1166829-70-4|Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate| Ambeed

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Quality Control of [ 1166829-70-4 ] Purity: 98% SDS Specification

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Product Details of [ 1166829-70-4 ]

CAS No. :	1166829-70-4
Formula :	C₁₆H₂₇BO₄
M.W :	294.19
SMILES Code :	O=C(OCC)CC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
MDL No. :	MFCD18383324
InChI Key :	QIAHVZXOVXLJRI-UHFFFAOYSA-N
Pubchem ID :	57992079

Safety of [ 1166829-70-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of [ 1166829-70-4 ]

* 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 [ 1166829-70-4 ]

[ 1166829-70-4 ] Synthesis Path-Downstream 1~35

1
[ 1166829-70-4 ]
[ 121219-03-2 ]
[ 1166829-68-0 ]

Yield	Reaction Conditions	Operation in experiment
43.5%	With potassium carbonate;1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride; In N,N-dimethyl-formamide; at 20 - 100℃; for 4h;	Intermediate 43-6: Ethyl 2-f4-f2-fluoro-4-hvdroxyphenyl)cvclohex-3-enyl)acetateA solution of Intermediate 43-7 (18.48 g, 62.82 mmol) in DMF (100 mL) was added to a stirred suspension of 4-bromo-3-fluorophenol (10 g, 52.36 mmol), potassium carbonate (21.71 g, 157.07 mmol) and [l,l-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.163 g, 1.41 mmol) in DMF (100 mL) at ambient temperature. The resulting suspension was stirred at 80 0C under nitrogen for 2 hours. The reaction was incomplete so the temperature was increased to 100 0C and the reaction mixture was stirred for a further 30 minutes and then further [l,l-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.163 g, 1.41 mmol) was added and the suspension was stirred at 100 0C for a further 45 minutes and then further [l,l-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (400 mg, 0.487 mmol) was added and the suspension was stirred at 100 0C for a further 45 minutes. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL) and 2M HCl (250 mL) was cautiously added. The aqueous layer was further extracted with EtOAc (3 x 200 mL) and the organic extracts were combined, washed saturated brine (300 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude <n="133"/>product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (6.34 g, 43.5 %) as a pale yellow oil.1H NMR (400 MHz, CDCl3) δ 1.27 (3H, t), 1.41 - 1.50 (IH, m), 1.85 - 1.95 (2H, m), 2.14 - 2.21 (IH, m), 2.32 (2H, d), 2.32 - 2.48 (3H, m), 4.16 (2H, q), 4.98 (IH, s), 5.81 (IH, s), 6.51 - 6.56 (2H, m), 7.05 - 7.09 (IH, m); m/z 277 (M-H)".

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10610 - 10629.
[2]Patent: WO2009/81195,2009,A1 .Location in patent: Page/Page column 131-132.

2
[ 58012-34-3 ]
[ 1166829-70-4 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10610 - 10629.
[2]Patent: WO2016/73774,2016,A2 .
[3]Patent: WO2016/73770,2016,A1 .
[4]Patent: WO2019/101188,2019,A1 .
[5]Patent: CN109956927,2019,A .
[6]Patent: WO2019/168866,2019,A1 .
[7]Patent: WO2020/233677,2020,A1 .
[8]Patent: WO2020/233676,2020,A1 .

3
[ 1166829-72-6 ]
[ 73183-34-3 ]
[ 1166829-70-4 ]

