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[ CAS No. 50488-42-1 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 50488-42-1

Chemical Structure| 50488-42-1

Chemical Structure| 50488-42-1

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Quality Control of [ 50488-42-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 50488-42-1 ]

Product Details of [ 50488-42-1 ]

CAS No. :	50488-42-1	MDL No. :	MFCD00153086
Formula :	C₆H₃BrF₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GSKMWMFOQQBVMI-UHFFFAOYSA-N
M.W :	225.99	Pubchem ID :	2736434
Synonyms :

Calculated chemistry of [ 50488-42-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.94
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) :	-5.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.9
Log Po/w (XLOGP3) :	2.76
Log Po/w (WLOGP) :	4.02
Log Po/w (MLOGP) :	2.33
Log Po/w (SILICOS-IT) :	3.05
Consensus Log Po/w :	2.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.32
Solubility :	0.109 mg/ml ; 0.000481 mol/l
Class :	Soluble
Log S (Ali) :	-2.69
Solubility :	0.466 mg/ml ; 0.00206 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.77
Solubility :	0.0383 mg/ml ; 0.000169 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.89

Safety of [ 50488-42-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 50488-42-1 ]

* 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 [ 50488-42-1 ]
Downstream synthetic route of [ 50488-42-1 ]

[ 50488-42-1 ] Synthesis Path-Upstream 1~15

1
[ 68-12-2 ]
[ 50488-42-1 ]
[ 31224-82-5 ]

Reference： [1] Patent: WO2015/100232, 2015, A2, . Location in patent: Page/Page column 153; 154
[2] Patent: WO2016/209635, 2016, A1, . Location in patent: Page/Page column 44

2
[ 50488-42-1 ]
[ 31181-84-7 ]

Reference： [1] Patent: WO2013/166621, 2013, A1,

3
[ 50488-42-1 ]
[ 74784-70-6 ]

Reference： [1] Chemical Communications, 2010, vol. 46, # 6, p. 925 - 927

4
[ 52334-81-3 ]
[ 50488-42-1 ]

Reference： [1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568

5
[ 73290-22-9 ]
[ 81290-20-2 ]
[ 50488-42-1 ]

Reference： [1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330

6
[ 624-28-2 ]
[ 50488-42-1 ]

Reference： [1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330

7
[ 124-38-9 ]
[ 50488-42-1 ]
[ 80194-69-0 ]

Reference： [1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568

8
[ 50488-42-1 ]
[ 80194-69-0 ]

Reference： [1] Patent: US4367336, 1983, A,

9
[ 544-92-3 ]
[ 50488-42-1 ]
[ 95727-86-9 ]

Reference： [1] Patent: US2005/113576, 2005, A1, . Location in patent: Page/Page column 68

10
[ 50488-42-1 ]
[ 95727-86-9 ]

Reference： [1] Patent: US6933311, 2005, B2,
[2] Patent: US2004/157849, 2004, A1,

11
[ 144025-03-6 ]
[ 50488-42-1 ]
[ 387827-64-7 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 43, p. 14090 - 14094[2] Angew. Chem., 2018, vol. 130, p. 14286 - 14290,5
[3] Angewandte Chemie - International Edition, 2016, vol. 55, # 34, p. 9969 - 9973[4] Angew. Chem., 2016, vol. 128, # 34, p. 10123 - 10127,5
[5] Journal of the American Chemical Society, 2018, vol. 140, # 2, p. 741 - 747
[6] Organic Letters, 2018,
[7] European Journal of Inorganic Chemistry, 2009, # 32, p. 4850 - 4859

12
[ 50488-42-1 ]
[ 387827-64-7 ]

Reference： [1] Journal of the American Chemical Society, 2015, vol. 137, # 6, p. 2195 - 2198
[2] Organic Letters, 2015, vol. 17, # 13, p. 3294 - 3297

13
[ 67-56-1 ]
[ 201230-82-2 ]
[ 50488-42-1 ]
[ 124236-37-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 80℃; for 3 h;	A solution of 2-bromo-5-(trifluoromethyl)pyridine (9 g, 40 mmol) in MeOH (130 mL) was added to Pd-dppf (0.813 g, 0.996 mmol) and Et₃N (11 mL, 80 mmol) in a 250 mL pressure bottle. The mixture was pressurized with carbon monoxide (60 psi), and stirred 3 hr at 80° C. The reaction was cooled to ambient temperature, filtered, and the solvents evaporated at reduced pressure. The residue was partitioned between water and ethyl acetate. The separated organic layer was washed with water and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix.(R). 40*240 column, 10percent-40percent EtOAc/hexanes eluant) to afford 8.52 g (104percent) of the title compound as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 9.01 (m, 1H), 8.28 (d, J=8.1, 1H), 8.12 (dd, J=2.1, 8.2, 1H), 4.06 (s, 3H). MS (ESI⁺) m/z 206 (M+H).

Reference： [1] Patent: US2009/124666, 2009, A1, . Location in patent: Page/Page column 25

14
[ 201230-82-2 ]
[ 50488-42-1 ]
[ 124236-37-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	at 80℃;	III. methyl 5-trifluoromethyl-pyridine-2-carboxylate A mixture of 2-bromo-5-trifluoromethyl-pyridine (10 g, 44.25 mmol), TEA (17.9 g, 177 mmol) and Pd(dppf)Cl₂ (3.24 g, 4.42 mmol) was stirred at 80°C under an average pressure of 1.5 MPa with CO gas. The reaction mixture was filtered and the filtrate was concentrated. The residue was extracted between EA (100 mL) and H₂0 (100 mL). The EA layer was washed with saturated aqueous NaHC0₃ (2 X 100 mL), brine (1 X 100 mL), dried, concentrated and purified by column chromatography on silica gel to give the title compound as a white solid (6 g, 66percent yield): 1H NMR (400 MHz, CDC1₃) δ ppm 8.97-8.98 (m, 1H), 8.23-8.25 (m, 1H), 8.07-8.09 (m, 1H), 4.03 (s, 3H); ES-LCMS m/z 206 ( +H)⁺.

