185099-68-7|8-Boc-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene| Ambeed

Structure of 185099-68-7

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

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

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 185099-68-7 ] Purity: 95% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 185099-68-7 ]

CAS No. :	185099-68-7
Formula :	C₁₃H₁₈F₃NO₅S
M.W :	357.35
SMILES Code :	O=S(OC1=CC2CCC(N2C(OC(C)(C)C)=O)C1)(C(F)(F)F)=O
MDL No. :	MFCD14635483
InChI Key :	CJDKVEWDWXIBSM-UHFFFAOYSA-N
Pubchem ID :	22648094

Safety of [ 185099-68-7 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H318
Precautionary Statements:	P264-P270-P280-P301+P312-P305+P351+P338-P310-P330-P501
Class:	9
UN#:	3077
Packing Group:	Ⅲ

Application In Synthesis of [ 185099-68-7 ]

* 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.

Downstream synthetic route of [ 185099-68-7 ]

[ 185099-68-7 ] Synthesis Path-Downstream 1~35

1
[ 37595-74-7 ]
[ 185099-67-6 ]
[ 185099-68-7 ]

Yield	Reaction Conditions	Operation in experiment
95%		To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.2 mmol) in THF (21.1 mL) was added LHMDS (4.64 mL, 4.64 mmol) dropwise under N2 at-50 C and the solution was warmed to-30 C and stirred for 1 h. 1,1,1-trilluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.66 g, 4.64 mmol) in THF (1.0 mL) was added dropwise at-30 C and the resulting mixture was warmed to 25 C and stirred for 4 h. Aqueous sat. NH4CI (10 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 30 %) EtOAc in hexanes to afford the title compound (2.2 g, 95 % yield)MS (ES+) C13H18F3NO5S requires: 357, found 358 [M+H]+.
90%		To a solution of N-Boc-nortropinone (6 g, 26.6 mmol) in THF (70 ml) at -78C was added LDA (2 M in haptane/TBF/ethyl benzene, 20ml, 40 mmol) slowly and the reaction mixture was stirred for 10 min. A solution of N-phenylbis(trifluoromethanesulfonimide) (10.5 g, 29.3 mmol) in THF (48 ml) was added. The reaction mixture was stirred at -78C for 30 min and the cooling bath was removed to warm it up to room temperature for 1.5 h until all N-Boc- nortropinone was utilized. Saturated NH4CI solution (~10 mL) was added and stirring was continued for 5 minutes before the reaction mixture was transferred to a separatory funnel using EtOAc (150 mL). The organics were then extracted with EtOAc (2 x 125 ml), and washed with water (2 x 30 ml), brine (1 x 30 ml), and dried over MgS04. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution withEtOAc/Hexanes (0-35%) gave the desired product, tert-butyl 3-(trifluoromethylsulfonyloxy)-8- azabicyclo[3.2.1]oct-3-ene-8-carboxylate (8.5 g, 90%).
84%		Example 108 - Preparation of Intermediate 35 The synthesis of Intermediate 35 followed the procedure of General Procedure 23 following: Intermediate 35 To a cooled solution (-78C) of tert-butyl-3-oxo-8-azabicyclo[3.2.1]octane-8- carboxylate (30 g, 133.3 mmol) in dry THF (300 mL) was added LiHMDS (lithium hexamethyldisilazide, 1M in THF, 146 mL, 146.7 mmol). After stirring for 30 minutes, a solution of N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf2, 52 g, 146.7 mmol) in dry THF (30 mL) was added and the mixture stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated ammonium chloride solution (80 mL), and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), eluting with 3-5% EtOAc/n-hexane, to afford tert- butyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (Intermediate 35, 40 g, yield: 84%) as a pale yellow liquid; TLC System: 20% ethyl acetate in hexane. Rf-0.5.