Yield	Reaction Conditions	Operation in experiment
73.5%		Step 2. Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate. A vial was charged with ethyl 2-[4-(trifluoromethanesulfonyloxy)cyclohex-3-en-l- yl] acetate (1.71 g, 0.01 mol), l,l'-bis(diphenylphosphino)ferrocene (150 mg, 0.27 mmol), potassium acetate (1.59 g, 16.2 mmol) and bis(pinacolato)diboron (1.51 g, 5.94 mmol). The vial was purged with N2 (x3), then dioxane (5.4 mL) was added and the mixture degassed for 5 min. [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (221 mg, 0.27 mol) was then added and the resulting mixture degassed again for 5 min. The resulting orange reaction mixture was stirred at 80C overnight. After 18 h, the reaction was cooled to room temperature. A saturated aqueous solution of NaHCCb (2 mL) was added and the aqueous layer was extracted with EtOAc (3 x 2 mL). The organic layers were combined and removed solvent in vacuo. Purified by flash chromatography (silica, 0- 10% MeOH/DCM) to afford the title compound (1.17 g, 73.5%). 1H NMR (400 MHz, CDCb) d 6.52 (d, / = 1.96 Hz, 1H), 4.14 (d, / = 7.09 Hz, 2H), 1.99 - 2.36 (m, 6H), 1.69 - 1.91 (m, 2H), 1.55 (s, 1H), 1.21 - 1.34 (m, 15H).
51%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere;	ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate 1b (3.0 g, 9.3 mmol), bis(pinacolato)diboron (2.9g, 11.4mmol), Potassium acetate (1.86 g, 19.0 mmol),[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (347 mg, 0.47 mmol) and 1,4-dioxane (40 ml) were heated to 80 C under nitrogen and stirred for overnight. Cooled to room temperature, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0-10% ethyl acetate / petroleum ether) used, To give the desired product ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate 35a (1.4 g, white solid), yield: 51%.
50.2%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;	In 2 liter 4 neck flask was taken ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate (120 g, 379 mmol), BISPN (106 g, 417 mmol), and potassium acetate (112 g, 1138 mmol) in 1,4-dioxane (1200 mL) under nitrogen. Nitrogen was purged inside the reaction mixture for 10 minutes. Then 1,1 ‘-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane complex (15.49 g, 18.97 mmol) was added. The reaction mixture was heated at 80 C for 16 h. The reaction mixture wasconcentrated. The residue was partitioned between ethyl acetate and water, filtered through CELITE bed. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3X). Combined organic layer was washed with water, brine, and dried over sodium sulfate and concentrated in vacuo. The crude material was purified through flash column chromatography, eluting with 0-10% ethyl acetate in petroleumether to give Intermediate 164E (pale yellow oil, 56 g, 190 mmol, 50.2% yield). GC-MS Anal. Calc’d for C,6H27B04, 294.20 found [M] 295.3. T = 1.10 mm (Method A). ‘H NMR (400MHz, chloroform-d) ö: 6.52 (dd, J=4.i, 1.9 Hz, 1H), 4.14 (q, J=7.i Hz, 2H), 2.62- 1.97 (m, 6H), 1.94- 1.68 (m, 2H), 1.33- 1.21 (m, 16H).

50.2%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere;	In 2 liter 4 neck flask was taken Intermediate 154D (120 g, 379 mmol), bis(pinacolato)diboron (106 g, 417 mmol), and potassium acetate (112 g, 1138 mmol) in 1,4-dioxane (1200 mL) under nitrogen. Nitrogen was purged inside the reaction mixture for 10 minutes. Then 1 , 1 '-bis(diphenylphosphino)ferrocene -palladium dichloride dichloromethane complex (15.49 g, 18.97 mmol) was added. The reaction mixture was heated at 80 C for 16 h. The reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water, filtered through CELITE bed. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3X). Combined organic layer was washed with water, brine, and dried over sodium sulfate and concentrated in vacuo. The crude material was purified through flash column chromatography, eluting with 0-10% ethyl acetate in petroleum ether to give Intermediate 154E (pale yellow oil, 56 g, 190 mmol, 50.2% yield). GC-MS Anal. Calc'd for Ci6H27B04, 294.20 found [M+H]+ 295.3. Tr = 1.10 min (Method A). 1H NMR (400MHz, chloroform-d) δ: 6.52 (dd, J=4.1, 1.9 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.62 - 1.97 (m, 6H), 1.94 - 1.68 (m, 2H), 1.33 - 1.21 (m, 16H)
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 95℃; for 18h;Inert atmosphere;	To a mixture of ethyl 2- (4- ( ( (trifluoromethyl) sulfonyl) oxy) cyclohex-3-en-1-yl) acetate (30.32 g, crude, 96 mmol, 1.00 eq) dissolved in 1, 4-dioxane (400 ml) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (26.8 g, 106 mmol, 1.10 eq) , CH 3COOK (38.02 g, 192 mmol, 2.00 eq) and Pd (dppf) Cl 2 (14.04 g, 19.2 mmol, 0.20 eq) were added. The mixture was stirred at 95 under nitrogen protection for 18 hours. The solution was filtered and concentrated to dryness. The crude (12.50 g, 100 %yield) was filtered through the silica gel pad and washed with PE/EA = 6: 1. The filtrate was concentrated to dryness to give a black oil (33.2 g, 112.3 %yield) which was used in next step without further purification. 1H NMR (CDCl 3) δ H 6.51 (s, 1H) , 4.13 (q, J = 7.2 Hz, 3H) , 1.99-2.40 (m, 9H) , 1.68-1.94 (m, 3H) and 1.18-1.26 (m, 12H) .