Reference： [1] Patent: WO2013/166621, 2013, A1, . Location in patent: Page/Page column 48

15
[ 50488-42-1 ]
[ 124236-37-9 ]

Reference： [1] Chemistry - A European Journal, 2016, vol. 22, # 9, p. 2930 - 2934

[ 50488-42-1 ] Synthesis Path-Downstream 1~88

1
[ 124-38-9 ]
[ 50488-42-1 ]
[ 80194-69-0 ]

Reference： [1]European Journal of Organic Chemistry,2003,p. 1559 - 1568

2
[ 749257-56-5 ]
[ 50488-42-1 ]
[ 749258-45-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 15h;	A mixture of Description 4 (0.25 g, 0.88 mmol), tris (dibenzylidene) dipalladium (0.016 g, 0.018 mmol), 2-BROMO-5-TRIFLUOROMETHYLPYRIDINE (0.22 g, 0.97 mmol) and cesium carbonate (0.41 g, 1.26 mmol) in anhydrous 1, 4-dioxane (5 ml) was degassed by bubbling nitrogen through for 10 min. The mixture was heated at 100 C for 15 h, allowed to cool to room temperature and poured into a mixture of ethyl ACETATE/WATER (20/5 ml). The phases were separated and the aqueous phase was extracted two times with ethyl acetate (10 ml each). The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash chromatography (ethyl ACETATE/ISO-HEXANE = 1: 1) gave the title compound (0.18 g, 48 %) as a canary-yellow solid, MS (ES (M+1)) 426. 1H NMR (360 MHz, DMSO) 8 7.47 (1H, D, J= 8.7 Hz), 7.79-7. 83 (1H, m), 8. 05- 8.07 (1H, m), 8.44-8. 50 (3H, m), 8.75 (1H, d, J= 1.4 Hz), 9.02 (1H, d, J= 1.4 Hz), 10.51 (1H, s) ppm.

Reference： [1]Patent: WO2004/74290,2004,A1 .Location in patent: Page 65-66

3
[ 794591-83-6 ]
[ 50488-42-1 ]
N-(5-trifluoromethyl-2-pyridinyl)-2-(3-trifluoromethyl-2-pyridinyl)pyrido[2,3-d]pyridazin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 16h;Heating / reflux;	Intermediate XVI (56.9 mg, 1.96 x 104 mol) was dissolved in dioxane (4 ml) and <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> (44 mg, 196, UMOL), caesium carbonate (90 mg), Xantphos (6.3 mg) and tris (dibenzylideneacetone) dipalladium (0) (4.2 mg) were added. The reaction was degassed (by bubbling with N2) and heated to reflux. After stirring for 16 h the reaction was allowed to cool to room temperature and filtered through celite (washing with ethyl acetate). The reaction was then quenched with saturated sodium bicarbonate, extracted three times with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Column chromatography (30% ethyl acetate in hexanes) was followed by trituration from methanol to give the product (63 mg, 73%)

Reference： [1]Patent: WO2004/99177,2004,A1 .Location in patent: Page 35

4
[ 544-92-3 ]
[ 50488-42-1 ]
[ 95727-86-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 180℃; for 2h;	5-(trifluoromethyl)-2-pyridinecarbonitrile Copper (I) cyanide (14.1 g) and 2-bromo-5-trifluoromethylpyridine (3.00 g, 13.3 mmol) in dry DMSO (70 mL) were combined and heated at 180 C. for 2 hours, cooled, and poured into NH4OH (3M). The mixture was then extracted with ethyl acetate (3500 mL), washed with water (1200 mL), dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO, 300 MHz) delta 8.22 (m, 1H), 8.42 (m, 1H), 9.01 (s, 1H).

Reference： [1]Patent: US2005/113576,2005,A1 .Location in patent: Page/Page column 68

5
[ 50488-42-1 ]
[ 439813-70-4 ]
[ 863679-62-3 ]

Yield	Reaction Conditions	Operation in experiment
24%	With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 20 - 80℃; for 1.5h;	Preparation 50: 2- [1- (Phenylmethyl)-2, 5-dihydro-1 H-pyrrol-3-yl]-5- (trifluoromethyl) pyridine; To a solution of 2-bromo-5- (trifluoromethyl) pyridine (4.42 mmol) in dry tetrahydrofuran (45 mL) 1- (phenylmethyl)-3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-2, 5-dihydro-1 H- pyrrole (3.4 mmol), tetrakis (triphenylphosphine) palladium (0) (0.196 mmol) and cesium fluoride (13,2 mmol) were added at room temperature. The resulting mixture was stirred at 80 C for 1.5 hours. After cooling solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (25 mL) and sodium hydroxyde (15 mL, 1 M). The organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (AcOEt: cyclohexane=1 : 10 to 4: 6) to give 0.33 g of the title compound (y= 24%). NMR (1H, CDC13) : 6 9.8 (s, 1H), 7.85 (dd, 1H), 7.5-7. 2 (m, 6H), 6.7 (s, 1H), 3.95 (m, 2H), 3.9 (s, 2H), 3.75 (m, 2H). MS (m/z) : 305 [MH] +.
24%	With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 80℃; for 1.5h;	To a solution of 2-bromo-5-(thfluoromethyl)pyridine (4.42 mmol) in dry tetrahydrofuran (45 ml.) 1 -(phenylmethyl)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,5-dihydro-1 H- pyrrole (3.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.196 mmol) and cesium fluoride (13,2 mmol) were added at room temperature. The resulting mixture was stirred at 80 0C for 1.5 hours. After cooling solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (25 mL) and sodium hydroxyde (15 ml_, 1 M). The organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (AcOEt: cyclohexane=1 :10 to 4:6) to give 0.33 g of the title compound (y= 24%).NMR (1H, CDCI3): delta 9.8 (s,1 H), 7.85 (dd, 1 H), 7.5 - 7.2 (m, 6H), 6.7 (s, 1 H), 3.95 (m, 2H), 3.9 (s, 2H), 3.75 (m, 2H). MS (mlz): 305 [MH]+.

