[ CAS No. 924287-65-0 ] {[proInfo.proName]}

Name: 924287-65-0|Methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate|98%
Brand: Ambeed
SKU: A121631
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Quality Control of [ 924287-65-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 924287-65-0 ]

SDS Specification

Alternatived Products of [ 924287-65-0 ]

Product Details of [ 924287-65-0 ]

CAS No. :	924287-65-0	MDL No. :	MFCD23705964
Formula :	C₉H₅BrFNO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SGWVZBCLQAXEJM-UHFFFAOYSA-N
M.W :	290.11	Pubchem ID :	57527206
Synonyms :

Calculated chemistry of [ 924287-65-0 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.11
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	58.56
TPSA :	67.43 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.52
Log Po/w (XLOGP3) :	3.36
Log Po/w (WLOGP) :	3.4
Log Po/w (MLOGP) :	2.48
Log Po/w (SILICOS-IT) :	4.05
Consensus Log Po/w :	3.16

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.07
Solubility :	0.0248 mg/ml ; 0.0000856 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.45
Solubility :	0.0102 mg/ml ; 0.0000352 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.17
Solubility :	0.0196 mg/ml ; 0.0000675 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.41

Safety of [ 924287-65-0 ]

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

Application In Synthesis of [ 924287-65-0 ]

* 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 [ 924287-65-0 ]
Downstream synthetic route of [ 924287-65-0 ]

[ 924287-65-0 ] Synthesis Path-Upstream 1~4

1
[ 924287-64-9 ]
[ 924287-65-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0 - 20℃; for 4 h;	To a solution of CuBr2 (2.7 g, 12 mmol) in CH3CN (30 mL) at 0 °C was added t-BuONO (1.65 g, 16.0 mmol) dropwise,followed by the addition of methyl 2-amino-4-fluorobenzo[djthiazole-6-carboxylate (1.8 g,8.0 mmol) in one portion. The reaction was stirred for 4 h at rt before diluting with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound (2.0 g, 86percent) as a yellow solid. MS (ES+) C10H8BrNO3S requires: 289, found: 290 [M+Hf’.
507.9 mg	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0 - 30℃;	To a 250 rnL rmmd-bottom Hask was added CuBr2 (2.96 g, 1.50 equiv.) :md MeCN(l 00 mL) The resulting mixture vvas cooled at (l'C and t-BuONO (2.4 mL) was addeddrop'.vise followed by the batchvvise addition of ethyl 2-amino-4-t1uoro- L3-benzothiazole-6-5 carboxylate A-lb (2 g, 8.84 mmol, 1.0 equiv.) at 0 °C. The reaction mixture was stirredovemight at 30 °C. and then concentrated under reduced pressure. The crude product waspurified by Flash-Prep-HPLC, using the following conditions: Colunm, silica gel; mobilephase, eluting with PE:EA, 100:0 to 90:10 over 10 min; Detector, UV 254 nm, to afford507.9 mg (20percent) of methyl 2-bromo-4-fluoro-1,3-benzothiazole-6-ca.rboxylate A-las a light10 yellow solid. 1H NMR (300 MHz, DMSO-d6) 8: 8.67 (d, J = 1.4 Hz, lH), 7.84 (dt, J = 11.1,1.2 Hz, lH), 3.92 (s, 3H). MS (ES, mlz): [M+ 1] = 290.

Reference： [1] Patent: WO2018/81276, 2018, A1, . Location in patent: Page/Page column 155
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 9960 - 9973
[3] Patent: WO2007/16392, 2007, A2, . Location in patent: Page/Page column 35; 48-49
[4] Patent: WO2012/87519, 2012, A1, . Location in patent: Page/Page column 84; 85; 86
[5] Patent: WO2012/87520, 2012, A1, . Location in patent: Page/Page column 43; 44
[6] Patent: WO2018/39386, 2018, A1, . Location in patent: Page/Page column 129; 130

2
[ 185629-31-6 ]
[ 924287-65-0 ]

Reference： [1] Patent: WO2012/87520, 2012, A1,
[2] Patent: WO2018/81276, 2018, A1,
[3] Patent: WO2012/87519, 2012, A1,

3
[ 185629-32-7 ]
[ 924287-65-0 ]

Reference： [1] Patent: WO2012/87520, 2012, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 9960 - 9973
[3] Patent: WO2018/39386, 2018, A1,
[4] Patent: WO2018/81276, 2018, A1,
[5] Patent: WO2012/87519, 2012, A1,

4
[ 403-21-4 ]
[ 924287-65-0 ]

Reference： [1] Patent: WO2012/87520, 2012, A1,
[2] Patent: WO2012/87519, 2012, A1,

[ 924287-65-0 ] Synthesis Path-Downstream 1~88

1
[ 924287-64-9 ]
[ 924287-65-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 4h;	To a solution of CuBr2 (2.7 g, 12 mmol) in CH3CN (30 mL) at 0 C was added t-BuONO (1.65 g, 16.0 mmol) dropwise,followed by the addition of methyl 2-amino-4-fluorobenzo[djthiazole-6-carboxylate (1.8 g,8.0 mmol) in one portion. The reaction was stirred for 4 h at rt before diluting with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound (2.0 g, 86%) as a yellow solid. MS (ES+) C10H8BrNO3S requires: 289, found: 290 [M+Hf?.
27.6%	With tert.-butylnitrite; copper(ll) bromide; at 0 - 35℃; for 0.5h;	2-Amino-4-fluorobenzo[d]thiazolidine-6-carboxylic acid methyl ester (452 mg, 2.0 mmol), copper bromide (892 mg, 4.Ommol), acetonitrile (10 mL) in. T-butyl nitrite (412 mg, 4.Ommol) was added dropwise at 0 C, and the addition was completed.The reaction was stirred at 35 C for 0.5 hours, and water and ethyl acetate (100 mL) were added, and the organic phase was concentrated and purified by silica gel column chromatography (ethyl ether: ethyl acetate = 5:1).The title compound (160 mg, yield: 27.6%) was obtained.
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 20h;	4. Methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate; EPO <DP n="50"/>[00157] To a mixture of copper (II) bromide (1.79 g, 7.91 mmol) in acetonitrile (30 niL) was added tert-butyl nitrite (1.35 mL, 90%, 10.2 mmol) at O0C, followed by the addition of the above prepared crude methyl 2-amino-4-fluorobenzo[d]thiazole-6- carboxylate (1.17 g) in one portion. The resulting mixture was stirred at rt for 20 hr before it was diluted with AcOEt (150 mL), washed successively with water and brine, and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was subjected to silca gel chromatography (7% AcOEt/hexane) to afford the title compound (0.335 g, 10% yield over two steps) as a pale solid.