79%		under nitrogen protection,3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.2 g, 5.3 mmol)The 15 mL THF solution was cooled to -70 C.LDA (1M in THF, 8 mL, 8.0 mmol) was added dropwise with stirring.The temperature of the control system is around -70 C.After stirring the system for 1 h, N-phenylbis(trifluoromethanesulfonyl)imide (1.9 g, 5.3 mmol) was added portionwise.After the addition, the system was naturally warmed under stirring and stirred at room temperature overnight.TLC showed that after completion of the reaction, the reaction system was poured into 100 mL of saturated ammonium chloride solution and extracted with EA (50 mL x 3).The organic phase is washed with saturated brine.Dry anhydrous Na2SO4 and concentrate under reduced pressure.The crude product was purified by column (PE:EA=20:1) to give 1.5 g.(yield: 79%) of the target compound,It is a white solid.
72.6%		(0519) Tert-butyl 3-oxo-8-azabicyclo[3.2.1]octan-8-carboxylate (8.5 g, 37.8 mmol) was dissolved in tetrahydrofuran (80 mL), and a solution of lithium diisopropylamide in tetrahydrofuran/ n-heptane/ ethylbenzene (28 mL, 56 mmol, 2 M) was added slowly to the system at -78 C. After stirring for 10 min, a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (14.8 g, 41.6 mmol) in tetrahydrofuran (50 mL) was added. After stirring for 30 min, the reaction was carried out at room temperature for 2 h. After the reaction, the mixture was concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to get the title compound (9.8 g, yield: 72.6%).
63%		A. A 300 mL round bottom flask was charged with Compound 6a (1.0 g,4.44 mmol) and THF (30 mL). The mixture was cooled to -78 0C using a dry ice/acetone bath. A 20% solution of LiN(SiMe3)2 in THF (5.OmL, 5.32 mmol) was added dropwise over 15 min. The mixture was stirred at- 78 0C for 40 min. A solution of PhN(SO2CF3)2 (1.6 g, 4.48 mmol) in THF (33 mL) was added dropwise via addition funnel. The mixture was stirred for 18 h with gradual warming to room temperature. The mixture was concentrated in vacuo and purified via flash chromatography (230-400 mesh silica gel 60, 95:5 hexanes:EtOAc ) to give 1.O g (63%) of Compound 6b as a white solid. 1H NMR (300 MHz, CDCI3) delta 6.08 (d, J = 5.3 Hz, 1 H), 4.31-4.45 (m, 2 H), 3.04-3.21 (m, 2 H), 1.97-2.24 (m, 4 H), and 1.46 (s, 9 H).
63.0%		1360A. tert-Butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate To a stirred solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.44 mmol) in tetrahydrofuran (10 mL) at -78 C. was added LDA (3.33 mL, 6.66 mmol) and stirred at that temperature for 30 min. Then N,N-bis(trifluoromethylsulfonyl) aniline (1.586 g, 4.44 mmol) in tetrahydrofuran (5 mL) was added and stirred for 1 h. The reaction mixture was warmed to room temperature and stirred for 2 h. Reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2*100 mL). The organic layer was washed with brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude, which was purified by silica gel flash chromatography to afford 1360A (brown oil, 1 g, 2.80 mmol, 63.0% yield).
		A solution of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (15.8 g, 70.0 mmol) and THF (150 mL) was cooled to -78 C. and 1.0 M sodium hexamethyldisilazane in THF (84 mL) was added dropwise over 5 min. The reaction mixture was stirred for 1 h and then N-phenylbis(trifluoromethane-sulphonimide) (25.0 g, 70.0 mmol) was added and the reaction mixture was stirred for 1 h. The solution was warmed to room temperature, 1.0 N NaOH (100 mL) was added, and the reaction mixture was stirred for 15 min. Approximately 75 mL of solvent was evaporated. The resulting solution was diluted with ethyl acetate:hexanes (100 mL:100 mL) and water (100 mL), extracted and washed with 1.0 N NaOH (2*200 mL). The organic layer was washed with saturated NaCl solution (200 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (18.2 g) as a dark oil, which was used without further purification.
	With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; n-heptane; at -60 - 20℃; for 24.25h;	10 ml of a 2.5N solution n-butyl lithium in hexane are added, dropwise to a solution of 3.73 ml of diisopropylamine in 100 ml of tetrahydrofuran cooled to -60 C., in a 500 ml three-necked flask under nitrogen. After stirring for 1/4 hour, 5 g of N-tert-butyloxycarbonyl nortropinone in tetrahydrofuran (50 ml) at 0 C. are added. Finally, still at 0 C., 8.32 g of N-phenyltrifluoromethanesulfonimide are added. After stirring for 24 hours at ambient temperature, the tetrahydrofuran is evaporated off and the product is purified by rapid filtration over alumina, using a 2/1 mixture of heptane/ethyl acetate as eluent. 6.13 g of tert-butyl 3-[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate are obtained.
		1.1/3-Trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester 3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5 g, 22.2 mmol) is placed in 24 ml of anhydrous THF and the solution is cooled to -70 C. under nitrogen, 1N lithium bis(trimethylsilyl)amide in THF (24.4 ml, 24.4 mmol) is added dropwise. After stirring for 45 min at -70 C., N-phenyltrifluoromethane-sulfonimide (8.7 g, 24.4 mmol) placed in 25 ml of anhydrous THF is added dropwise. The temperature of the reaction medium is left to rise slowly. Stirring is maintained for 16 h at ambient temperature. After concentration to dryness, the crude product obtained is chromatographed on silica gel, elution being carried out with a cyclohexane/ether mixture (90/10). 10.2 g of expected 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester are obtained. [M+H+]=258 (-OtBu)
		To a solution of N-Boc-nortropinone (6 g, 26.6 mmol) in THF (70 ml) at -78C was added LDA (2 M in haptane/THF/ethyl benzene, 20ml, 40 mmol) slowly and the reaction mixture was stirred for 10 min. A solution of N~phenylbis(trifluoromethanesulfonimide) (10.5 g, 29.3 mmol) in THF (48 ml) was added. The reaction mixture was stirred at -78C for 30 min and the cooling bath was removed to warm it up to room temperature for 1.5 h until all N-Boc- nortropinone was utilized. Saturated NH4C1 solution (-10 mL) was added and stirring was continued for 5 minutes before the reaction mixture was transferred to a separatory funnel using EtOAc (150 mL). The organics were then extracted with EtOAc (2 x 125 ml), and washed with water (2 x 30 ml), brine (1 x 30 ml), and dried over MgS04 The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution withEtOAc/Hexanes (0-35%) gave the desired product, tert-butyl 3-(trifluoromethylsulfonyloxy)-8- azabicyclo[3.2. l]oct-3-ene-8-carboxylate.
		To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 44.4 mmol) in tetrahydrofuran (100 mL) was added 2M lithium diisopropylamide (26.6 mL, 53.3 mmol) dropwise at -60C under argon and the mixture was stirred at -60C for 1 hour. A solution of 1, 1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (17.44 g, 48.8 mmol) in tetrahydrofuran (100 mL) was added dropwise at -60C and the mixture was stirred at -60C for 30 minutes, and was allowed to warm to room temperature. The mixture was stirred under argon overnight, quenched with water (200 mL), and extracted with ethyl acetate (three times). The organic extracts were washed with 5% aqueous citric acid (twice) and stirred with 1M aqueous sodium hydroxide (200 mL) for 30 minutes. The wash process was repeated one additional time. The organic phase was dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel using an ISCO Companion eluting with ethyl acetate/petroleum ether (1 :20) to provide the title compound.
		To a 250 mL 3-necked round-bottom flask was placed a solution of (lR,5S)-tert- butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (5.00 g, 22.2 mmol) in tetrahydrofuran (100 mL). Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 26.6 mL, 26.6 mmol) was added dropwise at -78C. The mixture was stirred at -78C for 1 hour. Then a solution of l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (9.51 g, 26.6 mmol) in tetrahydrofuran (30 mL) was added at -78C. The mixture was stirred for an additional 16 h at ambient temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (100 mL), washed with water (2 x 50 mL) and brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified on silica, eluting with ethyl acetate/petroleum ether (5: 100) to afford the title compound. LRMS (ESI) calc'd for Ci3Hi9F3N05S [M + H]+: 358, found 358; 1H NMR (400 MHz, CDC13) 56.08 (d, / = 5.4 Hz, 1H), 4.59-4.33 (m, 2H), 3.12-2.94 (m, 1H), 2.31-2.13 (m, 1H), 2.09-1.93 (m, 3H), 1.79-1.63 (m, 1H), 1.46 (s, 9H).
		Starting material 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.0 g, 26.63 mmol, 1.0 eq)Dissolved in anhydrous tetrahydrofuran solution (30 mL),Nitrogen protection drops to -70 C ~ -60 C,A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 mol/L, 32 mL, 1.2 eq) was added dropwise.After the drop, stir at -70 C ~ -60 C for 1 h,A solution of N-phenylbis(trifluoromethanesulfonyl)imide (11.4 g, 31.96 mmol, 1.2 eq) in tetrahydrofuran (30 mL).After the addition of 0 C or less, the reaction was carried out for 3 h, and the mixture was naturally stirred at room temperature for 12 h.The mixture was cooled to 0 C to 10 C, and brine (50 mL) and brine (50 mL)The filtrate was concentrated under reduced pressure to give a product.
		To a solution of ferf-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Int 23a) (1.00 g, 4.33 mmol) in THF (10 mL) was added LDA (2 N, 3.3 mL) at -78 C and the mixture was stirred for 10 min at the same temperature. A solution of N- phenylbis(trifluoromethanesulfonimide) (1.75 g, 4.88 mmol) in THF (8 mL) was added. The mixture was stirred at -78 C for 30 min. The cooling bath was removed and the mixture was stirred for 1.5 h. Saturated aqueous NH4CI (30 mL) was added and stirring was continued for 5 min. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (EtOAc/PE = 1 :2) to give the title compound as a yellow oil.

