[ CAS No. 145100-51-2 ] {[proInfo.proName]}

Name: 145100-51-2|2-[N,N-Bis(Trifluoromethylsulphonyl)amino]-5-chloropyridine|98%
Brand: Ambeed
SKU: A131286
Price: 5.0 USD
Availability: InStock
Rating: 91 (26 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 145100-51-2 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 145100-51-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 145100-51-2 ]

SDS Specification

Alternatived Products of [ 145100-51-2 ]

Product Details of [ 145100-51-2 ]

CAS No. :	145100-51-2	MDL No. :	MFCD00191833
Formula :	C₇H₃ClF₆N₂O₄S₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TUFGVZMNGTYAQD-UHFFFAOYSA-N
M.W :	392.68	Pubchem ID :	388544
Synonyms :

Calculated chemistry of [ 145100-51-2 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.29
Num. rotatable bonds :	5
Num. H-bond acceptors :	11.0
Num. H-bond donors :	0.0
Molar Refractivity :	61.76
TPSA :	101.17 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.6 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.97
Log Po/w (XLOGP3) :	2.95
Log Po/w (WLOGP) :	6.92
Log Po/w (MLOGP) :	-0.09
Log Po/w (SILICOS-IT) :	0.86
Consensus Log Po/w :	2.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.0
Solubility :	0.0388 mg/ml ; 0.0000989 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.74
Solubility :	0.0072 mg/ml ; 0.0000183 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.53
Solubility :	0.116 mg/ml ; 0.000296 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.67

Safety of [ 145100-51-2 ]

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

Application In Synthesis of [ 145100-51-2 ]

* 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 [ 145100-51-2 ]
Downstream synthetic route of [ 145100-51-2 ]

[ 145100-51-2 ] Synthesis Path-Upstream 1~5

1
[ 79099-07-3 ]
[ 145100-51-2 ]
[ 138647-49-1 ]

Yield	Reaction Conditions	Operation in experiment
2.9 g	Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; Inert atmosphere	Reaction under N₂. BuLi (1.6 M in hexane) (8.28 ml, 13.2 mmol) was added dropwise at -20°C to a solution of DIP A (1.86 ml, 13.2 mmol) in THF (20 ml) then the mixture was stirred at -20°C for 20 minutes. A solution of l-tert-butyloxycarbonyl-4-piperidone (2.2 g, 11.0 mmol) in THF (20ml) was then added at -78°C and the resulting mixture was stirred for 30 minutes at -78°C. A solution of 2-[N,N-bis(trifluoromethylsulfonyl)- amino]-5-chloropyridine (4.97 g, 12.1 mmol) in THF (10ml) was added at -78°C then the mixture was allowed to reach room temperature and was stirred overnight. The mixture was concentrated and the purification of the residue was carried out by flash chromatography over silica gel (silicagel 30μιη, 80g, heptane/EtOAc 75/25. The desired product was collected and the solvent was evaporated, yielding 2.9 g of intermediate (4).
2.9 g	Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃;	Reaction under N2. BuLi (1.6 M in hexane) (8.28 ml, 13.2 mmol) was added dropwiseat -20°C to a solution of DIPA (1.86 ml, 13.2 mmol) in THF (20 ml) then the mixturewas stirred at -20°C for 20 minutes. A solution of l-tert-butyloxycarbonyl-4-piperidone (2.2 g, 11.0 mmol) in THF (20m1) was then added at -78°C and the resulting mixture was stirred for 30 minutes at -78°C. A solution of 2-[N,N-bis(trifluoromethylsulfonyl)- amino]-5-chloropyridine (4.97 g, 12.1 mmol) in THF (lOml) was added at -78°C thenthe mixture was allowed to reach room temperature and was stirred overnight. The mixture was concentrated and the purification of the residue was carried out by flash chromatography over silica gel (silicagel 30jim, 80g, heptane/EtOAc 75/25. The desired product was collected and the solvent was evaporated, yielding 2.9 g of intermediate (A4).

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4544 - 4567
[2] Patent: US2010/216764, 2010, A1, . Location in patent: Page/Page column 17
[3] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 20
[4] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 21
[5] Patent: WO2013/21052, 2013, A1, . Location in patent: Page/Page column 20
[6] Patent: WO2014/23815, 2014, A1, . Location in patent: Page/Page column 38

2
[ 1072-98-6 ]
[ 358-23-6 ]
[ 145100-51-2 ]

Reference： [1] Tetrahedron Letters, 1992, vol. 33, # 42, p. 6299 - 6302
[2] Organic Syntheses, 1997, vol. 74, p. 77 - 77
[3] Organic Letters, 2008, vol. 10, # 2, p. 285 - 288
[4] Organic letters, 2000, vol. 2, # 15, p. 2291 - 2293

3
[ 29943-42-8 ]
[ 145100-51-2 ]
[ 188975-30-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 2 h; Inert atmosphere Stage #2: at 0℃; for 3.25 h; Inert atmosphere	In a 50 mL round-bottomed flask under nitrogen, a solution of n-butyllithium (1.45 M in hexanes, 1.90 mL, 2.76 mmol) was added dropwise to a solution of diisopropylamine (0.39 mL, 2.74 mmol) in THF (5 mL) at 0 °C and the resulting mixture was stirred for 15 min. The reaction mixture was then cooled to -78 °C and a solution of dihydro-2H-pyran-4(3H)-one (0.23 mL, 2.481 mmol) in THF (7.5 mL) was slowly added and the mixture was at -78 °C for another 2 h. To this mixture was added a solution of 2- (N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (1.082 g, 2.76 mmol) in THF (5 ml) over 15 min and the mixture was then allowed to warm to 0 °C and stirred for 3 h. The reaction was then quenched with water (15 mL) and the mixture was extracted with Et₂O (x3). The combined organic extract was washed successively with 15percent aqueous NaOH and brine and then it was dried over anhydrous Na₂SO4, filtered and concentrated. The crude product was chromatographed on a silica gel column (22 mm x 80 mm) which was eluted with 0 to 20percent EtOAc in hexanes. This afforded 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 53percent) as a colorless oil which was used as such in the following step. ¹H NMR (400 MHz, acetone-d6): δ ppm 6.01 (tt, J= 2.8, 1.5 Hz, 1 H) 4.25 (q, J= 3.0 Hz, 2 H) 3.88 (t, J= 5.5 Hz, 2 H) 2.48 (ttd, J= 5.5, 2.8, 1.4 Hz, 2 H). In a 25 mL round-bottomed flask, the obtained 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 1.322 mmol) and potassium fluoride (0.270 g, 4.65 mmol) were added to a solution of (3-(hydroxymethyl)phenyl)boronic acid (0.250 g, 1.645 mmol) in THF (7.5 ml) and the flask was evacuated and purged with nitrogen three times. Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.024 g, 0.029 mmol) was then added in one portion and the mixture was stirred at room temperature for 66 h. The resulting mixture was diluted with ethyl acetate, filtered through CELITE® and concentrated. The residue was purified on the ISCO using a REDISEP® Gold 24 g column (elution with hexanes-EtOAc) to give the title compound (0.131 g, 52percent) as yellowish oil. LC (Method B): 1.614 min. LCMS (APCI): calcd for C12H13O [M+H]⁺- H₂0 m/z 173.096, found 173.2. ¹H NMR (400 MHz, acetone-d6): δ ppm 7.46 (s, 1H) 7.22-7.36 (m, 3H) 6.21 (tt, J= 3.0, 1.5 Hz, 1H) 4.64 (d, J= 5.9 Hz, 2H) 4.24 (q, J= 3.0 Hz, 2H) 4.17 (t, J= 5.7 Hz, 1H) 3.86 (t, J= 5.5 Hz, 2H) 2.49 (ttd, J= 5.4, 2.8, 1.6 Hz, 2H).
800 mg	Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Stage #2: Cooling	A solution of LiHMDS (1.0 M in THF, 11 mL, 11 mmol) was added dropwise to a cooled solution of 4-tetrahydropyranone (1 g, 10 mmol) in dry THF (5 mL) at -78° C. and the resulting reaction was maintained at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.93 g, 10 mmol) in dry THF (6 mL) was added dropwise and the reaction maintained overnight, allowing the cooling bath to expire. The reaction was quenched with water (10 mL) and partitioned with DCM. The layers were separated and the aqueous portion was extracted with DCM (2*). The combined organic portions were dried (Na₂SO₄) and evaporated. The crude residue was purified by flash chromatography (neutral alumina, 80:20 DCM-hexanes) to provide 800 mg of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 5.82-5.81 (m, 1H), 4.27-4.25 (m, 2H), 3.91-3.88 (m, 2H), 2.48-2.45 (m, 2H).