References: [1]Patent: WO2019/168866,2019,A1 .Location in patent: Page/Page column 99.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10610 - 10629.
[3]Patent: CN109956927,2019,A .Location in patent: Paragraph 0367-0368.
[4]Patent: WO2016/73774,2016,A2 .Location in patent: Paragraph 0418.
[5]Patent: WO2016/73770,2016,A1 .Location in patent: Paragraph 0473.
[6]Patent: WO2019/101188,2019,A1 .Location in patent: Paragraph 0242; 0244.
[7]Patent: WO2020/233677,2020,A1 .Location in patent: Paragraph 069; 073; 076-077.
[8]Patent: WO2020/233676,2020,A1 .Location in patent: Paragraph 0112; 0116.

4
[ 1166829-70-4 ]
[ 13631-21-5 ]
[ 1166829-95-3 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10610 - 10629.

5
[ 1166829-70-4 ]
[ 19524-06-2 ]
C₁₅H₁₉NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 85℃; for 24h;	Prepared using General Procedures Q, P, G, H, K, L, M. In General Procedure Q, 4-bromopyridine hydrochloride was used. In General Procedure P, AcOH and Degussa Pd/C were used. In General Procedure H, 3-chloroaniline was used. In General Procedure L, NaHC03 was replaced with K2C03. The desired products were obtained as a mixture of diastereomers as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.40- 8.33 (m, 2H), 7.33-7.23 (m, 3H), 7.17 - 7.08 (m, 2H), 7.14-7.04 (m, 1H), 2.56-2.42 (m, 2H), 2.32 (d, J= 7.2 Hz, 1H), 1.81 (t, J= 13.0 Hz, 3H), 1.63 - 1.16 (m, 5H), 1.15 - 0.98 (m, 1H) ppm. m/z 172.7 (M+2H)2+.

References: [1]Patent: WO2015/188085,2015,A1 .Location in patent: Paragraph 0279.

6
[ 51656-91-8 ]
[ 1166829-70-4 ]

References: [1]Patent: WO2016/73774,2016,A2 .
[2]Patent: WO2016/73770,2016,A1 .
[3]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 1143 - 1150.

7
[ 4746-97-8 ]
[ 1166829-70-4 ]

References: [1]Patent: WO2016/73774,2016,A2 .
[2]Patent: WO2016/73770,2016,A1 .
[3]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 1143 - 1150.

