[ CAS No. 103008-51-1 ] {[proInfo.proName]}

Name: 103008-51-1|2-(Trifluoromethoxy)benzene-1-sulfonyl chloride|98%
Brand: Ambeed
SKU: A823479
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Quality Control of [ 103008-51-1 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 103008-51-1 ]

CAS No. :	103008-51-1	MDL No. :	MFCD00052316
Formula :	C₇H₄ClF₃O₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JLTBWYIUMFEOTN-UHFFFAOYSA-N
M.W :	260.62	Pubchem ID :	2777215
Synonyms :

Calculated chemistry of [ 103008-51-1 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	3
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.21
TPSA :	51.75 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.04
Log Po/w (XLOGP3) :	3.13
Log Po/w (WLOGP) :	4.85
Log Po/w (MLOGP) :	1.71
Log Po/w (SILICOS-IT) :	1.97
Consensus Log Po/w :	2.74

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.53
Solubility :	0.0777 mg/ml ; 0.000298 mol/l
Class :	Soluble
Log S (Ali) :	-3.89
Solubility :	0.0339 mg/ml ; 0.00013 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.57
Solubility :	0.0703 mg/ml ; 0.00027 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.24

Safety of [ 103008-51-1 ]

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

Application In Synthesis of [ 103008-51-1 ]

* 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.

Upstream synthesis route of [ 103008-51-1 ]
Downstream synthetic route of [ 103008-51-1 ]

[ 103008-51-1 ] Synthesis Path-Upstream 1~3

1
[ 103008-51-1 ]
[ 37526-59-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 9, p. 2222 - 2225

2
[ 1535-75-7 ]
[ 103008-51-1 ]
[ 37526-59-3 ]

Reference： [1] Patent: US6610853, 2003, B1,

3
[ 1535-75-7 ]
[ 103008-51-1 ]

Reference： [1] Patent: US6365780, 2002, B1, . Location in patent: Page column 5
[2] Patent: US6365780, 2002, B1, . Location in patent: Page column 6
[3] Patent: US6365780, 2002, B1, . Location in patent: Page column 5

[ 103008-51-1 ] Synthesis Path-Downstream 1~88

1
[ 944935-61-9 ]
[ 103008-51-1 ]
C₂₇H₂₇F₃N₂O₆S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3271 - 3275

2
[ 103008-51-1 ]
[ 864443-60-7 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 6827 - 6832

3
[ 103008-51-1 ]
(+/-)-(S_RS,SR)-S-(2-phenylbut-3-enyl)-S-phenyl-N-[2-(trifluoromethoxy)benzenesulfonyl]sulfoximine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 6827 - 6832

4
[ 103008-51-1 ]
(+/-)-(S_RS,RS)-S-(2-phenylbut-3-enyl)-S-phenyl-N-[2-(trifluoromethoxy)benzenesulfonyl]sulfoximine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 6827 - 6832

5
[ 103008-51-1 ]
[ 864443-68-5 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 6827 - 6832

6
[ 103008-51-1 ]
[ 197959-85-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1 - 4

7
[ 103008-51-1 ]
[ 197959-84-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1 - 4

8
[ 103008-51-1 ]
C₁₈H₁₉F₃N₄O₅S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1 - 4

9
[ 288321-54-0 ]
[ 103008-51-1 ]
C₃₀H₃₉F₃N₄O₁₁S [ No CAS ]

Reference： [1]Patent: US6344484,2002,B1 .Location in patent: Page column 58

10
[ 1535-75-7 ]
[ 103008-51-1 ]

Reference： [1]Patent: US6365780,2002,B1 .Location in patent: Page column 5
[2]Patent: US6365780,2002,B1 .Location in patent: Page column 6
[3]Patent: US6365780,2002,B1 .Location in patent: Page column 5

11
[ 87482-09-5 ]
[ 103008-51-1 ]
[ 727974-65-4 ]

Yield	Reaction Conditions	Operation in experiment
	With silver trifluoromethanesulfonate; In nitrobenzene; at 125℃; for 16h;	EXAMPLE 57 Preparation of N,N-Dimethyl-N-[2-(3-[2-(trifluoromethoxy)phenyl]sulfonyl}-1H-indol-1-yl)ethyl]amine Hydrochloride A stirred solution of N,N-dimethyl-N-[2-(1H-indol-1-yl)ethyl]amine (1.88 g, 10.0 mmol) in nitrobenzene is treated with 2-(trifluoromethoxy)phenylsulfonyl chloride (2.87 g, 11.0 mmol) under nitrogen followed by silver trifluoromethanesulfonate (3.35 g, 13.0 mmol), heated to 125 C. for 16 h, cooled and treated with saturated aqueous NaHCO3.The mixture is extracted with CH2Cl2.The extracts are combined, dried over MgSO4 and concentrated in vacuo.The resultant residue is chromatographed eluding with ethanol to give the free amine of the title product.The amine is dissolved in ethanol, treated with 4M HCl in dioxane, stirred for 16 h. and filtered.The filtercake is washed with ether and dried to afford the title compound as a pink solid, mp 198-201 C., identified by mass spectral and HNMR analyses.

