[ CAS No. 210240-20-3 ] {[proInfo.proName]}

Name: 210240-20-3|4-Aminotetrahydro-2H-thiopyran 1,1-dioxide|95%
Brand: Ambeed
SKU: A104032
Price: 15.0 USD
Availability: InStock
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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 210240-20-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 210240-20-3 ]

CAS No. :	210240-20-3	MDL No. :	MFCD09540491
Formula :	C₅H₁₁NO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KZKYCKOUODFYBV-UHFFFAOYSA-N
M.W :	149.21	Pubchem ID :	418808
Synonyms :

Calculated chemistry of [ 210240-20-3 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.71
TPSA :	68.54 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.66
Log Po/w (XLOGP3) :	-0.78
Log Po/w (WLOGP) :	0.6
Log Po/w (MLOGP) :	-0.48
Log Po/w (SILICOS-IT) :	0.03
Consensus Log Po/w :	0.01

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.27
Solubility :	79.4 mg/ml ; 0.532 mol/l
Class :	Very soluble
Log S (Ali) :	-0.18
Solubility :	98.3 mg/ml ; 0.659 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.58
Solubility :	38.9 mg/ml ; 0.261 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.64

Safety of [ 210240-20-3 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P362+P364-P403+P233-P501	UN#:	3077
Hazard Statements:	H315-H318-H335-H411	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 210240-20-3 ]

* 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 [ 210240-20-3 ]
Downstream synthetic route of [ 210240-20-3 ]

[ 210240-20-3 ] Synthesis Path-Upstream 1~7

1
[ 99586-63-7 ]
[ 210240-20-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrogen In methanol at 20℃; for 3 h;	To a stirred solution of compound 4.3 (0.14 g, 0.85 mmol) in methanol, was added Raney Ni, and the resulting mixture was stirred at room temperature for 3 h under a hydrogen atmosphere. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was filtered and the methanol filtrate concentrated under reduced pressure to give compound 4.4 (0.10 g, 78percent).

Reference： [1] Patent: US2009/82423, 2009, A1, . Location in patent: Page/Page column 24
[2] Journal of the American Chemical Society, 1955, vol. 77, p. 3866,3867

2
[ 402927-99-5 ]
[ 210240-20-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	for 15 h;	To a mixture of 10 g (0.026 mole) of the N-ben-zoyloxycarbonyl-sulfone 20 in 150 mL of ethanol in a Parr bottle was added 0.5 g of palladium hydroxide (20percent on Carbon, Pearlman's catalyst). This was subjected to the Parr hydrogenator at 50 psi for 15 hours until completion. This was filtered over Celite and concentrated in vacuo affording 5.0 g of the free amine 21 (68percent yield).

Reference： [1] Patent: US2003/232847, 2003, A1, . Location in patent: Page 16

3
[ 595597-01-6 ]
[ 210240-20-3 ]

Reference： [1] Patent: WO2008/33562, 2008, A2, . Location in patent: Page/Page column 49
[2] Patent: US2009/76005, 2009, A1, . Location in patent: Page/Page column 21
[3] Patent: WO2013/149362, 2013, A1, . Location in patent: Page/Page column 60-61

4
[ 17396-35-9 ]
[ 210240-20-3 ]

Reference： [1] Journal of the American Chemical Society, 1955, vol. 77, p. 3866,3867

5
[ 6309-59-7 ]
[ 210240-20-3 ]

Reference： [1] Patent: WO2013/149362, 2013, A1,

6
[ 21926-00-1 ]
[ 210240-20-3 ]

Reference： [1] Patent: WO2013/149362, 2013, A1,

7
[ 1072-72-6 ]
[ 210240-20-3 ]

Reference： [1] Patent: WO2013/149362, 2013, A1,

[ 210240-20-3 ] Synthesis Path-Downstream 1~73

1
[ 99586-63-7 ]
[ 210240-20-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrogen;nickel; In methanol; at 20℃; for 3h;	To a stirred solution of compound 4.3 (0.14 g, 0.85 mmol) in methanol, was added Raney Ni, and the resulting mixture was stirred at room temperature for 3 h under a hydrogen atmosphere. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was filtered and the methanol filtrate concentrated under reduced pressure to give compound 4.4 (0.10 g, 78%).

Reference： [1]Patent: US2009/82423,2009,A1 .Location in patent: Page/Page column 24
[2]Journal of the American Chemical Society,1955,vol. 77,p. 3866,3867

3
[ 595597-01-6 ]
[ 210240-20-3 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 0.5h;	Step 3: To a solution of compound 18d (509mg, 2.34mmol) in 5mL of THF was added 85% mCPBA (1.25g, 6.15mmol) with stirring under ice cooling. The resulting mixture was diluted with ethyl acetate and washed successively with saturated aq. NaHCO3, water and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was re-crystallized from EA/hexane to give compound 18e as white solid (0.55 Ig, 94%). To a solution of 18e in DCM (15mL) was added TFA (2.5mL). The mixture was stirred for 0.5h at r.t. and evaporated to give crude compound 18f (1.12g) as yellow oil which was used in the next step without further purification.
	With trifluoroacetic acid; In dichlromethane; at 20℃; for 0.5h;	Step 3: To a solution of compound 18d (509 mg, 2.34 mmol) in 5 mL of THF was added 85% mCPBA (1.25 g, 6.15 mmol) with stirring under ice cooling. The resulting mixture was diluted with ethyl acetate and washed successively with saturated aq. NaHCO3, water and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was re-crystallized from EA/hexane to give compound 18e as white solid (0.551 g, 94%). To a solution of 18e in DCM (15 mL) was added TFA (2.5 mL). The mixture was stirred for 0.5 h at r.t. and evaporated to give crude compound 18f (1.12 g) as yellow oil which was used in the next step without further purification.
	With trifluoroacetic acid; In dichloromethane; for 2h;	Step 5 : 1 , 1 -D ioxo-tetrahydro- 1 lambda6-thiopyran-4-ylamine A mixture of tert-butyl (l,l-dioxidetetrahydro-2H-thiopyran-4-yl)carbamate (30 g, 120 mmol), DCM (80 ml) and TFA (20 mL) was stirred for 2 h. The mixture was then concentrated in vacuo to give l,l-dioxo-tetrahydro-^6-thiopyran-4-ylamine for next reaction without purification: lR NMR (400 MHz, CD3OD) delta 3.50-3.10 (m, 5H), 2.36-2.16 (m, 4H).