Reference： [1] Patent: WO2013/163241, 2013, A1, . Location in patent: Paragraph 00181
[2] Patent: US2013/210818, 2013, A1, . Location in patent: Paragraph 0351
[3] Patent: WO2008/153858, 2008, A1, . Location in patent: Page/Page column 307
[4] Patent: WO2009/115572, 2009, A2, . Location in patent: Page/Page column 105

4
[ 145100-51-2 ]
[ 185099-67-6 ]
[ 185099-68-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 3.5 h;	Part A: Tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1 ]octane-8-carboxylate (450 mg, 2.0 mmol) in THF (15 ml) at -78° C. was added lithium bis(trimethylsilyl)amide (1 M in THF, 2.2 ml, 2.2 mmol) and the reaction solution was stirred for 1 h. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (864 mg, 2.2 mmol) in THF (20 ml) was added drop wise. The reaction mixture was stirred for another 0.5 h and allowed to warm to room temperature over 3 h and quenched with saturated sodium bicarbonate. The reaction mixture was diluted with ethyl acetate and washed with 15percent potassium hydrogen sulfate, saturated sodium bicarbonate solution, 1 N sodium hydroxide, water and brine. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Flash chromatography (silica gel, 10percent ethyl acetate/hexane) gave the product as a colorless oil (659 mg, 92percent yield) ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 6.08 (s, 1H), 4.32-4.58 (m, 2H), 2.90-3.15 (m, 1H), 2.23 (br. s, 1H), 1.98-2.07 (m, 3H), 1.67-1.78 (m, 1H), 1.57 (s, 1H), 1.45 (s, 9H).
80%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.5 h; Stage #2: at -78 - 20℃;	3.2 3-Trifluorosulfonyl-8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene (N-Boc-nortropanone enol triflate) (104KS22). LDA was generated by adding BuLi (20 mL, 1.68M, 32.6 mmol) to a solution of diisopropylamine (2.38 g, 32.6 mmol) in dry THF (10 mL) at -78° C. under argon. The mixture was kept at that temperature for 30 min followed by the addition of a solution of N-Bocnortropinone (5.27 g, 23.4 mmol) in dry THF (20 mL). The mixture was then left stirring for 1 h while maintaining the temperature at 78° C. Then a solution of 2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (10.08 g, 25.7 mmol) in dry THF (20 mL) and the mixture was slowly allowed to reach room temperature overnight and subsequently concentrated and exposed to column chromatography (SiO₂; EtOAc/heptane 1:6, R_f(product)=0.31) to give the title compound (104KS22) (6.68 g, 80percent) which on prolonged standing crystallized into a white solid. ¹H NMR (CDCl₃) δ 1.43 (s, 9H, Boc-C₃), 1.72 (m, 1H), 1.93-2.03 (m, 2H), 2.07 (d, J=16.6 Hz, 1H), 2.23 (broad m, 1H), 3.05 (broad s, 1H), 4.42 (broad m, 2H, H1+H5), 6.10 (broad s, 1H, H2). ¹³C NMR (CDCl₃) δ 28.4 (Boc H₃), 30.1 and 29.2 (rotameric), 34.7 and 34.9 (rotameric), 36.5 and 37.1 (rotameric), 51.9, (broad s), 80.5 ((CH₃)₃-), 118.7 (-F₃, q, J=300 Hz), 124.0 (broad s, C2), 148.0 (broad s, C3), 153.9 (Boc C=O).

Reference： [1] Patent: US2006/235037, 2006, A1, . Location in patent: Page/Page column 59
[2] Patent: US2004/67931, 2004, A1, . Location in patent: Page/Page column 13

5
[ 145100-51-2 ]
[ 101385-93-7 ]
[ 630121-86-7 ]

Yield	Reaction Conditions	Operation in experiment
34%	Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 3.5 h;	Part A: Tert-butyl 3-(trifluoromethylsulfonyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (370 mg, 2.0 mmol) in THF (15 ml) at -78° C. was added lithium bis(trimethylsilyl)amide (1M in THF, 2.2 ml, 2.2 mmol) and the reaction solution was stirred for 1 h. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (864 mg, 2.2 mmol) in THF (20 ml) was added drop wise. The reaction mixture was stirred for another 0.5 h and allowed to warm to room temperature over 3 h and quenched with saturated sodium bicarbonate. The reaction mixture was diluted with ethyl acetate and washed with 15percent potassium hydrogen sulfate, saturated sodium bicarbonate solution, 1 N sodium hydroxide, water and brine. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Flash chromatography (silica gel, 10percent ethyl acetate/hexane) gave the product as a colorless oil (214 mg, 34percent yield)

Reference： [1] Patent: US2006/235037, 2006, A1, . Location in patent: Page/Page column 60
[2] Patent: WO2010/51245, 2010, A1, . Location in patent: Page/Page column 50
[3] Patent: WO2010/77624, 2010, A1, . Location in patent: Page/Page column 48

[ 145100-51-2 ] Synthesis Path-Downstream 1~40

1
[ 13185-18-7 ]
[ 145100-51-2 ]
[ 586352-25-2 ]

Reference： [1]Organic letters,2003,vol. 5,p. 2683 - 2686

2
[ 145100-51-2 ]
[ 174636-32-9 ]
(S)-N-(1-phenylpropyl)-2-phenyl-3-[(trifluoromethyl)sulfonyl]oxy}quinoline-4-carboxamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 2161 - 2165

3
[ 585-34-2 ]
[ 145100-51-2 ]
[ 201851-06-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	With dmap In dichloromethane at 20℃; for 18h;	A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (Aldrich, 2g, 13.3mmol) in anhydrous dichloromethane (15mL) was treated with 2- [N, N'- bis (trifluoromethylsulfonyl) amino]-5-chloropyridine (7.8g, 20mmol) followed by 4- (dimethylamino) pyridine (3.2g, 26. 6mmol). The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 18h. It was diluted with ethyl acetate, washed with 2N hydrochloric acid, 2N sodium hydroxide, and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400mesh) using 10% ethyl acetate in hexane as the eluent afforded the title product as a clear oil (3.06g, 82%).'H NMR (300 MHz, CDC13) : 8 7.42-7. 32 (m, 2H), 7.24 (d, 1H, J= l. 8Hz), 7.10-7. 06 (m, 1H), 1.33 (s, 9H).
82%	With dmap In dichloromethane at 0 - 20℃; for 18h;	Trifluoro-methanesulfonic acid 3-tert-butyl-phenyl ester (Intermediate 101); A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (Aldrich, 2g, 13. 3mmol) in anhydrous dichloromethane (15mL) was treated with 2- [N, N'- bis (trifluoromethylsulfonyl) amino]-5-chloropyridine (7.8g, 20mmol) followed by 4- (dimethylamino) pyridine (3.2g, 26.6mmol). The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 18h. It was diluted with ethyl acetate, washed with 2N hydrochloric acid, 2N sodium hydroxide, and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400mesh) using 10% ethyl acetate in hexane as the eluent afforded the title product as a clear oil (3. 06g, 82%). 1H NMR (300 MHz, CDC13) : 5 7.42-7. 32 (m, 2H), 7. 24 (d, 1H, J = 1. 8Hz), 7.10- 7. 06 (m, 1H), 1.33 (s, 9H).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2005/58301, 2005, A1 Location in patent: Page/Page column 170-171
[2]Current Patent Assignee: ABBVIE INC - WO2005/58798, 2005, A2 Location in patent: Page/Page column 132-133

