichloromethane at 20℃; for 1.58333h;	33 A 100ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (6R)-6-[(lR, 3aR, 4S, 7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a- methyl-octahydro-inden- 1 -yl]- 1 ,1,1 -trideutero-6-methyl-2-trideuteromethyl-non-8-yn-2-ol (3.80 g, 8.62 mmol) and dichloromethane (30 ml). l-(trimethylsilyl)imidazole (3.7 ml, 25.22 mmol) was added dropwise. The mixture was stirred at room temperature for Ih 35min. Water (100ml) was added and the mixture was extracted with hexane (3x70ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (250 cm3) using hexane: ethyl acetate - 20:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (4.09 g, 93%).

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 175-174
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 76; 169
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 174

52
[ 910624-13-4 ]
[ 18156-74-6 ]
[ 910624-18-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane at 20℃; for 1.5h;	33 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lR)-6,6,6-trifluororo-5-hydroxy-l- methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5-trifluoromethyl-hex-3-ynyl]- octahydro-inden-4-one (ca. 1.58 mmol) and dichloromethane (8 ml). l-(trimethylsilyl)imidazole (1.90 ml, 12.95 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5h. Hexane (150ml) was added and the mixture was washed with water (3x50ml), dried (Na2SO4) and evaporated.The oil residue was chromatographed on column (50cm3) using hexane:ethyl acetate - 5:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (918 mg, 95%).[α]3D°= -20.8 (c=0.61, DMSO)1H NMR (CDCl3): 2.41(1H, dd, J=I 1.3, 7.2 Hz), 2.31-2.12(4H, m), 2.05-1.24(15H, m), 1.00(3H, s), 0.73(3H, s), 0.27(9H, s), 0.10(9H, s)MS HRES Calculated for: C30H44D6F6O3Si2 [M+Na]+ 657.3471Observed: [M+Na]+ 657.3467
95%	In dichloromethane at 20℃; for 1.5h;	31 (lR, 3aR, 7aR)-7a-Methyl-l-[(lR)-6,6,6-trifluoro-l-methyl-l-(5,5,5-trideutero-4- trideuteromethyl-4-trimethylsilanyloxy-pentyl)-5-trifluoromethyl-5- trimethylsilanyloxy-hex-3-ynyl] -octahydro-inden-4-one (117)A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lR)-6,6,6-trifluororo-5- hydroxy-l-methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5- trifluoromethyl-hex-3-ynyl]-octahydro-inden-4-one (ca. 1.58 mmol) and dichloromethane (8 ml). l-(trimethylsilyl)imidazole (1.90 ml, 12.95 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5h. Hexane (150ml) was added and the mixture was washed with water (3x50ml), dried (Na2SO4) and evaporated. The oil residue was chromatographed on column (50cm ) using hexanerethyl acetate - 5:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (918 mg, 95%).[α]3D°= -20.8 (c=0.61, DMSO)1H NMR (CDCl3): 2.41(1H, dd, J=I 1.3, 7.2 Hz), 2.31-2.12(4H, m), 2.05-1.24(15H, m), 1.00(3H, s), 0.73(3H, s), 0.27(9H, s), 0.10(9H, s)MS HRES Calculated for: C30H44D6F6O3Si2 [M+Na]+ 657.3471Observed: [M+Naf 657.3467
95%	In dichloromethane at 20℃; for 1.5h;	33 A 25 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with (IR, 3aR, 7aR)-7a-methyl-l-[(lR)-6,6,6-trifluororo-5-hydroxy-l- methyl-l-(5,5,5-trideutero-4-hydroxy-4-trideuteromethyl-pentyl)-5-trifluoromethyl-hex-3-ynyl]- octahydro-inden-4-one (ca. 1.58 mmol) and dichloromethane (8 ml). l-(trimethylsilyl)imidazole (1.90 ml, 12.95 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5h. Hexane (150ml) was added and the mixture was washed with water (3x50ml), dried (Na2SO4) and evaporated.The oil residue was chromatographed on column (50cm ) using hexane:ethyl acetate - 5:1 as mobile phase. Fractions containing product were pooled and evaporated to give product as colorless oil (918 mg, 95%).[α]3D°= -20.8 (c=0.61, DMSO)1H NMR (CDCl3): 2.41(1H, dd, J=I 1.3, 7.2 Hz), 2.31-2.12(4H, m), 2.05-1.24(15H, m), 1.00(3H, s), 0.73(3H, s), 0.27(9H, s), 0.10(9H, s)MS HRES Calculated for: C30H44D6F6O3Si2 [M+Na]+ 657.3471Observed: [M+Na]+ 657.3467

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 178
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2006/102647, 2006, A1 Location in patent: Page/Page column 78
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 177

53
[ 7515-73-3 ]
[ 18156-74-6 ]
[ 60628-96-8 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile;	EXAMPLE 3 167 g (0.6 mol) of biphenyl-4-yl-phenyl-chloromethane [alternatively named as diphenyl-phenyl-chloromethane or as alpha-(biphenyl-4-yl)benzyl chloride] and 92 g (0.66 mol) of trimethylsilylimidazole, dissolved in 500 ml of acetonitrile, are heated under reflux for 15 hours. After distilling off the solvent, the crystalline residue is purified by recrystallization from ethyl acetate. 97 g (52% of theory) of (biphenyl-4-yl)-imidazol-1-yl-phenylmethane of melting point 142 C. are obtained.