Reference： [1]Patent: WO2005/80382,2005,A1 .Location in patent: Page/Page column 63
[2]Patent: WO2007/22980,2007,A1 .Location in patent: Page/Page column 53

6
[ 736990-02-6 ]
[ 50488-42-1 ]
[ 871829-38-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80.0℃; for 24.0h;	A stirred mixture of 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaboiOlan-2-yl)rndole-2- carboxylic acid ethyl ester (3.00 g, 9.52 mmol; see step (a) above), 2-bromo-5- trifluoromethylpyridine (3.23 g5 14.28 mmol), Na2CO3 (aq, 2 M, 14.3 mL, 28.6 mmol), Pd(PPh3)4 (540 mg, 0.50 mmol), EtOH (10 mL) and toluene (40 mL) was heated at 80 C for 24 h. The mixture was cooled to rt, poured into water and extracted with EtOAc. The combined extracts were washed with water, brine, dried (Na2SO4), concentrated and purified by chromatography yielding the subtitle compound (3.0 g, 94%).
94%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80.0℃; for 24.0h;	A stirred mixture of 5-(4,4,5,5-tetramethyl[1,3,2]dloxaborolan-2-yl)-lH- indole-2-carboxylic acid ethyl ester (3.00 g, 9.52 mmol; see step (a) above), 2-bromo-5-(trifluoromethyl)pyridine (3.23 g, 14.28 mmol), sodium carbonate (2M, 14.30 mL, 28.56 mmol); Pd(PPh3)4 (540 mg, 0.50 mmol), EtOH (10 mL) and toluene (40 mL) were heated at 80C for 24 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The combined extracts were washed with water, brine and dried (Na(at)S04). Solvent removal and purification by chromatography gave the sub-title compound (3.0 g, 94%).
77%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80.0℃; for 18.0h;	A stirred mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indole- 2-carboxylic acid ethyl ester (300 mg, 0.95 mmol; see step (a) ), 2-bromo-5- (trifluoromethyl) pyridine (323 mg, 1.43 mmol), sodium carbonate (2M, 1.43 mL, 2.85 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), EtOH (5 mL) and toluene(20 mL) was heated at 80C for 2 h. Another portion of Pd(PPh3)4 (54 mg, 0.05 mmol) was added and the heating continued for 16 h. The mixture was diluted with EtOAc, washed with brine, dried over MgS04, concentrated and purified by chromatography to give the sub-title compound (247 mg, 77%).

Reference： [1]Patent: WO2006/77367,2006,A1 .Location in patent: Page/Page column 101
[2]Patent: WO2005/123674,2005,A1 .Location in patent: Page/Page column 58-59
[3]Patent: WO2005/123673,2005,A1 .Location in patent: Page/Page column 50-51

7
[ 252990-05-9 ]
[ 50488-42-1 ]
[ 866785-42-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 5.0h;	<strong>[252990-05-9](R)-Piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester</strong> (120 mg, 0.49 mmol) and 2-Bromo-5-trifluoromethyl-pyridine (133 mg, 0.59 mmol) were dissolved into 2.0 mL of anhydrous toluene (degassed). In a separate, septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium (0) (22 mg, 0.024 mmol), 1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (42 mg, 0.1 mmol) and sodium t-butoxide (57 mg, 0.59 mmol). This "catalytic" vial was equipped with a magnetic stir bar and flushed with dry nitrogen. The reactant solution was next transferred to the "catalytic" vial and the mixture was stirred at 100 C. for 5 h. After this period the mixture was combined with 20 mL of hexane/EtOAc (2:1) and was passed through a pad of Celite. The resulting filtrate was evaporated in vacuo and purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 110 mg (58%) of (R)-4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, intermediate IX-B, as a yellow residue. 1H NMR (400 MHz, CDCl3) delta 8.39-8.38 (m, 1H), 7.65 (d, 1H), 6.68 (m, 1H), 4.89-4.68 (m, 2H), 4.29 (dd, 1H), 3.95 (dd, 1H), 3.69 (s, 3H), 3.43-3.26 (m, 2H), 3.12-2.97 (m, 1H), 1.51-1.46 (m, 9H).

Reference： [1]Patent: US2005/234046,2005,A1 .Location in patent: Page/Page column 54

8
[ 871829-81-1 ]
[ 50488-42-1 ]
[ 871829-82-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃; for 3h;	A mixture of 3-chloro-5-(dihydroxyboryl)-l-(4-isopropoxyphenyl)indole-2- carboxylic acid ethyl ester (200 mg, 0.50 mmol; see step (d) above), 2-bromo-5- trifluoromethylpyridine (170 mg, 0.75 mmol), Na2CO3 (aq, 2 M, 0.75 mL, 1.5 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), EtOH (0.4 mL) and toluene (1.6 mL) was heated at 85 0C for 3 h. The mixture was diluted with EtOAc, washed with brine, dried (MgSO4), concentrated and purified by chromatography to give the sub-title compound (239 mg, 95%).
95%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 85℃; for 3h;Product distribution / selectivity;	A stirred mixture of 3-chloro-5-(dihydroxyboryl)-l-(4-isopropoxyphenyl)- lH-indole-2-carboxylic acid ethyl ester (200 mg, 0.50 mmol; see step (b) above), 2-bromo-S-(trifluoromethyl)pyridine (170 mg, 0.75 mmol), sodium carbonate (2M in water, 0.75 mL, 1.5 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), EtOH (0.4 mL) and toluene (1.6 mL) was heated at 85C for 3 h. The reaction was diluted with EtOAc, washed with brine, dried over MgS04, concentrated and purified by chromatography to give the sub-title compound (239 mg, 95%).