Reference： [1]Patent: WO2008/33562,2008,A2 .Location in patent: Page/Page column 49
[2]Patent: US2009/76005,2009,A1 .Location in patent: Page/Page column 21
[3]Patent: WO2013/149362,2013,A1 .Location in patent: Page/Page column 60-61

4
[ 452105-55-4 ]
[ 210240-20-3 ]
5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1,1-dioxo-hexahydro-thiopyran-4-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Step 4: To the solution of A4 (107mg, 0.256mmol) in 1OmL of DMF solution, was added compound 18f (238mg) and DIEA(133mg, 1.03mmol), the reaction mixture was stirred at r.t. for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25mL) under sonication. The solid was collected by filtration and washed with methanol, dried under vacuum to provide title compound (102mg, 92%) as orange solid. 1H NMR (300 MHz, DMSO-d6): delta=13.68(s, IH), 10.89(s, IH), 7.72-7.78(m, 3H), 6.82-6.96(m, 2H), 4.13- 4.15(m, IH), 3.08-3.12(d, 2H), 2.40-2.42(ds, 6H),1.97-2.16(m, 4H). LC/MS: 430.3 [M-H]+.
92%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Step 4: To the solution of A4 (107 mg, 0.256 mmol) in 10 mL of DMF solution, was added compound 18f (238 mg) and DIEA(133 mg, 1.03 mmol), the reaction mixture was stirred at r.t. for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol, dried under vacuum to provide title compound (102 mg, 92%) as orange solid. 1H NMR (300 MHz, DMSO-d6): delta=13.68(s, 1H), 10.89(s, 1 H), 7.72-7.78(m, 3H), 6.82-6.96(m, 2H), 4.13-4.15(m, 1 H), 3.08-3.12(d, 2H), 2.40-2.42(ds, 6H),1.97-2.16(m, 4H). LC/MS: 430.3 [M-H]+.

Reference： [1]Patent: WO2008/33562,2008,A2 .Location in patent: Page/Page column 49
[2]Patent: US2009/76005,2009,A1 .Location in patent: Page/Page column 21

5
[ 210240-20-3 ]
[ 65224-66-0 ]
[ 937365-13-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2188 - 2192

6
[ 17396-35-9 ]
[ 210240-20-3 ]

Reference： [1]Journal of the American Chemical Society,1955,vol. 77,p. 3866,3867

7
[ 610786-20-4 ]
[ 210240-20-3 ]
C₂₀H₁₈ClN₅O₂S*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		Amixture of 1.4 g (0.41 mmol) of sulfoxide 10 and 1.22 g (8.2 mmol) of 4-aminotetrahydrothiopyran-dioxide 21 in 3 mL of NMP was heated to 70 C. for 2 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate (2x75 mL). The combined ethyl acetate solution was washed with water (3x75 mL), brine and dried (MgSO4) and the crude material was purified by column chromatography with silica eluting with 4% methanol in dichloromethane affording 1.5 g of desired product. This was dissolved in 3 mL of dichloromethane and 4.5 mL of 1M HCl/ether was added dropwise. The suspension was stirred for 30 minutes and the solid was filtered and washed with ether affording 1.86 g (98% yield) of compound 5. (mass spec. M+l=428, MP=221.8-226.8 C.).

Reference： [1]Patent: US2003/232847,2003,A1 .Location in patent: Page 16

8
[ 402927-99-5 ]
[ 210240-20-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	palladium(II) hydroxide/carbon; In ethanol; under 2585.81 Torr; for 15h;	To a mixture of 10 g (0.026 mole) of the N-ben-zoyloxycarbonyl-sulfone 20 in 150 mL of ethanol in a Parr bottle was added 0.5 g of palladium hydroxide (20% on Carbon, Pearlman's catalyst). This was subjected to the Parr hydrogenator at 50 psi for 15 hours until completion. This was filtered over Celite and concentrated in vacuo affording 5.0 g of the free amine 21 (68% yield).

Reference： [1]Patent: US2003/232847,2003,A1 .Location in patent: Page 16

10
[ 98026-88-1 ]
[ 210240-20-3 ]
[ 1089669-48-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 18h;	A solution of 4-bromo-2-methyl-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridine (1.2g, 3.42mmol) in anhydrous DCM (60ml) was de-gassed for 15 min then palladium acetate (0.0384g, 0.171 mmol) and potassium acetate (1.006g, 10.26mmol) were added and the mixture stirred for 5 min under nitrogen at room temperature. 4, 4, 4', 4', 5, 5,5', 5'- Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (2.18g, 8.55mmol) was added, the reaction was flushed with nitrogen and heated at 650C for 6 h, stirred at room temperature overnight then heated for a further 4 h at 650C under nitrogen. The reaction mixture was allowed to cool to room temperature then concentrated in vacuo. The residue was partitioned between water (100ml) and DCM (100ml). The layers were separated and the aqueous extracted with DCM (2x100ml). The combined DCM extracts were filtered then <n="109"/>evaporated in vacuo. The residue was triturated with cyclohexane, filtered and the filtrate evaporated in vacuo to give 2-methyl-1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine as a yellow oily solid (3.21 g). A mixture of 2- chloro-5-pyrimidinesulfonyl chloride (0.3g, 1.41 mmol), tetrahydro-2H-thiopyran-4-amine 1 ,1-dioxide (0.21g, 1.41 mmol), triethylamine (0.393ml, 2.82mmol) in anhydrous DCM (6ml) was stirred at room temperature under N2 for 18 h. The reaction mixture was washed with water (20ml) after diluting with DCM (20ml) and the layers were separated. The aqueous was extracted with EtOAc (20ml), washed with 2M HCI and evaporated in vacuo to give 2-chloro-lambda/-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5- pyrimidinesulfonamide (0.038g). The DCM extract was evaporated in vacuo and purified by Flashmaster SPE (Silica,, 1 Og) eluted with 0-100% EtOAc/cyclohexane over 20min. Fractions containing product were combined and evaporated to give 2-chloro-lambda/-(1 ,1- dioxidotetrahydro-2H-thiopyran-4-yl)-5-pyrimidinesulfonamide (0.078g). A mixture of 2- methyl-1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3- b]pyridine (0.17g, 0.179mmol), 2-chloro-lambda/-(1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5- pyrimidinesulfonamide (0.1 16g, 0.358mmol), sodium carbonate (0.038g, 0.358mmol), 1 ,1'-bis(diphenylphosphino)ferrocenedichloro palladium(ll) (0.0073g, 0.00998mmol) in dioxane (4ml) water (0.6ml) was heated in a sealed tube in the Biotage Initiator microwave at 15O0C for 60min. The reaction mixture was diluted with methanol, filtered through celite (10g cartridge) and evaporated in vacuo and purified by MDAP to give the title compound as a white solid (0.037g). MH+ = 562, rt = 3.16 min

