59340-27-1|1,3,5-Trimethyl-1H-pyrazole-4-sulfonyl chloride| Ambeed

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Structure of 59340-27-1

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

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

Change View

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

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

{[ item.pr_size ]}

In Stock

- +

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

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

Quality Control of [ 59340-27-1 ] Purity: 97% SDS Specification

COA

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

NMR

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

CNMR

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

HPLC

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

LC-MS

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

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 59340-27-1 ]

CAS No. :	59340-27-1
Formula :	C₆H₉ClN₂O₂S
M.W :	208.67
SMILES Code :	O=S(C1=C(C)N(C)N=C1C)(Cl)=O
MDL No. :	MFCD02180944
InChI Key :	QLSAMUCENQZGHN-UHFFFAOYSA-N
Pubchem ID :	2737340

Safety of [ 59340-27-1 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H314
Precautionary Statements:	P280-P305+P351+P338-P310
Class:	8
UN#:	3261
Packing Group:	Ⅲ

Computational Chemistry of [ 59340-27-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	5
Fraction Csp3	0.5
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	46.5
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	60.34 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.71
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.06
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.05
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.24
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.76
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.16

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.04
Solubility	1.89 mg/ml ; 0.00904 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.92
Solubility	2.52 mg/ml ; 0.0121 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.12
Solubility	1.59 mg/ml ; 0.0076 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.82 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.97

Application In Synthesis of [ 59340-27-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 59340-27-1 ]

[ 59340-27-1 ] Synthesis Path-Downstream 1~29

2
[ 287202-42-0 ]
[ 59340-27-1 ]
4-(4-but-2-ynyloxy-benzenesulfonylmethyl)-1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-piperidine-4-carboxylic acid tert-butoxy-amide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 34 - 39.

3
[ 59340-27-1 ]
4-(4-but-2-ynyloxy-benzenesulfonylmethyl)-1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-piperidine-4-carboxylic acid hydroxyamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 34 - 39.

4
(S)-2-((S)-2-amino-4-phenylbutanamido)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)pentanamide 2,2,2-trifluoroacetate [ No CAS ]
[ 59340-27-1 ]
C₄₀H₅₆N₆O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; at 20℃;	Compound (CC) (23.6 mg, 0.034 mmol) was mixed with TFA/DCM (80%) and was stirred at room temperature for 1 hr at which time the mixture was concentrated and placed under high vacuum for 2 hr giving the TFA salt of the tetra-peptide amine. To a DCM solution of the TFA salt was added <strong>[59340-27-1]1,3,5-trimethyl-1-H-pyrazole-4-sulfonyl chloride</strong> (1.2 eq., 0.041 mmol, 8.5 mg) and TEA (4 eq., 0.136 mmol, 26 muL) and the mixture was stirred at room temperature overnight. The crude mixture was concentrated to dryness and the residue was taken up in EtOAc. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil that was purified by flash chromatography to afford compound 8 (2 mg) (IC50 20S CT-L <100 nM, Cell-Based CT-L <100 nM)

References: [1]Patent: US2005/245435,2005,A1 .Location in patent: Page/Page column 34-35.

5
[ 943152-44-1 ]
[ 59340-27-1 ]
(R)-1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With triethylamine; In dichloromethane; at 20℃;	(R)-1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-amide Palladium acetate (56 mg, 0.25 mmol) was added to a mixture of 5-fluoro-2-methoxyphenylboronic acid (850 mg, 5.0 mmol) and (R)-1-(4-bromophenyl)ethylamine (500 mg, 2.5 mmol) in water (20 ml). This mixture was heated for 5 min at 200 C. in a Smithcreator microwave oven and then diluted with methanol (200 ml). The mixture was purified on a SCX column (20 g) using 2M ammonia in methanol to elute the intermediate amine. Evaporation of solvents under reduced pressure gave (R)-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethylamine as a gum (580 mg, 2.37 mmol, 96.6%). Triethylamine (41.1 mul, 0.295 mmol) and <strong>[59340-27-1]1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride</strong> (20.5 mg, 0.0984 mmol) were added to a solution of (R)-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 mul), the dichloromethane layer separated, dried over magnesium sulfate and the solvent evaporated. Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (13.8 mg, 0.033 mmol, 40%): 1H NMR (400 MHz, CDCl3): delta7.37, 7.14 (a/b, 4H), 7.02-6.87 (m, 3H), 4.68 (m, 1H), 4.48 (t, 1H), 3.78 (s, 3H), 3.55(s, 3H), 2.35(s, 3H), 2.22(s, 3H), 1.50(d, 3H) ppm; MS (ESI) m/z: 417 [M+H]+.

References: [1]Patent: US2007/149577,2007,A1 .Location in patent: Page/Page column 5.