	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 30℃; for 48h;	Into a 2000-mL 3- necked round-bottom flask, was placed a suspension of CuBr2 (61 g, 272.32 mmol, 1.54 equiv) in acetonitrile (800 mL). This was followed by the addition of t-BuONO (48 mL) at 0 C dropwise over the course of 10 min. To this solution was added methyl 2-amino-4- fluorobenzo[d]thiazole-6-carboxylate (40 g, 176.99 mmol, 1.00 equiv), and the reaction mixture was stirred at 30C for 48 h. The reaction mixture was then diluted with EtOAc (1 L), and the organic layer was washed with water (3x400 mL) and brine (3x400 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1: 100-1:5) to give methyl 2-bromo-4- fluorobenzo[d]thiazole-6-carboxylate as a white solid. LCMS (m z): Calc'd for [M+l]+=290, found 290. 1H-NMR: (CDCl3, ppm) 8.22 (d, 1H, J =0.9 Hz), 7.86 (dd, 1H, J = 1.2,9.6Hz), 3.99(s, 3H).
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 30℃; for 48h;	Into a 2000-mL 3- necked round-bottom flask, was placed a suspension of CuBr2 (61 g, 272.3 mmol, 1.5 equiv) in acetonitrile (800 mL). This was followed by the addition of t-BuONO (48 mL) at 0 C in 10 min. To this was added methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate (40 g, 177.0 mmol, 1.0 equiv). The resulting solution was stirred for 48 h at 30C. The resulting solution was diluted with 1000 mL of EtOAc. The organic layer was washed with water (3x400 mL) and brine (3x400 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether(1: 100-1 :5), and methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate was obtained as a white solid. LCMS (m z): Calc'd for C9H5BrFN02S [M+l]+=290, found 290. 1H-NMR:(CDC13, ppm): 8.22 (d, 1H, J =0.9 Hz), 7.86 (dd, 1H, J = 1.2,9.6Hz), 3.99(s, 3H).
507.9 mg	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 30℃;	To a 250 rnL rmmd-bottom Hask was added CuBr2 (2.96 g, 1.50 equiv.) :md MeCN(l 00 mL) The resulting mixture vvas cooled at (l'C and t-BuONO (2.4 mL) was addeddrop'.vise followed by the batchvvise addition of ethyl 2-amino-4-t1uoro- L3-benzothiazole-6-5 carboxylate A-lb (2 g, 8.84 mmol, 1.0 equiv.) at 0 C. The reaction mixture was stirredovemight at 30 C. and then concentrated under reduced pressure. The crude product waspurified by Flash-Prep-HPLC, using the following conditions: Colunm, silica gel; mobilephase, eluting with PE:EA, 100:0 to 90:10 over 10 min; Detector, UV 254 nm, to afford507.9 mg (20%) of methyl 2-bromo-4-fluoro-1,3-benzothiazole-6-ca.rboxylate A-las a light10 yellow solid. 1H NMR (300 MHz, DMSO-d6) 8: 8.67 (d, J = 1.4 Hz, lH), 7.84 (dt, J = 11.1,1.2 Hz, lH), 3.92 (s, 3H). MS (ES, mlz): [M+ 1] = 290.
507.9 mg	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 30℃;	To a 250 mL round-bottom flask was added CuBr2 (2.96 g, 1.50 equiv.) and MeCN (100 mL). The resulting mixture was cooled at 0C, and t-BuONO (2.4 mL) was added dropwise followed by the batchwise addition of ethyl 2-amino-4-fluoro-l,3-benzothiazole-6-carboxylate 30b (2 g, 8.84 mmol, 1.0 equiv.) at 0C. The reaction mixture was stirred overnight at 30C and then concentrated under reduced pressure. The crude product was purified by Flash-Prep- HPLC, using the following conditions: Column, silica gel; mobile phase, eluting with PE:EA , 100:0 to 90: 10 over 10 min; Detector, UV 254 nm, to afford 507.9 mg (20%) of methyl 2- bromo-4-fluoro-l,3-benzothiazole-6-carboxylate 30c as a light yellow solid. 1HNMR (300 MHz, DMSO-d6) delta: 8.67 (d, J = 1.4 Hz, 1H), 7.84 (dt, J = 11.1, 1.2 Hz, 1H), 3.92 (s, 3H). MS (ES, m/z): [M+l] = 290.
507.9 mg	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 30℃;	To a 250 mL round-bottom flask containing CuBr2 (2.96 g, 1.5 equiv.) and MeCN (100 mL) at 0 C was added tert- uONO (2,4 mL) dropwise followed by the batchwise addition of methyl 2-amino-4-fluoro-l ,3-benzothiazole-6-carboxylate A-lb (2 g, 8.84 mmol, 1.0 equiv.). The resulting mixture was stirred overnight at 30 C and then concentrated in vacuo. The crude product was purified by Flash-Prep-HPLC, using the following conditions: Column, silica gel; mobile phase, PE:EtOAc = 100:0 increasing to PE:EtOAc ==9 0: 10 within 10 min; Detector, UV 254 nm, to afford methyl 2-bromo-4-fluoro-l,3-benzothiazole-6-carboxylate Al (507.9 mg, 20%) as a light yellow solid. IW (300 MHz, DMSO-de) delta: 8.67 (d, J - 1 .4 Hz, ), 7.84 (dt, J ---- 11.1, 1.2 Hz, 1H), 3.92 (s, 3H); MS (ES, m/z): [M+l] = 290.

Reference： [1]Patent: WO2018/81276,2018,A1 .Location in patent: Page/Page column 155
[2]Patent: CN109265471,2019,A .Location in patent: Paragraph 0438; 0446; 0447; 0448
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[4]Patent: WO2007/16392,2007,A2 .Location in patent: Page/Page column 35; 48-49
[5]Patent: WO2012/87519,2012,A1 .Location in patent: Page/Page column 84; 85; 86
[6]Patent: WO2012/87520,2012,A1 .Location in patent: Page/Page column 43; 44
[7]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 129; 130
[8]Patent: WO2019/55808,2019,A1 .Location in patent: Page/Page column 149-150
[9]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00328

2
[ 924287-65-0 ]
[ 924287-66-1 ]

Yield	Reaction Conditions	Operation in experiment
89%		5. (2-Bromo-4-fluorobenzo[d]thiazol-6-yl)methanol[00158]; To a solution of <strong>[924287-65-0]methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate</strong> (0.335 g, 1.15 mmol) in toluene (10 mL) and THF (5 mL) was added Dibal-H (4.8 mL, 4.8 mmol) at -780C over 10 min. The resulting mixture was allowed to warm to rt and stirred at rt for 3 hr before it was poured into ice cold water (100 mL). The mixture was stirred at rt for 30 min and then filtered through Celite 545. The organic layer was separated and the aqueous layer was extracted twice with AcOEt. The combined organic phase was dried over anhydrous MgSO4 and concentrated under vacuum. Evaporation of solvent under vacuum gave the title compound (0.269 g, 89% yield) as a white solid.
66%	With diisobutylaluminium hydride; In tetrahydrofuran; at 0 - 20℃; for 19h;	DIBAL-H (17.3 mL, 17.3 mmol, 1M in THF) was added to a mixture of methyl 2-bromo-4-fluorobenzo[djthiazole-6-carboxylate (2.0 g, 6.9 mmol) in THF (20 mL) at 0C. The resulting mixture was stirred at rt for 16 h. An additional portion of DIBAL-H (13.8 mL, 13.8 mmol, 1.OM in THF) was added. After stirring at rt for 3 h, the reaction was diluted with water, the solid filtered, and the filtrate wasextracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound (1.2 g, 66%) as a yellow oil. MS (ES+) C8H5BrFNOS requires: 261, found:262 [M+Hj.

Reference： [1]Patent: WO2007/16392,2007,A2 .Location in patent: Page/Page column 35; 49
[2]Patent: WO2018/81276,2018,A1 .Location in patent: Page/Page column 155

3
[ 185629-31-6 ]
[ 924287-65-0 ]

Reference： [1]Patent: WO2012/87520,2012,A1
[2]Patent: WO2018/81276,2018,A1
[3]Patent: WO2012/87519,2012,A1
[4]Patent: CN109265471,2019,A

4
[ 185629-32-7 ]
[ 924287-65-0 ]

Reference： [1]Patent: WO2012/87520,2012,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[3]Patent: WO2018/39386,2018,A1
[4]Patent: WO2018/81276,2018,A1
[5]Patent: WO2012/87519,2012,A1
[6]Patent: CN109265471,2019,A
[7]Patent: WO2019/55808,2019,A1
[8]Patent: WO2018/39384,2018,A1
[9]Patent: US2019/194216,2019,A1

5
[ 924287-65-0 ]
[ 1383816-29-2 ]

Reference： [1]Patent: WO2012/87519,2012,A1

6
[ 924287-65-0 ]
[ 1383816-38-3 ]

Reference： [1]Patent: WO2012/87519,2012,A1

7
[ 924287-65-0 ]
[ 1383822-31-8 ]
[ 1383816-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In ISOPROPYLAMIDE; at 60℃; for 1h;	Into a 25 -mL round-bottom flask equipped with a stir bar was added sequentially 4-((8- azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-IH) (0.525 g, 1.29 mmol), 3.6 mL of Nu,Nu-dimethylacetamide, cesium carbonate (1.08 g, 3.31 mmol), and <strong>[924287-65-0]methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate</strong> (1.12 g, 3.87 mmoles). After stirring the resulting slurry at room temperature for 10 minutes, the mixture was then warmed to 60 C and stirred for 1 h. The reaction slurry was allowed to cool to RT, and was diluted with 200 mL of ethyl acetate and washed with water (3 x 30 mL). The organic extracts were concentrated under vacuum and directly purified using normal phase silica gelchromatography (40 g silica column) with a 15 min gradient of 10 % to 60 % ethylacetate/hexanes. Desired fractions were concentrated in vacuo, and the resulting residue crystallized upon standing to give the desired product as a white crystalline solid.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[2]Patent: WO2012/87519,2012,A1 .Location in patent: Page/Page column 124

