[ CAS No. 49713-56-6 ] {[proInfo.proName]}

Name: 49713-56-6|4-Chloro-6-(trifluoromethyl)quinoline|96%
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Quality Control of [ 49713-56-6 ]

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Product Details of [ 49713-56-6 ]

CAS No. :	49713-56-6	MDL No. :	MFCD00153106
Formula :	C₁₀H₅ClF₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FTNQANJWBFKPIP-UHFFFAOYSA-N
M.W :	231.60	Pubchem ID :	2736711
Synonyms :

Calculated chemistry of [ 49713-56-6 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.1
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.76
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.46
Log Po/w (XLOGP3) :	3.7
Log Po/w (WLOGP) :	5.06
Log Po/w (MLOGP) :	3.39
Log Po/w (SILICOS-IT) :	4.04
Consensus Log Po/w :	3.73

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.03
Solubility :	0.0214 mg/ml ; 0.0000924 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.66
Solubility :	0.0505 mg/ml ; 0.000218 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.21
Solubility :	0.00143 mg/ml ; 0.00000617 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.46

Safety of [ 49713-56-6 ]

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

Application In Synthesis of [ 49713-56-6 ]

* 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 [ 49713-56-6 ]
Downstream synthetic route of [ 49713-56-6 ]

[ 49713-56-6 ] Synthesis Path-Upstream 1~7

1
[ 40107-07-1 ]
[ 81290-20-2 ]
[ 49713-56-6 ]

Reference： [1] Organic Letters, 2014, vol. 16, # 16, p. 4268 - 4271

2
[ 49713-51-1 ]
[ 49713-56-6 ]

Yield	Reaction Conditions	Operation in experiment
60 mg	at 90℃; for 2 h;	(50 mg, 0.2 mmol, prepared according to the well-known method disclosed in Bioorganic & Medicinal Chemistry Letters, 2005, 15 (4), 1015-1018) Was added to phosphorus oxychloride (108 mg, 0.7 mmol). Upon completion of the addition, the reaction solution was heated to 90 DEG C and stirred for 2 hours, then a saturated solution of sodium bicarbonate was added dropwise to adjust the pH to 8 to 9 and extracted with ethyl acetate (30 mL x 3) . The organic phases were combined and concentrated under reduced pressure to give the title compound 4-chloro-6- (trifluoromethyl) quinoline 2b (60 mg, colorless oil) which was used directly in the next step.
60 mg	at 90℃; for 2 h;	6-(trifluoromethyl)quinolin-4-ol 2a (50 mg, 0.2 mmol, prepared by a well known method disclosed in "Bioorganic & Medicinal Chemistry Letters, 2005, 15(4), 1015-1018") was added to phosphorus oxychloride (108 mg, 0.7 mmol). Upon completion of the addition, the reaction solution was heated to 90° C. and stirred for 2 hours, then added dropwise with a saturated solution of sodium bicarbonate to adjust the pH to 8˜9, and extracted with ethyl acetate (30 mL*3). The organic phases were combined, and concentrated under reduced pressure to obtain the title compound 4-chloro-6-(trifluoromethyl)quinoline 2b (60 mg, a colorless oil), which was used directly in the next step.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018
[2] Patent: KR2016/6207, 2016, A, . Location in patent: Paragraph 0188; 0191-0194
[3] Patent: US2016/108035, 2016, A1, . Location in patent: Paragraph 0136-0137

3
[ 681472-89-9 ]
[ 49713-56-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018

4
[ 71083-01-7 ]
[ 49713-56-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 19, p. 7679 - 7690

5
[ 49713-51-1 ]
[ 49713-56-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 19, p. 7679 - 7690

6
[ 455-14-1 ]
[ 49713-56-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 19, p. 7679 - 7690

7
[ 641993-21-7 ]
[ 49713-56-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 19, p. 7679 - 7690

[ 49713-56-6 ] Synthesis Path-Downstream 1~68

1
[ 49713-56-6 ]
[ 111-26-2 ]
6-(trifluoromethyl)-4-(n-pentylamino)quinoline [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 1877 - 1883

3
[ 49713-51-1 ]
[ 49713-56-6 ]

