[ CAS No. 69045-82-5 ] {[proInfo.proName]}

Name: 69045-82-5|2-Fluoro-5-(trifluoromethyl)pyridine|96%
Brand: Ambeed
SKU: A631690
Price: 6.0 USD
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Quality Control of [ 69045-82-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 69045-82-5 ]

Product Details of [ 69045-82-5 ]

CAS No. :	69045-82-5	MDL No. :	MFCD07437945
Formula :	C₆H₃F₄N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UUODQIKUTGWMPT-UHFFFAOYSA-N
M.W :	165.09	Pubchem ID :	5463754
Synonyms :

Calculated chemistry of [ 69045-82-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.2
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) :	-5.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.61
Log Po/w (XLOGP3) :	2.17
Log Po/w (WLOGP) :	3.81
Log Po/w (MLOGP) :	2.01
Log Po/w (SILICOS-IT) :	2.79
Consensus Log Po/w :	2.48

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.57
Solubility :	0.446 mg/ml ; 0.0027 mol/l
Class :	Soluble
Log S (Ali) :	-2.07
Solubility :	1.39 mg/ml ; 0.00844 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.18
Solubility :	0.109 mg/ml ; 0.000658 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.91

Safety of [ 69045-82-5 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P273-P280	UN#:	1993
Hazard Statements:	H225-H317-H412	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 69045-82-5 ]

* 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 [ 69045-82-5 ]
Downstream synthetic route of [ 69045-82-5 ]

[ 69045-82-5 ] Synthesis Path-Upstream 1~10

1
[ 72537-17-8 ]
[ 85148-26-1 ]
[ 69045-82-5 ]

Reference： [1] Molecules, 2013, vol. 18, # 1, p. 398 - 407

2
[ 52334-81-3 ]
[ 69045-82-5 ]

Yield	Reaction Conditions	Operation in experiment
95.56%	With potassium fluoride; N-benzyl-N,N,N-triethylammonium chloride In N,N-dimethyl acetamide at 135℃; for 10 h;	1, to 1L three-necked flask was added KF46.20g (0.80mol),500 mL of N, N-dimethylacetamide, warmed to 125 ° C.,Stir for 30 minutes,Connected to the distillation unit,Micro-vacuum distillation, collecting fractions, tracking three bottles of water content, water <500ppm, stop distillation, stand-by. 2, to three bottles of benzyl triethyl ammonium chloride 7g (0.03mol),100 g (0.55 mol) of 2-chloro-5-trifluoromethylpyridine.Connect the condenser, warmed to 135 ,Stirring, incubated for 10 hours.Gas chromatography followed the reaction, when the reaction solution 2-chloro-5-trifluoromethylpyridine content <1percent, stop the reaction.The reaction solution was directly distilled under reduced pressure to collect 40-45 ° C / 11 mmHg fraction,87.80 g of 2-fluoro-5-trifluoromethylpyridine was obtained,Purity 98.95percent (GC), yield 95.56percent.

Reference： [1] Patent: CN106946769, 2017, A, . Location in patent: Paragraph 0028; 0029; 0030; 0031; 0032; 0033-0045
[2] Chemistry Letters, 1993, # 3, p. 509 - 512
[3] Angewandte Chemie - International Edition, 2006, vol. 45, # 17, p. 2720 - 2725
[4] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[5] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145

3
[ 69045-78-9 ]
[ 69045-82-5 ]

Yield	Reaction Conditions	Operation in experiment
85.45%	at -5 - 180℃; for 17 h; Autoclave; Inert atmosphere	In a 200 mL autoclave, 46.0 g (0.2 mol) of the first product 2-chloro-5-trichloromethylpyridine was added,on a good kettle cover, filling nitrogen 10.0MPa to maintain the pressure 5h, the reactor leak. After confirming that the kettle does not leak, empty the kettle pressure.And then the reactor was placed in an ice-salt bath for cooling. When the temperature of the kettle dropped below -5 ° C, the reactor was filled with 40.0 g (~ 2.0 mol) of anhydrous HF and the reaction was heated to 180 , the insulation reaction 12h.After completion of the reaction, the temperature was lowered to 25 ° C, and the inside of the autoclave was replaced with nitrogen for half an hour (the replaced gas was neutralized and absorbed in a 10percent aqueous solution of sodium hydroxide.)Adding the 20percent sodium hydroxide solution to the reaction solution to adjust the pH to 7 to 8, washing the mixture three times, collecting the organic phase, adding anhydrous sodium sulfate or anhydrous sodium carbonate to the organic phase for 6 hours, filtering out the solid, 2-Fluoro-5-trifluoromethylpyridine crude.(3) The crude 2-fluoro-5-trifluoromethylpyridine was put into a distillation column under reduced pressure and the boiling point was collected at 40 to 45 ° C / 11 mmHg to obtain 2-fluoro-5-trifluoromethylpyridine product 28.55g, analysis of the product measured in the 2-fluoro-5-trifluoromethyl pyridine content of 98.77percent (GC), weighing the amount of distillation and kettle residue weight, and do gas chromatography, calculated 2 - The results of the fluorination of 5-trifluoromethylpyridine were: conversion rate: 96.33percent; selectivity: 91.17percent; yield: 85.45percent.

Reference： [1] Patent: CN106866509, 2017, A, . Location in patent: Paragraph 0030; 0032; 0044; 0046

4
[ 77152-08-0 ]
[ 351019-18-6 ]
[ 69045-82-5 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 2, p. 298 - 301

5
[ 33252-63-0 ]
[ 69045-82-5 ]

Reference： [1] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 280 - 284[2] Angewandte Chemie, 2015, vol. 127, # 1, p. 282 - 286,5

6
[ 76041-72-0 ]
[ 69045-82-5 ]

Reference： [1] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 280 - 284[2] Angewandte Chemie, 2015, vol. 127, # 1, p. 282 - 286,5

7
[ 7783-56-4 ]
[ 69045-82-5 ]

Reference： [1] Patent: US4184041, 1980, A,

8
[ 72537-17-8 ]
[ 85148-26-1 ]
[ 69045-82-5 ]

Reference： [1] Molecules, 2013, vol. 18, # 1, p. 398 - 407

9
[ 69045-78-9 ]
[ 52334-81-3 ]
[ 69045-82-5 ]

Reference： [1] European Journal of Medicinal Chemistry, 1989, vol. 24, # 3, p. 249 - 258

10
[ 69045-82-5 ]
[ 76041-72-0 ]

Reference： [1] Chemical Communications, 2017, vol. 53, # 95, p. 12738 - 12741

[ 69045-82-5 ] Synthesis Path-Downstream 1~88

1
[ 52334-81-3 ]
[ 69045-82-5 ]