8
[ 403-21-4 ]
[ 924287-65-0 ]

Reference： [1]Patent: WO2012/87520,2012,A1
[2]Patent: WO2012/87519,2012,A1

9
[ 924287-65-0 ]
4-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole [ No CAS ]
methyl 2-[(1R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl acetamide; at 20 - 60℃; for 1.16667h;	Methyl 2-[(1 R,3r,5S)-3-(i5-cvclopropyl-3-r2-(trifluoromethoxy)phenyll-1 ,2-oxazol-4- yl}methoxy)-8-azabicvcloi3.2.1 loctan-8-yll-4-fluoro-1 ,3-benzothiazole-6-carboxylate (1 -1 A). Into a 25-mL round-bottom flask equipped with a stir bar was added sequentially 4-(((1 R,3r,5S)- 8-azabicyclo[3.2.1 ]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (1 .29 mmol), N,N-dimethylacetamide (3.6 mL), cesium carbonate (3.31 mmol), and methyl 2- bromo-4-fluorobenzo[d]thiazole-6-carboxylate (3.87 mmol). After stirring the resulting slurry at room temperature for 10 minutes, the mixture was then warmed to 60 C and stirred for 1 h. The reaction slurry was allowed to cool to room temperature, and was diluted with 200 mL of ethyl acetate and washed with water (3 chi 30 mL). The organic extracts were concentrated under vacuum and directly purified using normal phase silica gel chromatography (40 g silica column) with a 15 min gradient of 10 % to 60 % ethyl acetate/hexanes. Desired fractions were concentrated in vacuo, and the resulting residue crystallized upon standing to give methyl 2- [(1 R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1 ,2-oxazol-4-yl}methoxy)-8- azabicyclo[3.2.1 ]octan-8-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylate (1-1 A) as a white crystalline solid. MS (m/z) : 618.2 (M+1 ).

Reference： [1]Patent: WO2016/97933,2016,A1 .Location in patent: Page/Page column 18

10
[ 924287-65-0 ]
4-(((1R,5S)-8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole [ No CAS ]
2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2016/97933,2016,A1

11
[ 924287-65-0 ]
[ 1383822-31-8 ]
[ 1383816-29-2 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973

12
[ 924287-65-0 ]
[ 1383822-36-3 ]
[ 1383816-45-2 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973

13
[ 924287-65-0 ]
[ 1383822-36-3 ]
[ 1383816-46-3 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973

14
[ 924287-65-0 ]
[ 1383822-34-1 ]
[ 1383816-31-6 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973

15
[ 924287-65-0 ]
[ 1383822-34-1 ]
[ 1383816-30-5 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973

16
[ 924287-65-0 ]
(1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy)-2-azabicyclo[2.2.1]heptane [ No CAS ]
2-[(1S,4S,5R)-5-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl}methoxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

17
[ 924287-65-0 ]
(1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy)-2-azabicyclo[2.2.1]heptane [ No CAS ]
methyl 2-[(1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;	To a 100-n1L round-bottom flask was added (1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-l,2-oxazol-4-y]methoxy)-2-azahicydo2.2.l]heptane 19d (125 mg,0.33 mmoL LO equiv ), methyl 2-bromo-4-fluoro-l ,3-benzoihiazole-6-carboxylate A-l (J 15mg, 0.40 mmol, 1.20 equiv.), DMA (.5 mL), and Cs2C03 (323 mg, 0.99 mmol, 3.0 equiv.).The resulting mixture was stirred at 60 '-'C overnight. The mixture was then diluted with H2020 and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washedv~th brine (30 mL x 2), dried over anhydrous sodium sulfate, flltered, ::md concentrated underreduced pressure. The residue was purified by silica gel column chromatography eluting vvithethyl acetate/petroleum ether (1:3) to afford 160 mg (82~6) ofmethyl2-[(1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethy l)pheny l ]-1 ,2-oxazol-4-yl]methoxy)-2-2.5 azabicyclo[2.2.1 ]heptan-2-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylate l9e a<; a light yellowoil.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 167; 169

18
[ 924287-65-0 ]
( 1S,4S,.5R)-5-[ (3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
2-[(1S,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

19
[ 924287-65-0 ]
( 1S,4S,.5R)-5-[ (3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
methyl 2-[(1S,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃; for 2h;	To a 50-n1L round-bottom t1ask was added (lS,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-1 ,2-oxazol-4-yl)methoxy ]-2-azabicyclo[2.2.l]hepta.ne 2lh (166 mg, 0.52 mmol,10 1.0 equiv.), methyl2-bromo-4-fluoro-L3-benzothiazole-6-carboxylate A-l (183 rng, 0.63mmol, 1.20 equiv.), DMA (5 mL), Cs2C01 (343 mg, 1.05 mmoL 2.0 equiv.). The resultingmixtme wa;;; stirred at 60C for 2h. The mixtme vas diluted with off-bO. The aqueousmixture was extracted with of ethyl acetate (50 mL x 3): the combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, tl.ltered, and concentrated under15 reduced pressme. The residue was purified by silica gel colunm chromatography eluting Vithethyl acetate/petroleum ether (l :5) to afl'ord 131 mg ( 48(%) of methy 1 2-[(1 S,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-l ,2-oxazol-4-yl)rnethoxy ]-2-azabicyclo[ 2.2.1 ]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate 2li as a white oil.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 172; 175

20
[ 924287-65-0 ]
( 1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
2-[(1S,4S,5R)-5-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

21
[ 924287-65-0 ]
( 1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
methyl 2-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃; for 6h;Inert atmosphere;	To a 25-mL round-bottom flask purged and maintained under an inert atmosphere ofnitrogen was added (lSAS,SR)-5-[[3-(2,6-dichlorophenyl)-5-(l-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.l]heptane 24d ( 40 mg, 0.10 mmol, 1.0 equiv.),Cs£(h (65 mg, 0.20 mmoL 2.0 equiv ), methyl2-bromo-4-t1uoro-l ,3-benzoihiazole-6-carboxylate A-1 (35 mg, 0.12 mmol, 1.20 equiv.), and DMA (l mL) and the resulting mixture15 was stirred at 60 C for 6 h. H20 was added and the aqueous mixture was extracted withethyl acetate (200 mL). The organic extract v.·as washed with brine (30 mL x 4), dried overanhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residuevas purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether(l: 5) to yield 40 mg ( 66%) of methyl 2-[(1 S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(l-20 t1uorocydopropyl)-1 ,2-oxazol-4-y]methoxy ]-2-azabicydo[2.2.l]heptan-2-yl]-4-f1uoro-l,3-benzothiazole-6-carboxylate 24e as a light yellow oil

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 182; 184

22
[ 924287-65-0 ]
2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-N-methanesulfonyl-1,3-benzothiazole-6-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

23
[ 924287-65-0 ]
2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-N-(propane-1-sulfonyl)-1,3-benzothiazole-6-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

24
[ 924287-65-0 ]
N-(cyclopropanesulfonyl)-2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

25
[ 924287-65-0 ]
(1S,4S,5R)-2-[ 4-fluoro-6-(methanesulfonylcarbamoyl)-1,3-benzothiazol-2-yl]-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

26
[ 924287-65-0 ]
( 1S,4S,5R)-2-{ 4-fluoro-6-[(propane-1-sulfonyl)carbamoyl]-1,3-benzothiazol-2-yl}-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

27
[ 924287-65-0 ]
(1S,4S,5R)-2-{6-[(cyclopropanesulfonyl)carbamoyl]-4-fluoro-1,3-benzothiazol-2-yl}-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

28
[ 924287-65-0 ]
2-[(1R,4R,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

29
[ 924287-65-0 ]
2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

30
[ 924287-65-0 ]
2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-{spiro[2.5]octan-6-yl}-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

31
[ 924287-65-0 ]
2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichloro-4-methoxyphenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