Yield	Reaction Conditions	Operation in experiment
60 mg	With trichlorophosphate; at 90℃; for 2.0h;	(50 mg, 0.2 mmol, prepared according to the well-known method disclosed in Bioorganic & Medicinal Chemistry Letters, 2005, 15 (4), 1015-1018) Was added to phosphorus oxychloride (108 mg, 0.7 mmol). Upon completion of the addition, the reaction solution was heated to 90 DEG C and stirred for 2 hours, then a saturated solution of sodium bicarbonate was added dropwise to adjust the pH to 8 to 9 and extracted with ethyl acetate (30 mL x 3) . The organic phases were combined and concentrated under reduced pressure to give the title compound 4-chloro-6- (trifluoromethyl) quinoline 2b (60 mg, colorless oil) which was used directly in the next step.
60 mg	With trichlorophosphate; at 90℃; for 2.0h;	6-(trifluoromethyl)quinolin-4-ol 2a (50 mg, 0.2 mmol, prepared by a well known method disclosed in "Bioorganic & Medicinal Chemistry Letters, 2005, 15(4), 1015-1018") was added to phosphorus oxychloride (108 mg, 0.7 mmol). Upon completion of the addition, the reaction solution was heated to 90° C. and stirred for 2 hours, then added dropwise with a saturated solution of sodium bicarbonate to adjust the pH to 8?9, and extracted with ethyl acetate (30 mL*3). The organic phases were combined, and concentrated under reduced pressure to obtain the title compound 4-chloro-6-(trifluoromethyl)quinoline 2b (60 mg, a colorless oil), which was used directly in the next step.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1015 - 1018
[2]Patent: KR2016/6207,2016,A .Location in patent: Paragraph 0188; 0191-0194
[3]Patent: US2016/108035,2016,A1 .Location in patent: Paragraph 0136-0137

4
[ 49713-56-6 ]
[ 104-78-9 ]
N,N-diethyl-N'-(6-trifluoromethyl-quinolin-4-yl)-propane-1,3-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1015 - 1018

5
[ 49713-56-6 ]
[ 140-80-7 ]
N¹,N¹-diethyl-N⁴-(6-trifluoromethyl-quinolin-4-yl)-pentane-1,4-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1015 - 1018

6
[ 49713-56-6 ]
[ 1701-93-5 ]
4-isothiocyanato-6-trifluoromethyl-quinoline [ No CAS ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 2161 - 2164

7
[ 1196-79-8 ]
[ 49713-56-6 ]
4-(2,5-dimethyl-1H-indol-3-yl)-6-trifluoromethyl-quinoline [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4287 - 4290

8
[ 49713-56-6 ]
[2,5-dimethyl-3-(6-trifluoromethyl-quinolin-4-yl)-indol-1-yl]-acetic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4287 - 4290

9
[ 49713-56-6 ]
[2,5-dimethyl-3-(6-trifluoromethyl-quinolin-4-yl)-indol-1-yl]-acetic acid ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4287 - 4290

10
[ 681472-89-9 ]
[ 49713-56-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1015 - 1018

11
[ 49713-56-6 ]
1-(p-chlorobenzyl)-6-(trifluoromethyl)-4-(n-pentylimino)-1,4-dihydroquinoline hydroiodide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 1877 - 1883

12
[ 49713-56-6 ]
[ 942-24-5 ]
3-methoxycarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 20.0h;	1.04 g (7.5 [MMOL)] of potassium carbonate and 0.695 g (3 [MMOL)] of 4-chloro-6- (tri- fluoromethyl) [QUINOLINE] are added to 0.525 g (3 [MMOL)] of 3-methoxycarbonyl-1 [H-INDOLE] in 10 cm3 [OF DIMETHYLFORMAMIDE] under an argon atmosphere. After stirring at a temperature in the region of [100°C] for 20 hours, the reaction mixture is cooled and diluted with 100 [CM3] of ethyl acetate and 100 cm3 of water. The organic phase is separated off by settling and washed with twice 100 cm3 of water and 100 [CM3] of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 [KPA),] resulting in an orange-coloured oil. This oil is triturated in 20 cm3 of isopropyl ether and the resulting precipitate is filtered off, giving 0.94 g of [3-METHOXYCARBONYL-1-(6-] [(TRIFLUOROMETHYL)] [QUINOL-4-YL)-1] [H-INDOLE] in the form of a yellow powder. Mass spectrum [(EL)] : m/e 370 [(M+),] m/e 339.