References: [1]Patent: WO2018/218197,2018,A2 .Location in patent: Paragraph 0372; 0373.
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1817 - 1820.
[3]Patent: WO2012/27234,2012,A1 .Location in patent: Page/Page column 41.
[4]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0343.
[5]Patent: CN109575022,2019,A .Location in patent: Paragraph 0315-0318.
[6]Patent: US2017/112833,2017,A1 .Location in patent: Paragraph 0518-0519.
[7]Patent: WO2007/81995,2007,A2 .Location in patent: Page/Page column 186.
[8]Patent: US2016/289171,2016,A1 .Location in patent: Paragraph 2867.
[9]Patent: US2009/62333,2009,A1 .Location in patent: Page/Page column 12.
[10]Patent: US2009/170894,2009,A1 .Location in patent: Page/Page column 7-8.
[11]Patent: US2011/294809,2011,A1 .Location in patent: Page/Page column 7.
[12]Patent: WO2012/27240,2012,A1 .Location in patent: Page/Page column 49.
[13]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 458.
[14]Patent: WO2014/146490,2014,A1 .Location in patent: Page/Page column 146; 147.
[15]Patent: CN109721620,2019,A .Location in patent: Paragraph 0515-0518.
[16]Patent: WO2019/115586,2019,A1 .Location in patent: Page/Page column 71; 72.

2
[ 24424-99-5 ]
[ 185099-68-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1817 - 1820.
[2]Patent: US2017/112833,2017,A1 .
[3]Patent: CN109575022,2019,A .

3
[ 532-24-1 ]
[ 185099-68-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1817 - 1820.

4
[ 25602-68-0 ]
[ 185099-68-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1817 - 1820.
[2]Patent: CN109575022,2019,A .

5
[ 912971-33-6 ]
[ 185099-68-7 ]
[ 912971-56-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 100℃;	Part B: Tert-butyl 3-(2-(2-methoxyphenyl)-1H-indol-5-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate A mixture of 2-(2-methoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (prepared using procedure provided for Part C of example 98) (279 mg, 0.80 mmol), tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (286 mg, 0.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (39 mg, 0.048 mmol) and Cesium carbonate (782 mg, 2.40 mmol) in DMF (4 ml) was heated at 100 C. under nitrogen overnight. The reaction mixture was partitioned between ethyl acetate and water, The organic layer was washed with saturated sodium bicarbonate (3 times), dried over magnesium sulfate and concentrated in vacuo, purification by flash column chromatography, eluding with 10% ethyl acetate/hexane, afforded the desired product as white solid (287 mg, 83% yield). MS (ESI) m/z 431 (M+H). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 9.72 (br. s, 1H), 7.84 (dd, J=7.80, 1.65 Hz, 1H), 7.58 (d, J=1.54 Hz, 1H), 7.32-7.36 (m, 1H), 7.23-7.31 (m, 3H), 7.01-7.08 (m, 2H), 6.37-6.43 (m, 1H), 4.46-4.54 (m, 2H), 4.02 (s, 3H), 3.19 (dd, J=17.03, 4.28 Hz, 1H), 2.34 (d, J=16.70 Hz, 1H), 2.16-2.26 (m, 1H), 1.93-2.04 (m, 2H), 1.69-1.78 (m, 1H), 1.40-1.48 (m, 9H).