Yield	Reaction Conditions	Operation in experiment
95.56%	With potassium fluoride; N-benzyl-N,N,N-triethylammonium chloride; In N,N-dimethyl acetamide; at 135℃; for 10h;	1, to 1L three-necked flask was added KF46.20g (0.80mol),500 mL of N, N-dimethylacetamide, warmed to 125 C.,Stir for 30 minutes,Connected to the distillation unit,Micro-vacuum distillation, collecting fractions, tracking three bottles of water content, water <500ppm, stop distillation, stand-by. 2, to three bottles of benzyl triethyl ammonium chloride 7g (0.03mol),100 g (0.55 mol) of 2-chloro-5-trifluoromethylpyridine.Connect the condenser, warmed to 135 ,Stirring, incubated for 10 hours.Gas chromatography followed the reaction, when the reaction solution 2-chloro-5-trifluoromethylpyridine content <1%, stop the reaction.The reaction solution was directly distilled under reduced pressure to collect 40-45 C / 11 mmHg fraction,87.80 g of 2-fluoro-5-trifluoromethylpyridine was obtained,Purity 98.95% (GC), yield 95.56%.

Reference： [1]Patent: CN106946769,2017,A .Location in patent: Paragraph 0028; 0029; 0030; 0031; 0032; 0033-0045
[2]Chemistry Letters,1993,p. 509 - 512
[3]Angewandte Chemie - International Edition,2006,vol. 45,p. 2720 - 2725
[4]Organic Letters,2015,vol. 17,p. 1866 - 1869
[5]Journal of Organic Chemistry,2015,vol. 80,p. 12137 - 12145

2
[ 69045-78-9 ]
[ 52334-81-3 ]
[ 69045-82-5 ]

Reference： [1]European Journal of Medicinal Chemistry,1989,vol. 24,p. 249 - 258

3
[ 726127-45-3 ]
[ 69045-82-5 ]
2-[(1-[4-(2-methyl(1,2,3,4-tetraazol-5-yl))phenyl]methyl}(4-piperidyl))[4-(trifluoromethoxy)phenyl]methoxy]-5-(trifluoromethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In dimethyl sulfoxide; at 85 - 90℃; for 3h;	A stirred mixture of 0.89 gram (0.002 mole) of {1-[(2-METHYL (1, 2,3, 4- tetraazol-5-yl) ) methyl] (4-PIPERIDYL)} [4- (TRIFLUOROMETHOXY) phenyl] methanol, 0.36 gram (0.002 mole) of <strong>[69045-82-5]2-fluoro-5-trifluoromethylpyridine</strong>, and 0.08 gram (0.002 mole) of 60% sodium hydride (in mineral oil) in about 10 mL of DMSO was heated at 85-90 C for three hours. After this time, the reaction mixture was allowed to cool to ambient temperature, and then it was poured into water. The mixture was extracted with diethyl ether and the combined extracts were dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using mixtures of methylene chloride and methanol eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.63 gram of Compound 434. The NMR spectrum was consistent with the proposed structure.

Reference： [1]Patent: WO2004/60371,2004,A1 .Location in patent: Page/Page column 65-66

4
[ 885229-32-3 ]
[ 69045-82-5 ]
5-chloro-N-(1-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)thieno[2,3-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; dimethyl sulfoxide; at 25℃; for 72h;	A mixture of <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (142 mg), 2-[(5-chlorothieno[2,3-d]pyrimidinyl-4)amino]-1-propanol, (compound 94) (0.2 g) and 1M THF solution of potassium t-butoxide (1.0 mL) in DMSO (10 mL) was stirred at approximately 25 C. for 72 hours. The mixture was diluted with Et2O and washed with H2O and brine. The organic phase was then dried (Na2SO4) and filtered through silica gel. Solvent was removed in vacuo and the residue was purified via flash chromatography, yielding 118 mg of oil.

Reference： [1]Patent: US2006/89370,2006,A1 .Location in patent: Page/Page column 13

5
[ 69045-82-5 ]
[ 156-87-6 ]
[ 321535-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran;	3-[[5- (TRIFLUOROMETHYL)-2-PYRIDYL]-OXY]-1-PROPANAMINE. <strong>[69045-82-5]2-Fluoro-5-trifluoromethylpyridine</strong> (1.831 g, 11 mmol) was dissolved in anhydrous THF (15 mL) with stirring under nitrogen and cooled to 0 C. in an ice bath. To this was added dropwise over 30 minutes a solution of 3-amino-1-propanol (0.76 mL, 10 mmol) in anhydrous THF (15 mL) and 1M potassium tert-butoxide in THF (10 mL, 10 mmol). The yellow solution was allowed to stir and slowly warm to room temperature overnight. The reaction mixture was poured into water (75 mL) and extracted with ether (2*50 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and evaporated under vacuum to a yellow liquid, which was nearly pure by NMR and MS, and was used as such without further purification.