Reference： [1]Patent: WO2008/145688,2008,A2 .Location in patent: Page/Page column 106-107

11
[ 874959-68-9 ]
[ 210240-20-3 ]
[ 1089669-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 2h;	A mixture of 5-bromo-2-pyridinesulfonyl chloride (0.30Og, 1.17mmol), (1 ,1- dioxidotetrahydro-2H-thiopyran-4-yl)amine (0.175g, 1.17mmol) and TEA (0.326ml, 2.34mmol) in anhydrous DCM (6ml) was stirred at room temperature under nitrogen for 2 h. The reaction mixture was diluted with DCM (20ml), filtered and washed with water (20ml) to give the title compound as a white solid (0.22Og).The DCM extract was separated from the aqueous (hydrophobic frit) and evaporated in vacuo to give the title compound as a white solid (0.107g). MH+ = 371 , M-H+367/369, rt = 2.17 min

Reference： [1]Patent: WO2008/145688,2008,A2 .Location in patent: Page/Page column 104

12
[ 6684-39-5 ]
[ 210240-20-3 ]
[ 1089669-43-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In dichloromethane; at 20℃; for 19h;	A mixture of 6-chloro-3-pyridinesulfonyl chloride (0.50Og, 2.358mmol), (1 ,1- dioxidotetrahydro-2H-thiopyran-4-yl)amine (0.352g, 2.358mmol) and TEA (0.657ml, 4.716mmol) in anhydrous DCM (10ml) was stirred at room temperature under nitrogen for 19 h. The mixture was evaporated in vacuo, partitioned between EtOAc (50ml) and water (25ml), the layers separated, the aqueous layer extracted with EtOAc (25ml) and the combined EtOAc extracts were evaporated in vacuo to give the title compound as a white solid (0.705g, 92%). M-H+ = 323/325, rt = 2.04 min

Reference： [1]Patent: WO2008/145688,2008,A2 .Location in patent: Page/Page column 103

13
[ 1089669-63-5 ]
[ 210240-20-3 ]
[ 1089669-66-8 ]

Yield	Reaction Conditions	Operation in experiment
		of 2-(difluoromethyl)-4-[5-(1 H-imidazol-1-ylsulfonyl)-2-thienyl]-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridine (65mg, 0.125mmol) in anhydrous tetrahydrofuran (1 mL) at O0C was added methyltriflate (16muL, 0.137mmol). After 30min tetrahydro-2H-thiopyran-4-amine 1 ,1 -dioxide (20mg, 0.137mmol) was added and warmed to ambient temperature after 30 min the reaction was concentrated (nitrogen blowdown). Purification by MDAP gave the title compound (40mg). LCMS MH+ = 602, rt = 1.18min

Reference： [1]Patent: WO2008/145688,2008,A2 .Location in patent: Page/Page column 124

14
[ 210240-20-3 ]
[ 1548-13-6 ]
[ 1132783-16-4 ]

Yield	Reaction Conditions	Operation in experiment
6%	In chloroform; at 0 - 20℃; for 2h;	To a stirred solution of compound 4.4 (0.15 g, 1.07 mmol) in chloroform was added trifluoromethylphenyl isocyanate 1.2 (0.30 g, 1.10 mmol) at 0-5 C., and the resulting mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. Upon completion of reaction, the reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by using column chromatography eluding with 2% methanol in dichloromethane to give pure compound 4 (0.02 gm, 6%). 1H NMR (DMSO-d6) delta: 7.42-7.45 (m, 4H); 6.25 (bs, 1H); 4.0 (m, 1H); 3.20-3.15 (m, 4H); 2.40 (t, 2H); 2.20 (m, 2H); Mass: (M+1, 337, 100%); M.P.: 196-198 C.

Reference： [1]Patent: US2009/82423,2009,A1 .Location in patent: Page/Page column 24

15
[ 4411-25-0 ]
[ 210240-20-3 ]
[ 1132783-17-5 ]

Yield	Reaction Conditions	Operation in experiment
3.5%	In chloroform; at 0 - 20℃; for 2h;	Example 5 1-adamantan-1-yl-3-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)urea (7) To a stirred solution of compound 4.4 (0.20 g, 1.3 mmol) in chloroform was added adamantyl isocyanate 3.1 (0.26 g, 1.4 mmol) at 0-5 C., and the resulting mixture was allowed to warm with stirring to room temperature over 2 h. The progress of the reaction was monitored by TLC. Upon completion of reaction, the reaction mixture was poured into water. The organic layer was separated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified using column chromatography eluding with 1% methanol in dichloromethane to give pure compound 7 (0.015 g 3.5%). 1H NMR (CDCl3) delta: 4.20 (bs, 1H); 4.20 (t, 2H); 4.0 (m, 1H); 3.10 (m, 4H); 2.30 (m, 2H); 2.10 (m, 5H); 2.00-1.92 (m, 5H); 1.75 (m, 6H); Mass: (M+1, 327, 100%); M.P.: 244-246 C.