Reference： [1]Patent: WO2004/7479,2004,A1 .Location in patent: Page 23-24

13
[ 49713-56-6 ]
[ 666734-80-1 ]
5,6-Dimethyl-3-(6-trifluoromethyl-quinolin-4-yloxy)-[2,2']bipyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With dmap; caesium carbonate; In dimethyl sulfoxide; at 130℃;	4-Chloro-6-trifluoromethylquinoline (50 mg), 5,6-dimethyl-[2,2']bipyridinyl-3-ol (43 mg), and 4-dimethylaminopyridine (79 mg) were dissolved in dimethylsulfoxide (1 ml). Cesium carbonate (211 mg) was added to the solution, and the mixture was stirred at 130°C overnight. The mixture was cooled to room temperature, an aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the organic layer was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (77 mg, yield 89percent). 1H-NMR (CDCl3, 400 MHz): delta 2.42 (s, 3H), 2.68 (s, 3H), 6.57 (d, J = 5.6 Hz, 1H), 7.09 (ddd, J = 1.0, 4.9, 7.6 Hz, 1H), 7.41 (s, 1H), 7.63 (m, 1H), 7.95 - 7.97 (m, 2H), 8.28 (m, 2H), 8.67 (d, J = 5.4 Hz, 1H), 8.73 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 418 (M+Na)+

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 42

14
[ 49713-56-6 ]
[ 666735-37-1 ]
2-Phenyl-3-(6-trifluoromethyl-quinolin-4-yloxy)-[1,8]naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap; In 1,2-dichloro-benzene; at 130℃; for 4.5h;	2-Phenyl-[1,8]naphthyridin-3-ol (48 mg), <strong>[49713-56-6]4-chloro-6-trifluoromethylquinoline</strong> (50 mg), and 4-dimethylaminopyridine (79 mg) were suspended in 1,2-dichlorobenzene (1.5 ml), and the suspension was stirred at 130°C for 4.5 hr. The reaction mixture was cooled to room temperature, and an aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (88 mg, yield 96percent). 1H-NMR (CDCl3, 400 MHz): delta 6.52 (d, J = 5.4 Hz, 1H), 7.30 - 7.34 (m, 3H), 7.58 (dd, J = 4.1, 8.1 Hz, 1H), 7.97 (dd, J = 2.2, 9.0 Hz, 1H), 8.06 - 8.09 (m, 2H), 8.08 (s, 1H), 8.24 (m, 2H), 8.69 (d, J = 5.4 Hz, 1H), 8.74 (s, 1H), 9.22 (dd, J = 2.0, 4.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 440 (M+Na)+

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 60

15
[ 49713-56-6 ]
[ 108-42-9 ]
[ 873943-00-1 ]