Reference： [1]Patent: US6355660,2002,B1

6
[ 99-91-2 ]
[ 69045-82-5 ]
[ 145834-67-9 ]
2-(5-(Trifluoromethyl)-2-Pyridinyl)-1-(4-Chlorophenyl)Ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In tetrahydrofuran; hexane; water;	EXAMPLE 1 Preparation of 2-(5-(Trifluoromethyl)-2-pyridinyl)-1-(4-chlorophenyl)ethanone 4'-Chloroacetophenone (16 milliliters (mL), 19 grams (g), 120 millimoles (mmol)) was added rapidly dropwise to a stirring 21 C. slurry of sodium hydride (17.1 g, 428 mmol; freed of mineral oil by a hexane wash) in tetrahydrofuran (THF) (280 mL). After 1 hour (hr), the mixture was heated at reflux for 1 hr, then cooled to 21 C. <strong>[69045-82-5]2-Fluoro-5-(trifluoromethyl)pyridine</strong> was added rapidly dropwise to the stirring slurry causing a rapid color change to dark red. The solution was heated at reflux for 17 hr, at which time gas chromatography (GC) analysis showed complete conversion. The mixture was cooled to 0 C. and quenched by careful sequential addition of acetic acid (12 mL, 13 g, 210 mmol), water (125 mL), acetic acid (12 mL, 13 g, 210 mmol), and water (125 mL). The layers were treated separately due to the propensity of this material to form serious emulsions. The aqueous layer was extracted with ether (2*100 mL). The combined organic layer was extracted with water and brine, dried over magnesium sulfate, decolorized with activated charcoal, filtered, and evaporated to a wet brown solid residue. 1H NMR showed a 59:41 molar ratio of ketone to enol ether. The residue was triturated with hexane and applied to a porous plate to obtain a pale yellow solid. The hexane solvent was evaporated and the residue combined with the solid. The mixture was purified by flash chromatography, eluding with methylene chloride, to obtain 12.6 g (50 percent of theory) of the title compound as a yellow solid melting at 114-116 C. Attempts to recrystallize the compound generally resulted in some decomposition. Elemental Analysis: Calcd. for C14 H9 ClF3 NO: C, 56.11; H, 3.03; N, 4.67. Found: C, 55.71; H, 3.01; N, 4.59. The following were prepared similarly: 2-(6-Fluoro-2-pyridinyl)-I-(4-fluorophenyl)ethanone; a semi-solid (63 percent yield); Elemental Analysis: Calcd. for C13 H9 F2 NO: C, 66.95; H, 3.89; N, 6.01. Found: C, 67.11; H, 4.02; N, 6.09. 2-(5-(Trifluoromethyl)-2-pyridinyl)-1-(4-fluorophenyl)ethanone; a yellow powder melting at 82-83 C. and decomposing on recrystallization (45 percent of theory); 1H NMR (ketone tautomer) delta 4.53 (s,2), 7.13 (dd, 2, J =8.5, 8.5), 7.44 (d, 1, J=8.0), 7.85 (m, 1), 8.08 (dd, 2, J=5.4, 8.9), 8.81 (m, 1); 1H NMR (enol tautomer) delta 6.06 (s,1), 7.09 (dd, 2, J=8.7, 8.7), 7.13 (d, 1, J=8.5), 7.79 (dd, 1, J=2.4, 7.9), 7.83 (dd, 2, J=5.4, 9.0), 8.57 (br s, 1), 14.97 (s,1). Elemental Analysis: Calcd. for C14 H9 F4 NO: C, 59.37; H, 3.20; N, 4.95. Found: C, 59.72; H, 3.07; N, 4.82.
	With acetic acid; In tetrahydrofuran; hexane; water;	EXAMPLE 1 Preparation of 2-(5-(Trifluoromethyl)-2-Pyridinyl)-1-(4-Chlorophenyl)Ethanone 4'-Chloroacetophenone (16 milliliters (mL), 19 grams (g), 120 millimoles (mmol)) was added rapidly dropwise to a stirring 21 C. slurry of sodium hydride (17.1 g, 428 mmol; freed of mineral oil by a hexane wash) in tetrahydrofuran (THF) (280 mL). After 1 hour (hr), the mixture was heated at reflux for 1 hr, then cooled to 21 C. <strong>[69045-82-5]2-Fluoro-5-(trifluoromethyl)pyridine</strong> was added rapidly dropwise to the stirring slurry causing a rapid color change to dark red. The solution was heated at reflux for 17 hr, at which time gas chromatography (GC) analysis showed complete conversion. The mixture was cooled to 0 C. and quenched by careful sequential addition of acetic acid (12 mL, 13 g, 210 mmol), water (125 mL), acetic acid (12 mL, 13 g, 210 mmol), and water (125 mL). The layers were treated separately due to the propensity of this material to form serious emulsions. The aqueous layer was extracted with ether (2*100 mL). The combined organic layer was extracted with water and brine, dried over magnesium sulfate, decolorized with activated charcoal, filtered, and evaporated to a wet brown solid residue. 1H NMR showed a 59:41 molar ratio of ketone to enol tautomer. The residue was triturated with hexane and applied to a porous plate to obtain a pale yellow solid. The hexane solvent was evaporated and the residue combined with the solid. The mixture was purified by flash chromatography, eluding with methylene chloride, to obtain 12.6 g (50 percent of theory) of the title compound as a yellow solid melting at 114-116 C. Attempts to recrystallize the compound generally resulted in some decomposition. Elemental Analysis for C14 H9 ClF3 NO: Calc.: C, 56.11; H, 3.03; N, 4.67 Found: C, 55.71; H, 3.01; N, 4.59. The following were prepared similarly: 2-(6-Fluoro-2-pyridinyl)-1-(4-fluorophenyl)ethanone; a semi-solid (63 percent yield); Elemental Analysis for C13 H9 F2 NO: Calc.: C, 66.95; H, 3.89; N, 6.01 Found: C, 67.11; H, 4.02; N, 6.09. 2-(5-(Trifluoromethyl)-2-pyridinyl)-1-(4-fluorophenyl)ethanone; a yellow powder melting at 82-83 C. and decomposing on recrystallization (45 percent of theory); 1H NMR (ketone tautomer) delta4.53 (s,2), 7.13 (dd, 2, J=8.5, 8.5), 7.44 (d, 1, J=8.0), 7.85 (m, 1), 8.08 (dd, 2, J=5.4, 8.9), 8.81 (m, 1); 1H NMR (enol tautomer) delta6.06 (s,1), 7.09 (dd, 2, J=8.7, 8.7), 7.13 (d, 1, J=8.5), 7.79 (dd, 1, J=2.4, 7.9), 7.83 (dd, 2, J=5.4, 9.0), 8.57 (br s, 1), 14.97 (s,1). Elemental Analysis for C14 H9 F4 NO: Calc.: C, 59.37; H, 3.20; N, 4.95 Found: C, 59.72; H, 3.07; N, 4.82.

Reference： [1]Patent: US5250532,1993,A
[2]Patent: US5324837,1994,A

7
N-(5-hydroxy-2-nitrobenzoyl)-S,S,-dimethyl-sulphoximine [ No CAS ]
[ 69045-82-5 ]
N-[5-(5-trifluoromethyl-pyridin-2-yloxy)-2-nitrobenzoyl]-S,S-dimethyl-sulphoximine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; dimethyl sulfoxide; ethyl acetate;	EXAMPLE 8 0.14 g of sodium hydride is placed in 20 ml of dimethyl sulphoxide. A solution of 1.55 g of N-(5-hydroxy-2-nitrobenzoyl)-S,S-dimethyl-sulphoximine in 10 ml of dimethyl sulphoxide is added dropwise and the mixture is stirred at 40 C. for 3 hours. 1.0 g of <strong>[69045-82-5]2-fluoro-5-trifluoromethyl-pyridine</strong> is subsequently added to the mixture and the resulting mixture is heated at 70 C. for 16 hours. For the working-up, the cooled mixture is poured into 100 ml of 2N sodium hydroxide and the aqueous mixture is extracted three times with 50 ml of ethyl acetate each time. The combined organic phases are washed twice with 100 ml of water each time, dried and evaporated, and the residue is purified by chromatogaphy on silica gel with n-hexane/ethyl acetate (9:1). The thus-obtained product, N-[5-(5-trifluoromethyl-2-pyridyloxy)-2-nitrobenzoyl]-S,S-dimethyl-sulphoximine, has the same physical data as the corresponding compound I in Example 1 (9th end product). The N-(5-hydroxy-2-nitrobenzoyl)-S,S-dimethyl-sulphoximine used as the starting material can be prepared as follows:

Reference： [1]Patent: US4556413,1985,A

8
2-bromo-5-trichloromethylpyridine [ No CAS ]
[ 7783-56-4 ]
[ 69045-82-5 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 Preparation of 2-Fluoro-5-trifluoromethylpyridine 27.6 g of 2-bromo-5-trichloromethylpyridine was mixed with 17.9 g of antimony trifluoride in a flask equipped with a thermometer, a stirrer and a reflux condenser. Upon heating to 150 to 180 C., the reaction was immediately initiated and a formed low boiling product began to be refluxed. 20 minutes after the initiation of the reflux, the condenser was directed downward to distill out the refluxed product. The distillate was extracted with methylene chloride, and the extract was washed successively with water, 15% dilute hydrochloric acid, and water. After drying, the washed extract was concentrated and distilled to obtain 5.3 g of the title product having a boiling point of 115-120 C.