Reference： [1]Patent: US4118487,1978,A

54
[ 932383-72-7 ]
[ 18156-74-6 ]
[ 932383-73-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: (1R,3aR,7aR)-1-[1-(4-hydroxy-5,5,5-trideutero-4-trideuteromethyl-pentyl)-cyclopropyI]-7a-methyl-octahydro-inden-4-one; 1-(Trimethylsilyl)imidazole In dichloromethane at 20℃; for 1.75h; Stage #2: With water In dichloromethane for 0.166667h;	1 A 100 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.91 g (6.399 mmol) of (IR, 3aR, 7aR)-l-[l-(4- Hydroxy-5,5,5-trideutero-4-trideuteromethyl-pentyl)-cyclopropyl]-7a-methyl- octahydro-mden-4-one and 60 ml of dichloromethane. A 3.8 ml (25.90 mmol) of 1- (trimethylsilyl)imidasole was added dropwise. The mixture was stirred at room temperature for Ih 45 min.A 25 ml of water was added and the mixture was stirred for 10 min. The resulting mixture was dissolved by the addition of 200 ml of water. The aqueous layer was extracted five times with 50 ml of ethyl acetate. The combined organic layers were washed with 50 ml of brine, dried over Na2SO4 and evaporated.The oil residue was chromatographed on column (200 cm3) using hexane : dichloromethane (2:1, 1:1) and dichloromethane as mobile phases. Fractions containing product were pooled and evaporated to give 2.10 g (89%) of product as colorless oil.
89%	In dichloromethane; water at 20℃; for 1.91667h;	42 A 100 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.91 g (6.399 mmol) of (IR, 3aR, 7aR)-l-[l-(4-Hydroxy-5,5,5- trideutero-4-trideuteromethyl-pentyl)-cyclopropyl]-7a-methyl-octahydro-inden-4-one and 60 ml of dichloromethane. A 3.8 ml (25.90 mmol) of l-(trimethylsilyl)imidasole was added dropwise. The mixture was stirred at room temperature for Ih 45 min. A 25 ml of water was added and the mixture was stirred for 10 min. The resulting mixture was dissolved by the addition of 200 ml of water. The aqueous layer was extracted five times with 50 ml of ethyl acetate. The combined organic layers were washed with 50 ml of brine, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (200 cm3) using hexane : dichloromethane (2:1, 1 :1) and dichloromethane as mobile phases. Fractions containing product were pooled and evaporated to give 2.10 g (89%) of product as colorless oil.
89%	In dichloromethane; water at 20℃; for 1.91667h;	42 A 100 ml round bottom flask equipped with stir bar and Claisen adapter with rubber septum was charged with 1.91 g (6.399 mmol) of (IR, 3aR, 7aR)-l-[l-(4-Hydroxy-5,5,5- trideutero-4-trideuteromethyl-pentyl)-cyclopropyl]-7a-methyl-octahydro-inden-4-one and 60 ml of dichloromethane. A 3.8 ml (25.90 mmol) of l-(trimethylsilyl)imidasole was added dropwise. The mixture was stirred at room temperature for Ih 45 min. A 25 ml of water was added and the mixture was stirred for 10 min. The resulting mixture was dissolved by the addition of 200 ml of water. The aqueous layer was extracted five times with 50 ml of ethyl acetate. The combined organic layers were washed with 50 ml of brine, dried over Na2SO4 and evaporated. The oil residue was chromatographed on column (200 cm3) using hexane : dichloromethane (2:1, 1 :1) and dichloromethane as mobile phases. Fractions containing product were pooled and evaporated to give 2.10 g (89%) of product as colorless oil.

Reference： [1]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2007/38250, 2007, A2 Location in patent: Page/Page column 66
[2]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/43857, 2008, A2 Location in patent: Page/Page column 198-199
[3]Current Patent Assignee: COSMO PHARMACEUTICALS S.P.A. - WO2008/34908, 2008, A2 Location in patent: Page/Page column 198-199

55
[ 98541-64-1 ]
[ 18156-74-6 ]
[ 122225-53-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4187 - 4190

56
[ 71310-21-9 ]
[ 18156-74-6 ]
[ 1333319-14-4 ]

Yield	Reaction Conditions	Operation in experiment
60%	In dichloromethane at 60℃; for 18h; Inert atmosphere;

Reference： [1]Caldwell, Marissa A.; Albers, Aaron E.; Levy, Seth C.; Pick, Teresa E.; Cohen, Bruce E.; Helms, Brett A.; Milliron, Delia J. [Chemical Communications, 2011, vol. 47, # 1, p. 556 - 558]

57
[ 1194-02-1 ]
[ 18156-74-6 ]
[ 420-56-4 ]
[ 25372-03-6 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 1151 - 1154

58
[ 403-33-8 ]
[ 18156-74-6 ]
[ 420-56-4 ]
[ 101184-08-1 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 1151 - 1154

59
[ 1435-48-9 ]
[ 18156-74-6 ]
[ 420-56-4 ]
[ 190199-40-7 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 1151 - 1154

60
[ 18156-74-6 ]
[ 350-46-9 ]
[ 2301-25-9 ]
[ 420-56-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 1151 - 1154

61
[ 18156-74-6 ]
[ 460-00-4 ]
[ 420-56-4 ]
[ 10040-96-7 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 1151 - 1154

62
[ 1194-02-1 ]
[ 18156-74-6 ]
[ 25372-03-6 ]

Yield	Reaction Conditions	Operation in experiment
77%		Under a nitrogen atmosphere 362 mg (2.38 mmol) of CsF, previously activated with NaOH, were suspended in 5 ml of DMF and stirred for 30 min. Then, 1.00 g (8.26 mmol) of 4-fluorobenzonitrile was added. After 10 min 1.20 ml (8.18 mmol) N-trimethylsilylimidazole were added and the mixture was stirred at 60° C. for 20 hr. For workup, most of the solvent was removed under vacuum (oil pump), and then 5 ml of water and 5 ml of CH2Cl2 were added to the reaction mixture. The organic phase was separated, the aqueous phase was extracted with CH2Cl2, the organic phases were combined, washed several times with water and dried over MgSO4. The solvent was removed under vacuum, and the resulting solid was rinsed twice with pentane.Yield: 1.07 g (6.31 mmol, 77percent), appearance: colorless solid. 1H NMR (CDCl3, 25° C., 400.13 MHz): delta=7.25 (s, 1H, ImH), 7.33 (s, 1H, ImH), 7.51-7.53 (m, 2H, PhH), 7.79-7.81 (m, 2H, PhH), 7.94 (s, 1H, ImH). 13C NMR (CDCl3, 25° C., 100.61 MHz): delta=111.3 (C-1), 117.7 (C-9), 117.9 (-CN), 121.5 (C-3, C-5), 131.6 (C-8), 134.2 (C-2, C-6), 135.4 (C-7) 140.6 (C-4).