Yield	Reaction Conditions	Operation in experiment
7%		To a mixture of <strong>[49713-56-6]4-chloro-6-trifluoromethylquinoline</strong> (72 mg, 0.31 mmol) and 3- chloroaniline (40 mg, 33, 0.31 mmol) in 2-propanol (0.75 ml) was added concentrated HCl (1 drop), and the reaction was heated at 700C for 1 h. The reaction was then cooled to 200C, and concentrated to dryness. The residue was treated with water (15 ml) and saturated aqueous NaHCO3 (2 ml). This mixture was extracted with ethyl acetate (2 x 15 ml). The combined organic layers were dried (Na2SO4), and concentrated. The crude material was purified by preparative-TLC (20percent ethyl acetate: hexane). The resulting material was suspended in hexane (25 ml), heated, and filtered hot. This gave the desired product (7.2 mg, 7percent) as a white solid.1H NMR (CDCl3) delta ppm: 6.77 (bs, IH), 7.09 (d, J = 5 Hz, IH), 7.26-7.19 (m, 2H), 7.37-7.33 (m, 2H), 7.87 (d, J = 9 Hz, 1 H), 8.16 (d, J = 9 Hz, IH), 8.25 (s, IH), 8.69 (d, J = 5 Hz, IH). HPLC: 94percent at 1.783 minutes; Sunfire C18 4.6 x 50 mm; 10-90percent 10-90percent methanol: water with 0.1percent TFA; Gradient time = 2 min; 3.5 ml/min; 254 nm. MS = 323 M+H+.
7%		To a mixture of <strong>[49713-56-6]4-chloro-6-trifluoromethylquinoline</strong> (72 mg, 0.31 mmol) and 3- chloroaniline (40 mg, 33, 0.31 mmol) in 2-propanol (0.75 ml) was added concentrated HCl (1 drop), and the reaction was heated at 700C for 1 h. The reaction was then cooled to 200C, and concentrated to dryness. The residue was treated with water (15 ml) and saturated aqueous NaHCO3 (2 ml). This mixture was extracted with ethyl acetate (2 x 15 ml). The combined organic layers were dried (Na2SO4), and concentrated. The crude material was purified by preparative-TLC (20percent ethyl acetate: hexane). The resulting material was suspended in hexane (25 ml), heated, and filtered hot. This gave the desired product (7.2 mg, 7percent) as a white solid.1H NMR (CDCl3) delta ppm: 6.77 (bs, IH), 7.09 (d, J = 5 Hz, IH), 7.26-7.19 (m, 2H), 7.37-7.33 (m, 2H), 7.87 (d, J = 9 Hz, 1 H), 8.16 (d, J = 9 Hz, IH), 8.25 (s, IH), 8.69 (d, J = 5 Hz, IH). HPLC: 94percent at 1.783 minutes; Sunfire C18 4.6 x 50 mm; 10-90percent 10-90percent methanol: water with 0.1percent TFA; Gradient time = 2 min; 3.5 ml/min; 254 nm. MS = 323 M+H+.

Reference： [1]Patent: WO2008/89307,2008,A2 .Location in patent: Page/Page column 40
[2]Patent: WO2008/89310,2008,A2 .Location in patent: Page/Page column 43

16
[ 49713-56-6 ]
[ 462-94-2 ]
[ 1443448-14-3 ]

Yield	Reaction Conditions	Operation in experiment
55%	at 130 - 150℃; for 7.0h;	4-Chloro-6-trifluoromethylquinoline (VIII, R = 6-CF3, 1.16 g, 5 mmol) and 1,5-diaminopentane (0.255 g, 2.5 mmol) were heated in p-cresol (2.5 mL) at 130-150 °C for 7 h. After cooling, the mixture was crystallized from AcOEt. The resulting solid was dissolved in MeOH and basified with 1M NaOH to pH above 9. The resulting precipitate was collected and washed with Et2O to give the product as an off-white solid (0.7 g, 55percent).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 63,p. 907 - 923

17
[ 49713-56-6 ]
[ 462-94-2 ]
16,76-ditrifluoromethyl-8,14-diaza-l,7(1,4)-diquinolinacyclotetradecaphanium ditrifluoroacetate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 63,p. 907 - 923

18
[ 49713-56-6 ]
[ 92-67-1 ]
N-([1,1'-biphenyl]-4-yl)-6-(trifluoromethyl)quinolin-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

19
[ 49713-56-6 ]
(E)-N-(1-(2-(diethylamino)ethyl)-7-(trifluoromethyl)quinolin-4(1H)-ylidene)biphenyl-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

20
[ 49713-56-6 ]
(E)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-7-(trifluoromethyl)-quinolin-4(1H)-ylidene)biphenyl-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

21
[ 49713-56-6 ]
(E)-N-(1-(3-(piperidin-1-yl)propyl)-7-(trifluoromethyl)-quinolin-4(1H)-ylidene)biphenyl-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

22
[ 49713-56-6 ]
(E)-N-(1-(3-(piperidin-1-yl)propyl)-6-(trifluoromethyl)-quinolin-4(1H)-ylidene)biphenyl-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

23
[ 71083-01-7 ]
[ 49713-56-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

24
[ 49713-51-1 ]
[ 49713-56-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

25
[ 455-14-1 ]
[ 49713-56-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

26
[ 641993-21-7 ]
[ 49713-56-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7679 - 7690

27
[ 40107-07-1 ]
[ 81290-20-2 ]
[ 49713-56-6 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 4268 - 4271

28
[ 49713-56-6 ]
1-((6-(trifluoromethyl)quinolin-4-yl)thio)cyclobutanecarboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 277 - 282
[2]Patent: KR2016/6207,2016,A
[3]Patent: US2016/108035,2016,A1