4
[ 53400-41-2 ]
[ 145100-51-2 ]
[ 890028-85-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hexamethylsilazane; In tetrahydrofuran; at -78 - 20℃; for 16h;	To a solution of 1.75 g (12 mmol) of <strong>[53400-41-2]7,8-dihydroquinolin-5(6H)-one</strong> (step A) in dryTEtaF, under nitrogen atmosphere at -78 0C was added dropwise 30.53 mL (1.3 equiv.) of a 0.5 M solution of KEtaMDS in TEtaF. The reaction mixture was stirred at -78 0C to RT over in TEtaF, 2-[N5N- bis(trifluoromethylsulfonylamino)]-5-chloropyridine (5.1 g, 13 mmol) in 30 mL TEtaF was added dropwise. The resulting solution was stirred at RT for 16 hr. and the solvent was removed under vacuum. The residue was dissolved in CEtaCl3; and the resulting mixture was washed with 2 N aq. NaOH, dried over MgSO4 drying agent, filtered and the solvent evaporated under vacuum. This material was purified by column chromatography on silica gel eluting with CHCla/MeOH (95/5) to afford 2.25 g of the title compound that was used for the next step without purification.

Reference： [1]Patent: WO2006/60344,2006,A2 .Location in patent: Page/Page column 22

5
[ 29799-07-3 ]
[ 145100-51-2 ]
[ 263398-16-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	With hydrogenchloride; triethylamine; In hexane; dichloromethane;	4-(1-Adamantyl)phenyltrifluoromethanesulfonate (Compound 37) A stirred, cooled (0 C.) solution of 4-(1-adamantyl)phenol (3.2 g, 14 mmol, obtainable in accordance with the chemical literature) and triethylamine (3.3 mL, 22.4 mmol) in 40 mL of anhydrous dichloromethane was treated with 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (5.6 g, 14.2 mmol). The resulting solution was warmed to room temperature over 0.5 hour, then diluted with 20 mL of dichloromethane and washed with 30 mL of 3M HCl followed by 30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to yield an orange solid which on flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound as a white solid (3.72 g, 73%). 1H-NMR (300 MHz, CDCl3): d 1.78 (dd, J=10.0, 19.9 Hz, 6H), 1.91 (d, J=2.4 Hz, 6H), 2.12 (s, 3H), 7.21 (dd, J=2.3, 8.9 Hz, 2H), 7.43 (dd, J=8.9, 2.2 Hz, 2H).
73%	With hydrogenchloride; triethylamine; In hexane; dichloromethane;	4-(1-Adamantyl)phenyltrifluoromethanesulfonate (Compound 37) A stirred, cooled (0 C.) solution of 4-(1-adamantyl)phenol (3.2 g, 14 mmol, obtainable in accordance with the chemical literature) and triethylamine (3.3 mL, 22.4 mmol) in 40 mL of anhydrous dichloromethane was treated with 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (5.6 g, 14.2 mmol). The resulting solution was warmed to room temperature over 0.5 hour, then diluted with 20 mL of dichloromethane and washed with 30 mL of 3M HCl followed by 30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to yield an orange solid which on flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound as a white solid (3.72 g, 73%). 1 H-NMR (300 MHz, CDCl3): d 1.78(dd, J=10.0, 19.9 Hz, 6H), 1.91(d, J=2.4 Hz, 6H), 2.12(s, 3H), 7.21(dd, J=2.3, 8.9 Hz, 2H), 7.43(dd, J=8.9, 2.2 Hz, 2H).

Reference： [1]Patent: US6403638,2002,B1
[2]Patent: US6147224,2000,A

6
[ 1006364-88-0 ]
[ 145100-51-2 ]
[ 1006364-90-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium hexamethylsilazane In tetrahydrofuran; toluene at -78 - 20℃; for 4h;
67%	With potassium hexamethylsilazane In tetrahydrofuran; toluene at -78 - 20℃; for 4h;

Reference： [1]Donohoe, Timothy J.; Fishlock, Lisa P.; Procopiou, Panayiotis A. [Organic Letters, 2008, vol. 10, # 2, p. 285 - 288]
[2]Location in patent: experimental part Donohoe, Timothy J.; Bower, John F.; Basutto, José A.; Fishlock, Lisa P.; Procopiou, Panayiotis A.; Callens, Cedric K.A. [Tetrahedron, 2009, vol. 65, # 44, p. 8969 - 8980]

7
[ 145100-51-2 ]
[ 148404-28-8 ]
3-(tert-butoxycarbonyl)-7-(trifluoromethylsulfonyl)-3-azabicyclo[3.3.0]oct-6-ene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 10: Derivatives of 3-azabicyclo[3.3.0]oct-6-ene-7-carboxylic acid; Certain unsaturated analogs of 3-azabicyclo[3.3.0]octane-7-carboxylic acid, namely esters, amides and ketone derivatives of 3-azabicyclo[3.3.0]oct-6-ene-7- carboxylic acid, can be produced using techniques exemplified in the following procedures.Mthetathyl 3-(tert-butoxycarbonvh-3-a2abicvclof3.3.0l-oct-6-ene-7-carboxylate: To a solution of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-one (4.08 g, 18.1 mmol) (available as described by Dart et al. in PCTWO 04/016604) in THF (50 mL) at -78C was added a solution of lithium hexamethyldisilazide (1.00 M solution in THF, 21.8 mL, 21.8 mmol), and the reaction was stirred for 45 min at - 78C. A solution of N-(5-chloropyridin-2-yl)-bis-trifluoromethanesulfonimide (8.53 g, 21.8 mmol) in THF (10 mL) was added and the reaction was warmed to ambient temperature over 1.5 h. The solvent was evaporated, and the product was purified on a flash silica gel column, eluting with 20-30% ethyl acetate in hexanes, to obtain 6.3 g of 3-(tert-butoxycarbonyl)-7-(trifluoromethylsulfonyl)-3- azabicyclo[3.3.0]oct-6-ene, as an oil. This was combined with palladium acetate (0.20 g, 0.88 mmol), triphenylphosphine (0.46 g, 1.8 mmol), and triethylamine (4.94 mL, 35.3 mmol) in DMF-methanol (120 mL, 3:2) and carbon monoxide gas was bubbled through the solution for 15 min. The reaction mixture was stirred under a carbon monoxide atmosphere for 20 h at ambient temperature. Ether (300 mL) was added to the reaction, and the mixture was washed with water (500 mL), followed by 10% aqueous sodium chloride (200 mL). The organic layer was dried (anhydrous sodium sulfate), concentrated (rotary evaporation), and purified by silica gel column chromatography eluting with 10-20% ethyl acetate in hexanes to obtain 3.5 g (72% yield) of methyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]- oct-6-betane-7-carboxylate, as an oil (1H NMR (CDCI3, 300 MHz): delta 6.60 (bs, 1 H), 3,74 (s, 1H), 3.74-3.61 (m, 1H), 3.58-3.41 (m, 3H), 3.08-2.85 (m, 2H), 2.82-2.74 (m, 1H), 2.50-2.44 (m, 1H), 1.43 (s, 9H); MS (m/z): 268 (M+1), 212 (M+1-56)).