32
[ 924287-65-0 ]
2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichloro-4-hydroxyphenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

33
[ 924287-65-0 ]
2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

34
[ 924287-65-0 ]
(1S,4S,5S)-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1S,4S,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

35
[ 924287-65-0 ]
(1S,4S,5S)-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1S,4S,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a l 00-mL round-bottom flask purged and maintained under an inert atmosphere ofnitrogen was added a solution of (l S,4S,5S )-2-azabicyclo[2.2.1 ]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazoe-4-carboxylate 34b (200 mg, 0.51 mmol, 1.0 equiv.) inDMA (10 rnL), rnethyl 2-bromo-4-fluoro-1,3-benzothiazole-6-carboxylaie A-1 (178 mg, 0.61mmol, 1.20 equiv), and Cs2C03 (498 mg, 153 mmol, 3.0 equiv.) and the resulting mixture15 was stirred at 60 C overnight. The mixture was then diluted with 200 mL of ethyl acetateand the organic extract was washed v.·ith brine (30 mL x 3), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residue Vas purified by silicagel column chromatography eluting with ethyl acetate/petroleum ether (1:3) to afford 230 mg(7 5%) of methyl 2-[(1 S,4S,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-l ,2-oxazol-4-20 y l]cm·bony loxy ]-2-azabicyclo[ 2.2.1 ]heptan-2-yl]-4-fluoro-1 ,3-benzothiazole-6-carhoxy late34c as a light yellow solid.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 196; 197

36
[ 924287-65-0 ]
(1S,4S,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
methyl 2-[(1S,4S,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 1 00-mL round-bottom flask purged and maintained under an inert atmosphere ofnitrogen -vvas added a solution of ( l S,4S,5S)-5-[[5-cyclopropyl-3-(2,6-dichloropheny l)-1 ,2-oxazol-4-yl]methoxy ]-2-azabicyclo[2.2.l]heptane 36c (50 mg, 0.13 mmol, 1.0 equiv.) in15 DMA (5 mL), methyl2-bromo-4-fluoro-1,3-benzothiazole-6-carboxylate A-1 (46 mg, 0.16mmol, 1.2 equiv.), and Cs2C03 (129 mg, 0.40 mmol, 3.0 equiv.) and the resulting mixturevas stirred at 60 C ovemight. The resulting solids were filtered off and the filtrate wasconcentrated under reduced pressure to provide a crude product which '.vas purified by PrepHPLCusing the follmv·ing conditions: Column, XBridge C18 OBD Prep Column, 5 11m, 1920 mrn x 250 mm; rnobile pha , ."i.S.) -'-i -[["..i -cydopropy l-3-(2,6-dichlorophenyl)-1 ,2-oxazol-4-y l]methoxy ]-2-azabicyclo[ 2.2.l]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate I-36 was obtained as an off-vvhite solid. 1HNMR (400 MFz, CD30D) 8: 8.19 (d, J = 1.5 Hz, lH), 7.71 (dd, J = ll.6, 1.5 Hz, lH), 7.4525 (dd, J = 8. 1, 1.2 Hz, 1H), 7.29-7 14 (m, 2H), 4.88 (s, 14H), 4.35 (d, J = 11.9 Hz, lH), 4.20(d, J ··· 11.9 Hz, lH), 4.07 (dt, J ··· 8.2, 3.6 Hz, lH), 3.92 (s, 3H), 2.82 (d, J ··· 3.8 Hz, 1H),2 29- 2.18 (m, lH), 1.89 (d, J = 10.1 Hz, lH), l.70 (d, J = l 0.6 Hz, H-l), 123- 1.07 (m,'iH') JIS ·'['}Q I·. [~·r+l] <;;oo 'J ... . .. I {_.c.J, rt1;Z): JV = AHJ.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 199; 200

37
[ 924287-65-0 ]
(1S,4S,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
2-[(1S,4S,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

38
[ 924287-65-0 ]
(1R,4R,5S)-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate hydrochloride [ No CAS ]
(1R,4R,5S)-2-(4-fluoro-6-(methoxycarbonyl)benzo[d]thiazol-2-yl)-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With caesium carbonate; In N,N-dimethyl acetamide; at 80℃;	A mixture of (1R,4R,5S)-2-azabicyclo[2.2.1 ]heptan-5-yl 5-cyclopropyl-3-(2,6-10 dichlorophenyl)isoxazole-4-carboxylate HCl salt 38h (0.13 g, 0.30 mmol), methyl2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate A-1 (0.087 g, 0.30 mmol) and Cs2C01 (0.20 g, 0.60mmol) in DMA (5.0 mL) vas heated at 80 C with stirring ovemight. The reaction mixture-vvas cooled to room temperature and partitioned between EtOAc and water. The organiclayer was washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated.15 The residue was purified with column chromatography (20-30% EtOAc in hexanes) to give(1 R,4R,5 S )-2-( 4-f1uoro-6-( methoxy car bony l)benzold ]thiazol-2-y 1)-2-azabicyclo[2.2. l ]hept:m-5-yl 5-cyclopropy l-3-(2,6-dichloropheny l)isoxa.zole-4-carboxy late38c (0.16 g, 89~o) a<; a vvhite foam MS (ES, m/z): [M+l] = 602.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 201; 202; 203

39
[ 924287-65-0 ]
4-((((1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl)oxy)methyl)-5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole hydrochloride [ No CAS ]
methyl 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptan-2-yl)-4-fluorobenzo[d]thiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg	With triethylamine; In N,N-dimethyl acetamide; at 80℃;	To a solution of 4-((((1SAS,5R)-2-azabicyclo[2.2.1]heptan-5-yl)oxy)methyl)-.5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole hydrochloride 125k (.53.0 mg, 0.14 mmol) andmethyl2-bromo-4-f1uorobenzold]thiazole-6-carhoxylate A-1 (48.0 mg, 0.17 rnmo) in DMA(2mL) was added Et3N (40.0 p.L, 0.28 mrnol). The mixture was heated at 80C overnightAfter cooling to room temperature, the mixture was partitioned between EtOAc and water.15 The organic layer v.·as separated, dried (MgS04) and concentrated. The residue wa;;; purifiedby silica gel colunm chromatography to give methyl2-((1SAS,5R)-5-((5-cyclopropyl-3-(spiro [2. 5] octan-6-y l )isoxazol-4-y 1 )methoxy )-2-azabi cy clo[2 .2. 1 ]heptan-2 -y l )-4-fluorobenzo[d]thiazole-6-carboxylate 277a (30 mg) as a clear oil.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 432

40
[ 924287-65-0 ]
(1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 50 mL round-bot1om f1ask purged and maintained under an inert atmosphere ofnitrogen was added <strong>[924287-65-0]methyl 2-bromo-4-fluoro-1,3-benzothiazole-6-carboxylate</strong> A-1 (300 rng,1.03 mmoL LO equiv.), DMA (10 mL), (1SAS,5R)-2-azabicyclo[2.2.1]heptan-5-yl5-cydopropyl-3-(2,6-dichloropheny)-1,2-oxaz.ole-4-carboxyate (lj) (267 mg, 0.68 mmol, 1.25 equiv), and Cs2CCh (747 mg, 2.29 mmoL 3 0 equiv.) and the resulting mixture vvas stirred at60 C overnight. After cooling to room temperature, 200 mL ofEA was added and themixture Vas '.vashed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo. The crude product was purified by a silica gel column with ethylacetate/petroleum ether (1:5) to afford 300 mg (48%) ofmethyl2-[(lS,4S,5R)-5-[[5-1 0 cyclopropyl-3-(2,6-dichlorophenyl)-1 ,2-oxazol-4-yl]carbonyloxy ]-2-azabicyclo[2.2.1 ]heptan-2-yl]-4-t1uoro-1 ,3-benzothiazole-6-carboxylate (lk) as an off-'.vhite solid .15