Reference： [1]Patent: US2003/232828,2003,A1 .Location in patent: Page 18

12
[ 75-64-9 ]
[ 103008-51-1 ]
[ 200054-62-2 ]

Yield	Reaction Conditions	Operation in experiment
95.3%	With triethylamine; In acetonitrile; at 5 - 20℃; for 16h;	Example (II-1) At 5 C., 38.9 g (0.384 mol) of triethylamine and 28.0 g (0.384 mol) of tert-butylamine are added dropwise in succession to a solution of 99.0 g (0.384 mol) of 2-trifluoromethoxy-benzenesulfonyl chloride in 400 ml of acetonitrile. The reaction mixture is stirred at room temperature (about 20 C.) for 16 hours and then concentrated using water pump vacuum. The oily residue is dissolved in dichloromethane and the solution is washed with 2N hydrochloric acid, dried over magnesium sulfate and filtered. Using water pump vacuum, the solvent is carefully distilled off from the filtrate. 107.6 g (95.3% of theory) of N-tert-butyl-2-trifluoromethoxy-benzenesulfonamide are obtained as a crystalline residue of melting point 137 C.

Reference： [1]Patent: US6677277,2004,B1 .Location in patent: Page column 55
[2]Chemical Communications,2017,vol. 53,p. 5364 - 5367
[3]Chemistry - A European Journal,2018,vol. 24,p. 1241 - 1245
[4]Advanced Synthesis and Catalysis,2018,vol. 360,p. 4625 - 4633

13
4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride [ No CAS ]
[ 103008-51-1 ]
N-[1-(3,3-diphenylpropyl)-piperidin4-yl]-N-methyl-2-(trifluoromethoxy)benzenesulphonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; N-ethyl-N,N-diisopropylamine; In acetonitrile; for 15h;	To a solution of 2-trifluoromethoxybenzenesulphonyl chloride (1.3 mg, 5 muM) in acetonitrile (50 muL) was added a solution of 4-methylamino-1-(3,3-diphenylpropyl)-piperidine.dihydrochloride (Method A) (1.9 mg, 5 muM) and N,N-diisopropylethylamine (1.8 muL, 10 muM) in pyridine (50 muL). After 15 h the reaction mixture was concentrated to give the title compound which was characterised by LCMS; MS: 533. [0147] The procedure described in Example 3 can be repeated using different sulphonylchlorides (such as 4-acetamido,3-chlorobenzenesulphonyl chloride) in place of 2-trifluoromethoxybenzenesulphonyl chloride or different piperidines (such as 4amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride.

Reference： [1]Patent: US2004/6081,2004,A1 .Location in patent: Page/Page column 21

14
polymer-supported polyamine [ No CAS ]
[ 103008-51-1 ]
[ 2215-77-2 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine; dichloromethane; acetonitrile;	EXAMPLE 21 4-Phenoxybenzoic acid, 2-[2-(trifluoromethoxy)-phenylsulfonyl]hydrazide A solution of 2-phenoxybenzoic acid hydrazide (0.3 M) in pyridine (0.513 mL) was treated with a solution of the 2-(trifluoromethoxy)phenylsulfonyl chloride (1.0 M) in CH2Cl2 (0.225 mL). The reaction was placed in a Bohdan Miniblock apparatus and shaken at 45 C. for 16 hours. The reaction was cooled to room temperature, treated with polymer-supported polyamine quench resin (Aldrich, 100 mg), and shaken for 16 hours. The solution was filtered and concentrated. The residue was purified by preparative HPLC on a Phenomenex Develofil 28*100 mm C-18 column eluding with a gradient of 10% to 100% CH3CN/H2O+3% n-propanol. MS: 453 (M+1 for C20H15F3N2O5S); HPLC (Waters Alliance 2790 column, solvent gradient of 60% to 100% CH3CN/H2O+0.1% formic acid. Purity: 95%.