Reference： [1]Patent: WO2006/77365,2006,A1 .Location in patent: Page/Page column 87
[2]Patent: WO2005/123673,2005,A1 .Location in patent: Page/Page column 71

9
[ 871839-95-1 ]
[ 50488-42-1 ]
5-(4-tert-butylphenyl)-3-(4-isopropoxyphenyl)-1-(5-(trifluoromethyl)-pyrid-2-yl)indole-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium phosphate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 49h;	Cul (7.6 mg, 40 nmol), NjV-dimethyl-1,2-diaminoethane (13 ilL, 120 nmol) and toluene (0.5 mL) were added to a mixture of 5-(4-tei"t-butylphenyl)-3-(4- isopropoxyphenyl) indole-2-carboxylic acid ethyl ester (182 mg, 400 nmol; see Example l(c)), <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (181 mg, 800 mmol), K3P04 (196 mg, 800 nmol) and toluene (2 mL) under argon. The mixture was heated at 110C for 27 h. Additional portions of CuI (7.6 mg, 40 nmol) and N,N-dimethyl-1,2-diaminoethane (13 ill, 120 nmol) were added and the heating was continued for a further 22 h. The mixture was filtered through Celite(at) and the filter cake was washed with EtOAc. The filtrate was concentrated and purified by chromatography to give the sub-title compound (66mg, 28%).

Reference： [1]Patent: WO2005/123675,2005,A1 .Location in patent: Page/Page column 49

10
[ 879088-67-2 ]
[ 50488-42-1 ]
N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 160℃; for 0.166667h;Microwave irradiation;	A: Suzuki Coupling Procedure 2 M aq. Potassium carbonate (5.0 eq) and 4: 1 toluene:ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh3)4 (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 0C for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted with ethyl acetate (2 x 20 mL), dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. Example 53 N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6- (trifluoromethyl)nicotinamide N-(4-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6- (trifluoromethyl)nicotinamide (~ 0.5 mmol) was used in Procedure A with 5-trifluoromethyl-2- bromopyridine (113 mg, 0.5 mmol). Purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to yield N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6- (trifluoromethyl)nicotinamide as a white foam: TLC R/ = 0.30 (15% ethyl acetate/hexanes); MS (Ql) 460 (M)+.
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 160℃; for 0.166667h;Microwave irradiation;	A: Suzuki Coupling Procedure 2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene:ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh3)4 (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 C. for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted with ethyl acetate (2×20 mL), dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.; Example 53 N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.5 mmol) was used in Procedure A with <strong>[50488-42-1]5-trifluoromethyl-2-bromopyridine</strong> (113 mg, 0.5 mmol). Purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to yield N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white foam: TLC Rf=0.30 (15% ethyl acetate/hexanes); MS (Q1) 460 (M)+.

Reference： [1]Patent: WO2009/126863,2009,A2 .Location in patent: Page/Page column 68; 110
[2]Patent: US2006/63779,2006,A1 .Location in patent: Page/Page column 65; 83-84

11
[ 75336-86-6 ]
[ 50488-42-1 ]
[ 874646-12-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 140℃; for 14h;Microwave irradiation;	Intermediate 15;: (3R)-3-methyl-l-[5-(trifluoromethyl)pyridin-2-yl]piperazine; NA suspension of 2-bromo-5-trifluoromethyl-pyridine (2.37 g; 10.0 mmol; 1.0 eq.), (R)-2-methylpiperazine (2.00 g; 20.0 mmol; 2.0 eq.) and DIEA (1.94 g; 15.0 mmol; 1.5 eq.) in 4 mL of DMA was heated at 140°C for 14h. The mixture was cooled to room temperature. After evaporation of the solvent under vacuum, the residue was dissolved in a 1/1 mixture of DCM / Et2O. A 4N solution of HC1 was added (10 mL) then the resulting precipitate was collected and washed with Et2O. The solid was then poured to an aq. solution of NaOH (5N, 20 mL) and the resulting mixture was extracted with Et2O (3X). The combined organic layers were washed with brine, dried over MgSC>4, filtered and evaporated to give the title compound as an orange solid (1680 mg, 69percent) used without further purification for the next steps. M+(ESI): 246.3. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 99.9 percent).

Reference： [1]Patent: WO2006/10751,2006,A1 .Location in patent: Page/Page column 81

12
3-formyl-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester [ No CAS ]
[ 50488-42-1 ]
[ 902765-93-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 24h;	A mixture of 3-formyl-l-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl-[l,3,2]- dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (600 mg, 1.26 mmol; see step (a) above), <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (426 mg, 1.89 mmol), EPO <DP n="156"/>Na2CO3 (aq, 2 M5 1.89 mL, 3.78 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), EtOH (5 mL) and toluene (20 mL) was heated at 80 0C for 24 h, allowed to cool, poured into H2O and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. YieldSOO mg (80%).
80%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 24h;	A stirred mixture of 3-formyl-l-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl- [l,3,2]-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (600 mg, 1.26 mmol; see step (a)), 2-bromo-5-(trifluoromethyl)pyridrne (426 mg, 1.89 mmol), Na2CO3 (aq, 2 M, 1.89 mL, 3.78 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), EtOH (5 mL) and toluene (20 mL) was heated at 80 0C for 24 h. The mixture was allowed EPO <DP n="96"/>to cool, poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound (500 mg, 80%).

Reference： [1]Patent: WO2006/77366,2006,A1 .Location in patent: Page/Page column 154-155
[2]Patent: WO2006/77367,2006,A1 .Location in patent: Page/Page column 94-95

13
[ 902772-15-0 ]
[ 50488-42-1 ]
[ 902772-16-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 23h;	A stirred mixture of l-(4-cyclopentyloxyphenyl)-5-(4,4,5,5-tetramethyl-[l ,3,2]- dioxaborolan-2-yl)indole-2-carbonitrile (480 mg, 1.14 mmol; see step (d) above), <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (380 mg, 1.72 mmol), Na2CO3 (aq, 2 M, 1.70 mL, 3.42 mmol), Pd(PPh3)4 (64 mg, 0.06 mmol), EtOH (5 mL) and toluene (20 mL) was heated at 80 0C for 23 h. The mixture was diluted with EtOAc, washed with brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound (464 mg, 92%).