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 142; 144; 145

41
[ 924287-65-0 ]
(((1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yloxy)methyl)-5-cyclopropyl-3-(2,6-dichloro-4-methoxyphenyl)isoxazole hydroiodide [ No CAS ]
methyl 2-((1S,4S,5R)-5-((5-cyclopropyl-3-(2,6-dichloro-4-methoxyphenyl)isoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptan-2-yl)-4-fluorobenzo[d]thiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.51 g	With caesium carbonate; In N,N-dimethyl acetamide; at 65℃; for 16h;	A suspension of 4-(((lS,4S,5R)-2-azabicydo[2.2.l]heptan-5-yoxy)methy)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole hydroiodide 286h (0.45 g, l equiv.), methyl2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate A-1 (0.3 g, l equiv.) and cesium carbonate(0.82 gm, 2 equiv.) in DMA (10 mL) Vas heated at 65C for 16 h. The reaction mixture wascooled to room temperature and diluted with ethyl acetate. The organic layer was vvashed10 with water, saline, dried over sodium sulfate, filtered :md concentrated under reducedpressure. The crude material was purified by silica gel column chromatography using 30-40%ethyl acetate in hexanes as gradient to give the methy 1 2-((1 S,4S,5R)-5-((5-cydopropyl-3-(2,6-dichl oro-4-methoxypheny l)isoxazol-4-y l)methoxy )-2-azabi cyclo[2. 2. 1 ]heptan-2-y 1)-4-fluorobenzo[ d]thiazole-6-carboxylate 286i (0.51 g). 1H-NMR (400 MHz, DMSO-d6) 8: 8.2515 (d, J = 1.6 Hz, lH), 7.61 (dd, J = 11.5 & 1.6 Hz, lH), 7.23 (dd, J = 12.5 & 2.5 Hz, 2H), 4.26(s, 2H), 3.86 (s, 4H), 3.84 (s, 3H), 3.62 (d, J '" 5.8 Hz, 1H), 3,46-3.44 (m, lH), 2.59 (s, lH),2.33 (td, J "' 8.4 & 4.2 Hz, 1H), 191 (dd, J "' 13.2 & 6.9 Hz, 1H), 1.59 (dd, J "' 34.9 & 9.7 Hz,2H), 1.35 (d, J = 13.2 Hz, lH), 1.23- 1.01 (m, .SH)

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 437; 440

42
[ 924287-65-0 ]
(1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl 3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1S,4S,5R)-5-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

43
[ 924287-65-0 ]
(1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl 3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carboxylate [ No CAS ]
C₂₈H₂₁Cl₂F₂N₃O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 25 mL round-bottom flask purged and maintained under an ine1i atmosphere ofnitrogen was added ( 1 S,4S,5R)-2-azabicyclol2.2.1]heptan-5-y 1 3-(2,6-dichloropheny l)-5-(lt1uorocyclopropyl)-l,2-oxazole-4-carboxylate JOi (JOO mg, 0.24 mmol, 1.0 equiv.), DMA (5mL), methyl2-bromo-4-t1uoro-l,3-benzothiazole-6-carboxylate A-l (78 mg, 0.27 mmoL 1 1015 equiv), and Cs2C01 (238 mg, 0.73 mmoL 3.0 equiv.) and the resulting mixture was stirred at60 C overnight. 100 mL off-hO was then added, the aqueous mixtme was extracted v.·ithethyl acetate (1 00 mL x 2). The combined organic extracts were washed with brine (20 mL x2), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product Vaspurified by silica gel column chromatography eluting with PE:EA (3: 1) to give 80 mg (55%)20 of methyl 2-[ (lS,4S,5R)-5-[ [ 5-cyclopropyl-3-(2,6-dichorophenyl)-1 ,2-oxazol-4-y l]carbony loxy] -2-azabicycl o[2.2.1 ]heptan-2-y l] -4-fluoro-1 ,3-benzothiazole-6-carboxy late(l qj) as a light yellow oil.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 152; 155

44
[ 924287-65-0 ]
(1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl 3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1S,4S,5R)-5-(3-{bicyclo[2.2.2]octan-1-yl}-5-cyclopropyl-1,2-oxazole-4-carbonyloxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39386,2018,A1

45
[ 924287-65-0 ]
(1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl 3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazole-4-carboxylate [ No CAS ]
methyl-2-[(1S,4S,5R)-5-[(3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazol-4-yl)carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 25-mL round-bottom t1ask purged and maintained under an inert atmosphere of15 nitrogen was added (1 S,4S,5R)-2-azabicyclo[2.2.1 ]heptan-5-yl 3-[hicydo[2.2.2]octan-l-yl ]-5-cyclopropyl-1 ,2-oxazole-4-carboxylate 11n (80 mg, 0.22 mmol, l.O equiv.), methyl 2-bromo-4-fluoro-L3-benzothiazole-6-carboxylate A-1 (78 mg, 0.27 mmol, 1.20 equiv.), DMA(l .. 5 mL), and Cs2C03 (143 mg, 0.44 mmol, 2.0 equiv.) and the resulting mixture was stinedat 60 C overnight. fbO was added and the mixture vas extracted v.·ith 200 mL of ethyl20 acetate. The organic extract was washed with brine (20 rnL x 4), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. The residue was purifiedby silica gel colunm chromatography eluting with ethyl acetate/petroleum ether (1:5) toprovide 90 mg (71 ~o) of methy 1-2-[ ( 1 S,4S,5R)-5-[ (3-[bicyclo[ 2.2.2]octan-1-yll-5-cyclopropyl-1 ,2-oxazol-4-yl)carbonyloxy]-2-azabicyclo[2.2.l]heptan-2-yl ]-4-Huoro-l ,3-2.5 benzothiazole-6-carboxylate llo as a light yellovv oil.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 157; 161

46
[ 924287-65-0 ]
(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
methyl 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a J 00-rnL rmmd-bottom flask purged and maintained under an inert atrnosphere ofnitrogen was added (1 S,4S,5R)-5-[[5-cydopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.l]heptane l2d (300 mg, 0.79 mmol, 1.0 equiv.), DMA (10mL), <strong>[924287-65-0]methyl 2-bromo-4-fluoro-1,3-benzothiazole-6-carboxylate</strong> A-1 (253 mg, 0.87 mmol, l.l2.5 equiv), :md Cs2C03 (775 mg, 2.38 mmol, 3.0 equiv.) and the reaction mixture was stirred at60 C overnight. The resulting mixture Vas diluted with 200 mL of ethyl acetate, Vashedwith brine (30 mL x3), dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue ·was purified by silica gel column chromatography eluting with PE:EA(5:1) to provide 350 mg (75%) ofmethyl2-[(1S,4S,5R)-5-[[.5-cyclopropyl-3-(2,6-30 dichlorophenyl)-l,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1 ]heptan-2-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylate 12e as a light-yellow oiL

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 162; 164

47
[ 924287-65-0 ]
(1S,2S)-2-((4-fluoro-6-(((6-phenylpyrazin-2-yl)amino)methyl)benzo[d]thiazol-2-yl)amino)cyclohexan-1-ol [ No CAS ]

Reference： [1]Patent: WO2018/81276,2018,A1

48
[ 924287-65-0 ]
6-(azidomethyl)-2-bromo-4-fluorobenzo[d]thiazole [ No CAS ]

Reference： [1]Patent: WO2018/81276,2018,A1

49
[ 924287-65-0 ]
(1S,2S)-2-(6-(azidomethyl)-4-fluorobenzo[d]thiazol-2-ylamino)cyclohexanol [ No CAS ]

Reference： [1]Patent: WO2018/81276,2018,A1

50
[ 924287-65-0 ]
(1S,2S)-2-(6-(aminomethyl)-4-fluorobenzo[d]thiazol-2-ylamino)cyclohexanol [ No CAS ]

Reference： [1]Patent: WO2018/81276,2018,A1

51
[ 924287-65-0 ]
(1S,2S)-2-(6-((6-chloropyrazin-2-ylamino)methyl)-4-fluorobenzo[d]thiazol-2-ylamino)cyclohexanol [ No CAS ]

Reference： [1]Patent: WO2018/81276,2018,A1

52
[ 924287-65-0 ]
(1R,3R,5S)-N-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine hydrochloric acid salt [ No CAS ]
C₂₉H₂₇Cl₂FN₄O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃; for 16h;	General procedure: To ethyl 2-chlorobenzo[d]thiazole-6-carboxylate (1d-1) (305 mg, 1.263 mmol) and (1R,3R,5S)-N-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octan-3-amine hydrochloride (1c-1) (430 mg, 0.842 mmol, ?84% by weight) in DMA (5 ml) was added cesium carbonate (686 mg, 2.105 mmol). The resulting mixture was heated up to 60 C. for 16 h, cooled down to room temperature. The mixture was diluted with ethyl acetate, washed with water (4*), brine, dried, filtered, and concentrated. The residue was chromatographed by CombiFlash eluting with hexane to 70% ethyl acetate/hexane to give ethyl 2-((1R,3R,5S)-3-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (Example 1) (198 mg). LC/MS observed [M+H], 597.15.