Reference： [1]Patent: US2003/149110,2003,A1

15
[ 6153-39-5 ]
[ 103008-51-1 ]
[ 197959-83-4 ]

Yield	Reaction Conditions	Operation in experiment
57%	In diethyl ether; dichloromethane; sodium hydrogencarbonate; ethyl acetate;	a 5-Methyl-3-(2-trifluoromethoxyphenylsulfonyloxy)phenol Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-trifluoromethoxybenzenesulfonyl chloride (2.35 g, 9.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (350 mL). The organic phase was washed with brine (250 mL) and dried over Na2 SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a yellow oil (1.80 g, 57%). 1 H-NMR (300 MHz, CDCl3) delta 7.96 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.41 (s, 1H), 5.04 (s, 1H); 2.23 (s, 3H).

Reference： [1]Patent: US5891909,1999,A

16
[ 178049-64-4 ]
[ 103008-51-1 ]
isopropyl 2-trifluoromethoxy-6-methylbenzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium;	EXAMPLE 5 Preparation of isopropyl 2-trifluoromethoxy-6-methylbenzenesulfonate Isopropyl 2-trifluoromethoxybenzenesulfonate was made from 2-trifluoromethoxybenzenesulfonyl chloride and then treated first with butyl lithium and then with iodomethane in a manner analogous to that set forth above in Example 1A to yield isopropyl 2-trifluoromethoxy-6-methylbenzenesulfonate.
	With n-butyllithium;	EXAMPLE 28 Preparation of isopropyl 2-methyl-6-trifluoromethoxybenzenesulfonate Isopropyl 2-trifluoromethoxybenzenesulfonate was made from 2-trifluoromethoxybenzenesulfonyl chloride and treated first with butyl lithium and then with iodomethane in a manner analogous to that set forth above in Example 1B to yield isopropyl 2-methyl-6-trifluoromethoxybenzenesulfonate.

Reference： [1]Patent: US5670691,1997,A
[2]Patent: US5670691,1997,A

17
[ 178049-64-4 ]
[ 103008-51-1 ]
[ 178049-80-4 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium;	EXAMPLE 27 Preparation of isopropyl 2-fluoro-6-trifluoromethoxybenzenesulfonate Isopropyl 2-trifluoromethoxybenzenesulfonate was made from 2-trifluoromethoxybenzenesulfonyl chloride and treated first with butyl lithium and then with N-fluoro-O-benzenedisulfonimide in a manner analogous to that set forth above in Example 1B to yield isopropyl 2-fluoro-6-trifluoromethoxybenzenesulfonate.

Reference： [1]Patent: US5670691,1997,A

18
[ 178049-64-4 ]
[ 103008-51-1 ]
[ 178049-81-5 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium;	EXAMPLE 29 Preparation of isopropyl 2-ethyl-6-trifluoromethoxybenzenesulfonate Isopropyl 2-trifluoromethoxybenzenesulfonate was made from 2-trifluoromethoxybenzenesulfonyl chloride and treated first with butyl lithium and then with iodoethane in a manner analogous to that set forth above in Example 1B to yield isopropyl 2-ethyl-6-trifluoromethoxybenzenesulfonate.

Reference： [1]Patent: US5670691,1997,A

19
[ 4194-37-0 ]
[ 103008-51-1 ]
[ 128075-31-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In pyridine; dichloromethane;	STR386 10.0 g (0.088 mol) of 4-amino-5-methyl-2,4-dihydro-3H-1, 2,4-triazol-3-one are dissolved in 50 ml of dry pyridine, the mixture is cooled to -10 C., and 32.7 g (0.12 mol) of <strong>[103008-51-1]2-trifluoromethoxy-benzenesulphonyl chloride</strong> are added. The reaction mixture is allowed to reach room temperature approximately 20 C.) and stirred for approximately 12 hours. After the mixture has been concentrated, the residue is taken up in methylene chloride and shaken with 1N hydrochloric acid and then with water. The organic phase is dried with sodium sulfate and filtered. The solvent is carefully distilled off from the filtrate under a water pump vacuum. 23.1 g (80% of theory) of 4-(2-trifluoromethoxy-phenylsulphonylamino)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as an oily residue. 1 H-NMR) (DMSO, delta, ppm): 2.10 (s, CH3), 7.55, 7.83, 7.93 (m, 4H), approximately 11.5 (m, 2NH).