Reference： [1]Patent: US4184041,1980,A

9
[ 1000998-47-9 ]
[ 69045-82-5 ]
[ 1000998-49-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,2007,vol. 44,p. 1389 - 1393

10
[ 5203-98-5 ]
[ 69045-82-5 ]
[ 1000998-40-2 ]

Reference： [1]Journal of Heterocyclic Chemistry,2007,vol. 44,p. 1389 - 1393

11
[ 85094-07-1 ]
[ 69045-82-5 ]
[ 1000998-44-6 ]
[ 1000998-45-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,2007,vol. 44,p. 1389 - 1393

12
[ 1072269-75-0 ]
[ 69045-82-5 ]
[ 1072270-36-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydrogencarbonate; In acetonitrile; at 80℃; for 21h;	Example 7: {2-f4-(lH-Indol-4-yl)-6-morphoIin-4-vI-pyriinidin-2-yll-ethvU-(5- trifluoromethyl-pyridin-2-yl)-amine; To a solution of 2-[4-(l-benzenesulfonyl-lH-indol-4-yl)-6-mophiholin-4-yl-pyrimidin- 2-yl]-ethylamine (30 mg, 0.07 mmol) and NaHCO3 (6 mg, 0.07 mmol) in acetonitrile (3 mL) was added <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (12 mg, 0.07 mmol). The resulting mixture was heated at reflux for 21 h, then cooled to RT and concentrated in vacuo. The resulting residue was partitioned between water and DCM and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give {2-[4-(l-benzenesulfonyl-lH-indol-4-yl)-6- morpholin-4-yl-pyrimidin-2-yl]-ethyl}-(5-trifluoromethyl-pyridin-2-yl)-amine as a colourless oil (30 mg, 76 %). [M + H]+ 609.3

Reference： [1]Patent: WO2008/125833,2008,A1 .Location in patent: Page/Page column 32; 65

13
[ 935252-61-2 ]
[ 69045-82-5 ]
(5-Chlorothieno[2,3-d]pyrimidin-4-yl)-{2-[3-(5-trifluoromethylpyridin-2-yloxy)phenyl]ethyl}amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		(5-Chlorothieno[2,3-d]pyrimidin-4-yl)-{2-[3-(5-trifluoromethylpyridin-2-yloxy)phenyl]ethyl}amine To a Carousel reactor tube equipped with a magnetic stirrer under an atmosphere of nitrogen was added DMF (5 mL), 3-[2-(5-chlorothieno[2,3-d]-pyrimidin-4-ylamino) ethyl]phenol (678 mg, 2.2 mmol), and sodium hydride (60 percent dispersion in oil; 98 mg). After bubbling subsided to yield a brown solution, <strong>[69045-82-5]2-fluoro-5-trifluoromethylpyridine</strong> (366 mg, 2.2 mmol) then was added. The reaction was stirred at 40 C. for 15 h. Then the reaction mixture was partitioned between water (10 mL) and ethyl acetate (320 mL). The combined organic phases were diluted with pentane (15 mL), washed sequentially with water (210 mL) and brine (10 mL), then dried (MgSO4) and filtered through a silica gel/Celite plug. Most of the solvent was removed to give thick yellow oil (1.05 g), which was vigorously stirred with pentane (50 mL). The pentane was decanted to leave a tan solid. The solid was triturated in hot pentane, the suspension was cooled, and the solid removed by suction filtration to give product as an amorphous tan powder, 545 mg, 1.2 mmol, 55 percent yield, mp 67-69 C. Compound 69 was prepared similarly using the procedure of Compound 67.
20%		To a Carousel reactor tube equipped with a magnetic stirrer under an atmosphere of nitrogen was added DMF (5 mL), 3-[2-(5-chlorothieno[2,3-d]-pyrimidin-4- ylamino) ethyl]phenol (678 mg, 2.2 mmol), and sodium hydride (60 percent dispersion in oil; 98 mg). After bubbling subsided to yield a brown solution, 2- fluoro-5-trifluoromethylpyridine (366 mg, 2.2 mmol) then was added. The reaction was stirred at 40 C for 15 h. Then the reaction mixture was partitioned between water (10 mL) and ethyl acetate (3x20 mL). The combined organic phases were diluted with pentane (15 mL), washed sequentially with water (2x 10 mL) and brine (10 mL), then dried (MgSO4) and filtered through a silica gel/Celite plug. Most of the solvent was removed to give thick yellow oil (1.05 g), which was vigorously stirred with pentane (50 mL). The pentane was decanted to leave a tan solid. The solid was triturated in hot pentane, the suspension was cooled, and the solid removed by suction filtration to give product as an amorphous tan powder, 545 mg, 1.2 mmol, 55 percent yield, mp 67-69 C.Compound 69 was prepared similarly using the procedure of Compound 67.

Reference： [1]Patent: US2007/93498,2007,A1 .Location in patent: Page/Page column 8
[2]Patent: WO2007/46809,2007,A1 .Location in patent: Page/Page column 25

14
[ 1210070-30-6 ]
[ 69045-82-5 ]
[ 1210070-06-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		To a solution of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methoxyphenol (3.73 g, 11.25 mmol) in DMF (25 mL) in a dry 250 mL round bottom flask equipped with a dry nitrogen line and a magnetic stir bar was added sodium hydride (324 mg, 13.5 mmol). After gas evolution had subsided, <strong>[69045-82-5]2-fluoro-5-trifluoromethyl-pyridine</strong> (2.05 g, 12.3 mmol) was added, and the reaction mixture was stirred at 250C. After 20 h, additional sodium hydride (50 mg, 2.1 mmol) and <strong>[69045-82-5]2-fluoro-5-trifluoromethyl-pyridine</strong> (100 mg, 0.6 mmol) were added. After 20 min, the reaction mixture was quenched by addition of sat. aq. NH4Cl (30 mL) and concentrated in vacuo. The residue was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed on the filter with water. The filter cake again was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed with water. The filter cake was dried with suction on the filter overnight to provide 5.26 g (98% yield) of (5,8-difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(5- trifluoromethylpyridin-2-yloxy)-phenyl] -ethyl} -amine as an off-white powder, M. P. 119- 1210C. LC-MS: 477 (M++l); 1H NMR (CDCl3): delta 8.69 (s, IH), 8.4 (m, IH), 7.89 (dd, IH), 7.36 (m, IH), 7.12 (m, IH), 7.01 (m, 2H), 6.93 (m, 2H), 6.78 (bd, IH), 3.97 (m, 2H), 3.75 (s, 3H), 3.06 (m, 2H).