References: [1]Patent: US2006/235037,2006,A1 .Location in patent: Page/Page column 60.

6
[ 627-19-0 ]
[ 185099-68-7 ]
[ 509147-64-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N,N-dimethyl-ethanamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; for 2h;	To a mixture of 3-trifluorosulfonyl-8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene (104KS22) (0.107 g, 0.3 mmol, 1.0 equiv), CuI (0.011 g, 0.05 moles, 0.20 equiv), dimethylethylamine (0.219 g, 3.0 mmol, 10 equiv) and the alkyne (2.0 equiv) in dry THF (3 mL) was added (PPh3)4Pd (0.10 equiv) at room temperature under argon. The mixture was shaken for 2 h followed by filtration and concentration. The residual syrup was taken up in DCM (2 mL) followed by careful addition of TFA (0.5 mL). The mixture was shaken for 10 min before it was concentrated, basified with NaOH (2M, 3 mL), extracted (EtOAc), concentrated and put on an ionexchange column (Varian BondElut-SCX, H+). Elution with 2.5% NH4OH in MeOH and concentration gave the desired product.; 3.4 3-Pent-1-ynyl-8-azabicyclo[3.2.1]oct-2-ene (79KS36-5) [0186] 3-Trifluorosulfonyl-8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene (104KS22) (0.107 g, 0.3 mmol) and Pent-1-yne (0.041 g, 0.6 mmol) were reacted according to GP1 to give the title compound (79KS36-5) (0.033 g, 62%). HPLC-MS (ammonium acetate): [M+H]+=176.23

References: [1]Patent: US2004/67931,2004,A1 .Location in patent: Page/Page column 13.

7
[ 73183-34-3 ]
[ 185099-68-7 ]
[ 900503-08-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;	A mixture of tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3- ene-8-carboxylate (Int-le) (10.1 g, 28.4 mmol), bis(pinacolato)diboron (8.7 g, 34.1 mmol), KOAc (8.4 g, 85.3 mmol), PdCl2(dppf)2.CH2Cl2 (1.4g, 1.7mmol), and dppf (1 g, 1.8 mmol) in dioxane (170 ml) was flushed with argon and stirred at 80C for 16 h. On cooling, the solvent was rotoevaporated, and the crude residue was redissolved in EtOAc (500 ml), washed with water (1 x 125 ml), brine (1 x 125 ml), and dried over gS0 . The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-40%) gave the desired product, tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2~ene-8-carboxylate (8.6 g, 90%).
89%	With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 3h;	tert-Butyl 3-[(trifluoromethane)sulfonyloxy]-8-azabicyclo[3.2. l]oct-2-ene-8- carboxylate (100 mg, 0.28 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (85 mg, 0.36 mmol), 1 , -bis(diphenyl- phosphanyl)ferrocene (5 mg, 0.01 mmol) and potassium acetate (82 mg, 0.84 mmol) were dissolved in 1,4-dioxane (2 mL) and degassed for 5 minutes. Bis[3-(diphenyl- phosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (7 mg, 0.01 mmol) was added and the mixture was heated at 80C for a total of 3 h. The reaction mixture was cooled and filtered over celite. The solid was washed with EtOAc (2 x 10 mL) and the combined filtrate was concentrated under vacuum. The crude product was purified using FCC, eluting with a gradient of 0-50% EtOAc in heptanes, to afford the title compound (86.8 mg, 89%) as a colourless oil. deltaH (500 MHz, CDCl3) 6.76 (s, 1H), 4.33 (d, J29.8 Hz, 2H), 2.79 (d, J 17.5 Hz, 1H), 2.12 (dd, J 13.3, 7.3 Hz, 1H), 1.92 (m, 2H), 1.65 (m, 2H), 1.46 (d, J 7.1 Hz, 9H), 1.26 (d, J 6.3 Hz, 12H).
89%	With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 3h;Ionic liquid;	tert-Butyl 3-[(trifluoromethane)sulfonyloxy]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (100 mg, 0.28 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (85 mg, 0.36 mmol), 1,1?-bis(diphenyl-phosphanyl)ferrocene (5 mg, 0.01 mmol) and potassium acetate (82 mg, 0.84 mmol) were dissolved in 1,4-dioxane (2 mL) and degassed for 5 minutes. Bis[3-(diphenyl-phosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (7 mg, 0.01 mmol) was added and the mixture was heated at 80 C. for a total of 3 h. The reaction mixture was cooled and filtered over celite. The solid was washed with EtOAc (2×10 mL) and the combined filtrate was concentrated under vacuum. The crude product was purified using FCC, eluting with a gradient of 0-50% EtOAc in heptanes, to afford the title compound (86.8 mg, 89%) as a colourless oil. deltaH (500 MHz, CDCl3) 6.76 (s, 1H), 4.33 (d, J 29.8 Hz, 2H), 2.79 (d, J 17.5 Hz, 1H), 2.12 (dd, J 13.3, 7.3 Hz, 1H), 1.92 (m, 2H), 1.65 (m, 2H), 1.46 (d, J7.1 Hz, 9H), 1.26 (d, J6.3 Hz, 12H).