Reference： [1]Patent: WO2008/121686,2008,A1 .Location in patent: Page/Page column 59

8
[ 29943-42-8 ]
[ 145100-51-2 ]
[ 188975-30-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 2h; Inert atmosphere; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran; hexane at 0℃; for 3.25h; Inert atmosphere;	In a 50 mL round-bottomed flask under nitrogen, a solution of n-butyllithium (1.45 M in hexanes, 1.90 mL, 2.76 mmol) was added dropwise to a solution of diisopropylamine (0.39 mL, 2.74 mmol) in THF (5 mL) at 0 °C and the resulting mixture was stirred for 15 min. The reaction mixture was then cooled to -78 °C and a solution of dihydro-2H-pyran-4(3H)-one (0.23 mL, 2.481 mmol) in THF (7.5 mL) was slowly added and the mixture was at -78 °C for another 2 h. To this mixture was added a solution of 2- (N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (1.082 g, 2.76 mmol) in THF (5 ml) over 15 min and the mixture was then allowed to warm to 0 °C and stirred for 3 h. The reaction was then quenched with water (15 mL) and the mixture was extracted with Et2O (x3). The combined organic extract was washed successively with 15% aqueous NaOH and brine and then it was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was chromatographed on a silica gel column (22 mm x 80 mm) which was eluted with 0 to 20% EtOAc in hexanes. This afforded 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 53%) as a colorless oil which was used as such in the following step. 1H NMR (400 MHz, acetone-d6): δ ppm 6.01 (tt, J= 2.8, 1.5 Hz, 1 H) 4.25 (q, J= 3.0 Hz, 2 H) 3.88 (t, J= 5.5 Hz, 2 H) 2.48 (ttd, J= 5.5, 2.8, 1.4 Hz, 2 H). In a 25 mL round-bottomed flask, the obtained 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 1.322 mmol) and potassium fluoride (0.270 g, 4.65 mmol) were added to a solution of (3-(hydroxymethyl)phenyl)boronic acid (0.250 g, 1.645 mmol) in THF (7.5 ml) and the flask was evacuated and purged with nitrogen three times. Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.024 g, 0.029 mmol) was then added in one portion and the mixture was stirred at room temperature for 66 h. The resulting mixture was diluted with ethyl acetate, filtered through CELITE and concentrated. The residue was purified on the ISCO using a REDISEP Gold 24 g column (elution with hexanes-EtOAc) to give the title compound (0.131 g, 52%) as yellowish oil. LC (Method B): 1.614 min. LCMS (APCI): calcd for C12H13O [M+H]+- H20 m/z 173.096, found 173.2. 1H NMR (400 MHz, acetone-d6): δ ppm 7.46 (s, 1H) 7.22-7.36 (m, 3H) 6.21 (tt, J= 3.0, 1.5 Hz, 1H) 4.64 (d, J= 5.9 Hz, 2H) 4.24 (q, J= 3.0 Hz, 2H) 4.17 (t, J= 5.7 Hz, 1H) 3.86 (t, J= 5.5 Hz, 2H) 2.49 (ttd, J= 5.4, 2.8, 1.6 Hz, 2H).
800 mg	Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran Cooling;	10.1 Step 1. Preparation of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate A solution of LiHMDS (1.0 M in THF, 11 mL, 11 mmol) was added dropwise to a cooled solution of 4-tetrahydropyranone (1 g, 10 mmol) in dry THF (5 mL) at -78° C. and the resulting reaction was maintained at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.93 g, 10 mmol) in dry THF (6 mL) was added dropwise and the reaction maintained overnight, allowing the cooling bath to expire. The reaction was quenched with water (10 mL) and partitioned with DCM. The layers were separated and the aqueous portion was extracted with DCM (2*). The combined organic portions were dried (Na2SO4) and evaporated. The crude residue was purified by flash chromatography (neutral alumina, 80:20 DCM-hexanes) to provide 800 mg of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.82-5.81 (m, 1H), 4.27-4.25 (m, 2H), 3.91-3.88 (m, 2H), 2.48-2.45 (m, 2H).
	Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 1h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78 - 20℃;	63.1 To a solution of 4-tetrahydropyranone (2g, 0.02 mol) in THF (10 ml_) at -78 °C, LiHMDS (1 M, 11 ml) was added dropwise through a syringe. The formed solution was then stirred at -78 °C for about 1 hour. The reaction was warmed up to room temperature briefly and was cooled back to -78 °C. Then 2-[N, N- bis(trifluoromethylsulfonyl)amino]-5-chloropyhne (7.85 g, 0.02 mol) was added in four portions. The resulted reaction mixture was gradually warmed up to room temperature and was stirred for overnight. After removal of solvent, the residue was purified using chromatography (eluted with DCM/Hexane = 80/20) to give product as a colorless oil(3g).

Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran

10.1 A solution of LiηMDS (1.0 M in TηF, 11 mL, 11 mmol) was added dropwise to a cooled solution of 4- tetrahydropyranone (Ig, 10 mmol) in dry TηF (5 mL) at -78 0C and the resulting reaction was maintained at -78 0C. for 1 h. A solution of 2-[N, N-bis(trifiuoromethanesulfonyl) amino]-5- chloropyridine (3.93 g, 10 mmol) in dry TηF (6 mL) was added dropwise and the reaction maintained overnight, allowing the cooling bath to expire. The reaction was quenched with water (10 mL) and partitioned with DCM. The layers were separated and the aqueous portion was extracted with DCM (2 X). The combined organic portions were dried (Na2SC^) and evaporated. The crude residue was purified by flash chromatography (neutral alumina, 80 : 20 DCM-hexanes) to provide 800 mg of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a colorless oil: η NMR (400 MHz, CDCl3) δ 5.82-5.81 (m, 1 H), 4.27-4.25 (m, 2 H), 3.91-3.88 (m, 2 H), 2.48-2.45 (m, 2 H).

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2013/163241, 2013, A1 Location in patent: Paragraph 00181
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2013/210818, 2013, A1 Location in patent: Paragraph 0351
[3]Current Patent Assignee: MERCK & CO INC - WO2008/153858, 2008, A1 Location in patent: Page/Page column 307
[4]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2009/115572, 2009, A2 Location in patent: Page/Page column 105

9
[ 145100-51-2 ]
[ 185099-67-6 ]
[ 185099-68-7 ]