Reference： [1]Patent: WO2010/25451,2010,A2 .Location in patent: Page/Page column 42-43

15
[ 1059191-35-3 ]
[ 69045-82-5 ]
[ 1059189-84-2 ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium hydrogencarbonate; In dimethyl sulfoxide; at 130℃; for 16h;Inert atmosphere;	Example 2; N-[7-(2,4-Dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]-N'-[5-(trifluoromethyl)pyridin-2-yl]ethane-1,2-diamine 50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 3 ml of dry DMSO, 51.2 mg (0.31 mmol) of <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> and 31.1 mg (0.31 mmol) of potassium bicarbonate are added, and the mixture is heated at 130 C. under argon for 16 h. Purification by preparative HPLC results in 22 mg (30% of theory) of the product as a solid.LCMS (method 3): Rt=2.06 min. (m/z=468 (M+H)+)1H-NMR (400 MHz, DMSO-d6): d=8.27 (s, 1H), 8.07 (t, 1H), 8.00 (s, 1H), 7.71 (d, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 7.54 (m, broad, 2H), 7.49 (dd, 1H), 7.10 (s, 1H), 6.57 (d, 1H), 3.68 (t, 2H), 3.64 (t, 2H).

Reference： [1]Patent: US2010/113441,2010,A1 .Location in patent: Page/Page column 62

16
[ 1227068-53-2 ]
[ 69045-82-5 ]
[ 1231923-68-4 ]

Yield	Reaction Conditions	Operation in experiment
68.4%	at 180 - 200℃; for 1h;Sealed tube; Microwave irradiation;	STEP 4. N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)-5-(TRIFLUOROMETHYL)PYRIDIN-2-AMINE 4-(3-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (0.1 g, 0.37 mmol) and 2-fluoro-5-(trifluoromethyl)puridine (0.073 mL, 0.44 mmol) were combined in a sealed tube and irradiated neat in a microwave synthesizer at 180 C. for 30 min, followed by 200 C. for 30 min. The cooled reaction mixture was directly chromatographed via flash column chromatography (15% to 50% EtOAc/Hexanes) to afford N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-5-(trifluoromethyl)pyridin-2-amine (0.105 g, 68.4% yield) as a white amorphous solid. MS (ESI, pos. ion) m/z: 417.0. IC50 (uM) 0.064.

Reference： [1]Patent: US2010/160280,2010,A1 .Location in patent: Page/Page column 151

17
meso-(3aS,4S,7R,7aR)-2-(4-hydroxy-2,6-dimethylphenyl)hexahydro-4,7-methanoindene-1,3-dione [ No CAS ]
[ 69045-82-5 ]
meso-(3aS,4S,7R,7aR)-2-[2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yloxy)phenyl]-hexahydro-4,7-methanoindene-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; potassium carbonate; at 140℃; for 0.666667h;Microwave irradiation;	Step 3 : Preparation of meso-(3aS,4S,7R,7aR)-2-[2,6-dimethyl-4-(5-trifluoromethylpyridin-2- yloxy)phenyl]-hexahydro-4,7-methanoindene-1 ,3-dioneTo a mixture of meso-(3aS,4S,7R,7aR)-2-(4-hydroxy-2,6-dimethylphenyl)hexahydro-4,7- methanoindene-1 ,3-dione (0.2Og, 0.0007mol), <strong>[69045-82-5]2-fluoro-5-trifluoromethylpyridine</strong> (0.1 16g, 0.0007mol) and potassium carbonate (0.2Og, 0.00087mol) is added Lambda/,Lambda/-dimethylaminopyridine (7ml), and the reaction mixture is then heated at 14O0C for 40 minutes under microwave irradiation. After cooling to room temperature 2M aqueous hydrochloric acid is added, and the crude product is extracted with dichloromethane. The organic phase is separated, washed with distilled water, then dried over magnesium sulfate and concentrated in vacuo. The residue is then dissolved again in diethyl ether, washed with distilled water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product is finally loaded onto silica and purified by flash column chromatography (methanol/dichloromethane eluant) to afford meso- (3aS,4S,7R,7aR)-2-[2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yloxy)phenyl]-hexahydro-4,7- methanoindene-1 ,3-dione as a white solid.

Reference： [1]Patent: WO2010/89210,2010,A1 .Location in patent: Page/Page column 59-60

18
4-(2-ethyl-4-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione [ No CAS ]
[ 69045-82-5 ]
4-(4-(5-trifluoromethylpyridin-2-yloxy)-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		4-(2-Ethyl-4-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.100 g, 0.34 mmol) is added to a mixture of <strong>[69045-82-5]2-fluoro-5-trifluoromethylpyridine</strong> (0.061 g, 0.41 mmol) and potassium carbonate (0.110 g, 0.69 mmol) in N,N-dimethylformamide (2 ml), and the mixture is heated at 140 0C under microwave irradiation for 1 hour. The mixture is cooled to room temperature, then acidified by addition of 2M aqueous hydrochloric acid. The mixture is diluted with dichloromethane and passed through a phase separation cartridge. The organic phase is concentrated to around 2 ml, and purified by preparative reverse phase HPLC to give 4-[4-(5-trifluoromethylpyridin-2-yloxy)-2-ethylphenyl]-2, 2,6,6- tetramethylpyran-3,5-dione.