79%	With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;	(0521) Tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]octan-2-en-8-carboxylate (9.8 g, 27.4 mmol), bis(pinacolato)diboron (10.4 g, 40.9 mmol), potassium acetate (5.4 g, 55 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (1.15 g, 1.4 mmol) and 1,1?-bis(diphenyphosphino)ferrocene (776 mg, 1.4 mmol) were dissolved in 1,4-dioxane (100 mL). Under the protection of nitrogen gas, the reaction was carried out at 80 C. under stirring for 16 h. After the reaction, the mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried with anhydrous sodium sulfate, filtrated, and concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to get the title compound (7.3 g, yield: 79%).
78%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 6h;Inert atmosphere;	Under nitrogen protection,To 3-((((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid tert-butyl ester (714 mg, 2.0 mmol),Pd(dppf)Cl2 (73 mg, 0.1 mmol) was added to a 20 mL 1,4-dioxane solution of boranoic acid pinacol ester (508 mg, 2.0 mmol) and KOAc (392 mg, 4.0 mmol).The reaction mixture was stirred at 90 C for 6 h under nitrogen.TLC showed the reaction was completed.The reaction system is poured into 100 mL of water.Extract with EA (50 mL x 3).The organic phase is washed once with saturated brine.The anhydrous Na2SO4 was sufficiently dried and concentrated under reduced pressure.Column chromatography with residue (PE: EA = 20:1)Purification afforded 520 mg (yield: 78%) of title compound.It is a pale yellow solid.
76%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 20h;	B. A 200 mL round bottom flask was charged with Compound 6b (1.4 g, 3.92 mmol), Pd(dppf)2CI2 (0.09 g, 0.12 mmol), K2CO3 (1.15 g, 11.7 mmol), and <n="188"/>dioxane (23.0 ml_). Bis(pinacolato)diboron (1.1 g, 4.33 mmol) was added and the mixture was heated to 80 0C for 20 h. The mixture was concentrated in-vacuo and purified via flash chromatography (230-400 mesh silica gel 60, DCM) to give 1.0 g (76%) of Compound 6c as a white solid. 1H NMR (300 MHz, CDCI3) delta 6.76 (d, J = 5.3 Hz, 1 H), 4.27-4.35 (m, 2 H), 2.80-2.90 (m, 1 H), 2.03-2.12 (m, 1 H), 1.88-1.94 (m, 4 H), 1.44 (s, 9 H), and 1.26 (s, 12 H).
42%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	To a solution of the product from the previous step (2.20 g, 4.00 mmol) in dioxane (13.3 mL) under N2were added KOAc (1.257 g, 12.81 mmol) , PdCl2(dppf) (0.293 g, 0.400 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.34 g, 9.20 mmol) and the resulting mixture was stirred at 100 C for 4 h. The reaction was cooled to RT, water (10 mL) was added and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 50 %) EtOAc in hexanes to afford the title compound (1.12 g, 42 % yield) as a colorless liquid.MS (ES+) C18H30BNO4 requires: 335, found 336 [M+H]+
	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃;	The product of Preparation 3 (7.65 g, 0.0214 mol) was dissolved in 1,4-dioxane (75 mL, 0.96 mol). To the reaction mixture was added bis(pinacolato)diboron (5.71 g, 0.0225 mol), and potassium acetate (6.30 g, 0.0642 mol), 1,1'-bis(diphenylphosphino)-ferrocene (0.5 g, 0.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (0.5 g, 0.6 mmol). The reaction mixture was purged with nitrogen, stirred at 80 C. overnight, and cooled to room temperature. The solution was filtered through Celite and concentrated. The crude product was purified by flash column chromatography eluting with (5-10%) ethyl acetate in hexanes to give the title compound (4.2 g) as an oil.
	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 16h;	A mixture of tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1 ]oct-3- ene-8-carboxylate (10.1 g, 28.4 mmol), bis(pinacolato)diboron (8.7 g, 34.1 mmol), KOAc (8.4 g, 85.3 mmol), PdCl2(dppf)2.CH2Cl2 (1.4g, Ummol), and dppf (1 g, 1.8 mmol) in dioxane (170 ml) was flushed with argon and stirred at 80C for 16 h. On cooling, the solvent was evaporated, and the crude residue was redissolved in EtOAc (500 ml), washed with water (1 x 125 ml), brine (1 x 125 ml), and dried over MgS04. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0- 40%) gave the desired product, tert-butyl 3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-8- azabicyc3o[3.2.1]oct-2-ene-8-carboxylate.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere;	A mixture of Example 223A (10 g, 28.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (7.82 g, 30.8 mmol), potassium acetate (7.42 g, 76 mmol), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (1.024 g, 1.399 mmol) in 1,4-dioxane (500 mL) was degassed with argon and the mixture was stirred at 80C under argon overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using an ISCO Companion eluting with ethyl acetate/petroleum ether (1 :50 to 1 :20) to provide the title compound. MS (DCI+) m/z 336.2 (M+H)+.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere;	The intermediate obtained in the above step was dissolved in anhydrous 1,4-dioxane (200 mL).Add boranoic acid pinacol ester (8.1 g, 31.96 mmol, 1.2 eq)And potassium acetate (9.1 g, 93.22 mmol, 3.5 eq),1,1'-bis(triphenylphosphine)ferrocene (737.8 mg, 1.33 mmol, 0.05 eq) was added under nitrogen.And 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane (974.3 mg, 1.33 mmol, 0.05 eq),The temperature was raised to 100 C for 3 h under nitrogen protection.After being cooled to room temperature, saturated brine (100 mL) was added, and extracted with ethyl acetate (100 mL×3), and the organic phase was combined, dried and filtered.The filtrate was concentrated under reduced pressure to give a product.