Reference： [1]Patent: US4988381,1991,A

20
(R)-1-[4-(2-ethoxy-pyridin-3-yl)-phenyl]-ethylamine [ No CAS ]
[ 103008-51-1 ]
(R)-N-{1-[4-(2-Ethoxy-pyridin-3-yl)-phenyl]-ethyl}-2-trifluoromethoxy-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With triethylamine; In dichloromethane; for 16h;	(R)-N-{1-[4-(2-Ethoxy-pyridin-3-yl)-phenyl]-ethyl}-2-trifluoromethoxy-benzenesulfonamide To a solution of (R)-1-(4-bromophenyl)ethylamine (1.0 g, 5 mmol) in methanol (10 ml) was added sodium hydrogen carbonate (1.26 g, 15.0 mmol) and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol). The reaction mixture was sonicated for 4 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to give (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.8 g, 6.0 mmol, 120%) as a white solid. To a solution of (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.73 g, 2.4 mmol) in 1,2-dimethoxyethane (10 ml) was added tetrakis (triphenylphosphine) palladium (0.14 g, 0.12 mmol), 2-chloropyridine-3-boronic acid (0.77 g, 4.9 mmol) and 2 M sodium carbonate. The reaction mixture was heated to reflux for 16 h and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was chromatographed over silica gel eluting with 3:1 heptane/ethyl acetate and the solvent removed under reduced pressure to give (R)-{1-[4-(2-chloro-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.56 g, 1.7 mmol, 71%) as an off white solid. A mixture of (R)-{1-[4-(2-chloro-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (100 mg, 0.3 mmol), sodium ethoxide (61 mg, 0.9 mmol) and tetrahydrofuran (5 ml) was heated under reflux under an argon atmosphere for 16 h. The solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) chromatography to give (R)-1-[4-(2-ethoxy-pyridin-3-yl)-phenyl]-ethylamine (66 mg, 0.27 mmol, 90%) as a yellow gum. To a solution of (R)-1-[4-(2-ethoxy-pyridin-3-yl)-phenyl]-ethylamine (13 mg, 0.05 mmol) in dichloromethane (1 ml) was added triethylamine (17 mg, 0.16 mmol) followed by <strong>[103008-51-1]2-(trifluoromethoxy)benzenesulfonyl chloride</strong> (17 mg, 0.065 mmol). The reaction mixture was stirred for 16 h and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (6 mg, 0.013 mmol, 26%). 1H NMR (400 MHz, DMSO-d6): delta 8.42 (d, 1H), 8.13 (dd, 1H), 7.81 (dd, 1H), 7.63 (m, 2H), 7.39 (m, 4H), 7.24 (d, 2H), 7.05 (m, 1H), 4.48 (q, 1H), 4.36 (q, 2H), 1.35 (d, 3H), 1.29 (t, 3H) ppm; MS (ESI) m/z: 467 [M+H]+.

Reference： [1]Patent: US2007/149577,2007,A1 .Location in patent: Page/Page column 6-7

21
[ 943152-65-6 ]
[ 103008-51-1 ]
N-[2,2,2-Trifluoro-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-2-trifluoromethoxy-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 100℃; for 72h;	N-[2,2,2-Trifluoro-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-2-trifluoromethoxy-benzenesulfonamide To a solution of 4-bromobenzaldehyde (3.06 g, 16.5 mmol) in toluene (60 ml) was added 5-fluoro-2-methoxyphenyl boronic acid (3.10 g, 18.2 mmol), 2M sodium carbonate solution (16.5 ml) and tetrakis(triphenylphosphine)palladium (0) (1 g, 0.86 mmol). The solution was refluxed for 48 h then cooled to ambient temperature, washed with water, brine and dried over anhydrous sodium sulfate. Evaporation of solvent gave a residue that was flash chromatographed over silica gel eluting with 1:1 ethyl acetate/heptane. Evaporation of solvent gave 5'-fluoro-2'-methoxy-biphenyl-4-carbaldehyde (2.63 g) as a crystalline solid. To a solution of 5'-fluoro-2'-methoxy-biphenyl-4-carbaldehyde (1.5 g, 6.9 mmol) in tetrahydrofuran (20 ml) was added titanium tetraisopropoxide (10 ml) and (+/-)-tert-butyl sulfinamine. The solution was stirred for 48 h then poured into brine and dichloromethane added with stirring. The organic layer was separated, dried over anhydrous magnesium sulfate and the solvent evaporated. Heptane was added to the oil which induced crystallisation and gave 2-methyl-propane sulfinic acid 5'-fluoro-2'-methoxy-biphenyl-4-ylmethylene amide (1.85 g) as a white solid. To a solution of 2-methyl-propane sulfinic acid 5'-fluoro-2'-methoxy-biphenyl-4-ylmethylene amide (1 g, 3 mmol) and tetrabutyl ammonium difluorotriphenylsilica gelte (1.8 g, 3.3 mmol) in tetrahydrofuran (50 ml) at -55 C. was added trifluoromethyltrimethylsilane with stirring. The reaction mixture was kept below -40 C. for 3 h then warmed to -10 C. for 1 h. The reaction mixture was cooled to -30 C. then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, evaporated to a low volume and heptane added. The crystalline 2-methyl-propane sulfinic acid [2,2,2-trifluoro-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-amide (0.75 g) was collected by filtration. To a solution of 2-methyl-propane sulfinic acid [2,2,2-trifluoro-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-amide (0.73 g, 1.8 mmol) in methanol (10 ml) at room temperature was added a 1M solution of Hydrogen chloride in ether with stirring. The reaction mixture was stirred for 2 h, then the solvent was evaporated and ether added. The crystalline 2,2,2-trifluoro-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethylamine hydrochloride (0.38 g) was collected by filtration. To a solution of 2,2,2-trifluoro-1-(5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethylamine hyrochloride (60 mg, 0.15 mmol) in pyridine (3 ml) was added 2-trifluoromethoxyphenyl sulfonyl chloride with stirring. The reaction was stirred for 3 days at 100 C. then cooled to room temperature and 5M Hydrogen chloride and dichloromethane added. The organic layer was separated and the solvent evaporated. The residue was flash chromatographed over silica gel eluting with 1:1 heptane/dichloromethane and the solvent evaporated to give the title compound (29 mg). 1H NMR (400 MHz, CDCl3): 7.58-7.41 (m, 4H), 7.27-7.11 (m, 3H), 7.04-6.90 (m, 3H), 5.51 (d, 1H), 5.00 (app quin, 1H), 3.78 (s, 3H) ppm; MS (ESI) m/z: 546 [M+Na]+.