Reference： [1]Patent: WO2010/89211,2010,A1 .Location in patent: Page/Page column 48

19
[ 1239602-86-8 ]
[ 69045-82-5 ]
[ 1239602-87-9 ]

Yield	Reaction Conditions	Operation in experiment
55%		Example 12 Preparation of 5-trifluoromethyl-2-{3-[2-((2R,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yloxy)-indan-5-yl]-pyrazol-1-yl}-pyridine (Compound 8C) To a solution of Compound E-28 (97 mg, 0.25 mmol) in THF (1 mL) cooled in a dry ice/isopropyl alcohol bath was added dropwise via syringe a 1.0 M solution of lithium hexamethyldisilazide in THF (0.25 mL, 0.25 mmol). After 15 minutes (min), a solution of <strong>[69045-82-5]2-fluoro-5-trifluoromethylpyridine</strong> (49 mg, 0.30 mmol) in THF (0.5 mL) was added dropwise via syringe. The contents were allowed to gradually warm to room temperature overnight with stirring. The solution was concentrated to a residue which was dissolved in Et2O and was washed once with saturated NaHCO3. The aqueous wash was extracted once with Et2O and the combined extracts were dried (MgSO4). Silica gel chromatography (CH2Cl2/EtOAc mixtures as eluent) afforded the title compound (73 mg, 55%): 1H NMR (CDCl3) delta 8.70 (m, 1H), 8.64 (d, J=2.7 Hz, 1H), 8.23 (m, 1H), 8.06 (m, 1H), 7.83 (s, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 5.03 (s, 1H), 4.69 (m, 1H), 3.66-3.46 (m, 3H), 3.58 (s, 3H), 3.53 (s, 3H), 3.49 (s, 3H), 3.28-3.02 (m, 5H), 1.36 (2d, J=6.3 Hz, 3H); ESIMS m/z 534 ([M+H+]+, 40), 346 (100); Anal. Calcd for C27H30F3N3O5: C, 60.78; H, 5.67; N, 7.88. Found: C, 60.69; H, 5.73; N, 7.78.

Reference： [1]Patent: US2010/204164,2010,A1 .Location in patent: Page/Page column 10

20
[ 69045-82-5 ]
[ 269409-70-3 ]
[ 1355052-60-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.333333h;Microwave irradiation;	Synthesis of compound 77[0333] A 100 mL round bottom flask was charged with 5-fluoro-3-trifluoromethyl pridine (Matrix, 0.825 g, 5 mmol), 4-hydroxyl phenyl bronate (1.1 g, 5 mmol), Cs2C03 (1.6 g, 5 mmol) and DMF (5 mL). The reaction mixture was stirred at 160 C in a microwave for 20 min, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated and concentrated and crude product (compound 77) was used in the next step without further purification (1.46 g, yield 80%, (m/z + H) = 366).
3.15 g	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;Sealed tube;	A sealable vessel was charged with <strong>[69045-82-5]2-fluoro-5-trifluoromethylpyridine</strong> (Compound 4?) (3.0 g, 18 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dixoaborolan-2-yl)phenol (Compound 5?) (4.0 g, 18 mmol) and Cs2CO3 (7.0 g, 21 mmol) in DMF (25 mL) and was heated at 80 C. for 4 h. After cooling to RT the mixture was diluted with brine (200 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (SiO2, 0-10% EtOAc/hexanes) to give 3.15 g of Compound 6?. LC/MS, m/z=366 [M+H]+ (Calc: 365).

Reference： [1]Patent: WO2012/7836,2012,A1 .Location in patent: Page/Page column 117
[2]Patent: US2014/249128,2014,A1 .Location in patent: Paragraph 0285; 0286

21
[ 69045-82-5 ]
[ 1355052-61-7 ]

Reference： [1]Patent: WO2012/7836,2012,A1

22
[ 69045-82-5 ]
[ 1355052-59-3 ]

Reference： [1]Patent: WO2012/7836,2012,A1

23
[ 69045-82-5 ]
[ 1355052-22-0 ]

Reference： [1]Patent: WO2012/7836,2012,A1

24
[ 69045-82-5 ]
[ 1355052-23-1 ]

Reference： [1]Patent: WO2012/7836,2012,A1

25
[ 1372149-68-2 ]
[ 69045-82-5 ]
C₁₈H₂₅F₃N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 32-((S)-2-Methanesulfonyl-1-(R)-pyrrolidin-3-yl-ethoxy)-5-trifluoromethylpyridine; (R)-3-((S)-1-Hydroxy-2-methylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 95.6 mumol, 1.0 eq.) was dissolved in DMF (1.0 mL). NaH (6.9 mg, 287 mumol, 3.0 eq.) was added and the resulting mixture was stirred for 10 minutes. <strong>[69045-82-5]2-Fluoro-5-(trifluoromethyl)pyridine</strong> (47.4 mg, 287 mumol, 3.0 eq.) was added and the mixture was heated at 70 C. for 1.5 hours. The mixture was cooled to room temperature and concentrated.

Reference： [1]Patent: US2012/88799,2012,A1 .Location in patent: Page/Page column 28

26
[ 72537-17-8 ]
[ 85148-26-1 ]
[ 69045-82-5 ]

Reference： [1]Molecules,2013,vol. 18,p. 398 - 407

27
[ 1286794-47-5 ]
[ 69045-82-5 ]
[ 1286794-22-6 ]

Yield	Reaction Conditions	Operation in experiment
28%		Step 1 :A flame dried flask was charged with anhydrous ZnCI2 (5.13 g, 37.6 mmol) and THF (29 mL). Once a clear solution was obtained, the flask was immersed in a cooling bath at -20 C. To this mixture was added LHMDS (1.0 M in THF, 34.2 mL, 34.2 mmol) via syringe. The resulting mixture was stirred for ~1 h while the bath was kept at -20 C.Meanwhile, another flame-dried flask was charged with 5R-(2,4,6-trifluorophenyl)-5,6- dihydro-N,N-bis[(4-methoxyphenyl)methyl]-2,5-dimethyl-2H-l,2,4-thiadiazin-3-amine-l,l- dioxide (0.50 g, 0-91 mmol), <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (1.51 g, 9.13 mmol), and THF (1 mL). The resulting mixture was stirred for 5 min, then a portion of the above base solution(0.54 M, 1.82 mmol, 3.4 mL) was added. After lh, sodium hexamethyldisiiazane (1.0 M in THF, 0.91 mL) was added. After an additonal 3h, lithium hexamethyldisilazide (1.0 M in toluene, 1.4 mL) was added. After an additional hour, a second aliquot of lithium hexamethyldisilazide (1.0 M in toluene, 1.4 mL) was added. After one additional hour, the reaction was diluted with 1 % w/v citric acid and EtOAc and stirred vigorously until both phases cleared. The phases were separated and the aqueous layer was extracted 2X with EtOAc. The organic portions were combined, washed with brine, dried over MgSQ4, filtered and concentrated. This crude sample was subjected to column chromatography (120 g silica, 85 mL/min, 0% to 20% EtOAc/hexanes) to give 6(R)-[5-(trifluoromethyl)-2-pyridyl]-5R-(2,4,6-trifluorophenyl)-5>6-dihydro-N,N-bis[(4- methoxyphenyl)methyl]-2,5-dimethyl-2H-l,2,4-thiadiazin-3-amine-l5l-dioxide (180 mg, 28%). The above product of step 1 was treated according to Scheme 14, step 2 to give Example 64. LCMS data (Ex. 64): Obs. MH+: 453.0, Ret. Time: 3.19 min, LCMS method: B.