Reference： [1]Patent: WO2006/77367,2006,A1 .Location in patent: Page/Page column 121

14
iPrNH₂/CH₂Cl₂ [ No CAS ]
[ 130658-65-0 ]
[ 50488-42-1 ]
1-(pyridin-4-yl)-4-(5-trifluoromethyl-pyridin-2-yloxy)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol;	EXAMPLE 71 1-(4-pyridyl)-4-(5-trifluoromethyl-2-pyridyloxy)piperidine Scale: 714 mg, 4 mmol Method B, using <strong>[130658-65-0]1-(4-pyridyl)-4-hydroxypiperidine</strong> and 2-bromo-5-trifluoromethylpyridine. The solvents were evaporated and the residue was purified by column chromatography on silica, eluding from 1%MeOH/1%iPrNH2/CH2Cl2 to 5%MeOH/5%iPrNH2/CH2Cl2 (in 1% increments). A second columnm, eluding with 1%MeOH/1%NH4OH/CH2Cl2 to 10%MeOH/1%NH4OH/CH2Cl2 (in 1% increments), gave a dark oil, which was extracted with Et2O/hexane. Evaporation and washing with hexane gave the product as a light brown solid. Yield=674 mg (52%) Rf=0.52 (10%MeOH/1%NH4OH/CH2Cl2) 1H-NMR (200 MHz, CDCl3): delta=1.9 (m, 2H), 2.1 (m, 2H), 3.32 (m, 2H), 3.68 (m, 2H), 5.38 (m, 1H), 6.70 (d, 2H), 6.62 (d, 2H), 7.77 (dd, 1H), 8.27 (d, 2H), 8.44 (s, 1H). MS (ESP+): m/e 324 (M+H)+. Found: C,57.7; H,5.1; N,12.4; C16H16F3N3O.(0.5H2O) requires: C,57.8; H,5.15; N,12.64%.

Reference： [1]Patent: US6313127,2001,B1

15
[ 74879-18-8 ]
[ 50488-42-1 ]
[ 888326-94-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine; In toluene; at 110℃; for 26h;	Step l; 3-(5)-Methyl-l-(5-trifluoromethyl-pyridin-2-yl)-piperazine:; 2-Bromo-5-trifluoromethyl-pyridine (1.06 g, 4.69 mmol), (5)-2-methylpiperazine (1.03 g, 10.28 mmol) and triethylamine (1.5 mL, 10.76 mmol) were stirred in toluene (10 mL) at 110 0C for 26 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with water and brine. The organic layer was dried (MgSC>4), filtered and concentrated. The crude mixture was purified by automated silica gel flash column chromatography (gradient eluent 0-20% MeOH/dichloromethane) to afford 3-(S)-methyl-l-(5-trifluoromethyI-pyridin-2-yl)- piperazine (926 mg, 81 %) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.38 (s, IH), 7.62 (dd, IH), 7.63 (d, IH), 4.29-4.20 (m, 2H), 3.16-3.12 (m, IH), 3.02-2.85 (m, 3H), 2.64-2.52 (m, 2H), 1.18 (d, 3H).

Reference： [1]Patent: WO2006/55187,2006,A1 .Location in patent: Page/Page column 46

16
[ 438631-77-7 ]
[ 50488-42-1 ]
[ 888327-23-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 5h;	Step 3; 4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester :; S-Methyl-piperazine-l^-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.49 mmol) and 2-Bromo-5- trifluoromethyl-pyridine (133 mg, 0.59 mmol) were dissolved in 2.0 mL of anhydrous toluene (degassed). In a separate, septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium (0) (22 mg, 0.024 mmol), l,3-bis(2,6-di-J-propylphenyl)imidazolium chloride (42 mg, 0,1 mmol) and sodium ^-butoxide (57 mg, 0.59 mmol). This "catalytic" vial was equipped with a magnetic stir bar and flushed with dry nitrogen. The reactant solution was next transferred to the "catalytic" vial and the mixture was stirred at 1000C for 5 h. After this period the mixture was combined with 20 mL of hexane/EtOAc (2:1) and was passed through a pad of Celite. The resulting filtrate was evaporated in vacuo and purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 110 mg (58%) of 4-(5-TrifIuoromethyl-pyridin-2-yl)- piperazine-l,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.

Reference： [1]Patent: WO2006/55187,2006,A1 .Location in patent: Page/Page column 61

17
[ 50488-42-1 ]
[ 80194-69-0 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation Example 2 The same procedure as in Preparation Example 1 was repeated except that 10 g of 2-bromo-5-trifluoromethylpyridine was used in place of 2-bromo-3-chloro-5-trifluoromethylpyridine, to thereby obtain 5.8 g of 5-trifluoromethylpyridine-2-carboxylic acid.

Reference： [1]Patent: US4367336,1983,A

18
[ 50488-42-1 ]
4-isopropyl-5'-(5-trifluoromethylpyridin-2-yl)-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%		Example 121 (General Procedure I) 4-lsopropyl-5'-(5-trif luoromethyl-pyridin-2-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl, trifluoroacetate5-Bromo-3,4,5,6-tetrahydro-2H-[1 ,2']bipyrazinyl (0.50 g, 1 .75 mmol) was dissolved in dry THF and cooled to -780C under an atmosphere of nitrogen. A 1 .6 N solution of n-butyl lithium in hexanes (0.124 g, 1 .93 mmol) was added keeping the temperature below -600C. Tributyltin chloride (0.628 g, 1 .93 mmol) was added and the reaction mixture was allowed to reach rt. The reaction mixture was transferred to a 5 ml_ microwave vial and 2-bromo-5-trifluromethyl- pyridine (0.33 g, 1 .93 mmol), triphenylphosphinpalladium(ll)dichloride (0.088 g, 0.0615 mmol), caesium fluoride (0.581 g, 3.85 mmol) and TEA (0.389 g, 0.385 mmol) were added. This reaction mixture was heated 1.6 h at 1000C in a microwave oven. The reaction mixture was evaporated in vacuo and the oily residue was purified on a silica gel column with DCM/MeOH (9:1 ) as eluent. The product isolated was treated with HCI in diethyl ether followed by evaporation. This afforded 49 mg (9 %) of the title compound. HPLC-MS (Method G): M+1 = 352; tr= 1 .29 min.