29
[ 49713-56-6 ]
6-(trifluoromethyl)quinoline-4-thiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In N,N-dimethyl-formamide; at 80℃; for 2.0h;	4-Chloro-6- (trifluoromethyl) quinoline 2b (50 mg, 0.2 mmol) and sodium sulfide (51 mg, 0.6 mmol) were added to 5 mL of N, N-dimethylformamide. Upon completion of the addition, the reaction solution was heated to 80 DEG C and stirred for 2 hours. 50 ml of water was added to the reaction solution, 1 M hydrochloric acid was added dropwise to adjust the pH to 5 to 6, and then extracted with ethyl acetate (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 6- (trifluoromethyl) quinoline-4-thiol 2c (40 mg, yellow solid), yield: 81percent
81%	With sodium sulfide; In N,N-dimethyl-formamide; at 80℃; for 2.0h;	<strong>[49713-56-6]4-chloro-6-(trifluoromethyl)quinoline</strong> 2b (50 mg, 0.2 mmol) and sodium sulphide (51 mg, 0.6 mmol) were added to 5 mL of N,N-dimethylformamide. Upon completion of the addition, the reaction solution was heated to 80° C. and stirred for 2 hours. The reaction solution was mixed with 50 mL of water and added dropwise with 1 M hydrochloric acid to adjust the pH to 5?6, then extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 6-(trifluoromethyl)quinoline-4-thiol 2c (40 mg, a yellow solid), yield: 81percent. MS m/z (ESI): 230.1 [M+1]
	With sodium sulfide; In N,N-dimethyl-formamide; for 2.0h;Inert atmosphere; Heating;	General procedure: Toa round-bottom flask with magnetic stirrer was added 6-bromo-4-chloroquinoline 16 (R1 = Br) (260 mg, 1.1 mmol) and DMF (4 mL). Sodium sulfide (100 mg, 1.3 mmol) was then added and the resulting mixture was heated to 80 °C and stirred for 2 hours under an atmosphere of argon. The solution was allowed to cool to room temperature and diluted with water (50 mL). Aqueous HCl(1 M) was added to acidify the mixture and pH value was adjusted to 5~6. The obtained mixture was extracted with EtOAc (50 mL×3), and the organic layer was separated and washed with water and brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give 17 (R1= Br) as an orange oil (257 mg, 97percent), which was used in next step without further purification.

Reference： [1]Patent: KR2016/6207,2016,A .Location in patent: Paragraph 0188; 0191; 0195-0197
[2]Patent: US2016/108035,2016,A1 .Location in patent: Paragraph 0136; 0138-0139
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 277 - 282

30
[ 49713-56-6 ]
ethyl 1-((6-(trifluoromethyl)quinolin-4-yl)thio)cyclobutanecarboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 277 - 282
[2]Patent: KR2016/6207,2016,A
[3]Patent: US2016/108035,2016,A1