Reference： [1]Patent: WO2011/44187,2011,A1 .Location in patent: Page/Page column 106

28
[ 69045-82-5 ]
[ 1432492-68-6 ]

Reference： [1]Patent: US2013/131036,2013,A1
[2]Patent: WO2013/62966,2013,A2

29
[ 4426-11-3 ]
[ 69045-82-5 ]
[ 1432492-67-5 ]

Yield	Reaction Conditions	Operation in experiment
31.8%	With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at 20℃; for 72h;	Example 115A 1-[5-(trifluoromethyl)pyridin-2-yl]cyclobutanecarbonitrile <strong>[69045-82-5]2-Fluoro-5-(trifluoromethyl)pyridine</strong> (0.603 mL, 5 mmol) and cyclobutane-carbonitrile (0.514 mL, 5.50 mmol) were dissolved in toluene (20 mL). 1M NaHMDS (5.50 mL, 5.50 mmol) in THF was added, and the reaction stirred at ambient temperature for 3 days. The reaction mixture was quenched with water and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was chromatographed on an AnaLogix SF25-60 g column and eluted with 5% EtOAc in hexanes to give Example 115A (0.36 g, 1.592 mmol, 31.8% yield). MS (DCI+): m/z 244.0 (M+NH4). 1H NMR (300 MHz, DMSO-d6) delta 9.09-9.02 (m, 1H), 8.33 (dd, J=8.3, 2.2 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 2.89-2.69 (m, 4H), 2.39-2.21 (m, 1H), 2.16-2.00 (m, 1H).
31.8%	With sodium hexamethyldisilazane; In toluene; at 20℃; for 72h;	l-[5-(trifluoromethyl)pyridin-2-yl]cyclobutanecarbonitrile[187] <strong>[69045-82-5]2-Fluoro-5-(trifluoromethyl)pyridine</strong> (0.603 mL, 5 mmol) and cyclobutane- carbonitrile (0.514 mL, 5.50 mmol) were dissolved in toluene (20 mL). 1M NaHMDS (5.50 mL, 5.50 mmol) in THF was added, and the reaction stirred at ambient temperature for 3 days. The reaction mixture was quenched with water and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried with MgS04, filtered, and concentrated. The residue was chromatographed on an AnaLogix SF25-60 g column and eluted with 5% EtOAc in hexanes to give Example 115A (0.36 g, 1.592 mmol, 31.8% yield). MS (DCI+): m/z 244.0 (M+NH4). XH NMR (300 MHz, DMSO-d6) ? 9.09 - 9.02 (m, 1H), 8.33 (dd, J= 8.3, 2.2 Hz, 1H), 7.85 (d, J= 8.3 Hz, 1H), 2.89 - 2.69 (m, 4H), 2.39 - 2.21 (m, 1H), 2.16 - 2.00 (m, 1H).

Reference： [1]Patent: US2013/131036,2013,A1 .Location in patent: Paragraph 1659; 1660
[2]Patent: WO2013/62966,2013,A2 .Location in patent: Paragraph 186; 187

30
[ 69045-82-5 ]
pyridin-2-yl{1-[5-(trifluoromethyl)pyridin-2-yl]cyclobutyl}methanol hydrochloride salt [ No CAS ]

Reference： [1]Patent: US2013/131036,2013,A1

31
[ 69045-82-5 ]
pyridin-2-yl{1-[5-(trifluoromethyl)pyridin-2-yl]cyclobutyl}methanol hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/62966,2013,A2

32
[ 1262397-26-1 ]
[ 69045-82-5 ]
[ 1431663-93-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 100℃;Microwave irradiation;	General procedure: To the solution of (5)-tert-butyl 6-(aminomethyl)-5-azaspi ro[2 .4]heptane-5-carboxylate(prepared according toW020ii006960, immol) in DMF (2m1/mmol), K2C03(2mmol) andAri-X (where X is ortho chloro or fluoro; i.immol) were added. The reaction mixture was heated (microwave) at 80-100C until complete conversion of the starting material. The resulting mixture was poured in aqueous solution of NaHCO3 and extracted with AcOEt; organics were collected, washed with water, dried and evaporated.
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 100℃;Microwave irradiation;	General procedure: To the solution of (S)-tert-butyl 6-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate (prepared according to WO2011006960, 1 mmol) in DMF (2 ml/mmol), K2CO3 (2 mmol) and Ar1-X (where X is ortho chloro or fluoro; 1.1 mmol) were added. The reaction mixture was heated (microwave) at 80-100 C. until complete conversion of the starting material. The resulting mixture was poured in aqueous solution of NaHCO3 and extracted with AcOEt; organics were collected, washed with water, dried and evaporated.

Reference： [1]Patent: WO2013/92893,2013,A1 .Location in patent: Page/Page column 24; 25
[2]Patent: US2014/357653,2014,A1 .Location in patent: Paragraph 0152; 0155

33
(3S)-tert-butyl 3-(aminomethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate [ No CAS ]
[ 69045-82-5 ]
[ 1456892-74-2 ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	General procedure: To a solution of D47 (6 mmol) in DMF (12 mL), K2CO3 (18 mmol) and Ar1-X (where X is 2- chloro or fluoro; 7.2 mmol) were added. The reaction mixture was heated at 120 C until complete conversion of the starting material. The resulting mixture was poured in water and extracted with DCM. The organic layer was concentrated to obtain a crude mixture which was purified by silica gel chromatography (cyclohexane/ethyl acetate from 10/0 to 75/25) togive the title compound as pure diasteroisomer.
38%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	General procedure: To a solution of D47 (6 mmol) in DMF (12 mL), K2CO3 (18 mmol) and Ar1-X (where X is 2-chloro or fluoro; 7.2 mmol) were added. The reaction mixture was heated at 120 C. until complete conversion of the starting material. The resulting mixture was poured in water and extracted with DCM. The organic layer was concentrated to obtain a crude mixture which was purified by silica gel chromatography (cyclohexane/ethyl acetate from 10/0 to 75/25) to give the title compound as pure diasteroisomer.