Yield	Reaction Conditions	Operation in experiment
92%		Part A: Tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1 ]octane-8-carboxylate (450 mg, 2.0 mmol) in THF (15 ml) at -78 C. was added lithium bis(trimethylsilyl)amide (1 M in THF, 2.2 ml, 2.2 mmol) and the reaction solution was stirred for 1 h. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (864 mg, 2.2 mmol) in THF (20 ml) was added drop wise. The reaction mixture was stirred for another 0.5 h and allowed to warm to room temperature over 3 h and quenched with saturated sodium bicarbonate. The reaction mixture was diluted with ethyl acetate and washed with 15% potassium hydrogen sulfate, saturated sodium bicarbonate solution, 1 N sodium hydroxide, water and brine. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Flash chromatography (silica gel, 10% ethyl acetate/hexane) gave the product as a colorless oil (659 mg, 92% yield) 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 6.08 (s, 1H), 4.32-4.58 (m, 2H), 2.90-3.15 (m, 1H), 2.23 (br. s, 1H), 1.98-2.07 (m, 3H), 1.67-1.78 (m, 1H), 1.57 (s, 1H), 1.45 (s, 9H).
80%		3.2 3-Trifluorosulfonyl-8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene (N-Boc-nortropanone enol triflate) (104KS22). LDA was generated by adding BuLi (20 mL, 1.68M, 32.6 mmol) to a solution of diisopropylamine (2.38 g, 32.6 mmol) in dry THF (10 mL) at -78 C. under argon. The mixture was kept at that temperature for 30 min followed by the addition of a solution of N-Bocnortropinone (5.27 g, 23.4 mmol) in dry THF (20 mL). The mixture was then left stirring for 1 h while maintaining the temperature at 78 C. Then a solution of 2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (10.08 g, 25.7 mmol) in dry THF (20 mL) and the mixture was slowly allowed to reach room temperature overnight and subsequently concentrated and exposed to column chromatography (SiO2; EtOAc/heptane 1:6, Rf(product)=0.31) to give the title compound (104KS22) (6.68 g, 80%) which on prolonged standing crystallized into a white solid. 1H NMR (CDCl3) delta 1.43 (s, 9H, Boc-C3), 1.72 (m, 1H), 1.93-2.03 (m, 2H), 2.07 (d, J=16.6 Hz, 1H), 2.23 (broad m, 1H), 3.05 (broad s, 1H), 4.42 (broad m, 2H, H1+H5), 6.10 (broad s, 1H, H2). 13C NMR (CDCl3) delta 28.4 (Boc H3), 30.1 and 29.2 (rotameric), 34.7 and 34.9 (rotameric), 36.5 and 37.1 (rotameric), 51.9, (broad s), 80.5 ((CH3)3-), 118.7 (-F3, q, J=300 Hz), 124.0 (broad s, C2), 148.0 (broad s, C3), 153.9 (Boc C=O).

Reference： [1]Patent: US2006/235037,2006,A1 .Location in patent: Page/Page column 59
[2]Patent: US2004/67931,2004,A1 .Location in patent: Page/Page column 13

10
[ 145100-51-2 ]
[ 1655-07-8 ]
[ 122135-83-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3163 - 3167

11
[ 75091-99-5 ]
[ 145100-51-2 ]
[ 865869-25-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a cooled (-78 C.) solution of 4-trifluoromethyl cyclohexanone (3.00 grams, 18.1 mmol) in anhydrous THF (100 mL) was added lithium bis(trimethylsilyl)amide (19.9 mL, 1.0 M in THF, 19.9 mmol) dropwise. After 10 min, a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]5-chloropyridine (7.09 g, 18.1 mmol) in THF (20 mL) was added, and the resulting mixture was allowed to warm slowly to ambient temperature overnight, at which point it was quenched by pouring into sat. aq. NaHCO3. The mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting enol triflate was used without further purification.

Reference： [1]Patent: US2009/209556,2009,A1 .Location in patent: Page/Page column 22

12
[ 145100-51-2 ]
[ 190906-92-4 ]
[ 252563-92-1 ]

Yield	Reaction Conditions	Operation in experiment
75%		A solution of 5 mL (49 mMol) 4-methoxypyridine in 200 mL tetrahydrofuran was cooled to -40C, and then 6.9 mL (55 mMol) phenyl chloroformate were added dropwise. After stirring for 15 minutes, 20 mL (60 mMol) methyl magnesium chloride (3M in tetrahydrofuran) were added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was cooled to -40C and treated with 340 mMol potassium tert-butoxide. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was cooled to -40C and was treated with. 200 mL saturated aqueous oxalic acid. The reaction was warmed to 20C and allowed to stir for 1 hour. The mixture was extracted 2 x 200 mL diethyl ether. The combined organic phases were washed sequentially with 4 x 100 mL 0.5 N sodium hydroxide, 2 x 100 mL saturated aqueous sodium bicarbonate, 3 x 100 mL deionized water, and 100 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing 40% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 4.9 gm (47%) <strong>[190906-92-4]1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine</strong>. EA: Calculated for: C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.78; H, 8.08; N, 6.76. A solution of 1.65 gm (7.81 mmol) <strong>[190906-92-4]1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine</strong> in 20 mL tetrahydrofuran was cooled to -40C and was then treated with 8.59 mL (8.59 mMol) lithium tri(sec-butyl)borohydride (1M in tetrahydrofuran). After stirring for 2 hours, the solution was treated with 3.37 gm (8.59 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine and the solution was allowed to warm to room temperature. After stirring for 1 hour, the reaction was diluted with 250 ml diethyl ether and filtered through celite. The celite pad was rinsed with 250 mL diethyl ether and the combined filtrates concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing from 0-9% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.02 gm (75%) of the title compound. ISMS: m/e = 346 (M+H)

Reference： [1]Patent: EP1204660,2004,B1 .Location in patent: Page 17

13
[ 28957-72-4 ]
[ 145100-51-2 ]
[ 949902-02-7 ]

Yield	Reaction Conditions	Operation in experiment
62%		Lithium bis(trimethylsilyl)amide (1 mol/L in tetrahydrofuran, 51.5 ml.) is added to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (10.6 g) in tetrahydrofuran (200 ml.) cooled to -78 0C. The solution is stirred at -78 0C for 1 h, before 2-(N,N-(bistrifluoromethylsulfonyl)amino)- 5-chloropyridine (20.8 g) dissolved in tetrahydrofuran (200 mL) is added dropwise. The resulting solution is stirred for another 0.5 h at this temperature and then warmed to room temperature by removing the cooling bath. Then, aqueous NaHCC>3 solution is added, the resulting mixture is extracted with ethyl acetate, and the combined extracts are dried (Na2SC>4). After removal of the solvent under reduced pressure, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1 :0->1 :1 ). Yield: 10.5 g (62% of theory)Mass spectrum (ESI+): m/z = 348 [M+H]+

Reference： [1]Patent: WO2010/46445,2010,A2 .Location in patent: Page/Page column 56-57

14
[ 954236-44-3 ]
[ 145100-51-2 ]
[ 1227472-19-6 ]

Yield	Reaction Conditions	Operation in experiment
80%		tert-butyl S-irftrifluoromethvOsulfonylloxyl-i-oxa-delta-azaspiro^.deltaldec-S-ene-delta-carboxylate A solution of <strong>[954236-44-3]tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate</strong> (5.0 g, 20 mmol) in anhydrous THF (50 ml_) was cooled to -78 0C and then treated with LiHMDS (1.0 M in THF, 27.4 ml_, 27.4 mmol). The solution was stirred for 1 h at -78 0C then treated with a solution of the 2-[N, N- bis(trifluoromethanesulphonyl)amino]-5-chloropyridine (9.2 g, 23.5 mmol; CASNo. 145100-51-2) in 5 ml of THF. The resulting solution was stirred at -78 0C for 1 h then warmed to room temperature for 30 min. The solution was quenched with water and extracted with ether. Ether layer was washed with water 3 times (5OmL). After drying in MgSO4, the filtrate was concentrated to dryness and provided a brownish solid (6.72 g). The crude was purified by flash chromatography (10-20% EtOAc/heptane) to give the title compound as a white solid (5.9 g, 80%). 1H NMR (400 MHz, CDCI3) delta ppm 1.46 (s, 9 H) 1.66 - 1.75 (m, 4 H) 3.13 - 3.34 (m, 2 H) 3.75 (br. s., 2 H) 4.64 (d, J=2.15 Hz, 2 H) 5.75 (t, J=2.05 Hz, 1 H). m/z 410.1 (M+Na).