Reference： [1]Patent: US2012/142937,2012,A1 .Location in patent: Page/Page column 5

63
[ 18598-63-5 ]
[ 18156-74-6 ]
[ 19083-00-2 ]
C₂₅H₅₉NO₇SSi₅ [ No CAS ]
C₂₂H₅₁NO₆SSi₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Each compound (1 mg) was treated with 2 M HCl (10 ml) under conditions of reflux at 80 C this being maintained for 4 h. Each reaction mixture was concentrated to dryness, partitioned between CHCl3 and H2O and then the H2O layer was concentrated to dryness to yield a mixture of sugars. Each mixture was dissolved in anhydrous pyridine (1 ml) and reacted with l-cysteine methyl ester hydrochloride (1 mg) in an oven at 60 C for 2 h. After the reaction mixture was evaporated under a stream of N2, trimethylsilyl imidazole (0.2 ml) was added, and the mixture warmed to 60 C for another 1 h. After drying the solution, the products were partitioned between cyclohexane and H2O. The same reactions were applied to standard sugars. Then the cyclohexane layers were analyzed by gas chromatography on a column, AT-SE-30 (0.5 mum × 0.32 mm × 30 m); column temperature, 250 C; detector temperature, 250 C; injection temperature, 230 C; carrier gas, N2. The derivatives of d-glucose, l-glucose, l-rhamnose, d-apiose, l-arabinose and d-xylose gave peaks at tR 25.67, 26.81, 16.33, 12.69, 13.09 and 12.94 min, respectively.

Reference： [1]Phytochemistry,2012,vol. 81,p. 133 - 143

64
[ 627-42-9 ]
[ 18156-74-6 ]
[ 1354713-28-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	In toluene; for 72h;Reflux; Darkness;	A.1 Synthesis of f(CH,OCH,CH7)?ImlCl (T) Chloromethylethylether (5.0 mL, 54.9 mmol) was added to a solution of trimethylsilylimidazole (2.229 g, 15.892 mmol) in toluene (5 mL). The mixture was refluxed in the dark for 72 h during which two layers formed. The top layer was syringed off and discarded. To the viscous bottom layer was added methylene chloride (10 mL) and pentane (20 mL). This mixture was stirred and the top layer was syringed off. The remaining colorless oil was dried in vacuum (3.489 g, 99%) resulting in the following analytical data: ? NMR (CD2C12, 5.32 ppm). 3.31 (s, 6H, 2 x OMe), 3.73 (t 4H, 2 x CH2), 4.53 (t, 4H, 2 x CH2), 7.59 (s, 2H, 2 x CH), 10.47 (s, 1H, NCHN). UC NMR (CD2C12, 53.5 ppm): 49.49 (2 x OMe), 58.65 (2 x CH2), 70.23 (2 x CH2), 122.49 (2 x CH), 137.71 (NCHN).

Reference： [1]Patent: WO2013/24119,2013,A1 .Location in patent: Page/Page column 29
[2]Organometallics,2013,vol. 32,p. 2168 - 2177

65
[ 4403-36-5 ]
[ 18156-74-6 ]
[ 1448126-68-8 ]

Reference： [1]Russian Journal of Organic Chemistry,2013,vol. 49,p. 934 - 935
Zh. Org. Khim.,2013,vol. 49,p. 947 - 948,2

66
[ 3027-21-2 ]
[ 18156-74-6 ]
[ 1453266-13-1 ]

Reference： [1]Russian Journal of General Chemistry,2013,vol. 83,p. 1365 - 1368
Zh. Obshch. Khim.,2013,vol. 83,p. 1113 - 1117,5

67
[ 3386-33-2 ]
[ 18156-74-6 ]
C₃₉H₇₇N₂⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]RSC Advances,2014,vol. 4,p. 12476 - 12481

68
[ 1435-48-9 ]
[ 18156-74-6 ]
[ 190199-40-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With copper(l) iodide; In methanol; N,N-dimethyl-formamide; at 100℃;Inert atmosphere;	General procedure: Activated zinc powder (5.75mmol, 1.15eq) was placed in a flame-dried round-bottom flask (50mL) fitted with a magnetic stir bar. 2,4-Dichlorobenzaldehyde (5mmol, 1eq) and propargylbromide (5.75mmol, 1.15eq) were added. The resulting mixture was vigorously stirred for 1h at room temperature. After reaction completion, sat. aq. soln of NH4Cl was poured into the mixture and stirred for several minutes. Diethyl ether was added and the organic layer was separated and dried over anhydrous MgSO4. The residue was purified by flash chromatography on silica gel giving 1-phenylpropargylalcohol (12). To a stirred solution of 12 (1mmol, 1eq) and CuI (0.05mmol, 0.05eq) in DMF/ MeOH solution (2mL 9:1) under an argon atmosphere was added trimethylsilyl azide (1.5mmol, 1.5eq). The resulting solution was stirred at 100C for 10-12h. After consumption of ethynyl substrate, the mixture was cooled to room temperature and the precipitate was filtered off and the solution concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to afford 13 as an oil in 60% yield.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 84,p. 284 - 301

69
[ 921-60-8 ]
[ 18598-63-5 ]
[ 18156-74-6 ]
C₂₅H₅₉NO₇SSi₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: L-glucose; L-cysteine methyl ester hydrochloride With pyridine Heating; Stage #2: 1-(Trimethylsilyl)imidazole