Reference： [1]Patent: US2018/99957,2018,A1 .Location in patent: Paragraph 0215; 0216; 0219; 0220

53
[ 924287-65-0 ]
(1R,5S,7s)-7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-oxa-9-azabicyclo[3.3.1]decane [ No CAS ]
C₂₉H₂₆Cl₂FN₃O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.3%	With caesium carbonate; In N,N-dimethyl acetamide; at 100℃; for 18h;Microwave irradiation;	Ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (100 mg, 0.34 mmol), (1R,5S,7s)-7-((5-cyclopropyl-3-) (2,6-Dichlorophenyl)isoxazol-4-yl)methoxy)-3-oxa-9-azabicyclo[3.3.1]nonane(50 mg, 0.12 mmol) and cesium carbonate ( 100mg, 0.31 mmol medium) was added to DMA (1.5mL), small microwave 100 deg.] C for 18when each of water and ethyl acetate were added 50mL, extraction, the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1)to give the title compound (50mg, yield: 67.3%).

Reference： [1]Patent: CN109265471,2019,A .Location in patent: Paragraph 0438; 0449; 0450; 0451

54
[ 924287-65-0 ]
(1R,5S,7s)-7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-oxa-9-azabicyclo[3.3.1]decane [ No CAS ]
2-((1R,5S,7s)-7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-oxa-9-azabicyclo[3.3.1]non-9-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: CN109265471,2019,A

55
[ 924287-65-0 ]
2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)spiro[3.5]nonane-2,7-diol [ No CAS ]
2-((2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)-2-hydroxyspiro[3,5]nonan-7-yl)oxy)-4-fluorobenzo[d]thiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2019/127362,2019,A1

56
[ 924287-65-0 ]
(1S,4S,5R)-5-[[1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
methyl 2-[(1S,4S,5R)-5-[[1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With N,N-dimethyl acetamide; caesium carbonate; at 60℃;Inert atmosphere;	To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added (1S,4S,5R)-5-[[l-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy]-2-azabicyclo [2.2.1] heptane 41g (80 mg, 0.21 mmol, 1.00 equiv.), DMA (2 mL), methyl 2-bromo-4-fluoro-l,3-benzothiazole-6-carboxylate 30c (74 mg, 0.26 mmol, 2.00 equiv.), and Cs2CO3 (137 mg, 0.42 mmol, 2.00 equiv.). The resulting mixture was heated at 60C overnight. Upon cooling to room temperature, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic extracts were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :5) to afford methyl 2-[(1S,4S,5R)-5-[[l-cyclopropyl-4-(2,6-dichlorophenyl)-1H- pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-l,3-benzothiazole-6- carboxylate 47a (50 mg, 40%) as an off-white solid.

Reference： [1]Patent: WO2019/55808,2019,A1 .Location in patent: Page/Page column 179

57
[ 924287-65-0 ]
(1S,4S,5R)-5-[[1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
2-[(1S,4S,5R)-5-[[1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/55808,2019,A1

58
[ 924287-65-0 ]
(1S,4S,5R)-5-[[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
methyl 2-[(1S,4S,5R)-5-[[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With N,N-dimethyl acetamide; caesium carbonate; at 60℃;	To a 50 mL round-bottom flask was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane 11 (80 mg, 0.21 mmol, 1.00 equiv.), DMA (2 mL), methyl 2-bromo-4-fluoro-l,3-benzothiazole-6-carboxylate 30c (74 mg, 0.26 mmol, 1.00 equiv.), and Cs2CO3 (205 mg, 0.63 mmol, 2.00 equiv.). The resulting mixture was heated at 60C overnight. After cooling to room temperature, water was added, the mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :5) to give methyl 2-[(1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-l,3- benzothiazole-6-carboxylate 30d (100 mg, 80%) as an off-white solid.

Reference： [1]Patent: WO2019/55808,2019,A1 .Location in patent: Page/Page column 149-150

59
[ 924287-65-0 ]
(1S,4S,5R)-5-[[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane [ No CAS ]
2-[(1S,4S,5R)-5-[[4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/55808,2019,A1

60
[ 924287-65-0 ]
2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)spiro[3.5]nonane-2,7-diol [ No CAS ]
methyl 2-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)-2-hydroxyspiro[3,5]nonan-7-yloxy)-4-fluorobenzo[d]thiazole-6-carboxlate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 0.0833333h;	A solution of 2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) spiro[3.5]nonane-2,7-diol (33 mg, 0.081 mmol) in anhydrous THF (1 mL) at room temperature was added KOtBu (19.0 mg, 0.17 mmol). After 5 minutes, <strong>[924287-65-0]methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate</strong> (28.1 mg, 0.097 mmol) was added and the reaction mixture was stirred at room temperature for 5 minutes. The reaction was quenched with saturated aqueous NH4Cl, and the resulting mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0-50% EtOAc/hexanes, Isco 12 g column) to give methyl 2-((2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)-2-hydroxyspiro[3.5]nonan-7-yl)oxy)-4-fluorobenzo[d]thiazole-6-carboxylate (33 mg, 0.053 mmol, 66% yield) as a white foam. MS (ESI) m/z: 617.2 [M+H]+.

Reference： [1]Patent: US2019/127362,2019,A1 .Location in patent: Paragraph 0913-0914

61
[ 924287-65-0 ]
(3R,3aR,6R,6aR)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrofuro[3,2-b]furan-3-ol [ No CAS ]
methyl 2-(((3R,3aR,6R,6aR)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-4-fluorobenzo[d]thiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With caesium carbonate; In N,N-dimethyl acetamide; acetonitrile; at 90℃; for 16h;	To (3R,3aR,6R,6aR)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa-hydrofuro[3,2-b]furan-3-ol (5a-2) (33 mg, 0.080 mmol) and <strong>[924287-65-0]methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate</strong> (5c) (27.9 mg, 0.096 mmol) in DMA (0.8 ml) and acetonitrile (0.800 ml) was added cesium carbonate (78 mg, 0.240 mmol). The mixture was heated up at 90 C. for 16 h and then diluted with EtOAc, washed with water, brine, dried, filtered and concentrated. The mixture was purified by CombiFlash eluting with 0 to 50% EtOAc/hexane to give methyl 2-(((3R,3aR,6R,6aR)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-4-fluorobenzo[d]thiazole-6-carboxylate (5d) (20 mg, 40%). LC/MS observed [M+H], 621.08; 1H NMR (400 MHz, Chloroform-d) delta 8.16 (d, J=1.5 Hz, 1H), 7.76 (dd, J=10.9, 1.5 Hz, 1H), 7.51-7.32 (m, 3H), 5.62 (td, J=6.4, 5.5 Hz, 1H), 4.94 (t, J=5.2 Hz, 1H), 4.58 (d, J=12.5 Hz, 1H), 4.48 (t, J=5.0 Hz, 1H), 4.34 (d, J=12.4 Hz, 1H), 4.13 (dd, J=9.7, 6.3 Hz, 1H), 4.07-3.90 (m, 2H), 3.94 (s, 3H), 3.84 (dd, J=8.7, 6.7 Hz, 1H), 3.57 (t, J=8.5 Hz, 1H), 2.32-2.20 (m, 1H), 1.35-1.24 (m, 2H), 1.22-1.09 (m, 2H).