References: [1]Patent: WO2012/27234,2012,A1 .Location in patent: Page/Page column 41; 42.
[2]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 93.
[3]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0476.
[4]Patent: US2017/112833,2017,A1 .Location in patent: Paragraph 0520-0521.
[5]Patent: CN109575022,2019,A .Location in patent: Paragraph 0315-0316; 0319-0320.
[6]Canadian Journal of Chemistry,2006,vol. 84,p. 555 - 560.
[7]Patent: WO2007/81995,2007,A2 .Location in patent: Page/Page column 186-187.
[8]Patent: WO2018/218197,2018,A2 .Location in patent: Paragraph 0372; 0374; 0375.
[9]Patent: US2009/62333,2009,A1 .Location in patent: Page/Page column 12.
[10]Patent: WO2012/27240,2012,A1 .Location in patent: Page/Page column 49.
[11]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 458.
[12]Patent: CN109721620,2019,A .Location in patent: Paragraph 0515; 0519-0521.

Yield	Reaction Conditions	Operation in experiment
82%		b. Preparation of 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester To a 1 L flask was added the product of the previous step (93 g, 400 mmol) and THF (400 mL). The mixture was stirred at room temperature until complete dissolution was observed, and then was cooled to -74 C. A NaHMDS solution (1 M in THF, 460 mL, 460 mmol) was added slowly to the reaction vessel over 3 h (temp <-70 C.). N-phenyl-bis(trifluoromethanesulfonimide (164 g, 460 mmol) was added to the reaction mixture in portions while maintaining the internal temperature <-70 C. Additional THF (200 mL) was added and the mixture was stirred at -74 C. for 90 min. The mixture was warmed to room temperature and slightly concentrated to remove about 200 mL solvent. To the remaining solution was added 1N NaOH (600 mL), hexanes (200 mL) and EtOAc (400 mL). The layers were separated and the organic layer was washed with 1 N NaOH (3*200 mL) and brine (200 mL), dried over Na2SO4, and then concentrated. The residue was dried and slowly solidified to give the title intermediate as yellowish solids (117.8 g, 82% yield). 1H NMR (d6-DMSO, 400 MHz): delta (ppm) 6.32 (d, J=6, 1H), 4.30-4.40 (m, 2H), 2.90 (d, J=16.4, 2H), 2.18-2.23 (m, 2H), 1.91-1.98 (m, 2H), 1.65-1.72 (m, 2H), 1.39 (s, 9H).

9
tricyclohexylphosphine tetrafluoroborate (PCy₃HBF₄) [ No CAS ]
(3-(aminocarbonyl)phenyl)boronic acid [ No CAS ]
[ 185099-68-7 ]
[ 1101869-79-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With KF; In tetrahydrofuran; N,N-dimethyl-formamide;	c. Preparation of 3-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester To a 250 mL flask was added <strong>[185099-68-7]3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester</strong> (20 g, 56 mmol), 3-carbamoylphenyl boronic acid (10.2 g, 61 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (2 g, 2.2 mmol), tricyclohexylphosphine tetrafluoroborate (PCy3HBF4) (1.65 g, 4.4 mmol) and KF (9.8 g, 168 mmol). The reagents were purged with nitrogen for 5 min, and then THF (120 mL) and DMF (30 mL) was added. The suspension was stirred and purged with nitrogen for another 5 min, then heated to 70 C. After 2 h at 70 C., the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was partitioned between EtOAc (350 mL) and 0.5 N NaOH (400 mL)/brine (50 mL). The organic layer was separated and dried with Na2SO4. A quarter of the solution was removed. The remainder of the solution was concentrated to ~100 mL to which hexanes (50 mL) was added. Solid precipitates were observed. The solution volume was reduced by 10 mL, hexanes (10 mL) was added, and the slurry was stirred at 0 C. for 1 h. The solids were filtered and dried to give the title intermediate (8.4 g) as light yellow solids. The mother liquor was further concentrated to give more solid precipitate, which was filtered to provide additional product (0.5 g). (Combined 66% yield). 1H NMR (d6-DMSO, 400 MHz): delta (ppm) 8.01 (s, 1H), 7.89 (t, J=1.6, 1H), 7.73-7.76 (m, 1H), 7.55 (d, J=8, 1H), 7.36-7.42 (m, 2H), 6.62 (d, J=5.2, 1H), 4.35-4.42 (m, 2H), 2.95-2.99 (m, 1H), 1.65-2.33 (m, 5H), 1.38 (s, 9H).

References: [1]Patent: US2009/23934,2009,A1 .

10
[ 100-58-3 ]
[ 185099-68-7 ]
[ 676366-90-8 ]

Yield	Reaction Conditions	Operation in experiment
77%		3.227 3-Phenyl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (79KS76) A reaction flask was charged with CuI (0.234 g, 1.23 mmol) in THF (5 mL) and stirred at -25 C. A 3.0 M solution of PhMgBr (0.82 ml, 2.46 mmol) in diethyl ether was added dropwise, and the mixture was stirred for 30 min at -25 C. A solution of <strong>[185099-68-7]3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester</strong> (79KS73) (0.220 g, 0.62 mmol) in THF (5 ml) was added dropwise at -25 C. The reaction was slowly warmed to r.t., and quenched with saturated NH4Cl. The aqueous layer was extracted with DCM, the combined organic layers were dried over Na2SO4, and concentrated. The crude product was purified by CC (SiO2; EtOAc/n-heptane 1:10) to give the title compound (79KS76) (0.137 g, 77%). 1H NMR (CDCl3) delta 7.37-7.24 (m, 5H), 6.43-6.42 (m, 1H), 4.51 (br. s, 2H), 3.10 (br. s, 1H), 2.25-2.18 (m, 2H), 2.04-1.92 (m, 2H), 1.74-1.67 (m, 1H), 1.46 (s, 9H); 13C NMR (CDCl3) delta 154.3, 140.3, 128.6, 127.6, 125.1, 79.6, 53.7, 52.3, 36.2, 34.7, 29.9, 28.7.