6
[ 1010816-09-7 ]
[ 59340-27-1 ]
[ 724443-82-7 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 861 - 874.

7
C₃₃H₄₆F₂N₄O₅ [ No CAS ]
[ 59340-27-1 ]
[ 1230558-95-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2837 - 2842.

8
2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetate [ No CAS ]
[ 59340-27-1 ]
[ 1255713-81-5 ]

Yield	Reaction Conditions	Operation in experiment
31%	With pyridine; at 20℃;	2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-l-one acetic acid salt (0.02 g, 0.05 mmol) was dissolved in pyridine (0.5 ml) at room temperature and 1,3,5-trimethyl- lH-pyrazole-4-sulfonyl chloride (0.013 g, 0.06 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in AcOEt and washed with 0. IM HCl and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography (4:1 AcOEt/heptane) to yield 2-(4-trifluoromethoxy-phenyl)-8-(l,3,5-trimethyl-lH-pyrazole- 4-sulfonyl)-2,8-diaza-spiro[4.5]decan-l-onel)-2,8-diaza-spiro[4.5]decan-l-one as an off- white solid (0.09g, 31%). MS (ESI): 487.3(MH+)

References: [1]Patent: WO2010/130665,2010,A1 .Location in patent: Page/Page column 160.

9
[ 1276643-15-2 ]
[ 59340-27-1 ]
[ 1276673-45-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; at 20℃; for 16h;	E. General coupling protocol for the synthesis of compounds with general structure (249)Exemplified by the synthesis of N-((ls,4s)-4-fluoro-4-(3-(trifluoromethyl)phi sulfonyl)cyclohexyl)- 1 , 3, 5-trimethyl- lH-pyrazole-4- sulfonamide (251) [00330] Cis-4-fluoro-4-(3-(trifluoromethyl)phenylsulfonyl)cyclohexanamine (110) (75 mg, 0.21 mmol), TEA (111 mu,, 0.8 mmol), and l,3,5-trimethyl-lH-pyrazole-4- sulfonyl chloride (250) (0.21 mmol) were stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and the crude material purified by reverse phase HPLC to give N-(Cis-4-fluoro-4-(3-(trifluoromethyl)phenylsulfonyl)cyclohexyl- 1 ,3,5-trimethyl- lH-pyrazole-4- sulfonamide (251).

References: [1]Patent: WO2011/35159,2011,A1 .Location in patent: Page/Page column 127-128.

10
[ 1294514-39-8 ]
[ 59340-27-1 ]
C₃₂H₃₈N₆O₆S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1852 - 1856.

11
C₂HF₃O*C₁₃H₁₈N₄S [ No CAS ]
[ 59340-27-1 ]
[ 1344125-14-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6500 - 6504.

12
[ 106-40-1 ]
[ 59340-27-1 ]
[ 958563-25-2 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 140 - 152.

13
[ 1426896-92-5 ]
[ 59340-27-1 ]
[ 1279889-90-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In tetrahydrofuran; at 20 - 40℃;Inert atmosphere;	Example N[0173] 1,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 33 mg of <strong>[59340-27-1]1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid chloride</strong> (0.16 mmol, 1.2 eq) were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) in dry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the tube was flushed with argon, closed with a screw cap, and shaken over night at 40 ???C. 0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h at room temperature and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19:1), filtered, and submitted to preparative reversed phase HPLC purification (water/acetonitrile gradient (+ 0.1% trifluoroacetic acid)). 1,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained as a white solid (42 mg, 63%).
63%		Example N 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide 33 mg of <strong>[59340-27-1]1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid chloride</strong> (0.16 mmol, 1.2 eq) were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) in dry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the tube was flushed with argon, closed with a screw cap, and shaken over night at 40 C. 0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h at room temperature and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19:1), filtered, and submitted to preparative reversed phase HPLC purification (water/acetonitrile gradient (+0.1% trifluoroacetic acid)). 1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained as a white solid (42 mg, 63%).
63%		Example N1 ,3,5-Trimethyl-1 H-pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5- ylmethyl]-amide33 mg of 1 ,3,5-trimethyl-1 H-pyrazole-4-sulfonic acid chloride (0.16 mmol, 1 .2 eq) were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) in dry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the tube was flushed with argon, closed with a screw cap, and shaken over night at 40 C. 0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h at room temperature and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19: 1 ), filtered, and submitted to preparative reversed phase HPLC purification(water/acetonitrile gradient (+ 0.1 % trifluoroacetic acid)). 1 ,3,5-Trimethyl-1 H- pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained as a white solid (42 mg, 63%).