8
[ 391-77-5 ]
[ 1166829-70-4 ]
ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Sealed tube; Inert atmosphere;	Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate (Intermediate 154E) (5 g, 17.00 mmol) was taken up in dioxane (28.3 ml) and water (7.08 ml). 4-Chloro-6-fluoroquinoline (2.57 g, 14.15 mmol) was added followed by K2C03 (5.87 g, 42.5 mmol). Mixture was bubble with nitrogen gas for 5 minutes before the addition of Pd(Ph3P)4 (0.327 g, 0.283 mmol). After addition, reaction was vacated and backfilled with N2 three times and then sealed (sealed vial parafilmed) and heated to 100 C for 16 hours. The reaction was concentrated in vacuo and purified directly via silica gel flash column chromatography to give Intermediate 154F (4.22 g, 13.47 mmol, 95% yield). LC-MS Anal. Calc'd for C19H20FNO2 313.15, found [M+H]+ 314.1 Tr = 0.75 min (Method A
95%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube;	Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate (WO 2016/073774, PCT/US 2015/059316 Intermediate 164E) (5 g, 17.00 mmol) was taken up in dioxane (28.3 ml) and water (7.08 ml). 4-chloro-6-fluoroquinoline (2.57 g, 14.15 mmol) was added followed by K2CO3 (5.87 g, 42.5 mmol). The reaction mixture was bubble with nitrogen gas for 5 minutes before the addition of Pd(Ph3P)4 (0.327 g, 0.283 mmol). After addition, reaction was vacated and backfilled with N2 three times and then sealed (sealed vial parafilmed) and heated to 100 C for 16 hours. The reaction was concentrated in vacuo and purified directly via silica gel flash column chromatography to give Intermediate 10A (4.22 g, 13.47 mmol, 95 % yield). LC-MS Anal. Calc'd for C19H20FNO2 313.15, found [M+H] 314.1 Tr = 0.75 min (Method A).
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube;	Ethyl 2-(4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en-i - yl)acetate (Intermediate 164E) (5 g, 17.00 mmol) was taken up in dioxane (28.3 ml) and water (7.08 ml). 4-Chloro-6-fluoroquinoline (2.57 g, 14.15 mmol) was added followed by K2C03 (5.87 g, 42.5 mmol). Mixture was bubbled with nitrogen gas for 5 minutesbefore the addition of Pd(Ph3P)4 (0.327 g, 0.283 mmol). After the addition, the reaction was evacuated and backfilled with N2 three times and then sealed (sealed vial parafilmed) and heated to 100 C for 16 hours. The reaction was concentrated in vacuo and purified directly via silica gel flash colunm chromatography to give Intermediate 164F (4.22 g,13.47 mmol, 95% yield). LC-MS Anal. Calc’d for C,9H20FN02 313.15, found [M+H]314.1 T = 0.75 mm (Method A).

References: [1]Patent: WO2016/73770,2016,A1 .Location in patent: Paragraph 0392.
[2]Patent: WO2018/209049,2018,A1 .Location in patent: Paragraph 00176.
[3]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 494 - 501.
[4]Patent: WO2016/73774,2016,A2 .Location in patent: Paragraph 0419.

9
[ 5332-24-1 ]
[ 1166829-70-4 ]
ethyl 2-(4-(quinolin-3-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube;	Ethyl 2-(4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en-i - yl)acetate (5.26 g, 17.88 mmol) was taken up in Dioxane (40 mL) and Water (10.00 mL).3 -bromoquinoline (3.1 g, 14.90 mmol) was added followed by potassium carbonate (6. 18g, 44.7 mmol). Mixture was bubble with N2 for 5 minutes before addition of tetrakis (triphenylphosphine) palladium(0) (0.344 g, 0.298 mmol). After addition, reaction was evacuated and backfilled with N2 three times and then sealed and heated to 100 C for6h. The Reaction was diluted with EtOAc and water. Organic was separated andwashed with brine, dried over MgSO4, filtered and concentrated in vacuo and purified directly via ISCO (120 g column, 85 mL/min, 0-30% EtOAc in hexanes) to give Preparation 200A (4.47 g, 14.38 mmol, 96 % yield). 1H NMR (400MHz, CHLOROFORM-d) ö 9.05 (d, J=2.3 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.86 - 7.76 (m, 1H), 7.67 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.58 - 7.45 (m, 1H), 6.38 -6.18 (m, 1H), 4.20 (q, J7.1 Hz, 2H), 2.67 - 2.56 (m, 2H), 2.55 - 2.43 (m, 1H), 2.42 - 2.35 (m, 2H), 2.30 - 2.18 (m, 1H), 2.12 - 1.92 (m, 2H), 1.57 (ddt, J12.8, 10.8, 7.9 Hz, 1H), 1.36 - 1.27 (m, 3H) LC-MS: M+H=296.2 tr=0.74 mm (Method A)

References: [1]Patent: WO2016/73774,2016,A2 .Location in patent: Paragraph 0448.