References: [1]Patent: US2004/67931,2004,A1 .Location in patent: Page/Page column 37.

11
[ 927-77-5 ]
[ 185099-68-7 ]
[ 509147-69-7 ]

Yield	Reaction Conditions	Operation in experiment
54%		To a slurry of CuI (2.0 equiv) in dry THF (5 mL) was added R-M (R=alkyl, M=Li or MgX) (4.0 equiv) at -25 C. and stirred at that temperature for 30 min before adding a solution of 3-trifluorosulfonyl-8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene (104KS22) (1.0 equiv) in dry THF (5 mL). The reaction mixture was kept stirring at -25 C. for 2 h before the cooling was removed. The reaction was then quenched by firstly addition of water (20 mL) and secondly addition of a saturated aqeuous solution of NH4Cl (20 mL) before extraction with DCM. The combined organic phase was washed with a saturated aqeuous solution of NH4Cl, dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. This was then purified by column chromatography (SiO2; EtOAc/heptane 1:10 which gave the desired products; 3.10 8-tert-Butyloxycarbonyl-3-propyl-8-aza-bicyclo[3.2.1]oct-2-ene (79KS74) [0198] CuI (0.234 g, 1.23 mmol), PrMgBr (1.3 mL, 2.0M, 2.46 mmol) 3-Trifluorosulfonyl-8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene (104KS22) (0.220 g, 0.616 mmol) were reacted according to GP2 to give the title compound (79KS74) (0.083 g, 54%). 1H NMR (CDCl3) delta 0.84 (t, 3H, J=7.1 Hz, -CH2CH2CH3), 1.36 (sixt, 2H, J=7.1 Hz, -CH2CH2CH3), 1.43 (s, 9H, Boc-CH3), 1.56 (dt, 1H, J=7.0 Hz, 13.2 Hz), 1.64 (d, 1H, J=17.0 Hz), 1.76-1.96 (m, 4H), 2.11 (m, 1H), 2.67 (d, 1H, J=17.0 Hz), 4.18-4.34 (m, 2H), 5.68 (d, 1H, J=4.8 Hz, H2); 13C NMR (CDCl3) delta 13.7 (-CH2CH2CH3), 20.7 (-CH2CH2CH3), 28.6 (Boc-CH3), 30.0, 34.9, 37.4, 38.5 (-CH2CH2CH3), 52.3, 53.3, 79.2 (-C(CH3)3), 126.6, 135.4 (C2, C3), 154.4 (CO).

References: [1]Patent: US2004/67931,2004,A1 .Location in patent: Page/Page column 13-14.

12
[ 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).

References: [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.

13
[ 3277-89-2 ]
[ 185099-68-7 ]
[ 676366-98-6 ]

Yield	Reaction Conditions	Operation in experiment
57%		3.245 3-(2-Phenylethyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic Acid Tert-butyl Ester (79KS77) A reaction flask was charged with CuI (0.234 g, 1.23 mmol) in THF (5 mL) and stirred at -25 C. A 1.0 M solution of PhCH2CH2MgBr (2.5 ml, 2.46 mmol) in THF was added dropwise, and the mixture was stirred for 30 min at -25 C. A solution of <strong>[185099-68-7]3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester</strong> (79KS73) (0.220 g, 0.62 mmol) in THF (5 ml) was added dropwise at -25 C. The reaction was slowly warmed to r.t., and quenched with saturated NH4Cl. The aqueous layer was extracted with DCM, the combined organic layers were dried over Na2SO4, and concentrated. The crude product was purified by CC (SiO2; EtOAc/n-heptane 1:10) to give the title compound (79KS77) (0.110 g, 57%).

References: [1]Patent: US2004/67931,2004,A1 .Location in patent: Page/Page column 40.

14
[ 185099-68-7 ]
[ 960524-52-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; for 3h;	2.76 g of tert-butyl 3-[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate in 13 ml of dioxane are placed in a 100 ml round-bottomed flask. 12.8 ml of a 4N solution of hydrochloric acid in dioxane are then carefully added. The reaction mixture is stirred for 3 h. The dioxane is evaporated off, to give 2.27 g of 8-azabicyclo[3.2.1]oct-2-ene-3-yl trifluoromethylsulfonate hydrochloride.

References: [1]Patent: US2009/170894,2009,A1 .Location in patent: Page/Page column 8.

15
[ 181219-01-2 ]
[ 185099-68-7 ]
[ 960524-58-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; lithium chloride;2?-(dimethylamino)-2-biphenylyl-palladium(II)chloride dinorbornylphosphine complex; In 1,4-dioxane; at 100℃; for 0.5h;Microwave irradiation;	1 g of tert-butyl 3-[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate, 0.975 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 0.24 g of lithium chloride, 1.78 g of potassium phosphate, 0.157 g of 2'-(dimethylamino)-2-biphenylpalladium(II)chloride dinorbornylphosphine and 10 ml of dioxane are introduced into an 80 ml glass tube. The tube is sealed and then heated at 100 C. under microwave irradiation for 30 minutes. Water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica gel with a mixture of heptane/ethyl acetate. 0.458 g of tert-butyl 3-pyridin-4-yl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate is obtained.

References: [1]Patent: US2009/170894,2009,A1 .Location in patent: Page/Page column 9.