63%		33 mg of 1 ,3,5-trimethyl-1 H-pyrazole-4-sulfonic acid chloride (0.16 mmol, 1 .2 eq) were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg of [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]amine (0.13 mmol) in dry tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the tube was flushed with argon, closed with a screw cap, and shaken over night at 40C. 0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the mixture was shaken for 2 h at room temperature and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19:1 ), filtered, and submitted to preparative reversed phase HPLC purification(water/acetonitrile gradient (+ 0.1 % trifluoroacetic acid)). 1 ,3,5-Trimethyl-1 H- pyrazole-4-sulfonic acid [2-(2-phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-amide was obtained as a white solid (42 mg, 63%).
63%		A solution of 33 mg of <strong>[59340-27-1]1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride</strong> (0.16 mmol, 1.2 equivalents) was weighed into a reaction tube and dissolved in anhydrous tetrahydrofuran (1 ml).A mixture of 44 mg of [2- (2-phenyl-chroman-6-yloxy) -thiazol-5-ylmethyl] amine (0.13 mmol) in anhydrous tetrahydrofuran (3 ml) and 30 mg of triethylamine Mmol, 2.3 equivalents),The tube was purged with argon, closed with a nut and shaken overnight at 40 C.0.008 ml of tris (2-aminoethyl) amine in 0.5 ml of tetrahydrofuran was added and the mixture was shaken at room temperature for 2 h and then evaporated. The residue was dissolved in 2 ml of a mixture of dimethylformamide / trifluoroacetic acid (19: 1), filtered and subjected to preparative reverse phase HPLC purification (water / acetonitrile gradient (+ 0.1% trifluoroacetic acid)).To give 1,3,5-trimethyl-1H-pyrazole-4-sulfonic acid [2- (2-phenyl-chroman-6-yloxy) -thiazol-5-ylmethyl] White solid (42 mg, 63%).

References: [1]Patent: EP2567958,2013,A1 .Location in patent: Paragraph 0173.
[2]Patent: US2013/65859,2013,A1 .Location in patent: Paragraph 0334; 0335.
[3]Patent: WO2013/37388,2013,A1 .Location in patent: Page/Page column 113; 114.
[4]Patent: JP5941637,2016,B2 .Location in patent: Paragraph 0204.
[5]Patent: CN102993195,2017,B .Location in patent: Paragraph 0511-0514.

14
4-(3,4-dichlorophenoxy)piperidine hydrochloride [ No CAS ]
[ 59340-27-1 ]
4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In dichloromethane; at 20℃; for 2h;	Example 1 4-(3,4-Dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine 4-(3,4-Dichlorophenoxy)piperidine hydrochloride (143 mg, 0.508 mmol) (prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) using 3,4-dichlorophenol) and triethylamine (142 muL, 1.16 mmol) in dichloromethane (10 mL) was treated with <strong>[59340-27-1]1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride</strong> (106 mg, 0.508 mmol). The reaction was stirred for 2 hours at room temperature. The crude reaction was washed with 1N hydrochloric acid, filtered through a phase separation cartridge and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with petrol/ethyl acetate to give the title compound. (160 mg, 76%) 1H NMR (400 MHz, DMSO-d6) delta ppm 1.62-1.75 (m, 2H) 2.00-2.15 (m, 2H) 2.30 (s, 3H) 2.45 (s, 3H) 2.78-2.86 (m, 2H) 3.34-3.42 (m, 2H) 3.75 (s, 3H) 4.45-4.54 (m, 1H) 6.95-6.98 (m, 1H) 7.28 (s, 1H) 7.24 (m, 1H) MS ES+: 419.
76%	With triethylamine; In dichloromethane; at 20 - 25℃; for 2h;	Example 1 4-(3,4-Dichlorophenoxy)-l-((l,3,5-trimethyl-lH-pyrazol-4- yl)sulfonyl)piperidine 4-(3,4-Dichlorophenoxy)piperidine hydrochloride (143 mg, 0.508 mmol) (prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10) using 3,4-dichlorophenol) and triethylamine (142muIota^, 1.16 mmol) in dichloromethane (10 mL) was treated with l,3,5-trimethyl-lH-pyrazole-4-sulfonyl chloride (106 mg, 0.508 mmol). The reaction was stirred for 2 hours at room temperature. The crude reaction was washed with IN hydrochloric acid, filtered through a phase separation cartridge and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with petrol/ethyl acetate to give the title compound. (160mg, 76%) lH NMR (400 MHz, DMSO-d6) delta ppm 1.62-1.75 (m, 2 H) 2.00-2.15 (m, 2H) 2.30 (s, 3H) 2.45 (s, 3H) 2.78-2.86 (m, 2H) 3.34-3.42 (m, 2H) 3.75 (s, 3H) 4.45-4.54 (m, 1H) 6.95- 6.98 (m, 1H) 7.28 (s, 1H) 7.24 (m, 1H) MS ES+: 419

References: [1]Patent: US2013/324576,2013,A1 .Location in patent: Paragraph 0711; 0712; 0713; 0714.
[2]Patent: WO2013/179024,2013,A1 .Location in patent: Page/Page column 72.