Reference： [1]Patent: WO2007/3604,2007,A2 .Location in patent: Page/Page column 131

19
[ 917896-02-7 ]
[ 50488-42-1 ]
cyclopentyl-[2-methyl-5-(5-trifluoromethyl-pyridin-2-yl)-pyrimidin-4-yl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With copper;tris-(dibenzylideneacetone)dipalladium(0); In dimethyl sulfoxide; at 100℃; for 40h;	Example 47: Cyclopentyl-[2-methyl-5-(5-trifluor omethyl-pyridin-2-yl)-pyrimidin-4-yl]- amine; In a parallel synthesis flask, 150 mg (0.59 mmoles, 1.0 eq.) of 5-bromo-Lambda/-cyclopentyl-2- methylpyrimidin-4-amine and 132 mg (0.58 mmoles, 1.0 eq.) of 2-bromo-5- trifluoromethylpyridine were dissolved in 1.75 mL of DMSO. 16 mg (0.02 mmoles, 0.03 eq.) EPO <DP n="77"/>of Pd2(dba)3 was added followed by 186 mg (2.93 mnnoles, 5.0 eq.) of Cu. The mixture was heated at 1000C under vigourous stirring for 26h. The mixture was allowed to cool to RT and 132 mg (0.58 mmoles, 1.0 eq.) of <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> were added. The solution was heated at 100C for additional 14h. The mixture was allowed to cool to RT and 25 ml_ of AcOEt were added. The resulting solution was filtered on a pad of Hyflo. The solids were washed five times with 10 ml_ of AcOEt. The combined filtrates were washed four times with 15 ml_ of water and once with 20 ml_ of brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude compound was purified first by flash chromatography on silica gel and then by preparative TLC to give 41 mg of a white solid.Yield : 22 %MP. : 130-1330CLC-MS : Tr = 4.31 min. (100 %) (ES-MS: m/z 323.2 (M+H)) [Column : Nucleosil C-18HD,4x70 mm, 3mum, gradient CH3CN/H2O/TFA 0.05% : 20-100% CH3CN (6 min.), 100% CH3CN(1.5 min.), flow : 1 mL/min].1H-NMR (CD3OD, 300 MHz) delta : 1.53-1.85 (m, 6H) ; 2.05-2.16 (m, 2H) ; 2.50 (s, 3H) ; 4.56(quint, J = 7.1 Hz, 1H) ; 8.13 (m, 2H) ; 8.64 (s, 1H) ; 8.89 (s, 1H).19 F-NMR (CD3OD, 282 MHz) delta : -64.6.

Reference： [1]Patent: WO2006/136442,2006,A1 .Location in patent: Page/Page column 75-76

20
[ 2942-13-4 ]
[ 50488-42-1 ]
6-methoxy-2-[5-(trifluoromethyl)pyridin-2-yl]-1,3-benzothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;bis(tri-t-butylphosphine)palladium(0); In N,N-dimethyl-formamide; at 150℃; for 3h;	6-Methoxy-l,3-benzothiazole (35 mg, 0.21 mmol) and 2-bromo-5- (trifluoromethyl)pyridine (1.1 equiv) were dissolved in dry, degassed DMF (1.5 mL). Cesium carbonate (72.5 mg, 0.22 mmol) and bis(tri-t-butylphosphine) palladium (0) (5.5 mg, 0.011 mmol) were added and the reaction was heated under argon at 150C for 3h. After cooling to about 4O0C, the reaction mixture was filtered, and the filter was washed with DMF. The filtrate was concentrated in a centrifuge, and the residue was taken up in DMSO and purified by preparative HPLC to give the title compound (11 mg) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-J) delta ppm 8.88-8.95 (m, 1 H) 8.44 (d, 1 H) 8.06 (dd, 1 H) 8.00 (d, 1 H) 7.42 (d, 1 H) 7.15 (dd, 1 H) 3.93 (s, 3 H); MS m/z (M+H) 311.

Reference： [1]Patent: WO2007/86800,2007,A1 .Location in patent: Page/Page column 83

21
[ 50488-42-1 ]
[ 95727-86-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide;	EXAMPLE 301A 5-(trifluoromethyl)-2-pyridinecarbonitrile Copper (I) cyanide (14.1 g) and 2-bromo-5-trifluoromethylpyridine (3.00 g, 13.3 mmol) in dry DMSO (70 mL) were combined and heated at 180 C. for 2 hours, cooled, and poured into NH4OH (3M). The mixture was then extracted with ethyl acetate (3500 mL), washed with water (1200 mL), dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO, 300 MHz) delta 8.22 (m, 1H), 8.42 (m, 1H), 9.01 (s, 1H).
	In dimethyl sulfoxide;	Example 301A 5-(trifluoromethyl)-2-pyridinecarbonitrile Copper (I) cyanide (14.1 g) and 2-bromo-5-trifluoromethylpyridine (3.00 g, 13.3 mmol) in dry DMSO (70 mL) were combined and heated at 180 C. for 2 hours, cooled, and poured into NH4OH (3M). The mixture was then extracted with ethyl acetate (3500 mL), washed with water (1200 mL), dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO, 300 MHz) delta 8.22 (m, 1H), 8.42 (m, 1H), 9.01 (s, 1H).