Reference： [1]Patent: WO2010/58318,2010,A1 .Location in patent: Page/Page column 61

15
[ 127956-11-0 ]
[ 145100-51-2 ]
[ 917911-25-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of this ketoester intermediate (0.450 g, 2.85 mmol) in anhydrous THF (20 mL) cooled to 0 C., was added sodium hydride (0.171 g, 4.27 mmol, 60% by weight). After 30 min, 2-[N,N-Bis(trifluromethylsulfonyl)amino]-5-chloropyridine (1.34 g, 3.42 mmol) was added. After stirring the reaction mixture at room temperature for 2 h, it was quenched with saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 30% ethyl acetate-hexanes to give the enol triflate as colorless oil.

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 12942 - 12946
[2]Patent: US2006/293364,2006,A1 .Location in patent: Page/Page column 33; 54
[3]Organic Letters,2015,vol. 17,p. 802 - 805

16
[ 689-67-8 ]
[ 145100-51-2 ]
C₁₄H₂₁F₃O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium hexamethylsilazane In tetrahydrofuran at -78℃;

Reference： [1]Location in patent: scheme or table Sawada, Masato; Kubo, Shin-Ichiro; Matsumura, Koji; Takemoto, Yasushi; Kobayashi, Hiroki; Tashiro, Etsu; Kitahara, Takeshi; Watanabe, Hidenori; Imoto, Masaya [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1385 - 1389]

17
[ 55145-45-4 ]
[ 145100-51-2 ]
[ 865869-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-(tert-butyldimethylsilyloxy)cyclohexanone With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78℃; for 2h;	16 Intermediate (16)Trifluoro-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxy)- -1 -enyl esterLDA (0.8 M, 32 mL, 25.47 mmol, 1 equiv.) was cooled to -78°C. To this was added a solution of 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone (5.82 g, 25.47 mmol, 1 equiv.) in THF (30 mL). The solution was stirred at -78°C for 30 min. To this enolate was transferred a solution of Pyr-NTf2 (CAS 145100-51 -2; 10 g, 25.47 mmol, 1 equiv.) in THF (60 mL) and kept stirring at -78°C for 2h. The reaction was diluted with EtOAc (50 mL) and NH CI aq. (50 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2X20 mL). The combined EtOAc extracts were washed with sodium bicarbonate (20 mL), brine (20 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to afford a liquid product. This was purified on a 120 g silica gel column eluted with 10% EtOAc in heptane to obtain 9 g (98% yield) of the title compound as a colorless liquid.TLC: Rf = 0.9 (silica gel, 30% EtOAc in heptane)1H NMR (300MHz, CDCI3) δ: 5.60 (bs, 1 H), 4.01 (m, 1 H), 2.61 -2.10 (m, 4H), 1 .80 (m, 1 H), 0.91 (s, 9H), 0.002 (s, 6H).

Reference： [1]Current Patent Assignee: SANOFI - WO2011/143150, 2011, A1 Location in patent: Page/Page column 46-47

18
[ 145100-51-2 ]
[ 163513-98-2 ]
[ 1399823-22-3 ]

Reference： [1]Chirality,2012,vol. 24,p. 543 - 551

19
[ 52313-35-6 ]
[ 68-11-1 ]
[ 145100-51-2 ]
[ 1394231-87-8 ]

Yield	Reaction Conditions	Operation in experiment
32%	Stage #1: 6-Chloro-2-quinolinecarbonitrile; mercaptoacetic acid With dmap; diisopropylamine In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; Molecular sieve; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at 20℃; for 96h; Inert atmosphere;

Reference： [1]Burckhardt, Tobias; Harms, Klaus; Koert, Ulrich [Organic Letters, 2012, vol. 14, # 17, p. 4674 - 4677]

20
[ 145100-51-2 ]
[ 148404-28-8 ]
[ 1416313-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 1h;	/ert-Butyl 5-{ itrifluoromethyl sulfonyl]oxy}-3,3a,4,6a-tetrahydrocyclo-penta- [c"\|pyrrole-2(lH)-carboxylate (8-2)tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (8-1, 2 g 8.8 mmol, 1.0 equiv) was added to anhydrous THF (44 mL) and cooled to 0C. To this solution was added LHMDS (9.7 mL, 9.7 mmol, 1.1 equiv, 1M solution in THF) followed by Comin's reagent (2-2, 3.5 g, 8.8 mmol, 1.0 equiv) in two equal portions. After 60 min at 0C, TLC analysis showed consumption of starting material. The reaction was quenched with brine (40 mL) and diluted with ethyl acetate (75 mL) and water (75 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to give a orange oil. Purification by normal- phase chromatography (0-30% EtOAc:Hex) afforded 8-2 as a pale yellow oil, which was immediately carried forward.

Reference： [1]Patent: WO2012/174199,2012,A1 .Location in patent: Page/Page column 40

21
[ 1408075-90-0 ]
[ 145100-51-2 ]
[ 1429122-68-8 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 3720 - 3730

22
[ 55704-60-4 ]
[ 145100-51-2 ]
[ 1449661-70-4 ]

Yield	Reaction Conditions	Operation in experiment
		An oven-dried flask charged with diisopropylamine (4.90 ml, 34.7 mmol) and tetrahydrofuran (30 ml), was cooled to 0 C. under nitrogen atmosphere. To the reaction mixture was added n-butyl lithium (1.6M in hexanes, 21.67 ml, 34.7 mmol) dropwise and then stirred at 0 C. for 15 minutes. The reaction mixture was cooled to -78 C. and added the solution of <strong>[55704-60-4]4-oxo-cyclohexane-1,1-dicarboxylic acid diethyl ester</strong> (7.0 g, 28.9 mmol) in tetrahydrofuran (15 ml) over 2 minutes. The reaction mixture was stirred at -30 C. for 30 minutes, and then cooled to -78 C., and followed by adding the solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (12.48 g, 31.8 mmol) in tetrahydrofuran (15 ml). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated and the resulting oil was partitioned between ethyl acetate/heptane (3/1; 200 ml) and water (100 ml). The layers were separated and the organic phase was washed with water (5×50 ml), dried over Na2SO4, and concentrated to afford the crude 4-trifluoromethanesulfonyloxy-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester (12.8 g, 80% purity, 94% yield) as brown oil. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.27 (t, J=7.20 Hz, 6H) 2.25-2.35 (m, 2H) 2.43 (dd, J=6.19, 1.89 Hz, 2H) 2.72-2.80 (m, 2H) 4.21 (q, J=7.20 Hz, 4H) 5.69-5.82 (m, 1H).

Reference： [1]Patent: US2013/289058,2013,A1 .Location in patent: Paragraph 0337; 0338

23
[ 3883-58-7 ]
[ 145100-51-2 ]
1,4-bis[(trifluoromethanesulfonyl)oxy]-5,5-dimethylcyclopenta-1,3-diene [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5970 - 5973
[2]Journal of the American Chemical Society,2014,vol. 136,p. 918 - 920

24
[ 98549-88-3 ]
[ 145100-51-2 ]
1H-pyrrolo[2,3-b]pyridin-5-triflate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 1285 - 1294

25
[ 7467-91-6 ]
[ 145100-51-2 ]
quinoxalin-6-yl triflate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 1285 - 1294

26
[ 1003-04-9 ]
[ 145100-51-2 ]
4,5-dihydrothiophen-3-yl trifluoromethanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.5%		Step 1. 4,5-dihydrothiophen-3-yl trifluoromethanesulfonate:_To freshly prepared LDA (10.5 mmol in 40 mL THF) between -75 to -65 C. was dropwise added dihydrothiophene-3-(2H)-one/THF solution (1.02 g/2 mL THF, 10 mmol) over 3 min, then the resulting reaction mixture was stirred at -75 C. for 3 h, followed by dropwise addition of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide/THF (4.12 g, 10.5 mmol in 5 mL THF) over 10 min, then the reaction mixture was stirred at -75 C. for at least 1 h, then with temperature gradually warm up to room temperature overnight. The reaction mixture was concentrated, and the residue was partitioned between Et2O/H2O (100 mL/50 mL); the ether layer was sequentially washed with water (2×50 mL), 3 M sodium acetate pH 4.8 buffer (2×50 mL), 3M NaOH (2×50 mL), and dried over magnesium sulfate, concentrated and a brown oil was obtained as crude product (2.05 g) which was further purified by flash chromatography on silica gel eluted with gradient EtOAc/heptane (0-15%) and desired product (0.9 g, 38.5% yield) was obtained as colorless oil.