Reference： [1]Patent: US2009/82423,2009,A1 .Location in patent: Page/Page column 24-25

16
[ 928656-94-4 ]
[ 210240-20-3 ]
[ 943434-47-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2504 - 2508

17
[ 32315-10-9 ]
2-(5-piperidinium-4-yl-1,2,4-oxadiazol-3-yl)quinolinium dichloride [ No CAS ]
[ 210240-20-3 ]
[ 76-05-1 ]
[ 1207261-29-7 ]

Yield	Reaction Conditions	Operation in experiment
41%		2- 5-( 1- { ( 1 , l-Dioxidotetrahvdro-2H-thiopyran-4-yl)aminol carbonyl}piperidin-4-yl)- 1 ,2,4- oxadiazol-3-yllalphauinolinium trifluoroacetate (Hl) To a solution of (Al) and DIPEA (4 eq.) in DCM (0.02 M) at -100C, triphosgene (1.1 eq.) was added. The reaction mixture was stirred at -100C for 20 min. Then, a solution of <strong>[210240-20-3]tetrahydro-2H-thiopyran-4-amine 1,1-dioxide</strong> (1.15 eq.) and DIPEA (2 eq.) in DMSO (0.09 M) was added and the resulting solution was heated to reflux overnight. After cooling down, the reaction mixture was concentrated to give a crude which was purified by preparative RP-EtaPLC, using water (+ 0.1 % TFA) and MeCN (+ 0.1 % TFA) as eluents (column: C 18). The desired fractions were lyophilized to yield (41%) the title compound as a white powder. 1H NMR (400 MHz, McOO-Ci4, 300 K) delta 8.56 (IH, d, J = 8.4 Hz), 8.24-8.21 (2H, m), 8.01 (IH, d, J = 8.4 Hz), 7.86 (IH, d, J = 7.6 Hz), 7.69 (IH, t, J = 7.6 Hz), 4.08 (2H, d, J = 13.6 Hz), 3.90-3.86 (IH, m), 3.41-3.36 (IH, m), 3.29-3.20 (2H, m), 3.09-3.02 (4H, m), 2.22-2.08 (6H, m), 1.92-1.83 (2H, m). MS (ES+) C22H25N5O4S required: 455, found: 456 (M+H)+.

Reference： [1]Patent: WO2010/13037,2010,A1 .Location in patent: Page/Page column 52

18
[ 27631-29-4 ]
[ 210240-20-3 ]
[ 1103521-34-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 64 - 73

19
[ 210240-20-3 ]
[ 1279093-55-8 ]

Reference： [1]Patent: WO2011/35417,2011,A1
[2]Patent: WO2012/126084,2012,A1

20
[ 210240-20-3 ]
[ 1279091-35-8 ]

Reference： [1]Patent: WO2011/35417,2011,A1
[2]Patent: WO2012/126084,2012,A1

21
[ 210240-20-3 ]
[ 123843-67-4 ]
[ 1279093-54-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 20℃;	A solution of 4-bromo-2,6-difluorobenzonitrile 12-a (587 mg, 2.69 mmol), 4- aminotetrahydro-2H-thiopyran- 1 , 1 -dioxyde (500 mg, 2.69 mmol) and triethylamine (831 uL, 5.92 mmol) in DMSO was stirred at room temperature overnight. Saturated aqueous ammonium chloride and ethyl acetate were added; the organic layer was separated, washed with saturated aqueous ammonium chloride and brine, dried over anhydrous MgS04, filtered and concentrated in vacuo to provide intermediate 12-b as a white solid.
	With triethylamine; In dimethyl sulfoxide; at 20℃;	A solution of 4-bromo-2,6-difluorobenzonitrile 5-d ( 1.17 g, 5.39 mmol), 4- aminotetrahydro-2H-thiopyran 1 , 1 -dioxyde ( 1.17 g, 5.39 mmol) and TEA ( 1.87 mL, 13.46 mmol) in DMSO was stirred at room temperature overnight. Saturated aqueous ammonium chloride and ethyl acetate were added; the organic layer was separated, washed with saturated aqueous ammonium chloride and brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 8-a as a white solid.
	With triethylamine; In dimethyl sulfoxide; at 20℃;	A solution of 4-bromo-2,6-difluorobenzonitrile 12-a (587 mg, 2.69 mmol), 4- aminotetrahydro-2H-thiopyran-l , l-dioxyde (500 mg, 2.69 mmol) and TEA (831 uL, 5.92 mmol) in DMSO was stirred at room temperature overnight. Saturated aqueous ammonium chloride and ethyl acetate were added; the organic layer was separated, washed with saturated aqueous ammonium chloride and brine, dried over anhydrous MgS04, filtered and concentrated in vacuo to provide intermediate 12-b as a white solid.

Reference： [1]Patent: WO2011/35417,2011,A1 .Location in patent: Page/Page column 60; 61
[2]Patent: WO2011/35416,2011,A1 .Location in patent: Page/Page column 56; 57
[3]Patent: WO2012/126084,2012,A1 .Location in patent: Page/Page column 49

22
[ 210240-20-3 ]
C₂₅H₂₈BrFN₂O₃S [ No CAS ]

Reference： [1]Patent: WO2011/35416,2011,A1

23
[ 210240-20-3 ]
C₂₅H₃₀BrFN₂O₄S [ No CAS ]

Reference： [1]Patent: WO2011/35416,2011,A1

24
4-cyclopentyl-N-(5-hydroxy-2-adamantyl)-2-methylsulfonylpyrimidine-5-carboxamide [ No CAS ]
[ 210240-20-3 ]
4-cyclopentyl-2-[(1,1-dioxothian-4-yl)amino]-N-(5-hydroxy-2-adamantyl)pyrimidine-5-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661

25
2-chloro-4-cyclobutyloxy-N-(5-hydroxy-2-adamantyl)pyrimidine-5-carboxamide [ No CAS ]
[ 210240-20-3 ]
4-(cyclobutoxy)-2-[(1,1-dioxothian-4-yl)amino]-N-(5-hydroxy-2-adamantyl)pyrimidine-5-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661

26
4-cyclobutyl-N-((2s,5r)-5-hydroxy-2-adamantyl)-2-methylsulfonylpyrimidine-5-carboxamide [ No CAS ]
[ 210240-20-3 ]
4-cyclobutyl-2-[(1,1-dioxothian-4-yl)amino]-N-(5-hydroxy-2-adamantyl)pyrimidine-5-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661

27
ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate [ No CAS ]
[ 210240-20-3 ]
[ 863438-78-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 422 - 425