Reference： [1]Patent: US6933311,2005,B2
[2]Patent: US2004/157849,2004,A1

22
[ 50488-42-1 ]
[ 408502-23-8 ]
[ 1108184-24-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃; for 1h;	2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), <strong>[408502-23-8]2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) and [1,1'-Bis-(diphosphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2dppf) (74 mg, 0.091 mmol) were stirred in DMSO (2 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90 C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.06-8.02 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.52-7.49 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
62%		a) 2'-Methoxy-5-(trifluoromethyl)-2,4'-bipyridine (CAS Registry Number 1108184-24-2) (WO 2009/015037 to Guzzo et al., which is hereby incorporated by reference in its entirety) 2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and <strong>[408502-23-8]2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (500 mg, 1.81 mmol) were reacted according to Example 3 (step a) to provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
62%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;	2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), <strong>[408502-23-8]2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) alphanudelta PdCl2 (dppf) (140 mg, 0.18 mmol) were stirred in DMSO (10 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80 C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) afforded the title compound title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).

62%

With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;

2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), <strong>[408502-23-8]2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) and PdCl2(dppf) (140 mg, 0.18 mmol) were stirred in DMSO (10 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80 C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc, 100:0 to 50:50) afforded the title compound title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).

Reference： [1]Patent: US2009/82359,2009,A1 .Location in patent: Page/Page column 61
[2]Patent: US2011/3737,2011,A1
[3]Patent: US2011/3738,2011,A1 .Location in patent: Page/Page column 25-26
[4]Patent: US2011/3739,2011,A1 .Location in patent: Page/Page column 22

23
[ 67-56-1 ]
[ 201230-82-2 ]
[ 50488-42-1 ]
[ 124236-37-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; at 80℃; under 3102.97 Torr; for 3h;	A solution of 2-bromo-5-(trifluoromethyl)pyridine (9 g, 40 mmol) in MeOH (130 mL) was added to Pd-dppf (0.813 g, 0.996 mmol) and Et3N (11 mL, 80 mmol) in a 250 mL pressure bottle. The mixture was pressurized with carbon monoxide (60 psi), and stirred 3 hr at 80 C. The reaction was cooled to ambient temperature, filtered, and the solvents evaporated at reduced pressure. The residue was partitioned between water and ethyl acetate. The separated organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix 40*240 column, 10%-40% EtOAc/hexanes eluant) to afford 8.52 g (104%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) delta 9.01 (m, 1H), 8.28 (d, J=8.1, 1H), 8.12 (dd, J=2.1, 8.2, 1H), 4.06 (s, 3H). MS (ESI+) m/z 206 (M+H).

Reference： [1]Patent: US2009/124666,2009,A1 .Location in patent: Page/Page column 25

24
[ 144025-03-6 ]
[ 50488-42-1 ]
[ 387827-64-7 ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 14090 - 14094
Angew. Chem.,2018,vol. 130,p. 14286 - 14290,5
[2]Journal of the American Chemical Society,2019,vol. 141,p. 16590 - 16594
[3]Angewandte Chemie - International Edition,2016,vol. 55,p. 9969 - 9973
Angew. Chem.,2016,vol. 128,p. 10123 - 10127,5
[4]Journal of the American Chemical Society,2018,vol. 140,p. 741 - 747
[5]Organic Letters,2018,vol. 20,p. 6794 - 6798
[6]Inorganic Chemistry,2019,vol. 58,p. 855 - 860
[7]European Journal of Inorganic Chemistry,2009,p. 4850 - 4859

25
[ 1227473-84-8 ]
[ 50488-42-1 ]
[ 1227473-85-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 85℃;	tert-butyl (3R)-3-(3-[5-(trifluoromethyl)pyridin-2-yllphenyl)-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate To tert-butyl (3R)-3-[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-1-oxa-8-azaspiro[4.5]decane-8- carboxylate (1.15 g, 2.59 mmol), <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (0.645 g, 2.85 mmol) and sodium carbonate (1.38 g, 13 mmol) suspended in CH3CN:H2O (1 :1 ) (16 ml_) was added Pd(PPh3)2CI2 (55 mg, 0.078 mmol). The reaction mixture was heated at 85 0C overnight. After cooling the reaction mixture was extracted with ethyl acetate (2x 10 ml_), diethyl ether (10 ml_), and concentrated in vacuo. The residue was dissolved in THF (-20 ml_) and treated with sodium sulfate and 3-mercaptopropyl silica gel (~ 0.3 g, Aldrich, silicycle). This mixture was stirred about 20 min, filtered and the filtrate evaporated. The resulting oil was chromatographed by flash chromatography (5-35% EA/heptane) to give the title compound as an oil (1.04 g, 87%). m/z 463 (MH+).

Reference： [1]Patent: WO2010/58318,2010,A1 .Location in patent: Page/Page column 82

26
[ 50488-42-1 ]
[ 336191-17-4 ]
[ 1246507-98-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 14h;Inert atmosphere; Heating; Reflux;	Step 1: tert-Butyl 8-(5-(trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate A mixture of <strong>[336191-17-4]ter<strong>[336191-17-4]t-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate</strong></strong> (2.5 mmol, 1.0 eq.) and 2-bromo-5-(trifluoromethyl)pyridine (2.5 mmol, 1.0 eq.) and tBuONa (7.5 mmol, 3.0 eq.) in toluene (12 ml) was degassed with argon for 10 min. BINAP (0.15 mmol, 0.06 eq.) and Pd(OAc)2 (0.05 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated under reflux for 14 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 22-25% ethyl acetate in hexane), in order to obtain the desired product. Yield: 40%

Reference： [1]Patent: US2010/249095,2010,A1 .Location in patent: Page/Page column 124-125

27
[ 50488-42-1 ]
[ 89570-85-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrazine hydrate; In ethanol; at 20 - 90℃;	General procedure for Compound 2:; To a stirred solution of 2-bromo-5- (trifluoromethyl)pyridine (compound-1) (1.0 g, 4.0 mmol) in ethanol (5 mL), hydrazine hydrate (980 mg, 20 mmol) was added at room temperature and the reaction mixture was heated to 9O0C for 12 h. After completion of reaction (TLC shows absent of S. M), the solvent was removed under high vacuum. The residue was treated with water (30 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was washed with brine (5OmL), dried over sodium sulfate, filtered and concentrated to provide the desired compound-2 as a brown color solid. (700 mg, 90% yield).1H NMR (500 MHz, DMSO-d6) delta: 8.42 (d, 2H), 8.25 (s, IH), 5.0 (bs, 3H); Mass (M+l): 178.