Reference： [1]Patent: US9242996,2016,B2 .Location in patent: Page/Page column 71; 72; 73

27
[ 1193-20-0 ]
[ 145100-51-2 ]
2-methyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.2 g	Stage #1: 2-methyltetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.5h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78 - 20℃;	11.1 Step 1. 2-methyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate Step 1. 2-methyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate:_To a solution of 2-methyldihydro-2H-pyran-4(3H)-one (2 g, 17.52 mmol) in THF (8.76 mL) was added LiHMDS (18.40 mL, 18.40 mmol) dropwise at -78° C. The reaction mixture was stirred at -78° C. for 1.5 h, then N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (7.22 g, 18.40 mmol) in THF (17 mL) was added at -78° C. The mixture was stirred at -78° C. for 1 h, and then allowed to warm up to room temperature, and stirred overnight. The reaction was monitored by TLC. After quenched with sat NaHCO3, The reaction mixture was extracted with EtOAc 3 times. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The desire compound (4.2 g, 17.06 mmol) was obtained as a brown oil by flash column chromatography eluting with 30% EtOAc in heptane.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US9242996, 2016, B2 Location in patent: Page/Page column 85; 86

28
[ 346593-03-1 ]
[ 145100-51-2 ]
tert-butyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of NaHMDS (1.0 M in THF, 41.0 mL, 41.0 mmol) in THF (130 mL) was cooled to -78 C. A separate solution of tert-butyl 2,2-dimethyl-4-oxopiperidine-1- carboxylate (7.76 g, 34.1 mmol) in THF (21 mL) was added slowly dropwise via syringe. The resulting solution turned into a slurry over the course of 1 h while maintaining the bath temperature at -78 C. A separately prepared solution of Comins reagent (16.1 g, 41.0 mmol) in THF (20 mL) was then added dropwise via syringe. The resulting slurry turned orange as it warmed slowly to 25 C over 12 h. Next, the reaction was concentrated, taken up in 15% EtOAc/heptane (100 mL), washed with ice cold water (30 mL), the water layer extracted with 15% EtOAc/heptane (2x100 mL). The combined organics were dried over MgS04, filtered, and concentrated to give the titled compound which required no further purification: 1 H NMR (400 MHz, CDCI3) 5.79-5.77 (m, 1 H), 4.09-4.07 (m, 2 H), 2.04 (s, 2 H), 1.50 (s, 6 H), 1.47 (s, 9 H).

Reference： [1]Patent: WO2016/120849,2016,A1 .Location in patent: Page/Page column 75

29
[ 50866-56-3 ]
[ 145100-51-2 ]
(1-benzyl-5-oxo-2,6-dihydropyridin-3-yl)trifluoromethanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran at 0℃; for 0.5h;	1.1 Step 1 : preparation of intermediate (1-benzyl-5-oxo-2,6-dihvdropyridin-3-yl) trifluoromethanesulfonate (1b) In a 500 mL round bottom flask, under nitrogen atmosphere, t-BuOK (2.7 g, 24.07 mmol) was dissolved in anhydrous THF (180 mL) and the resulting solution was cooled at 0°C. Ethyl N-benzy-lN-acetonylglycinate (1 a) (synthesized according to the procedures described in the litterature (J.Org.Chem. 2006, 7/(21 ), 8256, J.Med.Chem. 2012, 55(1 1 ), 5403, WO2013/181741 ) (6 g, 24.07 mmol) dissolved in anhydrous THF (60 mL) was added with a dropping funnel over 5 min. The resulting viscous solution was stirred for 30 min at 0°C (LC/MS showed the formation of the corresponding dione m/z ([M+H]+ 204, [M+H2O+H]+ 222, [M-H]-202). At 0°C, N-(5-Chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (Comins reagent) (9.7 g, 24.07 mmol) dissolved in THF (20 mL) was added and the reaction was stirred for an additional 30 min. The reaction mixture was diluted with Et20 and the solution was washed with H2O. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (toluene/acetone 100/0 to 95/5 or cyclohexane/EtOAc 100/0 to 50/50) to provide intermediate (1 b) which was triturated in a mixture of petroleum ether and diethyl ether (9/1 ) at -78°C. After filtration, intermediate (1 b) was obtained as a white solid (5.80 g, 17.29 mmol, 71 %) and stored in the freezer. MS m/z ([M+H]+) 336. 1H NMR (300 MHz, CDCl3): (ppm) 3.27 (s, 2H), 3.49 (s, 2H), 3.73 (s, 2H), 6.17 (t, J = 1 .3 Hz, 1 H), 7.27-7.40 (m, 5H).

Reference： [1]Current Patent Assignee: PHARMA OMNIUM INTERNATIONAL P O I - WO2018/60481, 2018, A1 Location in patent: Page/Page column 31-32

30
[ 1193-47-1 ]
[ 145100-51-2 ]
[ 32363-23-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 2,2-dimethyl-cyclohexanone With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78 - 20℃; Inert atmosphere;

Reference： [1]Tucker, James K.; Shair, Matthew D. [Organic Letters, 2019, vol. 21, # 7, p. 2473 - 2476]

31
[ 13388-94-8 ]
[ 145100-51-2 ]
[ 63438-16-4 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: spiro[4.5]decan-6-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78 - 20℃; Inert atmosphere;

Reference： [1]Tucker, James K.; Shair, Matthew D. [Organic Letters, 2019, vol. 21, # 7, p. 2473 - 2476]

32
[ 5453-88-3 ]
[ 145100-51-2 ]
[ 1171119-63-3 ]

Reference： [1]Organic Letters,2019,vol. 21,p. 2473 - 2476

33
[ 90-42-6 ]
[ 145100-51-2 ]
[1,1’-bi(cyclohexan)]-2-en-2-yl trifluoromethanesulfonate [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 2473 - 2476

34
[ 17206-54-1 ]
[ 145100-51-2 ]
1-methyl-1,4,5,6-tetrahydro-[1,1’-biphenyl]-2-yl trifluoromethanesulfonate [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 2473 - 2476

35
[ 132833-51-3 ]
[ 1728-25-2 ]
[ 145100-51-2 ]
(E)-3-(4-(morpholinomethyl)phenyl)cyclooct-1-en-1-yl trifluoromethanesulfonate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 9140 - 9144

36
[ 1539946-20-7 ]
[ 145100-51-2 ]
[ 2409674-07-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78℃; for 1h;	99.1 Step 1: tert-Butyl 2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1- carboxylate A solution of tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate (580 mg, 2.91 mmol) in THF (3 mL) was cooled to - 78 °C and [bis(trimethylsilyl)amino]lithium (3.78 mL of 1 M, 3.78 mmol) was added dropwise. After 30 mins at this temperature, a solution of N-(5-chloro- 2-pyridyl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (1.49 g, 3.78 mmol) in THF (3 mL) was added. The mixture was stirred at- 78 °C for 1 hour before being quenched by addition of 2 M aq. Na2CO3 (2 mL) and stored at 4 °C overnight. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, the layers separated and the organic layer dried (MgSO4) and concentrated in vacuo to give tert-butyl 2-methyl-3- (((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate as an amber oil, which was used without further purification.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD); MERCK KGAA - WO2019/148132, 2019, A1 Location in patent: Paragraph 001523