Reference： [1]Patent: US2019/194216,2019,A1 .Location in patent: Paragraph 0223; 0229; 0230

62
[ 924287-65-0 ]
2-[(1R,3R,5S)-3-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

63
[ 924287-65-0 ]
(1R,3R,5S)-8-(6-carbamoyl-4-fluoro-1,3-benzothiazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

64
[ 924287-65-0 ]
(1R,3R,5S)-8-(6-[[2-(tert-butoxy)-2-oxoethyl]carbamoyl]-4-fluoro-1,3-benzothiazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

65
[ 924287-65-0 ]
2-({2-[(1R,3R,5S)-3-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl}formamido)acetic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

66
[ 924287-65-0 ]
2-([2-[(1R,3R,5S)-3-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazol-6-yl]formamido)ethane-1-sulfonic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

67
[ 924287-65-0 ]
(1R,3R,5S)-8-[4-fluoro-6-(methanesulfonylcarbamoyl)-1,3-benzothiazol-2-yl]-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

68
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-phenyl-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-[(5-cyclopropyl-3-phenyl-1,2-oxazol-4-yl)carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
500 mg	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 100 mL round-bottom flask purged with nitrogen was added (lR,3R,5S)-8- azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-phenyl-l ,2-oxazole-4-carboxylate 13j (500 mg, 1.48 mmol, 1.0 equiv.) in DMA (20 mL), methyl 2-bromo-4-fluoro-l,3-benzothiazole-6- carboxylate Al (475 mg, 1.64 mmol, 1 .1 equiv,), and Cs2C03 (965 mg, 2.96 mmol, 2,0 equiv.). The resulting mixture was stirred overnight at 60 C and ethyl acetate (100 mL) was then added. The mixture was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :3) to give of methyl 2-[(lR,3R,5S)-3-[(5- cyclopropyl-3-phenyl-l,2-oxazol-4-yl)carbonyloxy]-8-azabicyclo[3.2.1] octan-8-yl]-4-fluoro- l,3-benzothiazole-6-carboxylate 13k (500 mg, 62%) as an off-white solid.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00380

69
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-phenyl-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1R,3R,5S)-3-[(5-cyclopropyl-3-phenyl-1,2-oxazol-4-yl)carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

70
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-([5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
440 mg	With cesium fluoride; In dimethyl sulfoxide; at 115℃;	To a 100 mL round-bottom flask purged with nitrogen was added (lR,3R,5S)-8- azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-l,2-oxazole-4- carboxylate 14e (360 nig, 0,85 mmol, 1.0 equiv.), DMSO (10 mL), methyl 2-bromo-4-fluoro- l,3-benzothiazole-6-carboxylate Al (294 mg, 1.01 mmol, 1.2 equiv.), and CsF (389 mg, 3.0 equiv.). The resulting mixture was stirred overnight at 115 C and then ethyl acetate was added (100 mL). The resulting mixture was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via silica gel chromatography eluting with ethyl acetate/petroleum ether (1 :2) to afford methyl 2- [(lR,3R,5S)-3-([5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-l,2-oxazol-4-yl]carbonyloxy)-8- azabicyclo[3.2.1]octan-8-yl]-4-fluoro-l ,3-benzothiazole-6-carboxylate 14f (440 mg, 82%) as a light yellow solid.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00386

71
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1R,3R,5S)-3-([5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

72
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-[2-chloro-6-(difluoromethoxy)phenyl]-5-cyclopropyl-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-([3-[2-chloro-6-(difluoromethoxy)phenyl]-5-cyclopropyl-1,2-oxazol-4-yl]carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
350 mg	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;	To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added (lR,3R,5S)-8-azabicyclo[3.2. l]octan-3-yl 3-[2-chloro-6-(difluoromethoxy) phenyl]-5-cyclopropyl-l,2-oxazole-4-carboxylate 15i (200 mg, 0.46 mmol, 1.0 equiv.), methyl 2- bromo-4-fluoro-l,3-benzothiazole-6-carboxylate (160 mg, 0.55 mmol, 1.2 equiv.), DMA (10 mL), and CS2CO3 (297 mg, 0.91 mmol, 2.0 equiv.) and the resulting mixture was stirred at 60 C overnight. The reaction was quenched with water and the resulting aqueous mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eiuting with ethyl acetate/petroleum ether (1 :4) to provide methyl 2-[(lR,3R,5S)-3-([3-[2-chloro-6-(difuoromethoxy)phenyl]-5- cyclopropyl-l,2-oxazol-4-yl]carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-l,3- benzothiazole-6-carboxylate 15j (350 mg) as a white solid.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00396

73
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-[2-chloro-6-(difluoromethoxy)phenyl]-5-cyclopropyl-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1R,3R,5S)-3-([3-[2-chloro-6-(difluoromethoxy)phenyl]-5-cyclopropyl-1,2-oxazol-4-yl]carbonyloxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

74
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cydopropyl-3-(2,6-difluorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-[[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
150 mg	With cesium fluoride; In dimethyl sulfoxide; at 115℃;	To a 100 mL round-bottom flask was added a solution of (lR,3S,5S)-8- azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-difluorophenyl)-l,2-oxazole-4-carboxylate 16h (330 mg, 0.88 mmol, 1.0 equiv.) in DMSO (5 mL), methyl 2-bromo-4-fluoro-l,3-benzothiazole- 6-carboxylate Al (280 mg, 0.97 mmol, 1.1 equiv.), CsF (400 mg, 2.63 mmol, 3.0 equiv.). The resulting solution was stirred overnight at 1 1 5 C. The reaction was quenched by the addition of EtOAc (200 mL). The mixture was washed with brine (30 mL x 3), dried over sodium sulfate, filtered, and concentrated in vacuo to a residue which was purified by silica gel column chromatography eiuting with PE:EtOAc (1 : 1) to afford methyl 2-[(lR,3R,5S)-3-[[5-cyclopropyl- 3-(2,6-difluorophenyl)-l,2-oxazol-4-yl]carbonyloxy]-^^ 1.3- benzothiazole-6-carboxylate 161 (150 mg, 29%) as an off-white solid.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00405

75
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cydopropyl-3-(2,6-difluorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1R,3R,5S)-3-[[5-cyclopropyl-3-(2,6-difluorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

76
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole-4-carboxylate [ No CAS ]
(1R,3R,5S)-8-(4-fluoro-6-(methoxycarbonyl)benzo[d]thiazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.064 g	With caesium carbonate; In N,N-dimethyl acetamide; at 100℃;	To a solution of (lR,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3- (spiro[2.5]octan-6-yl)isoxazole-4-carboxylate 19k (0.04 g, 0.1 1 mmol) and methyl 2-bromo-4- fluorobenzo[d]thiazole-6-carboxylate Al (0.052g, 0.18mmol) in DMA (2 ml.) was added CS2CO3 ( 0.056 g, 0.17 mmol). The mixture was stirred overnight at 100 C. The reaction mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The residue was purified via silica gel chromatography hexane-EtOAc (EtOAc 20-30%) to give (lR,3r,5S)-8-(4-iluoro-6- (methoxycarbonyl)benzo[d]thiazol-2-yl)-8-azabicyclo[3.2.1 ]octan-3-yf 5-cyclopropyl-3- (spiro[2.5]octan-6-yl)isoxazole-4-carboxylate 191 (0.064 g) as a white foam. MS (ES, m/z): [M+1] = 580.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00420

77
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole-4-carboxylate [ No CAS ]
2-((1R,3R,5S)-3-((5-cyclopropyl-3-(spiro[2.5]octan-6-yl)isoxazole-4-carbonyl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

78
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-[(3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazol-4-yl)carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;	To a 25-mL round-bottom flask purged with nitrogen was added (lR,3R,5S)-8- azabicyclo[3.2.1]octan-3-yl 3-[bicyclo[2.2.2]octan-l-yl]-5-cyclopropyl-l,2-oxazole-4- carboxylate 20ss (27 mg, 0.09 mmol, 1.0 equiv.), methyl 2-bromo-4-fluoro- l,3-benzothiazole-6- carboxylate Al (29 mg, 0.09 mmol, 1.0 equiv.), DMA (1 mL), and Cs2C03 (55 mg, 0.17 mmol, 2,0 equiv.). The reaction mixture was stirred overnight at 60 C, cooled to RT and diluted with H2O. The aqueous mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (5 : 1) to provide methyl 2-[(lR,3R,5S)-3-[(3-[bicyclo[2.2.2]octan- l-yl]-5- cyclopropyl-l,2-oxazol-4-yl)carbonyloxy]-8-azabicyclo[3.2. l ]octan-8-yl]-4-fluoro-l,3- benzothiazole-6-carboxylate 20o (27 mg, 54%) as a light yellow oil.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00433