15
[ 6091-44-7 ]
[ 59340-27-1 ]
1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		Intermediate 8: 1-(1,3,5-Trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one[0574] To a solution of 4-piperidine hydrochloride (3.67 g, 23.9 mmol) in dichloromethane (250 mL) was added magnesium sulfate (5 g) and the reaction was stirred at room temperature. After 15 minutes, <strong>[59340-27-1]1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride</strong> ((1.0 g, 4.79 mmol) and triethylamine (2.42 g, 23.9 mmol) were added successively and stirred overnight at room temperature. The reaction was filtered, treated with water (25 mL) and extracted into dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product, 1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (1.24 g, 95%). [0575] MS ES+: 272

References: [1]Patent: US2013/324576,2013,A1 .Location in patent: Paragraph 0573; 0574; 0575.

16
[ 59340-27-1 ]
4-chloro-N-[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline [ No CAS ]

References: [1]Patent: US2013/324576,2013,A1 .

17
[ 59340-27-1 ]
4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol [ No CAS ]

References: [1]Patent: US2013/324576,2013,A1 .
[2]Patent: WO2013/179024,2013,A1 .

18
[ 59340-27-1 ]
4-(4-chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine [ No CAS ]

References: [1]Patent: US2013/324576,2013,A1 .
[2]Patent: WO2013/179024,2013,A1 .

19
[ 41979-39-9 ]
[ 59340-27-1 ]
1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		Intermediate 8: l-(l,3,5-Trimethyl-lH-pyrazole-4-sulfonyl)piperidin-4-one To a solution of 4-piperidine hydrochloride (3.67g, 23.9 mmol) in dichloromethane (250 mL) was added magnesium sulfate (5g) and the reaction was stirred at room temperature. After 15 minutes, l,3,5-trimethyl-lH-pyrazole-4-sulfonyl chloride ( (l .Og, 4.79 mmol) and triethylamine (2.42g, 23.9 mmol) were added successively and stirred overnight at room temperature. The reaction was filtered, treated with water (25 mL) and extracted into dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product, 1- (l,3,5-trimethyl-lH-pyrazole-4-sulfonyl)piperidin-4-one (1.24g, 95%). MS ES+: 272

References: [1]Patent: WO2013/179024,2013,A1 .Location in patent: Page/Page column 49-50.

20
[ 59340-27-1 ]
4-chloro-N-[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline [ No CAS ]

References: [1]Patent: WO2013/179024,2013,A1 .

21
[ 3964-86-1 ]
[ 59340-27-1 ]
N-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; In N,N-dimethyl-formamide; at 0 - 25℃; for 2h;	A solution of 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propan-1-amine hydrochloride (0.100 g, 0.346 mmol) in DMF (1.1 mL) was cooled to 0 C, treated with Et3N (0.193 g, 1.38 mmol), and <strong>[59340-27-1]1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride</strong> (0.080 g, 0.381 mmol). The mixture was warmed to 25 C, and stirred for 2 h. The mixture was partitioned between water (50 mL) and CH2Cl2 (50 mL). The organic layer was washed with saturated aqueous NaCl (5 30 mL), dried (Na2SO4), and concentrated in vacuo. The residue was dissolved in a minimal amount of CH2Cl2 and purified by flash chromatography (SiO2, 13-16% ethyl acetate-hexanes) to afford the title compound (0.127 g, 86%) as a white solid. 1H NMR (600 MHz, CD3OD) 7.07-7.01 (6H, m), 6.88-6.86 (2H, m), 3.69 (2H, t, J = 6.6 Hz), 3.60 (3H, s), 2.99 (4H, br s), 2.84 (2H, J = 6.6 Hz), 2.24 (3H, s), 2.22 (3H, s), 1.66 (2H, quintet, J = 6.6 Hz); 13C NMR (150 MHz, CD3OD) 148.2, 147.3, 142.3, 134.1, 129.6, 126.2, 122.5, 119.5, 115.6, 47.0, 39.9, 35.2, 31.9, 27.1, 11.8, 9.2; LCMS m/z 425.3 ([M + H+], C23H29N4O2S requires 425.2).

References: [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6528 - 6534.

22
[ 59340-27-1 ]
6-[3-[[1-(trifluoromethyl)cyclopropyl]methoxy]pyrazol-1-yl]-N-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide [ No CAS ]