Reference： [1]Patent: US2007/149577,2007,A1 .Location in patent: Page/Page column 7-8

22
1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine [ No CAS ]
[ 103008-51-1 ]
(R)-N-{1-[3-Methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethyl}-2-trifluoromethoxy-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane;	(R)-N-{1-[3-Methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethyl}-2-trifluoromethoxy-benzenesulfonamide A mixture of acetovanillone (0.332 g, 2.0 mmol), N-phenyl-bis(trifluoromethane-sulfonimide) (710 mg, 2.0 mmol), potassium carbonate (830 mg, 6.0 mmol) and tetrahydrofuran (3.0 ml) was heated to 120 C. for 6 min in a microwave oven. 2-Methoxypyridine-3-boronic acid (611 mg, 4 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 100 mumol), N-methylpyrrolidinone (1 ml) were then added and the mixture heated in the microwave at 120 C. for 10 min. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated to give 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethanone in quantitative yield. Reductive amination with ammonium acetate (20 equivalents) in methanol (50 ml) containing sodium cyanoborohydride (1 equivalent) followed by aqueous work-up with saturated aqueous sodium bicarbonate and extraction into ethyl actetate gave, after solvent was evaporated 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine. To 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine was added 2-trifluoromethoxy-benzenesulfonyl chloride (1 equivalent) in dichloromethane, diisopropylethylamine (4 equivalents) and the mixture overnight. The racemic product was isolated by normal phase HPLC on silica gel eluting with heptane/ethyl acetate and the solvent evaporated to give a clear oily solid (72 mg). 1H NMR (400 MHz, CDCl3): delta 8.15 (d, 1H), 7.9 (d, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3-7.2 (m, 2H), 7.05 (d, 1H), 6.9 (m, 1H), 6.75-6.65 (m, 2H), 5.0 (d, 1H), 4.55 (m, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 1.51 (d, 3H) ppm; MS (ESI) m/z: 483.3 [M+1]+. The racemate was resolved by chiral HPLC (CHIRALPAK-AS, eluting with 9:1 isohexane/ethanol) to give the title compound (11 mg) and its enantiomer (11) mg.