Reference： [1]Zhang, Xiaopo; Chen, Changyu; Li, Yonghui; Chen, Deli; Dong, Lin; Na, Wei; Wu, Chongming; Zhang, Junqing; Li, Youbin [Journal of Natural Products, 2016, vol. 79, # 5, p. 1249 - 1258]

70
[ 27129-86-8 ]
[ 18156-74-6 ]
C₂₁H₂₅N₂⁽¹⁺⁾*Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran; acetonitrile; at 60℃; for 0.166667h;	5 mmol of trimethylsilylimidazole was dissolved in acetonitrile and diluted to 50 ml of phase A; 10 mmol of 3,5-Dimethyl benzyl bromide dissolved in tetrahydrofuran, diluted to 50ml for the B phase. According to A phase and B phase volume ratio of 1: 1Of the mixture was pumped into the microreactor (sandwichreactorHC), and the reaction was stopped at 60 C for 10 minutes. The microreactorThe material is introduced into a separator and precipitated, filtered and dried to obtain N, N-disubstituted 3,5-dimethylbenzimidazolium salt,The yield was 99%.

Reference： [1]Patent: CN105541722,2016,A .Location in patent: Paragraph 0039; 0040

71
1-(1-chloroethyl)-2,3-dimethylbenzene [ No CAS ]
[ 18156-74-6 ]
[ 86347-14-0 ]

Yield	Reaction Conditions	Operation in experiment
84.8%	Stage #1: 1-(Trimethylsilyl)imidazole With titanium tetrachloride In dichloromethane at 10℃; for 0.5h; Cooling with ice; Stage #2: 1-(1-chloroethyl)-2,3-dimethylbenzene In dichloromethane for 3h; Reflux;	3 Example 3 9.58 g (0.0505 mol) of titanium tetrachloride was put into a reaction flask containing 16 ml of methylene chloride,Under ice bath, 14.026 g of N-trimethylsilyl imidazole dissolved in 16 mL of methylene chloride was dropped,Dropping process control internal temperature below 10 ,After the addition was complete and stirred for 30min,Then, 8.433 g of 1- (1-chloroethyl) -2,3-dimethylbenzene was added dropwise,Bi completed,Heated to reflux for 3h,Slowly add dropwise 16mL water to terminate the reaction,Dropping process control internal temperature below 20 ,Let stand for 15 minutesThe solution is divided into three layers.Discard the bottom water layer,Divided metoid mid-level,The upper organic layer was extracted with 15 mL of water,The water layer was collected and 10 mL of water was added to the water layer,Then combined with the middle of medetomidine,Stir for 10 minutes, liquid separation,Discard the upper strong acid water layer;Material layer with 15mL water extract material,The aqueous phase was collected and the organic impurities remaining in the aqueous layer were washed twice with 2 x 10 mL of methylene chloride,Add 10 mL of methylene chloride to the aqueous layer,The organic phase is adjusted to a strongly alkaline (pH> 10) with 30% NaOH solution,Points to the water layer, the organic layer washed twice with 15mL,15mL saturated sodium chloride solution was washed until the solution was clear,Concentrated to give an oil 8.55g,The crude yield was 85.4%. refined:To the oily substance was added 2 times its weight of acetone and 1 time of water,Heated to return to the state,Then cooled to below 10 ,Stirring crystallization,So a large number of solid precipitation and then add double the water,Continue stirring for about 4 hours at low temperature,Filter, the filter cake was dried to give medetomidine,Refined yield of about 84.8%.
62.3%	With titanium tetrachloride; triethylamine In dichloromethane at -3 - 20℃;	The specific process for the preparation of dexmedetomidine hydrochloride using N-TMS-imidazole as starting material is the same as that described in Examples 1, 4 and 5.
	With titanium tetrachloride In dichloromethane at 40 - 50℃;	1 First step reaction: Preparation of intermediate 1 medetomidine Specifically, the reaction is carried out by one-pot feeding, as shown in Figure 1: In a 200L glass-lined reactor, the reaction solvent dichloromethane is added first, the mechanical stirring device is turned on, and the temperature is reduced to -10 ~ 10 , followed by adding Lewis acid titanium tetrachloride, starting material N-TMS imidazole, starting material 1-(1-chloroethyl)-2,3,-dimethylbenzene, turn on the heat conduction oil heating and reflux device, and gradually heat up, The reaction temperature is controlled between 40 ~ 50 , under the action of Lewis acid, the starting materials 1-(1-chloroethyl)-2,3,-dimethylbenzene and N-TMS imidazole in a non-polar solvent two The Fuch reaction occurs in methyl chloride, and the reaction is incubated for 3 to 4 hours. The reaction produces intermediate medetomidine. During the reaction, thin layer chromatography (TLC) is used to detect the progress of the reaction. /0, dichloromethane: methanol = 10/1), the starting material 1-(1-chloroethyl)-2,3,-dimethylbenzene spots are not visible and the reaction is completed; after the reaction is completed, the temperature is reduced to -10 10, after quenching with water, let stand for 16h for layer separation, take the middle layer of material and dilute with dichloromethane, adjust pH=89 with 6mol/L NaOH; after removing titanium salt by filtration, separate the organic layer, Wash and dry, concentrate under reduced pressure to obtain crude medetomidine; dissolve the crude product in acetone, add water and stir to crystallize.The crystallization temperature is controlled between 10°C and 25°C, and the crystallization time is 16 hours. After the crystallization is completed, centrifugation is performed to obtain a wet cake, which is dried at normal pressure in a hot air circulation box, and the centrifuge is at 55°C After drying at ~65°C for 5h, the intermediate 1 medetomidine was obtained.