16
[ 185099-67-6 ]
[ 185099-68-7 ]

Yield	Reaction Conditions	Operation in experiment
78%		To a solution of potassium bis(trimethylsilyl)amide (60 mL, 30 mmol, 0.5 M in toluene) at -78 C was added a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.1 g, 27.2 mmol) dropwise over a 10 min period. After 5 h, a solution of N-phenyl bistrifluoromethanesulfonamide (10.2 g, 28.7 mmol) in THF (10 mL) was added. After 5 h, the cooling bath was removed, and the mixture was stirred at rt for 2 h. The mixture was partitioned between H2O and EtOAc. The two layers were separated, and the organic layer was washed with 1 M NaOH and brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 7.6 g (78%) of the product as clear colorless oil. 1H NMR (CDCl3, 282.2 MHz) delta 6.10 (d, J = 4.2 Hz, 1H), 4.65-4.30 (m, 2H), 3.15-2.90 m, 1H), 2.35-1.90 (m, 4H), 1.85-1.50 (m, 2H), 1.46 (s, 9H); 19F NMR (CDCl3, 282.2 MHz) delta-73.20 and -73.32 (total 3F)

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1606 - 1610.

17
[ 185099-68-7 ]
[ 1222495-64-8 ]

References: [1]Patent: US2011/294809,2011,A1 .

18
[ 185099-68-7 ]
[ 1222495-66-0 ]

References: [1]Patent: US2011/294809,2011,A1 .

19
[ 1222495-59-1 ]
[ 185099-68-7 ]
[ 1222495-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 6h;Inert atmosphere; Reflux;	1.4/ 3-[4-(4-Methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester 1-Methanesulfonyl-4-[4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)phenyl]-piperazine (1.8 g, 4.9 mmol) and 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]-oct-2-ene-8-carboxylic acid tert-butyl ester (3.8 g, 5.9 mmol) are placed in 35 ml of DME and 6.14 ml of a 2N aqueous solution of K2CO3. After degassing with nitrogen, tetrakis(triphenylphosphine)palladium (1.136 g, 0.98 mmol) is added. The reaction medium is refluxed for 6 h. After hydrolysis and addition of ethyl acetate, the reaction medium is filtered on Celite. The aqueous phase is then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaHCO3 and than with water. After drying over MgSO4 and concentration to dryness, the crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in dichloromethane ranging from 0% to 20%. 0.83 g of 3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester is obtained. [M+H+]=448

References: [1]Patent: US2011/294809,2011,A1 .Location in patent: Page/Page column 7.

20
[ 13939-06-5 ]
[ 185099-68-7 ]
[ 1204809-89-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; at 120℃; for 5h;Inert atmosphere; Sealed tube;	Example 109 - Preparation of Intermediate 36 The synthesis of Intermediate 36 followed the procedure of General Procedure 24 following: Intermediate 35 Intermediate 36 To a stirred solution of tert-butyl-3-(trifluoromethylsulfonyloxy)-8- azabicyclo[3.2.1]oct-3-ene-8-carboxylate (Intermediate 35, 21 g, 58.8 mmol) in 1,4- dioxane:water (5:1, 125 mL) in a sealed tube was added molybdenum hexacarbonyl (Mo(CO)6, 7.7 g, 29.4 mmol), 4-dimethylaminopyridine (DMAP, 14.3 g, 117.6 mmol), and N,N-diisopropylethylamine (DIEA, 25 mL, 141.2 mmol). After degassing with a stream of argon for 15 minutes, palladium acetate (Pd(OAc)2, 1.3 g, 5.9 mmol) was added, followed by 1,1'-bis(diphenylphosphino)ferrocene (dppf, 3.3 g, 5.9 mmol). The reaction mixture was stirred at 120C for 5 hours. The reaction mixture was filtered through a Celite pad and poured into aqueous sodium bicarbonate (60 mL) and extracted with EtOAc (200 mL). The aqueous layer was acidified with HCl (2N, to pH = 2) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-ene-3-carboxylic acid (Intermediate 36, 14 g, yield: 94%) as a light brown liquid; TLC System: 50% ethyl acetate in hexane. Rf-0.2.
	With dmap; N-ethyl-N,N-diisopropylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; water; at 150℃; for 0.166667h;Microwave irradiation;	8.1/ 8-Azabicyclo[3.2.1]oct-2-ene-3,8-dicarboxylic acid 8-tert-butyl ester 3-Trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (2.0 g, 5.6 mmol), hexacarbonylmolybdenum (0.74 g, 2.8 mmol), palladium diacetate (0.13 g, 0.56 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.31 g, 0.56 mmol), 4-dimethylaminopyridine (1.37 g, 11.2 mmol) and diisopropyl-ethylamine (2.24 ml, 12.9 mmol) are placed in 2.0 ml of water and 12 ml of dioxane in a microwave reaction vessel. The medium is microwave-heated at 150 C. for 10 min. The crude product is taken up with water and with dichloromethane. The organic phase is extracted with a saturated aqueous NaHCO3 solution. The aqueous phase is acidified with KHSO4 and then extracted with ethyl acetate. The organic phase is washed with water and then with a saturated aqueous sodium chloride solution and dried over MgSO4. After concentrating to dryness, 2.7 g of expected 8-aza-bicyclo[3.2.1]oct-2-ene-3,8-dicarboxylic acid 8-tert-butyl ester are obtained. [M+H+]=253

References: [1]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0344.
[2]Patent: US2011/294809,2011,A1 .Location in patent: Page/Page column 13.

21
[ 185099-68-7 ]
1,1-dimethylethyl (endo)-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

References: [1]Patent: US2011/294809,2011,A1 .

22
[ 185099-68-7 ]
3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid (trans-5-hydroxyadamantan-2-yl)amide [ No CAS ]

References: [1]Patent: US2011/294809,2011,A1 .

23
[ 185099-68-7 ]
endo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylic acid 8-tert-butyl ester [ No CAS ]

References: [1]Patent: US2011/294809,2011,A1 .

24
[ 1196396-14-1 ]
[ 185099-68-7 ]
[ 1222495-67-1 ]