10
[ 49713-56-6 ]
[ 1166829-70-4 ]
ethyl 2-(4-(6-(trifluoromethyl)quinolin-4-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	To a solution of 4-chloro-6-(trifluoromethyl)quinoline (2.05 g, 8.85 mmol), ethyl 2-(4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en-i -yl)acetate (3.1210.62 mmol) in 1,4-dioxane (35 mL) was added potassium carbonate (3.67 g, 26.6 mmol) and water (7 mL). The reaction mixture was purged with nitrogen stream for 3 mm, followed by addition of Pd(Ph3P)4 (0.409 g, 0.354 mmol). The resulting mixture washeated at 100 C under nitrogen stream for over night. The reaction mixture was cooled down and diluted with ethyl acetate and saturated NaHCO3 solution. The organic layer was separated and washed with sat. NaHCO3 solution, and dried over Mg504. The filtrate was concentrated in vacuo and the residue was purified via silica gel flash column chromatography, eluting with 0-50% ethyl acetate in hexane to give Intermediate 230A(oil, 3.0 g, 8.26 mmol, 93% yield). LC-MS Anal. Calc’d for C20H20F3N02, 363.14,found [M+H] 364.5. T = 0.97 mm (Method A). ‘H NMR (400MHz, CHLOROFORM-d)8.95 (d,J=4.5 Hz, 1H), 8.31 (s, 1H), 8.22 (d,J=8.8 Hz, 1H), 7.87 (dd,J=8.8, 2.0 Hz,1H), 7.29 (d, J=4.5 Hz, 1H), 5.86 (dd, J=2.8, 1.7 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 2.65 -2.24 (m, 5H), 2.15 - 1.96 (m, 2H), 1.73 - 1.54 (m, 2H), 1.36 - 1.29 (m, 3H)
93%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	To a solution of 4-chloro-6-(trifluoromethyl)quinoline (2.05 g, 8.85 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)acetate (3.12 g, 10.62 mmol) in 1,4-dioxane (35 mL) was added potassium carbonate (3.67 g, 26.6 mmol) and water (7 mL). The reaction mixture was purged with nitrogen stream for 3 min, followed by addition of Pd(Ph3P)4 (0.409 g, 0.354 mmol). The resulting mixture was heated at 100 C under nitrogen stream for over night. The reaction mixture was cooled down and diluted with ethyl acetate and saturated NaHC03 solution. The organic layer was separated and washed with sat. NaHCCb solution, and dried over MgS04. The filtrate was concentrated in vacuo and the residue was purified via silica gel flash column (0288) chromatography, eluting with 0-50% ethyl acetate in hexane to give Intermediate 11A (oil, 3.0 g, 8.26 mmol, 93% yield). LC-MS Anal. Calc'd for C20H20F3NO2, 363.14, found [M+H] 364.5. Tr = 0.97 min (Method A). NMR (400MHz, chloroform-d) δ: 8.95 (d, J=4.5 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.87 (dd, J=8.8, 2.0 Hz, 1H), 7.29 (d, J=4.5 Hz, 1H), 5.86 (dd, J=2.8, 1.7 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 2.65 - 2.24 (m, 5H), 2.15 - 1.96 (m, 2H), 1.73 - 1.54 (m, 2H), 1.36 - 1.29 (m, 3H).

References: [1]Patent: WO2016/73774,2016,A2 .Location in patent: Paragraph 0476.
[2]Patent: WO2018/209049,2018,A1 .Location in patent: Paragraph 00182.
[3]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 494 - 501.