28
[ 1465782-92-6 ]
[ 210240-20-3 ]
[ 1465782-57-3 ]

Yield	Reaction Conditions	Operation in experiment
19%		Example 73 : 4-(5-Chloro-thiazol-2-ylmethoxy)- l-{6-[(l,l -dioxo-hexahydro- 1 lambda6- thiopyran-4-ylamino)-methyl]- -dihydro-naphthalen-2-yl}-lH-pyridin-2-one A mixture of 6-[4-(5-chloro-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (20 mg, 0.05 mmol) and l ,l-dioxo-hexahydro-^6- thiopyran- 4-ylamine (40 mg, 0.27 mmol) was dissolved in dry CH2CI2 (6 mL). The mixture was stirred at rt for 2.5 hours, NaBH(OAc)3 (1 13 mg, 0.54 mmol) was then added. Then the mixture was stirred at rt overnight. Water (20 mL) was added and the mixture was washed with DCM (2 x 10 mL). The combined organic DCM was washed with brine (30 mL), dried over a2S04, filtered and concentrated in vacuo to give 4-(5-chloro-thiazol-2-ylmethoxy)-l- {6- [( 1 , 1 - dioxo-hexahydro- 1 lambda6-thiopyran-4-ylamino)-methyl]-3 ,4-dihydro-naphthalen-2-yl} - lH-pyridin-2-one (4.95 mg, yield 19%): lR NMR (400 MHz, CD3OD) delta 7.72 (s, 1H), 7.60 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 6.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 6.31 (dd, J = 7.6, 2.4 Hz, 1H), 6.14 (d, J= 2.8 Hz, 1H), 5.41 (s, 2H), 4.26 (s, 2H), 3.61-3.52 (m, 1H), 3.36- 3.35 (m, 2H) 3.22-3.11 (m, 2H), 3.09-3.07 (m, 2H), 2.72-2.68 (m, 2H), 2.66-2.57 (m, 2H), 2.26-2.10 (m, 2H); ES-LCMS m/z 533.1 (M+H).

Reference： [1]Patent: WO2013/149362,2013,A1 .Location in patent: Page/Page column 113

29
[ 6309-59-7 ]
[ 210240-20-3 ]

Reference： [1]Patent: WO2013/149362,2013,A1

30
[ 21926-00-1 ]
[ 210240-20-3 ]

Reference： [1]Patent: WO2013/149362,2013,A1

31
1,1-dimethylethyl (tetrahydro-2H-thiopyran-4-yl)carbamate [ No CAS ]
[ 210240-20-3 ]

Reference： [1]Patent: WO2013/149362,2013,A1

32
[ 1072-72-6 ]
[ 210240-20-3 ]

Reference： [1]Patent: WO2013/149362,2013,A1

33
6-[4-[(5-trifluoromethyl-2-pyridinyl)methyl]oxy}-2-oxo-1(2H)-pyridinyl]-7,8-dihydronaphthalene-2-carbaldehyde [ No CAS ]
[ 210240-20-3 ]
1-(6-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]methyl}-3,4-dihydronaphthalen-2-yl)-4-[5-(trifluoromethyl)pyridin-2-yl]methoxy}pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.4%		Example 256: 1 -(6- { [( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]methyl} -3,4- dihydronaphthalen-2-yl)-4-[5-(trifluoromethyl)pyridin-2-yl]methoxy}pyridin-2(lH)-one dihydrochloride A mixture of 6-[4- [(5-trifluoromethyl-2-pyridinyl)methyl]oxy}-2-oxo-l (2H)-pyridinyl]-7,8- dihydronaphthalene-2- carbaldehyde (0.5 g, 1.17 mmol), tetrahydro-l ,l-dioxido-2H- thiopyran-4-ylamine (0.26 g, 1.404 mmol) and Et3N (0.24 g, 2.34 mmol) in dry DCM (10 mL) was stirred at room temperature overnight. Then, to the reaction mixture was added NaHB(OAc)3 (0.50 g, 2.34 mmol), the mixture was stirred at room temperature overnight. LC-MS showed that the reaction was finished. The reaction mixture was dissolved in DCM (30 mL). The organic phase was washed with H20 (3 X 10 mL). The organic phase was dried over a2S04 and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound as a white solid (140 mg, 21.4% yield): FontWeight="Bold" FontSize="10" H NMR (400 MHz, MeOH-d4) delta rhorhoiotaeta 8.90 (s, 1H), 8.21 -8.18 (m, 1H), 7.78-7.76 (m, 1H), 7.58-7.56 (m, 1H), 7.33-7.32 (m, 2H), 7.26-7.24 (m, 1H), 6.62 (s, 1H), 6.32 (dd, J = 2.8 Hz, 4.8 Hz, 1H), 6.04 (d, J = 2.4 Hz, 1H), 5.34 (s, 2H), 4.24 (s, 2H), 3.57-3.48 (m, 2H), 3.32-3.30 (m, 1H), 3.20-3.16 (m, 2H), 3.09-3.05 (m, 2H), 2.71-2.64 (m, 2H), 3.59-3.51 (m, 2H), 2.30-2.13 (m, 2H); LC-MS m/z 560 ( +H)+.

Reference： [1]Patent: WO2013/166621,2013,A1 .Location in patent: Page/Page column 142; 143

34
[ 1174020-25-7 ]
[ 210240-20-3 ]
[ 1552306-83-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 780 - 785

35
[ 210240-20-3 ]
[ 1552306-84-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 780 - 785

36
[ 210240-20-3 ]
[ 1174019-23-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 780 - 785