37
[ 145100-51-2 ]
[ 256487-77-1 ]
(R)-4-trifluoromethane sulfonyloxy-2,5-dihydropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		Step 1 To a stirred solution of <strong>[256487-77-1]1-(tert-butyl) 2-methyl (R)-4-oxopyrrolidine-1,2-dicarboxylate</strong> (1.50 g, 6.16 mmol) in THF (15 mL) at -78 C. was slowly added lithium bis(trimethylsilyl)amide (7.40 mL, 7.40 mmol, 1 M in THF) under Ar. After stirring for 1 h at -78 C., Comins' reagent (2.99 g, 7.40 mmol) in THF (5 mL) was added and the stirring continued for an additional 1 h. The reaction mixture was stirred at -20 C. for additional 18 h. The reaction mixture was quenched with 20 mL water and extracted with diethyl ether (3*60 mL). The combined extracts were washed with 2 N NaOH solution, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by chromatography (EtOAc-hexanes) to give 1-(tert-butyl) 2-methyl (R)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.85 g, 80% yield).

Reference： [1]Patent: US2019/367452,2019,A1 .Location in patent: Paragraph 1702-1704

38
[ 1138480-98-4 ]
[ 145100-51-2 ]
methyl 6-(((trifluoromethyl)sulfonyl)oxy)spiro[3.3]hept-5-ene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: 6-oxo-spiro[3.3]heptane-2-carboxylic acid methyl ester With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.75h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78 - 20℃; for 1h;	590.A STEP A. Intermediate 590A. Preparation of methyl 6-(((trifluoromethyl)sulfonyl)oxy) spiro[3.3 ]hept-5 -ene-2-carboxyl ate To a stirred solution of LiHMDS (8.92 mL, 8.92 mmol) in THF (2 mL) -78 °C was added a solution of methyl 6-oxospiro[3.3]heptane-2-carboxylate (500 mg, 2.97 mmol) in THF (2 mL) dropwise at -78 °C and stirred for 45 min. Subsequently, a solution of N-(5-chloropyridin-2-yl)- 1, 1,1 -trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.34 g, 5.95 mmol) in THF (5 mL) was added dropwise at -78 °C and the reaction mixture was allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was quenched with water (10 mL) and the reaction mixture was extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with water (10 mL) followed by brine solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (12 g silica gel cartridge; A = Hex, B = EtOAc; 30 min grad.; 0% B to 50% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to afford methyl 6-(((trifluoromethyl)sulfonyl)oxy)spiro[3.3]hept-5-ene-2-carboxylate (500 mg, 1.665 mmol, 56% yield) as yellow oil. MS (ESI) 318 (M+18).

Reference： [1]Current Patent Assignee: BIOCON LIMITED; BRISTOL-MYERS SQUIBB CO - WO2020/168143, 2020, A1 Location in patent: Page/Page column 642; 643

39
[ 145100-51-2 ]
[ 6622-92-0 ]
[ 154447-08-2 ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; Schlenk technique;

Reference： [1]Dibenedetto, Tarah A.; Kang, Kai; Loud, Nathan L.; Weix, Daniel J. [Journal of the American Chemical Society, 2021, vol. 143, # 51, p. 21484 - 21491]

40
[ 1363382-39-1 ]
[ 145100-51-2 ]
[ 2411223-33-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	With SiO₂	Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.66 mmol) in THF (16.6 mL) at -78° C. was added LiHMDS (1.06 M in THF, 9.12 mL, 9.12 mmol) dropwise via syringe and the reaction stirred at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.07 g, 7.82 mmol) in THF (1.7 mL) was then added dropwise, and the reaction stirred at -78° C. for an additional 1 h before removing the cold bath and allowing the mixture to warm to rt for 30 min. The reaction was quenched with H2O and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via FCC (SiO2, 0-50% EtOAc in hexanes) to afford the title compound as a white solid (1.89 g, 79% yield). MS (ESI): mass calcd. for C13H18F3NO5S, 357.1; m/z found, 302.0 [M-tBu+2H]+. 1H NMR (500 MHz, Chloroform-d) δ 5.79 (t, J=1.9 Hz, 1H), 3.96 (d, J=8.7 Hz, 2H), 3.86 (d, J=8.7 Hz, 2H), 2.65-2.61 (m, 2H), 2.31-2.26 (m, 2H), 1.44 (s, 9H).
79%	Stage #1: tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;	Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.66 mmol) in THF (16.6 mL) at -78° C. was added LiHMDS (1.06 M in THF, 9.12 mL, 9.12 mmol) dropwise via syringe and the reaction stirred at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.07 g, 7.82 mmol) in THF (1.7 mL) was then added dropwise, and the reaction stirred at -78° C. for an additional 1 h before removing the cold bath and allowing the mixture to warm to rt for 30 min. The reaction was quenched with H2O and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via FCC (SiO2, 0-50% EtOAc in hexanes) to afford the title compound as a white solid (1.89 g, 79% yield). MS (ESI): mass calcd. for C13H18F3NO5S, 357.1; m/z found, 302.0 [M-tBu+2H]+. 1H NMR (500 MHz, Chloroform-d) δ 5.79 (t, J=1.9 Hz, 1H), 3.96 (d, J=8.7 Hz, 2H), 3.86 (d, J=8.7 Hz, 2H), 2.65-2.61 (m, 2H), 2.31-2.26 (m, 2H), 1.44 (s, 9H).
79%	Stage #1: tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;	Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.66 mmol) in THF (16.6 mL) at -78° C. was added LiHMDS (1.06 M in THF, 9.12 mL, 9.12 mmol) dropwise via syringe and the reaction stirred at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.07 g, 7.82 mmol) in THF (1.7 mL) was then added dropwise, and the reaction stirred at -78° C. for an additional 1 h before removing the cold bath and allowing the mixture to warm to rt for 30 min. The reaction was quenched with H2O and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via FCC (SiO2, 0-50% EtOAc in hexanes) to afford the title compound as a white solid (1.89 g, 79% yield). MS (ESI): mass calcd. for C13H18F3NO5S, 357.1; m/z found, 302.0 [M-tBu+2H]+. 1H NMR (500 MHz, Chloroform-d) δ 5.79 (t, J=1.9 Hz, 1H), 3.96 (d, J=8.7 Hz, 2H), 3.86 (d, J=8.7 Hz, 2H), 2.65-2.61 (m, 2H), 2.31-2.26 (m, 2H), 1.44 (s, 9H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2022/89538, 2022, A1
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2022/89538, 2022, A1 Location in patent: Paragraph 0310; 0311
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - US2022/89538, 2022, A1 Location in patent: Paragraph 0310; 0311

Same Skeleton Products

Related Products

Historical Records

Pharmaceutical Intermediates of
[ 145100-51-2 ]

Maxacalcitol Related Intermediates

[ 6485-40-1 ]

(R)-2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enone

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

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

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

[ CAS No. 145100-51-2 ] {[proInfo.proName]}

Quality Control of [ 145100-51-2 ]

Related Doc. of [ 145100-51-2 ]

Product Details of [ 145100-51-2 ]

Calculated chemistry of [ 145100-51-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 145100-51-2 ]

Application In Synthesis of [ 145100-51-2 ]

[ 145100-51-2 ] Synthesis Path-Upstream 1~5

[ 145100-51-2 ] Synthesis Path-Downstream 1~40

Pharmaceutical Intermediates of [ 145100-51-2 ]

Maxacalcitol Related Intermediates

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 145100-51-2 ]