11
[ 1166829-70-4 ]
[ 872365-91-8 ]
ethyl 2-(4-(6-(difluoromethyl)pyridin-2-yl)cyclohex-3-enyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 110℃; for 20h;Inert atmosphere;	To the reaction mixture of 2-bromo-6-(difluoromethyl)pyridine (1.55 g, 7.45 mmol), ethyl 2-(4-(4,4 ,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en-iyl)acetate (2.52 g, 8.57 mmol) in 1,4-Dioxane (20 mL) was added K2C03 (7.45 mL, 22.36 mmol) solution and the resulting mixture was purged with nitrogen stream for 3mm, followed by addition of Pd(Ph3P)4 (0.43 1 g, 0.373 mmol) and the reaction mixture was further purged with nitrogen stream and then heated at 110 C under nitrogen for 20 h. The reaction mixture was diluted with brine and ethyl acetate. The organic layer was separated, dried over MgSO4. The filtrate was concentrated in vacuo.and the residue was purified via silica gel flash column chromatography, eluting with 0-20% ethyl acetate inhexane to give Intermediate 231A (oil, 2.2 g, 7.45 mmol, 99% yield). LC-MS Anal.Calc’d for C,6H,9F2N02, 295.14, found [M+H] 296.2 . T = 1.10 mm (Method A). ‘HNMR (400MHz, METHANOL-d4) ö: 7.92 - 7.80 (m, 1H), 7.60 (dd, J=8.0, 0.8 Hz, 1H),7.47 (d, J7.7 Hz, 1H), 6.71 (dd, J3.1, 2.0 Hz, 1H), 6.65 - 6.44 (m, 1H), 4.20 - 4.08 (m,2H), 2.79 - 2.65 (m, 1H), 2.56 - 2.39 (m, 2H), 2.36 (d, J=7.0 Hz, 2H), 2.20 - 1.92 (m, 3H),1.48 (dtd,J=13.0, 10.6, 5.5 Hz, 1H), 1.30- 1.22 (m, 3H)

References: [1]Patent: WO2016/73774,2016,A2 .Location in patent: Paragraph 0482.

12
[ 1166829-70-4 ]
(R)-2-((1S,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl) propanoic acid [ No CAS ]

References: [1]Patent: WO2016/73770,2016,A1 .
[2]Patent: WO2019/101188,2019,A1 .
[3]Patent: WO2019/101188,2019,A1 .
[4]Patent: WO2020/233677,2020,A1 .
[5]Patent: WO2020/233676,2020,A1 .
[6]Patent: WO2021/96542,2021,A1 .

13
[ 1166829-70-4 ]
ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetate [ No CAS ]

References: [1]Patent: WO2016/73770,2016,A1 .
[2]Patent: WO2018/209049,2018,A1 .
[3]Patent: WO2019/101188,2019,A1 .
[4]Patent: WO2020/233677,2020,A1 .
[5]Patent: WO2020/233676,2020,A1 .
[6]Patent: WO2021/96542,2021,A1 .

14
[ 1166829-70-4 ]
2-(4-(6-fluoroquinolin-4-yl)-cyclohexyl)acetic acid [ No CAS ]

References: [1]Patent: WO2016/73770,2016,A1 .
[2]Patent: WO2019/101188,2019,A1 .
[3]Patent: WO2020/233677,2020,A1 .
[4]Patent: WO2020/233676,2020,A1 .
[5]Patent: WO2021/96542,2021,A1 .

15
[ 1166829-70-4 ]
(R)-3-((R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

References: [1]Patent: WO2016/73770,2016,A1 .
[2]Patent: WO2019/101188,2019,A1 .
[3]Patent: WO2020/233677,2020,A1 .
[4]Patent: WO2020/233676,2020,A1 .
[5]Patent: WO2021/96542,2021,A1 .

16
[ 63927-22-0 ]
[ 1166829-70-4 ]
C₁₉H₂₁NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl) palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃;	General procedure: To ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate* (1.1 eq), aryl halide (1.0 eq), and Cs2C03 (2.2 eq), in 1 ,4-dioxane/water (10: 1 by volume, 0.25 M) was added catalytic amount of PEPPSI-IPr (2 mol.percent). The resulting reaction mixture was heated to 100 °C for 2-12 hours, upon which the crude reaction mixture was concentrated and loaded on silica gel. The crude reaction mixture was purified employing silica gel chromatography. * Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)acetate is a known compound that can be prepared from commercially available 1 ,4- dioxaspiro[4.5]decan-8-one using the procedures outlined in Barlind, J.G. et al, J. Med. Chem., 55: 10610-10629 (2012).