79
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1R,3R,5S)-3-[(3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazol-4-yl)carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

80
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-[[3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 100-mL round-bottom flask purged with nitrogen, was added (lR,3R,5S)-8- azabicyclo[3.2. l]octan-3-yl 3-(2,6-dichlorophenyl)-5-methyl-l ,2-oxazole-4-carboxylate 23f (522 mg, 1.37 mmol, 1.0 equiv.) in DMA (10 mL), methyl 2-bromo-4-fluoro-l,3-benzothiazole-6- carboxylate Al (400 mg, 1.38 mmol, 1 .0 equiv.), and CS2CO3 (896 mg, 2.75 mmol, 2.0 equiv.). The resulting mixture was stirred overnight at 60 C. The mixture was diluted with EtOAc (100 mL), washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a residue which was purified via silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :3) to yield methyl 2-[(lR,3R,5S)-3-[[3-(2,6- dichlorophenyl)-5-methyl-l,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1 ]octan-8-yl]-4- fluoro-l,3-benzothiazoie-6-carboxylate 23g (220 mg, 27%) as a light yellow solid.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00444

81
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1R,3R,5S)-3-[[3-(2,6-dichlorophenyl)-5-methyl-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

82
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With cesium fluoride; In dimethyl sulfoxide; at 115℃;	To a 100 mL round-bottom flask was added (lR,3S,5S)-8-azabicyclo[3.2.1 ]octan-3-yl 3- (2,6-dichlorophenyl)-5-(l-fluorocyclopropyi)-l,2-oxazole-4-carboxylate 27i (170 mg, 0.40 mmol, 1.0 equiv.) in DMSO (15 mL), methyl 2-bromo-4-fluoro-l ,3-benzothiazole-6-carboxylate Al (128 mg, 0.44 mmol, 1.1 equiv.) and CsF (183 mg, 1.20 mmol, 3.0 equiv.). The resulting mixture was stirred overnight at 115 C. After cooling to RT, the mixture was diluted with EtOAc (200 mL), washed with brine (30 mL x 3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography el u ting with PE:EtOAc (5: 1) to afford methyl 2-[(lR,3R,5S)-3-[[3-(2,6-dichlorophenyl)-5-(l - fluorocyclopropyl)-l,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-l,3- benzothiazole-6-carboxylate 27j (200 mg, 79%) as an off-white solid.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00463

83
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carboxylate [ No CAS ]
2-[(1R,3R,5S)-3-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

84
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]acetate [ No CAS ]
methyl 2-[(1R,3S,5S)-3-([2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]acetyl]oxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 25 mL round-bottom flask purged with nitrogen was added (lR,3R,5S)-8~ azabicyclo[3.2.1 ]octan-3-yl 2-[5-cyclopropyl-3-(2,6-dichlorophenyl)- 1 ,2-oxazol-4-yl]acetate 32 f (160 mg, 0.38 mmol, 1.0 equiv.), a solution of methyl 2-bromo-4-fluoro-l,3-benzothiazole-6- carboxylate Al(132 mg, 0.46 mmol, 1.2 equiv.) in DMA (8 mL), and CS2CO3 (248 mg, 0.76 mmol, 2.0 equiv.). The resulting solution was stirred overnight at 60 C, then quenched with H2O (30 mL). The aqueous mixture was extracted with ethyl acetate (15 mL x 3); and the combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :3) to give methyl 2-[(lR,3S,5S)-3-([2-[5-cyclopropyl-3- (2,6-dichlorophenyl)-l,2-oxazol-4-yl]acetyl]oxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-l,3- benzothiazole-6-carboxylate 32g (170 mg, 71%) as a yellow oil.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00485

85
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]acetate [ No CAS ]
2-[(1R,3S,5S)-3-([2-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]acetyl]oxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/39384,2018,A1

86
[ 924287-65-0 ]
(1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate [ No CAS ]
methyl 2-[(1R,3R,5S)-3-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.1 g	With caesium carbonate; In N,N-dimethyl acetamide; at 60℃;Inert atmosphere;	To a 100 mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added (lR,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl 5-cyclopropyl-3-(2,6- dichlorophenyl)-l,2-oxazole-4-carboxylate Ij (1 .6 g, 3.93 mmol, 1.0 equiv.), methyl 2-bromo-4- fluoro-l,3-benzothiazole-6-carboxylate A-l (1.4 g, 4.83 mmol, 1.2 equiv.), Cs2C03 (2.6 g, 7.98 mmol, 2.0 equiv,), and dimethyl acetamide (40 mL). The reaction mixture was stirred overnight at 60 C and the pH value of the resulting solution was adjusted to 6 using HQ ( IM). The resulting aqueous mixture was extracted with ethyl acetate (200 mL x 2) and the combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 : 1, v/v) to give methyl 2- [(lR,3R,5S)-3-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-l,2-oxazol-4-yl]carbonyloxy]-8- azabicyclo[3.2.1]octan-8-yl]-4-fluoro-l ,3-benzothiazole-6-carboxylate H as a light yellow oil . This product was further purified by Prep-HPLC using the following conditions: XB ridge CI 8 OBD Prep Column (19 mm x 250 mm); mobile phase: water (0.05 % TFA) and ACN (80,0% ACN up to 90.0% in 8 min); detector, UV 254 nm. The title compound 1-1 (2.1 g, 87%) was obtained as a colorless solid. -NMR (300 MHz, CD3OD) delta: 8.1 16 (1H, m), 7,650 (1H, m), 11 7.479 (3H, m), 5.1 10 (1H, m), 4.278 (2H, m), 3.869 (3H, m), 3.008 (1H, m), 2.293 (2H, m), 1.860 (41 1. m), 1.417 (2H, m), 1.335 (41 1. ni). MS (ES, m/z): [M+l] = 616.0.

Reference： [1]Patent: WO2018/39384,2018,A1 .Location in patent: Paragraph 00354

87
[ 924287-65-0 ]
(3R,3aR,6R,6aR)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrofuro[3,2-b]furan-3-ol [ No CAS ]
2-(((3R,3aR,6R,6aR)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-4-fluorobenzo[d]thiazole-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2019/194216,2019,A1

88
[ 540-80-7 ]
[ 924287-64-9 ]
[ 924287-65-0 ]

Yield	Reaction Conditions	Operation in experiment
5.43 g	With copper(ll) bromide; In acetonitrile; for 48h;	To copper(II) bromide (29.6 g, 133 mmol) and methyl 2-amino-4-fluorobenzo[d]thiazole-6-carboxylate (5b-2) (20 g, 88 mmol) in acetonitrile (300 ml) with water bath was slowly added tert-butyl nitrite (12.85 ml, 97 mmol) over 10 min. The resulting mixture was stirred for 2 days and diluted with MTBE and water, stirred for 10 min, a lot of precipitate formed. The mixture was filtered through celite and organic layer was separated, washed with water (3×), brine (2×), dried, filtered, concentrated. The residue was purified by CombiFlash eluting with 0 to 25% acetone/Hexane. The fractions containing product was combined and concentrated then trituated with hexane. The white solid was collected via filtration to give methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (5c) (5.43 g). 1H NMR (400 MHz, Chloroform-d) delta 8.34 (dd, J=1.4, 0.6 Hz, 1H), 7.85 (dd, J=10.5, 1.4 Hz, 1H), 3.97 (s, 3H), 1.56 (s, 9H).

Reference： [1]Patent: US2019/194216,2019,A1 .Location in patent: Paragraph 0223; 0227; 0228

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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. 924287-65-0 ] {[proInfo.proName]}

Quality Control of [ 924287-65-0 ]

Related Doc. of [ 924287-65-0 ]

Product Details of [ 924287-65-0 ]

Calculated chemistry of [ 924287-65-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

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Application In Synthesis of [ 924287-65-0 ]

[ 924287-65-0 ] Synthesis Path-Upstream 1~4

[ 924287-65-0 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 924287-65-0 ]

Fluorinated Building Blocks

Bromides

Esters

Precautionary Statements-General

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Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

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[ 924287-65-0 ]