37
[ 1561967-41-6 ]
[ 210240-20-3 ]
[ 1561961-30-5 ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1.5h;Inert atmosphere;	Step 5: 2-(4-(A/-(te t-Butyl)sulfamoyl)naphthalen-1-yl)-1-(cvclohexylmethyl)-//-(1 ,1- dioxidotetrahydro-2H-thiopyran-4-yl)-5-methyl-1 H-imidazole-4-carboxamide (320) A solution of compound 320d (120 mg, 248 muetaetaomicronIota), 4-aminotetrahydro-2H-thiopyran 1 ,1 - dioxide (46 mg, 248 muiotaetaomicronIota), HATU (94 mg, 248 muiotaetaomicronIota) and DIEA (128 mg, 994 pmol) in DCM (6 mL) was stirred at rt for 1.5 h under N2, concentrated and purified by prep-HPLC to give compound 320 (65 mg, 43%) as a white solid. 1H-NMR (CDCI3, 300 MHz) delta: 0.50-0.54 (m, 2H), 0.89-0.92 (m, 3H), 1.20 (s, 9H), 1.28-1.32 (m, 3H), 1.50-1.52 (m, 3H), 2.19-2.27 (m, 2H), 2.34-2.41 (m, 2H), 2.70 (s, 3H), 3.08-3.12 (m, 4H), 3.53 (d, J = 7.2 Hz, 2H), 4.22-4.25 (m, 1 H), 4.72 (s, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.59-7.65 (m, 3H), 7.70-7.76 (m, 1 H), 8.41 (d, J = 7.5 Hz, 1 H), 8.69 (d, J = 8.7 Hz, 1 H). MS 615.3 (M+1)+.

Reference： [1]Patent: WO2014/23367,2014,A1 .Location in patent: Page/Page column 143

38
[ 1595290-61-1 ]
[ 210240-20-3 ]
[ 76-05-1 ]
3-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		Example 20 3-(4-((lH-indazol-5-yl)amino)pyrimidin-2-yl)-N-(l,l-dioxidotetrahydro-2H-thiopyran-4- yl)benzamide TFA salt To the mixture of 3-(4-((lH-indazol-5-yl)amino)pyrimidin-2-yl)benzoic acid (400mg, 1.2mmol), 4-aminotetrahydro-2H-thiopyran 1,1 -dioxide (300 mg, 1.4 mmol), HATU (720mg, 1.89 mmol) and Et3N (200 mg, 2 mmol) in DMF (15mL) was stirred at 25 C overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2S04 and concentrated to give a residue, which was purified by HPLC to give the title compound (81 mg, 20%) as a solid. 1H NMR (400 MHz, CD3OD) 52.19-2.24 (m, 2H), 2.31- 2.33 (m, 2H), 3.12-3.15 (m, 2H), 3.34-3.38 (m, 2H), 4.23-4.28 (m, 1H), 6.93 (d, J = 6.8 Hz, 1H), 7.58-7.76 (m, 3H), 8.12 (s, 1H), 8.14 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.65 (s, 1H). MS (ES+) m/e 463 (M+H)+.
81 mg		To the mixture of 3-(4-((lH-indazol-5-yl)amino)pyrimidin-2-yl)benzoic acid (400mg, 1.2mmol), 4-aminotetrahydro-2H-thiopyran 1,1 -dioxide (300 mg, 1.4 mmol), HATU (720mg, 1.89 mmol) and Et3N (200 mg, 2 mmol) in DMF (15mL) was stirred at 25 C overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2S04 and concentrated to give a residue, which was purified by HPLC to give the title compound (81 mg, 20%) as a solid. 1H NMR (400 MHz, CD3OD) 52.19-2.24 (m, 2H), 2.31-2.33 (m, 2H), 3.12-3.15 (m, 2H), 3.34-3.38 (m, 2H), 4.23-4.28 (m, 1H), 6.93 (d, J = 6.8 Hz, 1H), 7.58-7.76 (m, 3H), 8.12 (s, 1H), 8.14 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.65 (s, 1H). MS (ES+) m/e 463 (M+H)+.

Reference： [1]Patent: WO2015/157556,2015,A1 .Location in patent: Paragraph 0211
[2]Patent: WO2014/55999,2014,A2 .Location in patent: Paragraph 0183

39
[ 1610520-29-0 ]
[ 210240-20-3 ]
[ 1610521-36-2 ]

Yield	Reaction Conditions	Operation in experiment
56%		A mixture of 7-bromo-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carbaldehyde (Intermediate 3) (250 mg, 0.919 mmol) and 4-aminotetrahydro-2H-thiopyran 1 ,1-dioxide (200 mg, 1.340 mmol) in MeOH (3.5 ml.) and acetic acid (0.35 ml.) was left to stir at 50 C for 4 hr. After this time the 2- picoline-borane complex (108 mg, 1.01 1 mmol) was added and the reaction mixture was left to stir for a further 20 hr. The volatile components were removed in vacuo and the resulting residue was diluted with sat. aq. NaHCOs (40 ml_). The aqueous layer was extracted with DCM (3 x 40 ml_). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 0-4% MeOH in DCM. The appropriate fractions were combined and evaporated in vacuo to give the title compound (210 mg, 0.52 mmol, 56%) as a pale yellow solid. LCMS (2 min, Formic Acid): Rt = 0.47 min, MH+ = 405/407.

Reference： [1]Patent: WO2014/78257,2014,A1 .Location in patent: Page/Page column 131

40
[ 1621273-35-5 ]
[ 210240-20-3 ]
[ 1621272-04-5 ]

Yield	Reaction Conditions	Operation in experiment
72 mg	In acetonitrile; for 1h;	N,N-Diisopropylethylamine (137 muL, 0.81 mmol), 4-dimethylaminopyridine (27 mg, 0.22 mmol) and 4-nitrophenyl chloroformate (45 mg, 0.22 mmol) is added to a solution of (R)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 1A, 80 mg, 0.20 mmol) in acetonitrile (2.0 mL), and the mixture is stirred at room temperature over night. 1,1-Dioxotetrahydro-2H-thiopyran-4-amine (74 mg, 0.40 mmol) is added, and the mixture is stirred for 1 h and purified by reversed phase HPLC (Waters SunFire-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 72 mg; ESI mass spectrum [M+H]+=573; Retention time HPLC: 1.01 min (Z018_S04).