Reference： [1]Current Patent Assignee: CSPC YINHU PHARMACEUTICAL - CN106749027, 2017, A Location in patent: Paragraph 0041; 0042; 0043; 0044; 0045; 0046; 0047-0074
[2]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN105254567, 2016, A Location in patent: Paragraph 0025; 0026; 0027; 0042
[3]Current Patent Assignee: SHAANXI BOSEN BIO PHARMACEUTICAL GROUP - CN111253316, 2020, A Location in patent: Paragraph 0036; 0038-0046

72
[ 706-14-9 ]
[ 18156-74-6 ]
C₁₃H₂₈O₂Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-hexyldihydro-2(3H)-furanone With diisobutylaluminium hydride In dichloromethane at -78℃; for 0.166667h; Stage #2: 1-(Trimethylsilyl)imidazole In dichloromethane at -78℃; for 0.583333h;	General Method C - Conversion of Esters to Acetals General procedure: Ester (1.0 eq.) was weighed out and added to a flamed dried, 10mL, pear shaped, two-necked flask that was placed under nitrogen, before DCM (1.0 M) was added. The ReactIR was prepared by cleaning the probe with MeOH and taking a background spectra. A solvent reference for DCM and hexanes was also loaded into the experiment file. The flask was attached to the ReactIR and spectra were set to collect every minute. The reaction was placed in a dewar and cooled to -78 °C using a dry ice/acetone bath. After cooling for 15-30 minutes, DIBAL-H (1.2 eq., 1.0 M solution in either hexanes or DCM) was added dropwise over a period of ~10 minutes (1 drop every 3-5 seconds). The reduction of the carbonyl peak was monitored by ReactIR, and the amount of DIBAL-H was increased by increments of 0.3 equivalents if complete reduction was not achieved. TMS-imid (3 eq.) was added dropwise and the reaction stirred for 35 minutes before being quenched with saturated aqueous NH4Cl. The quenched solution was warmed to room temperature and then DCM was added as well as Rochelle salts to assist with emulsions. The aqueous layer was extracted three times with DCM. The combined organic layers were collected, dried over Na2SO4, filtered, and concentrated in vacuo. The acetals were carried on without further purification.

Reference： [1]Hart, Alison; Kelley, Sarah A.; Harless, Tyler; Hood, John A.; Tagert, Michael; Pigza, Julie A. [Tetrahedron Letters, 2017, vol. 58, # 31, p. 3024 - 3027]

73
[ 593-71-5 ]
[ 6919-61-5 ]
[ 18156-74-6 ]
2-chloro-N-methoxy-N-methyl-1-phenyl-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 9498 - 9501

74
[ 593-71-5 ]
[ 6919-61-5 ]
[ 18156-74-6 ]
2-chloro2-iodo-N-methoxy-N-methyl-1-phenyl-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 9498 - 9501

75
[ 593-71-5 ]
[ 6919-61-5 ]
[ 18156-74-6 ]
2-chloro-N-methoxy-N-methyl-1-phenyl-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]
[ 532-27-4 ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 9498 - 9501

76
[ 6919-61-5 ]
[ 18156-74-6 ]
[ 74-95-3 ]
2,2-dibromo-N-methoxy-N-methyl-1-phenyl-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 9498 - 9501

77
[ 593-71-5 ]
[ 116332-61-7 ]
[ 18156-74-6 ]
2-chloro-N-methoxy-N-methyl-1-[4-(trifluoromethyl)phenyl]-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: Chloroiodomethane; N-methoxy-N-methyl-4-trifluoromethylbenzamide In tetrahydrofuran at -78℃; for 0.0333333h; Inert atmosphere; Stage #2: With methyllithium lithium bromide In tetrahydrofuran; diethyl ether at -78℃; for 0.75h; Inert atmosphere; Stage #3: 1-(Trimethylsilyl)imidazole Further stages;

Reference： [1]Castoldi, Laura; Holzer, Wolfgang; Langer, Thierry; Pace, Vittorio [Chemical Communications, 2017, vol. 53, # 68, p. 9498 - 9501]

78
[ 75-09-2 ]
[ 116332-61-7 ]
[ 18156-74-6 ]
2,2-dichloro-N-methoxy-N-methyl-1-[4-(trifluoromethyl)phenyl]-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: dichloromethane; N-methoxy-N-methyl-4-trifluoromethylbenzamide In tetrahydrofuran at -78℃; for 0.0333333h; Inert atmosphere; Stage #2: With 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran; diethyl ether at -78℃; for 0.75h; Inert atmosphere; Stage #3: 1-(Trimethylsilyl)imidazole Further stages;

Reference： [1]Castoldi, Laura; Holzer, Wolfgang; Langer, Thierry; Pace, Vittorio [Chemical Communications, 2017, vol. 53, # 68, p. 9498 - 9501]

79
[ 226260-01-1 ]
[ 593-71-5 ]
[ 18156-74-6 ]
2-chloro-1-(3-fluorophenyl)-N-methoxy-N-methyl-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 9498 - 9501

80
[ 198967-24-7 ]
[ 593-71-5 ]
[ 18156-74-6 ]
2-chloro-1-(2-fluorophenyl)-N-methoxy-N-methyl-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 9498 - 9501

81
[ 593-71-5 ]
[ 95091-92-2 ]
[ 18156-74-6 ]
2-chloro-1-(2-furyl)-N-methoxy-N-methyl-1-[(trimethylsilyl)oxy]ethanamine [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 9498 - 9501