31
[ 49713-56-6 ]
[ 1166829-70-4 ]
ethyl 2-(4-(6-(trifluoromethyl)quinolin-4-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	To a solution of <strong>[49713-56-6]4-chloro-6-(trifluoromethyl)quinoline</strong> (2.05 g, 8.85 mmol), ethyl 2-(4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en-i -yl)acetate (3.1210.62 mmol) in 1,4-dioxane (35 mL) was added potassium carbonate (3.67 g, 26.6 mmol) and water (7 mL). The reaction mixture was purged with nitrogen stream for 3 mm, followed by addition of Pd(Ph3P)4 (0.409 g, 0.354 mmol). The resulting mixture washeated at 100 °C under nitrogen stream for over night. The reaction mixture was cooled down and diluted with ethyl acetate and saturated NaHCO3 solution. The organic layer was separated and washed with sat. NaHCO3 solution, and dried over Mg504. The filtrate was concentrated in vacuo and the residue was purified via silica gel flash column chromatography, eluting with 0-50percent ethyl acetate in hexane to give Intermediate 230A(oil, 3.0 g, 8.26 mmol, 93percent yield). LC-MS Anal. Calc?d for C20H20F3N02, 363.14,found [M+H] 364.5. T = 0.97 mm (Method A). ?H NMR (400MHz, CHLOROFORM-d)8.95 (d,J=4.5 Hz, 1H), 8.31 (s, 1H), 8.22 (d,J=8.8 Hz, 1H), 7.87 (dd,J=8.8, 2.0 Hz,1H), 7.29 (d, J=4.5 Hz, 1H), 5.86 (dd, J=2.8, 1.7 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 2.65 -2.24 (m, 5H), 2.15 - 1.96 (m, 2H), 1.73 - 1.54 (m, 2H), 1.36 - 1.29 (m, 3H)
93%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	To a solution of <strong>[49713-56-6]4-chloro-6-(trifluoromethyl)quinoline</strong> (2.05 g, 8.85 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)acetate (3.12 g, 10.62 mmol) in 1,4-dioxane (35 mL) was added potassium carbonate (3.67 g, 26.6 mmol) and water (7 mL). The reaction mixture was purged with nitrogen stream for 3 min, followed by addition of Pd(Ph3P)4 (0.409 g, 0.354 mmol). The resulting mixture was heated at 100 °C under nitrogen stream for over night. The reaction mixture was cooled down and diluted with ethyl acetate and saturated NaHC03 solution. The organic layer was separated and washed with sat. NaHCCb solution, and dried over MgS04. The filtrate was concentrated in vacuo and the residue was purified via silica gel flash column (0288) chromatography, eluting with 0-50percent ethyl acetate in hexane to give Intermediate 11A (oil, 3.0 g, 8.26 mmol, 93percent yield). LC-MS Anal. Calc'd for C20H20F3NO2, 363.14, found [M+H] 364.5. Tr = 0.97 min (Method A). NMR (400MHz, chloroform-d) delta: 8.95 (d, J=4.5 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.87 (dd, J=8.8, 2.0 Hz, 1H), 7.29 (d, J=4.5 Hz, 1H), 5.86 (dd, J=2.8, 1.7 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 2.65 - 2.24 (m, 5H), 2.15 - 1.96 (m, 2H), 1.73 - 1.54 (m, 2H), 1.36 - 1.29 (m, 3H).

Reference： [1]Patent: WO2016/73774,2016,A2 .Location in patent: Paragraph 0476
[2]Patent: WO2018/209049,2018,A1 .Location in patent: Paragraph 00182

32
[ 49713-56-6 ]
[ 2836-00-2 ]
4-methyl-3-((6-(trifluoromethyl)quinolin-4-yl)amino)phenol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 4867 - 4880

33
[ 49713-56-6 ]
ethyl 2-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)cyclohex-3-en-1yl)acetate [ No CAS ]
ethyl 2-(4-(6-(trifluoromethyl)quinolin-4-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16.0h;Inert atmosphere; Sealed tube;	To a solution of 4chloro-6-(trifiuoromethyl)quinoline (2.05 g, 8.85 mmoi) and intermediate 15E (3.12 g, 10.62 mmoi) in 1,4-Dioxane (35 mL) was added potassium carbonate (3.67 g, 26.6 mmoi) and Water (7 mL). The reaction mixture was purged with a nitrogen stream for three minutes, followed by addition of Pd(Ph3P)4 (0409 g, 0354 minol). The resulting mixture purged with nitrogen once again, sealed, and was heated at 100 °C under nitrogen stream for 16 hours. The reaction mixture was cooled down and diluted with ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated and washed with saturated aqueous Na}-1C03 solution. dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified via silica gel column chromatography to give Intermediate 17A (3.0 g, 826 mmol, 93percent), LC-MSAnai. Caic?dforC2oH2oF3NO2363.15,found [M+Hj 364.5, Tr=0,97min (Method A).

Reference： [1]Patent: WO2018/39512,2018,A1 .Location in patent: Paragraph 00207

34
[ 49713-56-6 ]
[ 95-56-7 ]
4-(2-bromophenoxy)-6-(trifluoromethyl)quinoline [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2018,vol. 2018,p. 6140 - 6149

35
[ 49713-56-6 ]
[ 95-56-7 ]
2-(trifluoromethyl)benzofuro[3,2-c]quinoline [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2018,vol. 2018,p. 6140 - 6149

36
[ 49713-56-6 ]
3-(3-methyloxetan-3-yl)-2-(4-(6-(trifluoromethyl)quinolin-4-yl)cyclohexyl)propanoic acid [ No CAS ]