Reference： [1]Patent: US2007/149577,2007,A1 .Location in patent: Page/Page column 8-9

23
5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile [ No CAS ]
[ 103008-51-1 ]
N-[4-(5-Cyano-2-methoxy-pyridin-3-yl)-benzyl]-2-trifluoromethoxy-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With triethylamine; In dichloromethane; for 20h;	N-[4-(5-Cyano-2-methoxy-pyridin-3-yl)-benzyl]-2-trifluoromethoxy-benzenesulfonamide To a solution of 4-aminomethylphenylboronic acid hydrochloride (2.0 g, 13.2 mmol) in methanol (20 ml) was added di-tert-butyl dicarbonate (3.16 g, 15.5 mmol) and sodium bicarbonate (3.32 g, 19.8 mmol). The mixture was sonicated for 4 h then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give (4-bromo-benzyl)-carbamic acid tert-butyl ester (1.8 g, 13.2 mmol, 100%) as a white solid. To 6-chloro-nicotinonitrile (15 g, 0.11 mol) under argon atmosphere was added 25% sodium methoxide in methanol (11.7 g, 0.22 mol) and the mixture heated under reflux for 20 h. The methanol was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give 6-methoxy-nicotinonitrile (17.0 g, 0.13 mol, 117%) as a white solid. To 6-methoxy-nicotinonitrile (13.2 g, 99 mmol) in acetic acid (32 ml) was added sodium acetate (8.1 g, 99 mmol). The mixture was stirred and a solution of bromine (31.5 g, 197 mmol) in acetic acid (32 ml) added. The mixture was heated to 80 C. for 48 h. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was washed with 4M aqueous sodium hydroxide solution, 5% sodium thiosulfate solution, dried over anhydrous potassium carbonate and the solvent was evaporated to give 5-bromo-6-methoxy-nicotinonitrile (11.9 g, 56 mmol, 57%). To a solution of 2-methoxy-5-cyanopyridine-3-boronic acid (1.0 g, 4.0 mmol) in 1,2-dimethoxyethane (10 ml) was added (4-bromo-benzyl)-carbamic acid tert-butyl ester (0.42 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium (0) (114 mg, 0.1 mmol) and 2M aqueous sodium carbonate (1 ml, 2.0 mmol). The reaction was heated to 150 C. for 10 min in a microwave over. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was washed with water, then brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on silica gel eluting with 5:1 heptane/ethyl acetate to give [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester as a white solid (0.5 g, 1.47 mmol, 37%). To a solution of [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester (0.5 g, 1.5 mmol) in dichloromethane (5 ml) at 0 C. was added trifluoroacetic acid (5 ml, 28 mmol). The reaction mixture was stirred for 30 min at 0 C. before the solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) to give 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile as a clear glass (0.39 g, 1.6 mmol, 107%). To a solution of 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile (57.3 mg, 0.24 mmol) in dichloromethane (2 ml) was added triethylamine (73.0 mg, 0.72 mmol) and <strong>[103008-51-1]2-(trifluoromethoxy)benzenesulfonyl chloride</strong>. The reaction mixture was agitated for 20 hours and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (19.1 mg, 0.04 mmol, 17%). 1H NMR (400 MHz, DMSO-d6): delta 8.68 (d, 1H), 8.47 (t, 1H), 8.15 (d, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.45-7.55 (m, 4H), 7.31 (d, 2H), 4.19 (d, 2H), 3.96 (s, 3H) ppm; MS (ESI) m/z: 464.3 [M+H]+.

Reference： [1]Patent: US2007/149577,2007,A1 .Location in patent: Page/Page column 17-18

Yield	Reaction Conditions	Operation in experiment
		The following sulfonyl chlorides may be substituted for benzenesulfonyl chloride of Step One: ... 3-(Trifluoromethyl)benzenesulfonyl chloride 4-(Trifluoromethyl)benzenesulfonyl chloride 2-(Trifluoromethoxy)benzenesulfonyl chloride 3-(Trifluoromethoxy)benzenesulfonyl chloride ...

25
[ 540522-69-8 ]
[ 103008-51-1 ]
[ 1019217-19-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1345 - 1358

26
[ 540522-70-1 ]
[ 103008-51-1 ]
[ 1019217-61-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1345 - 1358

27
[ 106-50-3 ]
[ 103008-51-1 ]
[ 1030598-41-4 ]

Reference： [1]European Journal of Medicinal Chemistry,2008,vol. 43,p. 880 - 884

28
[ 1022953-85-0 ]
[ 103008-51-1 ]
C₂₃H₂₃F₃N₂O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		tert-Butyl l,3,4,8-tetrahydro-2H-[l,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2- (Trifluoromethoxy)benzenesulfonyl chloride (26 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/ 1 M HCl (3 : 1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C 18, 50 mM NH4HCO3 pH 10 - CH3CN) to give the title compound as an off-white solid (1.0 mg). MS m/z 413 [M + H]+.