82
[ 379-18-0 ]
[ 18156-74-6 ]
[ 118143-24-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	In tetrahydrofuran at 0 - 20℃; for 6.5h; Inert atmosphere;	1 A stirring bar was placed in a 100 mL three-neck eggplant flask, and under reduced pressure,Framed dry. The vessel was cooled to room temperature and then purged with nitrogen. Trifluoromethylcarbinol 1 was added with tetrahydrofuran (preliminarily dried with Na and distilled after 3.2 mL), and the solution was placed in a container with a syringe needle and stirred at 0 ° C. for 30 minutes. N-trimethylsilylimidazole (0.7 mL, 673 mg, 4.8 mmol) was slowly added at 0 ° C. and stirred at 0 ° C. for 30 minutes. It was taken out from the ice bath and stirred at 20 ° C. for 6 hours. After the reaction, the reaction was terminated by neutralization with an aqueous sodium hydrogen carbonate solution (5 mL). Extraction with hexane (3 × 20 mL) and washing with saturated aqueous sodium chloride solution (1 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and the sodium sulfate was removed by filtration. Hexane was removed with a rotary evaporator and purified by silica gel column chromatography (hexane), whereby silylated trifluoromethylcarbinol 2 was obtained as a colorless transparent liquid in 98% yield (based on compound 1)
98%	In tetrahydrofuran at 0 - 20℃; for 7h; Inert atmosphere;	1 The stir bar was placed in a 100 mL three-necked eggplant flask and frame-dried under reduced pressure conditions. container Was cooled to room temperature and then replaced with nitrogen. A solution prepared by adding tetrahydrofuran (pre-dried with Na and then distilled, 3.2 mL) to trifluoromethylcarbinol 1 was placed in a container with a syringe needle and stirred at 0 ° C. for 30 minutes. N-trimethylsilylimidazole (0.7 mL, 673 mg, 4.8 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. It was removed from the ice bath and stirred at 20 ° C. for 6 hours. After the reaction, the reaction was stopped by neutralizing with an aqueous sodium hydrogen carbonate solution (5 mL). It was extracted with hexane (3 x 20 mL) and washed with saturated aqueous sodium chloride solution (1 x 20 mL). Anhydrous sodium sulfate was added to the organic layer and dried, and sodium sulfate was removed by filtration. Hexane was removed by a rotary evaporator and purified by silica gel column chromatography (hexane) to obtain silylated trifluoromethylcarbinol 2 as a colorless transparent liquid in a yield of 98% (based on compound 1).
98%	In tetrahydrofuran at 0 - 20℃; for 7h; Inert atmosphere;	1 The stir bar was placed in a 100 mL three-necked eggplant flask and frame-dried under reduced pressure conditions. container Was cooled to room temperature and then replaced with nitrogen. A solution prepared by adding tetrahydrofuran (pre-dried with Na and then distilled, 3.2 mL) to trifluoromethylcarbinol 1 was placed in a container with a syringe needle and stirred at 0 ° C. for 30 minutes. N-trimethylsilylimidazole (0.7 mL, 673 mg, 4.8 mmol) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. It was removed from the ice bath and stirred at 20 ° C. for 6 hours. After the reaction, the reaction was stopped by neutralizing with an aqueous sodium hydrogen carbonate solution (5 mL). It was extracted with hexane (3 x 20 mL) and washed with saturated aqueous sodium chloride solution (1 x 20 mL). Anhydrous sodium sulfate was added to the organic layer and dried, and sodium sulfate was removed by filtration. Hexane was removed by a rotary evaporator and purified by silica gel column chromatography (hexane) to obtain silylated trifluoromethylcarbinol 2 as a colorless transparent liquid in a yield of 98% (based on compound 1).

98%

In tetrahydrofuran at 0 - 20℃; for 6.5h;

1 Put the stir bar in a 100 mL three-necked eggplant flask and put it in the flask.Frame dried under reduced conditions.The container was cooled to room temperature and then replaced with nitrogen.A solution prepared by adding tetrahydrofuran (pre-dried with Na and then distilled, 3.2 mL) to trifluoromethylcarbinol 1 was placed in a container with a syringe needle.The mixture was stirred at 0 ° C. for 30 minutes.Slowly add N-trimethylsilylimidazole (0.7 mL, 673 mg, 4.8 mmol) at 0 ° C.The mixture was stirred at 0 ° C. for 30 minutes.It was removed from the ice bath and stirred at 20 ° C. for 6 hours.After the reaction, the reaction was stopped by neutralizing with an aqueous sodium hydrogen carbonate solution (5 mL).Extract with hexane (3 x 20 mL) andWashed with saturated aqueous sodium chloride solution (1 x 20 mL).Add anhydrous sodium sulfate to the organic layer and dry.Sodium sulfate was removed by filtration.Remove hexane with a rotary evaporator and removePurification by silica gel column chromatography (hexane) gave silylated trifluoromethylcarbinol 2 as a colorless transparent liquid in a yield of 98% (based on compound 1).

Reference： [1]Current Patent Assignee: GUNMA UNIVERSITY; KANTO DENKA KOGYO COMPANY LIMITED - JP2018/165254, 2018, A Location in patent: Paragraph 0119; 0121
[2]Current Patent Assignee: KANTO DENKA KOGYO COMPANY LIMITED; GUNMA UNIVERSITY - JP2021/54833, 2021, A Location in patent: Paragraph 0119; 0121-0122
[3]Current Patent Assignee: KANTO DENKA KOGYO COMPANY LIMITED; GUNMA UNIVERSITY - JP2021/54834, 2021, A Location in patent: Paragraph 0119; 0121-0122
[4]Current Patent Assignee: GUNMA UNIVERSITY; KANTO DENKA KOGYO COMPANY LIMITED - JP2021/46434, 2021, A Location in patent: Paragraph 0119-0122

83
[ 18156-74-6 ]
[ 158851-30-0 ]
C₁₂H₂₅NO₄Si [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 18926 - 18931