Reference： [1]Patent: WO2013/139730,2013,A1 .Location in patent: Page/Page column 32
[2]Patent: US2015/65523,2015,A1 .Location in patent: Paragraph 0212; 0213

34
[ 69045-82-5 ]
(1R,3S,6S)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[4.1.0]heptane-2-carboxylate [ No CAS ]
[ 1456892-50-4 ]

Yield	Reaction Conditions	Operation in experiment
73%		General procedure: To a solution of 07 (1.32 mmol) in DMF (15 mL) cooled at 0 00, NaH 60% (1.58 mmol) was added. After stirring at room temperature for 10 minutes 2-F-Ar1 (1.58 mmol) was added and the reaction mixture was stirred at room temperature for 2-17 hours. An aqueous solution of NaHCO3 was added and the product was extracted with DCM, washed with brine, dried and concentrated to obtain a crude mixture which was purified by silica gel chromatography(cyclohexane/ethyl acetate from 10/0 to 7/3).
73%		General procedure: To a solution of D7 (1.32 mmol) in DMF (15 mL) cooled at 0 C., NaH 60% (1.58 mmol) was added. After stirring at room temperature for 10 minutes 2-F-Ar1 (1.58 mmol) was added and the reaction mixture was stirred at room temperature for 2-17 hours. An aqueous solution of NaHCO3 was added and the product was extracted with DCM, washed with brine, dried and concentrated to obtain a crude mixture which was purified by silica gel chromatography (cyclohexane/ethyl acetate from 10/0 to 7/3).

Reference： [1]Patent: WO2013/139730,2013,A1 .Location in patent: Page/Page column 27
[2]Patent: US2015/65523,2015,A1 .Location in patent: Paragraph 0185-0187

35
[ 1456892-30-0 ]
[ 69045-82-5 ]
[ 1456892-31-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	General procedure: To a solution of D9 (4.5 mmol) in DMF (5 mL), K2CO3 (13.5 mmol) and Ar1-X (5.4 mmol) were added. The reaction mixture was heated at 120C until complete conversion of the starting material. The resulting mixture was poured in water and extracted with DCM. The organic layer was concentrated to obtain a crude mixture which was purified by silica gel chromatography (cyclohexane/ethyl acetate from 10/0 to 7/3) to obtain intermediate D10-D13as detailed in below table.
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	General procedure: To a solution of D9 (4.5 mmol) in DMF (5 mL), K2CO3 (13.5 mmol) and Ar1-X (5.4 mmol) were added. The reaction mixture was heated at 120 C. until complete conversion of the starting material. The resulting mixture was poured in water and extracted with DCM. The organic layer was concentrated to obtain a crude mixture which was purified by silica gel chromatography (cyclohexane/ethyl acetate from 10/0 to 7/3) to obtain intermediate D10-D13 as detailed in below table.

Reference： [1]Patent: WO2013/139730,2013,A1 .Location in patent: Page/Page column 21; 22
[2]Patent: US2015/65523,2015,A1 .Location in patent: Paragraph 0163; 0164

36
[ 403-42-9 ]
[ 69045-82-5 ]
[ 145834-67-9 ]
C₁₄H₉F₄NO [ No CAS ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271
[2]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

37
[ 69045-82-5 ]
1-(4-fluorophenyl)-2-[5-(trifluoromethyl)-2-pyridyl]prop-2-en-1-one [ No CAS ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

38
[ 69045-82-5 ]
(2RS,4RS)-1,5-bis(4-fluorophenyl)-2,4-bis(5-trifluoromethyl-2-pyridyl)-1,5-pentanedione [ No CAS ]
(2RS,4SR)-1,5-bis(4-fluorophenyl)-2,4-bis(5-trifluoromethyl-2-pyridyl)-1,5-pentanedione [ No CAS ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

39
[ 69045-82-5 ]
C₁₅H₁₃F₄N₃O [ No CAS ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

40
[ 69045-82-5 ]
4,5-dihydro-3-(4-fluorophenyl)-4-(5-trifluoromethyl-2-pyridinyl)-1H-pyrazole [ No CAS ]
C₁₅H₁₃F₄N₃O [ No CAS ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

41
[ 69045-82-5 ]
C₁₇H₁₆F₄N₂O [ No CAS ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

42
[ 69045-82-5 ]
4,5-dihydro-3-(4-fluorophenyl)-4-(5-trifluoromethyl-2-pyridinyl)-1H-pyrazole [ No CAS ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271
[2]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

43
[ 69045-82-5 ]
[ 145833-95-0 ]

Reference： [1]Organic Process Research and Development,2003,vol. 7,p. 267 - 271

44
2-((2,2-dimethylpiperazin-1-yl)methyl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine [ No CAS ]
[ 69045-82-5 ]
[ 1616597-16-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 80℃;	Example 1 : Preparation of cycloamine-triazole compounds in Accordance with Scheme E2 - Coupling "Right-Side" Piperazine-Precursor with Aryl or HeteroAryl-halo Precursor [0183] Piperazine precursor compounds were prepared using the reaction chemistry shown in Scheme AlphaPiIota to provide Ex-E2-pre piperazine-functionalized compounds (where the piperazine functional group is HN-R15). Compounds of the invention were prepared from the piperazine precursor inaccordance with Scheme El . [0184] Thus, in accordance with Scheme El, the compound of Ex-187 was prepared by suspending 80 mg of dihydridochloride salt (80 mg) of a compound of 2-((2,2-dimemylpiperazin -yl)methyl)-7- metho -[l,2,4]triazolo[l,5-c]quinazolin-5-amine (the compound of Formula Ex-E2-pre where HNR15 is as shown below in Table VI for Ex-187) was suspended in DIPEA (101 micro-L) with 2- fluoro-5-(trifluoromethyl)pyridine (47.8 mg, reagent X-R16 for Ex-187 in Table VI) and heated at 80 C overnight, then diluted with DCM. The organic layer was separated, washed with sat. aq HCU then water, dried over MgSC , filtered and concentrated. The residue was purified by silica chromatography (EtOAc Hex = 1/1 to 100% EtOAc) to yield Ex-199.
	With N-ethyl-N,N-diisopropylamine; at 80℃;	the compound of Ex-199 was prepared by suspending 80 mg of dihydridochloride salt (80 mg) of a compound of 2-((2,2- dimethylpiperazin-1-yl)methyl)-7-methoxy-[1,2,4]triazolo[1,5-c]quinazolin-5-amine (the compound of Formula Ex-E2-pre where H NR15 is as shown below in Table V for Ex-199) was suspended in DIPEA (101 mu,) with <strong>[69045-82-5]2-fluoro-5-(trifluoromethyl)pyridine</strong> (47.8 mg, reagent X- R16 for Ex-199 in Table V) and heated at 80 C overnight, then diluted with DCM. The organic layer was separated, washed with sat. aq NHCl4 then water, dried over MgSO4, filtered and concentrated. The residue was purified by silica chromatography (EtO Ac/Hex = 1/1 to 100% EtOAc) to yield Ex-199

Reference： [1]Patent: WO2014/101113,2014,A1 .Location in patent: Paragraph 0184
[2]Patent: WO2014/105664,2014,A1 .Location in patent: Paragraph 0172

45
[ 123-08-0 ]
[ 69045-82-5 ]
[ 103962-21-6 ]