Reference： [1]Patent: US2014/221335,2014,A1 .Location in patent: Paragraph 0494; 0495

41
[ 1621269-90-6 ]
[ 210240-20-3 ]
[ 7693-46-1 ]
[ 1621272-04-5 ]

Yield	Reaction Conditions	Operation in experiment
72 mg		(R)-4-(4-Cyanophenyl)-2,5-dioxo-N-(1 , 1-dioxo-hexahydro- 116-thiopyran-4-y1)- 1-(3- (trifluoromethyl)phenyl)-4,5,6,7-tetrahydro- 1H-cyclopenta[d] pyrimkline-3(2H)-carboxamideN,N-Diisopropylethylamine (137 jiL, 0.81 mmol), 4-dimethylaminopyridine (27 mg, 0.22 mmol) and 4-nitrophenyl chioroformate (45 mg, 0.22 mmol) is added to a solution of (R)-4-(2,5 -dioxo- 1 -(3-(trifluoromethyl)phenyl)-2,3 ,4,5 ,6,7-hexahydro- 1H-cyclopenta[d] - pyrimidin-4-yl)benzonitrile (example 1A, 80 mg, 0.20 mmol) in acetonitrile (2.0 mL), andthe mixture is stirred at room temperature over night. 1,1-Dioxotetrahydro-2H-thiopyran-4- amine (74 mg, 0.40 mmol) is added, and the mixture is stirred for 1 h and purified by reversed phase HPLC (Waters SunFire?M-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 72 mg; ESI mass spectrum [M+H] = 573; Retention time HPLC: 1.01 mm (ZO 1 8S04).

Reference： [1]Patent: WO2014/122160,2014,A1 .Location in patent: Page/Page column 153

42
(2S,3R,4R)-1-acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid [ No CAS ]
[ 210240-20-3 ]
(2S,3R,4R)-1-acetyl-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a solution of (2S,3R,4R)- I -acetyl-2-ethyl-3-methyl-4-((4-methylpyrimidin-2-yl)amino)- 1,2,3,4-tetrahydroquinoline-6-carboxylic acid (for a preparation see Intermediate 318, 50 mg, 0.136 mmol)and HATU (61.9 mg, 0.163 mmol) in N,N-dimethylformamide (DMF) (0.8 mL) was added 4- aminotetrahydro-2H-thiopyran 1,1-dioxide (24.30 mg, 0.163 mmol) and DIPEA (0.095 mL, 0.543 mmol). The reaction mixture was stirred at rt for I h. The reaction was diluted to I mL with methanol and purified by MDAP (HpH). The solvent was concentrated in vacuo to give the product (32 mg,0.064 mmol, 47%) as an off-white solid. LCMS (2mm Eormic): Rt = 0.69 mi [MH] = 500.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 420

43
[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate [ No CAS ]
[ 210240-20-3 ]
C₂₁H₃₁N₃O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	Example 198 To a mixture of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (200 mg), DIPEA (139 muL), and DMF (3.0 mL) was added <strong>[210240-20-3]tetrahydro-2H-thiopyran-4-amine-1,1-dioxide</strong> (97 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture was added a saturated aqueous NH4Cl solution, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column and dissolved in EtOAc, and 4 M HCl/EtOAc (137 muL) was added dropwise. The precipitate was collected by filtration and then dried to obtain N-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}<strong>[210240-20-3]tetrahydro-2H-thiopyran-4-amine-1,1-dioxide</strong> hydrochloride (165 mg).

Reference： [1]Patent: US2015/111876,2015,A1 .Location in patent: Paragraph 0328

44
[ 38267-96-8 ]
[ 210240-20-3 ]
N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-(1,3-thiazol-5-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

45
[ 38267-96-8 ]
[ 210240-20-3 ]
6-bromo-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-quinazolinamine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571

46
[ 210240-20-3 ]
N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 15 N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide The titled compound was prepared using the reaction conditions described for Example 9A, substituting <strong>[210240-20-3]4-aminotetrahydro-2H-thiopyran 1,1-dioxide</strong> for 2,5-dihydro-1H-pyrrole. 1H NMR (300 MHz, DMSO-d6) delta ppm 9.03 (d, J=8.5 Hz, 1H), 8.62 (s, 1H), 8.53 (d, J=8.9 Hz, 1H), 8.32 (m, 1H), 8.23 (d, J=9.1 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 7.92 (d, J=2.7 Hz, 1H), 7.77 (m, 1H), 7.41 (d, J=8.9 Hz, 1H), 4.30 (m, 1H), 3.39-3.42 (m, 2H), 3.11-3.15 (m, 2H), 2.25-2.32 (m, 2H), 2.12-2.19 (m, 2H); MS (ESI+) m/z 466.1 [M+H]+.

Reference： [1]Patent: US2015/218102,2015,A1

47
2,4-dichloro-6-[4-(trifluoromethyl)phenyl]thieno[3,2-d]pyrimidine [ No CAS ]
[ 210240-20-3 ]
C₁₈H₁₅ClF₃N₃O₂S₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7572 - 7579

48
[ 1312208-19-7 ]
[ 210240-20-3 ]
1-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-3-[4-(trifluoromethyl)phenyl]benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1432 - 1448

49
[ 210240-20-3 ]
C₄₈H₅₀ClN₇O₁₁S₃ [ No CAS ]
4-(2-amino-1,3-benzothiazol-4-yl)-N₁-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-(1H-tetrazol-5-yl)benzene-1,2-disulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a set of vials each containing the requisite commercially available or known amine (0.13 mmol) was added a solution of the sulfonyl chloride (45 mg, 0.044 mmol) followed by Et3N (0.0 18 mL, 0.13 mmol). The vials were capped and the mixtures were stirred at RT for 5 hours. To the reaction mixture was then added TFA (0.5 mL) and the mixtures were stirred at RT for 1.5 hours. After that time, toluene (1 mL) was added to each vial and the mixtures were concentrated in vacuo. To each vial was then added TFA (1.0 mL) and anisole (0.019 mL, 0.17 mmol). The vials were capped and the reaction mixtures were heated to 80C with stirring for 45 mm. After that time, the reaction mixtures were concentrated in vacuo. The crude residues were then dissolved in DMSO (1.0 mL) and filtered. The crude products were purified by mass triggered preparative HPLC [Waters Sunfire C 18 column, 5 llm, 1 9x 100 mm, using a gradient range from 8-10% initial to 21-36% final MeCN (0.1% TFA) in water (0.1% TFA), 25 mL/min, 8-12 mm run time] to afford EXAMPLES1 11-181.