84
allyl ((2S)-1-((2S,4R)-4-((hydroxyhydrophosphoryl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate [ No CAS ]
[ 18156-74-6 ]
allyl ((2S)-1-((2S,4R)-4-((hydroxy(1H-imidazol-1-yl)phosphoryl)-oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In tetrachloromethane; acetonitrile at 25℃;	Step 3: Allyl ((2S)-1-((2S,4R)-4-((hydroxy(1H-imidazol-1-yl)phosphoryl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (DD). N-Trimethylsilylimidazole (727 mg, 5.2 mmol) was added to a solution of allyl ((2S)-1-((2S,4R)-4-((hydroxyhydrophosphoryl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate CC (750 mg, 1.3 mmol) andtriethylamine (0.72 mL, 5.2 mmol) in carbon tetrachloride (4 mL) and MeCN (4.0 mL) at25 °C. The reaction mixture was stirred at that temperature for 50 min, then MeOH (0.10mL) was added and stirring was continued for an additional 10 min. The solvent wasremoved under reduced pressure, and the residue was washed with 5/1 MTBE/EtOAc (3.0mL). The resulting precipitate was collected by filtration, washed with MTBE (3.0 mL), andwas air-dried to afford the title compound (830 mg, 95%).
95%	With triethylamine In tetrachloromethane; acetonitrile at 25℃; for 0.833333h;	vii.3 Step 3: Allyl ((2S)-1-((2S,4R)-4-((hydroxy(1H-imidazol-1-yl)phosphoryl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (UU). N-Trimethylsilylimidazole (727 mg, 5.2 mmol) was added to a solution of allyl ((2S)-1-((2S,4R)-4-((hydroxyhydrophosphoryl)oxy)-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (TT, 750 mg, 1.3 mmol) and Et3N (0.72 mL, 5.2 mmol) in carbon tetrachloride (4 mL) and MeCN (4.0 mL) at 25 °C. The reaction mixture was stirred at that temperature for 50 min then was treated with MeOH (0.10 mL) and stirred for an additional 10 min. The solvent was removed under reduced pressure, and the residue was washed with 5/1 MTBE/EtOAc (3.0 mL). The resulting precipitate was removed by filtration and was washed with MTBE (3.0 mL). Concentration of the filtrate and washings afforded compound UU (830 mg, 95%) that was used in the next step without additional purification. LCMS (ESI) m/z: 645.3 [M+H]+.
90%	With triethylamine In tetrachloromethane; acetonitrile at 23℃; for 0.666667h;

Reference： [1]Dragovich, Peter S.; Adhikari, Pragya; Blake, Robert A.; Blaquiere, Nicole; Chen, Jinhua; Cheng, Yun-Xing; den Besten, Willem; Han, Jinping; Hartman, Steven J.; He, Jintang; He, Mingtao; Rei Ingalla, Ellen; Kamath, Amrita V.; Kleinheinz, Tracy; Lai, Tommy; Leipold, Douglas D.; Li, Chun Sing; Liu, Qi; Lu, Jiawei; Lu, Ying; Meng, Fanwei; Meng, Lingyao; Ng, Carl; Peng, Kaishan; Lewis Phillips, Gail; Pillow, Thomas H.; Rowntree, Rebecca K.; Sadowsky, Jack D.; Sampath, Deepak; Staben, Leanna; Staben, Steven T.; Wai, John; Wan, Kunpeng; Wang, Xinxin; Wei, BinQing; Wertz, Ingrid E.; Xin, Jianfeng; Xu, Keyang; Yao, Hui; Zang, Richard; Zhang, Donglu; Zhou, Hao; Zhao, Yongxin [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 4]
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2020/86858, 2020, A1 Location in patent: Page/Page column 417-418
[3]Dragovich, Peter S.; Pillow, Thomas H.; Blake, Robert A.; Sadowsky, Jack D.; Adaligil, Emel; Adhikari, Pragya; Chen, Jinhua; Corr, Nicholas; Dela Cruz-Chuh, Josefa; Del Rosario, Geoffrey; Fullerton, Aaron; Hartman, Steven J.; Jiang, Fan; Kaufman, Susan; Kleinheinz, Tracy; Kozak, Katherine R.; Liu, Liling; Lu, Ying; Mulvihill, Melinda M.; Murray, Jeremy M.; O'Donohue, Aimee; Rowntree, Rebecca K.; Sawyer, William S.; Staben, Leanna R.; Wai, John; Wang, Jian; Wei, Binqing; Wei, Wentao; Xu, Zijin; Yao, Hui; Yu, Shang-Fan; Zhang, Donglu; Zhang, Hongyan; Zhang, Shenhua; Zhao, Yongxin; Zhou, Hao; Zhu, Xiaoyu [Journal of Medicinal Chemistry, 2021, vol. 64, # 5, p. 2576 - 2607]

85
[ 18156-74-6 ]
1H-imidazole-1-sulfonyl fluoride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With fluorosulfonyl fluoride; triethylamine at 25℃; for 96h; Autoclave;	3; 11-15; 25; 38 EXAMPLE 3: lH-imidazole-l-sulfonyl fluoride (FSCLIm). A 600 mL autoclave was charged with 1-trimethylsilyl-lH-imidazole (MesSilm, 15 lg, 1.1 moles) and triethylamine (30 mL), sealed, iced, and evacuated to constant static pressure (2.9 kPa). SO2F2 (123g, 1.21 moles) was added rapidly under pressure. The stirred pot was then held at 25°C for three days and the pot pressure dropped from 1275 kPa to 212 kPa. The pot was stirred another day and the pressure stayed around 212 kPa. The pot was then vented, sparged with nitrogen, and the pot contents distilled at 56°C/3.3 kPa to give the product FSChlm (153g, 1.02 moles, 94%. ) FSChlm supercools readily, m.p. 31.5°C.

Reference： [1]Current Patent Assignee: TRINAPCO - WO2020/210174, 2020, A2 Location in patent: Paragraph 0116; 0124-0128; 0138; 0151

86
[ 335-05-7 ]
[ 18156-74-6 ]
[ 29540-81-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With 1,8-diazabicyclo[5.4.0]undec-7-ene at 11℃; for 0.766667h; Cooling with ice;	2 [0100] EXAMPLE 2: l-(Trifluoromethanesulfonyl)imidazole (CFsSCEIm). A 250 mL, 1-necked round-bottom flask was equipped with a gas inlet and thermometer, and charged with 1-(trimethylsilyl)imidazole (Me3SiIm, 57.9 g, 0.41 moles) and DBU (0.26 grams, 1.7 mmoles). The pot was iced and evacuated to constant static pressure (1.3 kPa). CF3SO2F (66.4 grams, 0.436 moles) was added with stirring at low pressure over 46 minutes at 3-11°C. The volatile byproduct, Me3SiF, was distilled off at low pressure using a 40°C water bath. The residue distilled at 40°C/1.3 kPa to yield the product CFsSChlm (79.7 grams, 0.4 moles, 97%). GCMS m/e 200, single peak.