References: [1]Patent: WO2016/73770,2016,A1 .Location in patent: Paragraph 0248-0249; 0326.

17
[ 1166829-70-4 ]
[ 121219-03-2 ]
[ 1166829-64-6 ]
[ 1166829-66-8 ]

References: [1]Patent: WO2009/81195,2009,A1 .

18
[ 1166829-70-4 ]
[ 887583-90-6 ]
ethyl 2-(4-(2-(trifluoromethyl)pyridin-4-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.4%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;	A mixture of 4-bromo-2-trifiuoromcthyi)pyridine (1.5 mL, 1135 mmoi), ethyl 2-(-(4,4,5,5- tetramethyl- I ,3.2-dioxahoroian-2-yi)cvciohex-3-en- I -vl)acetate (3.44 g, Ii .69 mrnol). Na2CO3 (4.81 g, 45.4 rnmol), and Pd(Ph3P)4 (0.656 g, 0.567 mmol) in dioxane (105 mL) and water (35.0 rnL) was heated at 100 C overnight. The reaction was quenched with water and diluted with EtOAc. Layers were separaled, The aqueous phase was extracted with EtOAc (3X). The organics were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-45% EtOAc in hexanes over 27 mm, tr = 15, 23 mm) gave ethyl 2- (4-(2-(trifluorornethyl)pvridin-4-yl)cyclohex-3-en- I -vi)acetate (2.7477 g, & 33 mrnol, 73.4 % yield) as a colorless residue. ES MS (M-FI-I)± 314.1. HPLC Peak 1.03 minutes. HPLC conditions: A.

References: [1]Patent: WO2018/39512,2018,A1 .Location in patent: Paragraph 00262.

19
[ 1166829-70-4 ]
[ 128071-79-4 ]
ethyl 2-(4-(2-fluoro-3-methylpyridin-4-yl)cyclohex-3-en-1-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; Sealed tube;	To a reaction flask containing a solution of ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-en-l-yl)acetate (5.93 g, 20.17 mmol) in Dioxane (120 mL) were added 4-bromo-2-fluoro-3-methylpyridine (3.72 g, 19.58 mmol), Water (40.0 mL) and Na2C03 (8.30 g, 78 mmol). After the mixture was degassed with Ar for 10 min, Pd(Ph3P)4 (1.131 g, 0.979 mmol) was added. The flask was sealed and the mixture was heated to 100 C over night. The reaction mixture was cooled down and diluted with EtOAc and water, plus sonication to break up solids, then transferred to a separation funnel. The layers were separated and the aqueous layer was extracted once more with EtOAc. The organic layers were combined, washed with brine, dried over anhyd Na2S04, filtered and concentrated in vacuo to afford a white precipitate in a pale gold residue. The extract was purified via silica gel flash column chromatography, eluting with 0-25% ethyl acetate in hexane to give (0534) Intermediate 27B (gold pale oil, 5.01 g, 17.72 mmol, 91% yield). LC-MS Anal. Calc'd for C16H20FNO2 277.15, found [M+H] 278.1. Tr = 1.02 min (Method A). NMR (400MHz, chloroform-d) δ 7.94 (d, J=5.0 Hz, 1H), 6.89 (dd, J=5.1, 0.9 Hz, 1H), 5.79 - 5.49 (m, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.55 - 2.28 (m, 4H), 2.26 - 2.11 (m, 5H), 2.00 - 1.86 (m, 2H), 1.55 - 1.41 (m, 1H), 1.29 (t, J=7.2 Hz, 3H).

References: [1]Patent: WO2018/209049,2018,A1 .Location in patent: Paragraph 00244.
[2]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 1143 - 1150.

20
[ 1166829-70-4 ]
ethyl 2-(4-(2,3-difluoropyridin-4-yl)cyclohex-3-en-1-yl)butanoate [ No CAS ]