Reference： [1]Patent: WO2016/206101,2016,A1 .Location in patent: Page/Page column 208; 209

50
[ 1410737-09-5 ]
[ 210240-20-3 ]
[ 1410737-37-9 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2819 - 2839

51
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzene sulfonamide [ No CAS ]
[ 210240-20-3 ]
C₂₃H₂₅ClFN₃O₆S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With alkali carbonate; In N,N-dimethyl-formamide; for 12h;Inert atmosphere;	General procedure: Step A: A mixture of 19 TFA salt (9 mg, 0.06 mmol), 11 (32 mg,0.07 mmol) and Cs2CO3 (45 mg, 0.14 mmol) in DMF (0.63 mL)was stirred at 65 C for 12 h. The reaction mixture was filtered,and the crude product was purified by preparative TLC on silicagel eluting with 80% EtOAc/hexanes to give 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((hexahydrofuro[2,3-b]furan-3a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (20 mg, 54%)as a white foam. 1H NMR (500 MHz, CDCl3) d 7.77 (d, J = 6.9 Hz,1H), 7.40 (d, J = 3.5 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.98 (d,J = 3.5 Hz, 1H), 6.43-6.30 (m, 3H), 5.47 (s, 1H), 5.21 (s, 2H), 5.05-4.95 (m, 1H), 4.09 (dd, J = 8.8, 5.0 Hz, 4H), 3.82-3.70 (m, 7H),3.35 (d, J = 5.2 Hz, 2H), 2.14-1.98 (m, 4H). 584.2 (M+H)+. Step B:A solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((hexahydrofuro[2,3-b]furan-3a-yl)methyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (20 mg, 0.034 mmol) and TFA (0.05 mL) inDCM (0.34 mL) was stirred at rt for 1 h. The solvents wereremoved, and residue was purified via preparative HPLC (MethodC) to give 4 (6 mg).

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5490 - 5505

52
[ 210240-20-3 ]
2-[(1S)-1-cyclohexylethoxy]-5-fluoro-4-(3-oxo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)benzoic acid [ No CAS ]
2-[(1S)-1-cyclohexylethoxy]-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-fluoro-4-(3-oxo-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		To a solution of 2-[(1 S)-1 -cyclohexylethoxy]-5-fluoro-4-(3-oxo-5,6,7,8- tetrahydro[1 ,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)benzoic acid (intermediate 19) (100 mg, 248 muiotaetaomicronIota) in dichloromethane (1 .0 ml) was added two drops of Nu,Nu-dimethylformamide. The solution was cooled to 0 "C and oxalyl chloride (34 .6 mg, 273 muiotaetaomicronIota) was slowly added. The reaction was then warmed to room temperature and stirred for 90 minutes. The solvent was removed under reduced pressure and the residue was re-dissolved in dichloromethane (2.0 ml) and added dropwise to a cooled (0 C) solution of tetrahydro-2H-thiopyran-4-amine 1 ,1 - dioxide (40.7 mg, 273 muiotaetaomicronIota) and triethylamine (38 muIota, 270 muiotaetaomicronIota) in dichloromethane (2.0 ml). The mixture was warmed to room temperature and stirred for one hour. Then, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (X-Bridge Prep C185muiotaeta OBD, 0.1 % aqueous formic acid, acetonitrile), to yleld the title compound (90 mg, 67 %) as a solid.LC-MS (method A): R, = 1.13 min; MS (ESIpos): m/z = 536 [M+H]+1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.993 (0.97), 1.001 (0.94), 1.024 (1.23), 1.031 (1.16), 1.073(1.11), 1.080(1.06), 1.103(1.81), 1.109(1.58), 1.132(1.83), 1.159(2.02), 1.192 (16.00), 1.207(15.54), 1.220(1.40), 1.228(1.22), 1.559 (0.98), 1.566(1.00), 1.573 (0.99), 1.624 (1.13), 1.658 (1.62), 1.702 (3.47), 1.732 (1.88), 1.770 (0.90), 1.779 (1.94), 1.786 (2.30), 1.791 (2.69), 1.802 (2.75), 1.806 (2.85), 1.818 (1.95), 1.822 (2.10), 1.855 (2.20), 1.859 (2.40), 1.869 (3.17), 1.874 (3.14), 1.884 (2.92), 1.890 (2.39), 1.899 (1.73), 1.905 (0.96), 1.966 (1.39), 1.978 (1.48), 1.994 (1.59), 2.003 (1.63), 2.019 (0.90), 2.149 (1.26), 2.158 (1.81), 2.164 (1.88), 2.173 (1.74), 2.178 (1.52), 2.183 (1.51), 2.188 (1.38), 2.193 (1.38), 2.198 (1.29), 2.208 (0.91), 2.540 (1.18), 2.672 (3.37), 2.688 (6.60), 2.704 (3.61), 3.090 (1.33), 3.098 (1.72), 3.127 (2.11), 3.133 (2.37), 3.141 (1.80), 3.279 (1.62), 3.308 (2.42), 3.342 (1.21), 3.539 (3.92), 3.554 (7.13), 3.568 (3.12), 4.149 (0.85), 4.155 (1.13), 4.165 (0.99), 4.175 (1.13), 4.282 (1.76), 4.297 (2.63), 4.312 (1.76), 7.240 (4.66), 7.256 (4.66), 7.501 (6.75), 7.528 (6.43), 8.224 (3.25), 8.244 (3.16).

Reference： [1]Patent: WO2018/77944,2018,A2 .Location in patent: Page/Page column 347; 348

53
[ 1428368-75-5 ]
[ 210240-20-3 ]
4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 18h;	To a mixture of 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (6.60 g, 27.9 mmol) and 4-aminotetrahydro-2H-thiopyran 1, 1 -dioxide (5 g, 33.5 mmol) in DMF (40 mL) was added TEA (8.56 ml, 61.4 mmol). The mixture was stirred at 60C for 18 h, then quenched in ice water (200 mL). The solid was collected by filtration and washed with water to afford 4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)tetrahydro-2H- thiopyran 1, 1-dioxide (10.2 g, 92%) as a bright orange solid; Rt 1.91 min (method 1); m/z 366 (M+H)+ (ES+).

Reference： [1]Patent: WO2018/73586,2018,A1 .Location in patent: Page/Page column 92

54
[ 210240-20-3 ]
[ 1089667-68-4 ]