Reference： [1]Current Patent Assignee: TRINAPCO - WO2021/154345, 2021, A1 Location in patent: Paragraph 0100

87
(2S,4R)-allyl 4-((hydroxyhydrophosphoryl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]
[ 18156-74-6 ]
(2S,4R)-allyl 4-((hydroxy(1H-imidazol-1-yl)phosphoryl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In Carbon tetrachloride; acetonitrile at 23℃; for 0.666667h;	4 Preparation of compound 10 of Scheme 4. Synthesis of (2S,4R)-Allyl 4-((hydroxy(1H- imidazol-1-yl)phosphoryl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate To a 23 °C solution of (2S,4R)-allyl 4-((hydroxyhydrophosphoryl)oxy)-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (600 mg, 1.25 mmol) and Et3N (0.52 mL, 3.75 mmol) in CCl4 (8 mL) and acetonitrile (8 mL) was added 1- (trimethylsilyl)-1H-imidazole (0.53 g, 3.75 mmol) at 23 °C. The reaction mixture was stirred at 23 °C for 40 min then was concentrated. The residue was triturated with MTBE/EtOAc=5/1 (3 mL), and the resulting precipitate was collected by filtration, washed with MTBE (3 mL), and air-dried to afford the title compound (680 mg, 99%). LCMS (ESI) m/z: 546.3 [M+H]+.
99%	With triethylamine In Carbon tetrachloride; acetonitrile at 23℃; for 0.666667h;	4 Preparation of compound 10 of Scheme 4. Synthesis of (2S,4R)-Allyl 4-((hydroxy(1H- imidazol-1-yl)phosphoryl)oxy)-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate To a 23 °C solution of (2S,4R)-allyl 4-((hydroxyhydrophosphoryl)oxy)-2-(((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (600 mg, 1.25 mmol) and Et3N (0.52 mL, 3.75 mmol) in CCl4 (8 mL) and acetonitrile (8 mL) was added 1- (trimethylsilyl)-1H-imidazole (0.53 g, 3.75 mmol) at 23 °C. The reaction mixture was stirred at 23 °C for 40 min then was concentrated. The residue was triturated with MTBE/EtOAc=5/1 (3 mL), and the resulting precipitate was collected by filtration, washed with MTBE (3 mL), and air-dried to afford the title compound (680 mg, 99%). LCMS (ESI) m/z: 546.3 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2022/20288, 2022, A1 Location in patent: Page/Page column 146-147; 154-155
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2022/20288, 2022, A1 Location in patent: Page/Page column 146-147; 154-155

88
(9H-fluoren-9-yl)methyl (2-((hydroxyhydrophosphoryl)oxy)ethyl)carbamate [ No CAS ]
[ 18156-74-6 ]
(9H-fluoren-9-yl)methyl (2-((hydroxy(1H-imidazol-1-yl)phosphoryl)oxy)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.1%	With triethylamine In Carbon tetrachloride; acetonitrile at 25℃; for 0.666667h;	17.2 Step 2: (9H-fluoren-9-yl)methyl (2-((hydroxy(1H-imidazol-1-yl)phosphoryl)oxy)ethyl) carbamate To a solution of (9H-fluoren-9-yl)methyl (2-((hydroxyhydrophosphoryl)oxy)ethyl)carbamate (0.50 g, 1.44 mmol) and triethylamine (0.6 mL, 4.32 mmol) in carbon tetrachloride (5.0 mL) and acetonitrile (5.0 mL) was added 1-(trimethylsilyl)-1H-imidazole (0.61 g, 4.32 mmol) at 25 oC. The reaction mixture was stirred at 25 oC for 40 min. The mixture was treated with m ethanol (0.1 mL) and stirred at 25 oC for 10 min. The solvent was removed and the residue w as washed with methyl tert-butyl ether /ethyl acetate = 5/1 (3.0 mL), the precipitate was filter ed and washed with tert-butyl ether (3.00 mL), obtained the title compound (590 mg, 99.1% y ield) as a yellow oil. LCMS (ESI) m/z: 414.3 [M+H]+.
99.1%	With triethylamine In Carbon tetrachloride; acetonitrile at 25℃; for 0.666667h;	17.2 Step 2: (9H-fluoren-9-yl)methyl (2-((hydroxy(1H-imidazol-1-yl)phosphoryl)oxy)ethyl) carbamate To a solution of (9H-fluoren-9-yl)methyl (2-((hydroxyhydrophosphoryl)oxy)ethyl)carbamate (0.50 g, 1.44 mmol) and triethylamine (0.6 mL, 4.32 mmol) in carbon tetrachloride (5.0 mL) and acetonitrile (5.0 mL) was added 1-(trimethylsilyl)-1H-imidazole (0.61 g, 4.32 mmol) at 25 oC. The reaction mixture was stirred at 25 oC for 40 min. The mixture was treated with m ethanol (0.1 mL) and stirred at 25 oC for 10 min. The solvent was removed and the residue w as washed with methyl tert-butyl ether /ethyl acetate = 5/1 (3.0 mL), the precipitate was filter ed and washed with tert-butyl ether (3.00 mL), obtained the title compound (590 mg, 99.1% y ield) as a yellow oil. LCMS (ESI) m/z: 414.3 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2022/20288, 2022, A1 Location in patent: Page/Page column 213-214
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2022/20288, 2022, A1 Location in patent: Page/Page column 213-214

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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. 18156-74-6 ] {[proInfo.proName]}

Quality Control of [ 18156-74-6 ]

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[ 18156-74-6 ] Synthesis Path-Upstream 1~21

[ 18156-74-6 ] Synthesis Path-Downstream 1~88

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[ 18156-74-6 ]