Reference： [1]Patent: WO2008/54288,2008,A1 .Location in patent: Page/Page column 84

29
[ 166809-58-1 ]
[ 103008-51-1 ]
[ 1021170-61-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2215 - 2221

30
[ 1007873-89-3 ]
[ 103008-51-1 ]
[ 1007873-93-9 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 5 - 20℃;	To a cold (5 C.) solution of (2S)-benzofuran-4-carboxylic acid-(azetidine-2-ylmethyl)-amide hydrochloride (10 mg), DIEA (0.015 mL) in dry DMF (0.1 mL), was added portionwise 2-trifluoromethoxybenzene sulfonyl chloride (11.2 mg). The reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EA, washed with water. The organic extract was dried (MgSO4), filtered and concentrated to yield a crude oil.FC (EA/n-heptane: 1/1) gave 9 mg (46%) of the title compound as a solid.LC-MS: rt=0.87 min, 455 [M+H]+.

Reference： [1]Patent: US2010/222600,2010,A1 .Location in patent: Page/Page column 25

31
[ 1255650-11-3 ]
[ 103008-51-1 ]
[ 1255713-56-4 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 20℃;Inert atmosphere;	Crude 2- [4- (2,2,2-trifluoro- 1 -hydroxy-ethyl) -phenyl] -2,8-diaza-spiro [4.5 ] decan- 1 -one from step A) (0.327 g) dissolved in pyridine at RT and under an argon atmosphere was treated with 2-trifluoromethoxy-benzenesulfonyl chloride (0.286 g) and the mixture was then stirred at RT over night. Then the most of pyridine was evaporated off in vacuo, the residue was dissolved in AcOEt which was then washed with IM aqueous HCl and brine, dried over magnesium sulphate and concentrated in vacuo. The crude product was chromatographed over silica gel (eluent: AcOEt/Heptane, gradient from 0 to 30%) to give the desired product as a light brown solid. MS (ESI): 553.12 (MH+).

Reference： [1]Patent: WO2010/130665,2010,A1 .Location in patent: Page/Page column 148

32
[ 1333115-54-0 ]
[ 103008-51-1 ]
[ 1333115-55-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; In dichloromethane; at 20℃; for 12h;	To a solution of compound 31f (2.5 g, 14.5 mmol) in DCM (100 mL) was added 2- (trifluoromethoxy)benzene-l -sulfonyl chloride (4.2 g, 16.0 mmol) and TEA (4.4 g, 3.5 mmol). The mixture was stirred at rt for 12 h, then DCM (50 mL) and 2N HCI (20mL) were added to the mixture. The organic layer was separated and washed with brine and dried over anhydrous Na2S04. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA = 5:1 ) to give compound 31 g (4.2 g, 74% yield).

Reference： [1]Patent: WO2011/107248,2011,A1 .Location in patent: Page/Page column 68; 69

33
[ 187235-71-8 ]
[ 103008-51-1 ]
[ 1353753-70-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 312 - 326

34
[ 187235-71-8 ]
[ 103008-51-1 ]
[ 1353753-76-0 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 312 - 326

35
[ 1376770-17-0 ]
[ 103008-51-1 ]
[ 1376770-37-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine; In dichloromethane; at 20℃;	General procedure: In a solution of 6-(4-aminophenyl)-N-(3-(trifluoromethyl) phenyl) pyrimidin-4-amine (4) (1eq) in DCM (5ml), different substituted sulphonyl chlorides (l.1eq) and triethylamine (1.1eq) were added. Resulting reaction mixture was stirred at room temperature for 1-2 h and progress of reaction monitored by TLC in ethyl acetate- petroleum ether mixture. Resulting reaction mixture was diluted with DCM and water added. Organic layer washed by fresh water and brine, dried on Na2SO4 and concentrated under reduced pressure to afford crude product, which was purified by silica gel (100-200 No.) column chromatography in 10% ethyl acetate petroleum ether as eluent to obtain a title compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3445 - 3448

36
[ 100202-39-9 ]
[ 103008-51-1 ]
[ 1392442-29-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5035 - 5040

37
2C₂HF₃O₂*C₁₃H₁₈N₄O [ No CAS ]
[ 103008-51-1 ]
[ 1392441-80-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5035 - 5040

38
[ 103008-51-1 ]
[ 1392442-80-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5035 - 5040

39
[ 103008-51-1 ]
[ 1392441-80-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5035 - 5040

40
[ 1391979-31-9 ]
[ 103008-51-1 ]
[ 1391979-00-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With pyridine; In dichloromethane; at 20℃;	To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)- pyridin-3-ylamine (E-9) in 5 mL DCM is added 160 mg (0.61 mmol) 2,4-trifluoromethoxybenzenesulfonyl chloride and 72 mu. (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgS04 and concentrated under reduced pressure. The crude product is purified by RP chromatography (CI 8, 20-80% ACN in water containing 1% formic acid). Yield: 115 mg (68%). HPLC-MS: M+H = 550; tR=0.92 min.
68%	With pyridine; In dichloromethane; at 20℃;	To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 160 mg (0.61 mmol) 2,4-trifluoromethoxybenzenesulfonyl chloride and 72 muL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 115 mg (68%). HPLC-MS: M+H = 550; tR=0.92 min.

Reference： [1]Patent: WO2012/101186,2012,A1 .Location in patent: Page/Page column 99
[2]Patent: EP2546249,2013,A1 .Location in patent: Paragraph 0364; 0365

41
[ 103008-51-1 ]
N-hydroxy-2-trifluoromethoxybenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap; hydroxylamine hydrochloride; In pyridine; at 20℃; for 0.0833333h;Cooling with ice;	General procedure: To a mixture of hydroxylamine hydrochloride (2 equiv.) and DMAP (2 equiv.) in pyridine (20 mL) was added a portion of arylsulfonyl chloride (1 equiv.) on an ice-bath. Then, the mixture was stirred for 5 min at room temperature. The resulting suspension was poured into AcOEt (100 mL) and 1 N HCl aq. (100 mL). The AcOEt layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography under one of the gradient conditions indicated below, and recrystallized from Et2O/n-hexane to give N-hydroxyarylsulfonamide derivatives.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2340 - 2343

42
[ 1433992-89-2 ]
[ 103008-51-1 ]
[ 1433992-90-5 ]

Yield	Reaction Conditions	Operation in experiment
1.1 g	With pyridine; at 85℃; for 1h;Microwave irradiation;	Step 6: 3-Benzyl-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H-pyrido[3,2- ein ,41diazepin-2(3H)-one dot)A solution of crude compound 10e (1.6 g, 6.3 mmol) and <strong>[103008-51-1]2-(trifluoromethoxy)benzene-1-sulfonyl chloride</strong> (2.0 g, 7.6 mmol) in pyridine (20 mL) was stirred and heated by microwave irradiation at 85C for 1 h, then concentrated under reduced pressure and purified by CC (PE/EA = 1/2) to give compound lOf (1.1 g, 37% over 3 steps) as a yellow solid.

Reference： [1]Patent: WO2013/64231,2013,A1 .Location in patent: Page/Page column 52

43
[ 1433992-95-0 ]
[ 103008-51-1 ]
[ 1433992-96-1 ]

Yield	Reaction Conditions	Operation in experiment
7.6 g	With triethylamine; In dichloromethane; at 20℃; for 12h;	Step 5: (f?)-/V-(1-Cvano-3-phenylpropan-2-yl)-2-(trifluoromethoxy)benzenesulfonamide (14e)To a solution of compound 14d (4.3 g, 26.9 mmol) in DCM (100 mL) was added 2- (trifluoromethoxy)benzenesulfonyl chloride (7.0 g, 26.9 mmol) and TEA (8.2 g, 80.7 mmol). The mixture was stirred at rt for 12 h, then DCM (50 mL) and 2N HCI (20 mL) were added into the mixture. The organic layer was separated and washed with brine and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated in vacuo and the residue was purified by CC (hexane/EA = 5:1) to give compound 14e (7.6 g, 74% over two steps).

Reference： [1]Patent: WO2013/64231,2013,A1 .Location in patent: Page/Page column 56

44
[ 1433992-57-4 ]
[ 103008-51-1 ]
[ 1433992-58-5 ]

Yield	Reaction Conditions	Operation in experiment
32%	With pyridine; at 85℃; for 1.5h;Microwave irradiation;	Step 5: 3-((Methoxymethoxy)methyl)-4-(2-(trifluoromethoxy)phenylsulfonyl)-4,5-dihvdro-1 H- benzofein ,41diazepin-2(3/- )-one (4e)A solution of compound 4d (8.0 g, 34.1 mmol) and 2-(trifluoromethoxy)benzene-1 -sulfonyl chloride (13.2 g, 50.8 mmol) in pyridine (20 mL) was stirred at 85C under microwave irradiation for 1.5 h. The reaction mixture was concentrated and the residue was purified by CC (PE/EA = 1/1) to give compound 4e (5.0 g, 32%) as a yellow solid.

Reference： [1]Patent: WO2013/64231,2013,A1 .Location in patent: Page/Page column 36

45
[ 103008-51-1 ]
[ 1433992-98-3 ]