Reference： [1]Patent: WO2010/118063,2010,A2 .Location in patent: Page/Page column 113

28
[ 5950-34-5 ]
[ 50488-42-1 ]
[ 1200836-30-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃; for 48h;Inert atmosphere;	Synthetic Example 7; 3-Mercapto-2-(5-trifluoromethyI-pyridin-2-yIamino)-propionic acid hydrochloride; Step 1 : l-(5-Trifluoromethyl-pyridin-2-yl)-aziridine-2-carboxylic acid methyl ester; An oven dried pressure tube was charged with aziridine-2-carboxylic acid methyl ester (1.50 g, 6.64 mmol), <strong>[50488-42-1]2-bromo-5-trifluoromethyl-pyridine</strong> (2.01 g, 19.88 mmol), Pd(OAc)2 (45 mg, 0.20 mmol), Xantphos (156 mg, 0.27 mmol) and Cs2CO3 (4.30 g, 13.20 mmol). The vial was purged with argon, toluene (7 mL) was added, and the mixture was heated at 9O0C for 48 h. The reaction mixture was filtered through celite. The celite pad was washed with EtOAc (2 x 30 mL). Volatiles were removed in vacuum, and the residue was purified by flash column chromatography using PE/EtOAc (4/1) as eluent to give 0.95 g (58%) of l-(5-trifluoromethyl-pyridin- 2-yl)-aziridine-2-carboxylic acid methyl ester.

Reference： [1]Patent: WO2009/151744,2009,A1 .Location in patent: Page/Page column 97

29
[ 1450-14-2 ]
[ 50488-42-1 ]
[ 1323151-46-7 ]
[ 142946-80-3 ]

Yield	Reaction Conditions	Operation in experiment
14%Chromat.; 70%Chromat.	With potassium fluoride; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); water; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;	General procedure: 2-Bromo-5-trifluoromethylpyridine (50mg, 0.22mmol), the palladium (10mol%), the ligand (0.044mmol)(if required), KF (28mg, 0.484mmol) and hexamethyldisilane (0.180ml, 0.88mmol) were combined in a reaction tubes in a Radleys green-house parallel synthesiser under a flow of nitrogen. Degassed DMF (1ml) was added and the reaction mixtures stirred at 90 oC for 12 hours under nitrogen. Reactions were analysed by LC-MS at 1mg/1ml in methanol to determine the yield.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 4192 - 4195

30
[ 13737-04-7 ]
[ 50488-42-1 ]
[ 1219133-21-7 ]

Yield	Reaction Conditions	Operation in experiment
72%Chromat.	With potassium fluoride; copper(l) iodide; palladium diacetate; catacxium A; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere;	General procedure: 2-Trimethylsilylpyridine (1.2mmol), the aryl halide (1mmol), palladium acetate (0.10mmol), CataXCium A (0.2mmol), CuI (76mg, 0.4mmol) and KF (2.20mmol) were combined in reaction tubes in a Radleys green-house parallel synthesiser under a flow of nitrogen and degassed DMF (1ml) was added. The resulting suspensions were stirred at 90 oC under nitrogen for 12 hours. Reactions were analysed by LC-MS at 1mg/1ml in methanol to determine the yield.

Reference： [1]Organic Letters,2017,vol. 19,p. 5944 - 5947
[2]Tetrahedron Letters,2011,vol. 52,p. 4192 - 4195

31
[ 50488-42-1 ]
[ 142946-80-3 ]

Yield	Reaction Conditions	Operation in experiment
38%Chromat.	With potassium fluoride; tris-(dibenzylideneacetone)dipalladium(0); johnphos; In N,N-dimethyl-formamide; at 100℃; for 12h;Inert atmosphere;	2-Bromo-5-trifluoromethylpyridine (1g, 4.42mmol), Pd2(dba)3 (60mg, 0.066mmol), Johnphos (119mg, 0.398mmol) and KF (1.29g, 22.1mmol) were combined in a round bottom flask. This was evacuated and backfilled with nitrogen three times. Degassed DMF (10ml) was added followed by hexamethyldisilane (1.09ml, 777mmol) and water (0.159ml). The mixture was evacuated and backfilled with nitrogen, three times, then stirred at 100oC for 12 hours under nitrogen. LC-MS indicates a mixture of product and homo coupling of the bromide. Product retention time 5.94 mins less than 1%, Homo-coupled by-product retention time 6.56 mins 38% yield

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 7892 - 7895
Angew. Chem.,2014,vol. 126,p. 8026 - 8029,4
[2]Dalton Transactions,2019,vol. 48,p. 6910 - 6920
[3]Journal of the American Chemical Society,2018,vol. 140,p. 741 - 747
[4]Tetrahedron Letters,2011,vol. 52,p. 4192 - 4195
[5]Angewandte Chemie - International Edition,2016,vol. 55,p. 9969 - 9973
Angew. Chem.,2016,vol. 128,p. 10123 - 10127,5

32
[ 146374-27-8 ]
[ 50488-42-1 ]
[ 1338209-78-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	General procedure for coupling reaction: An oven-dried resealable Schlenk tube were charged with Pd(OAc)2 (6.7 mg, 0.03 mmol), Xantphos (34.7 mg, 0.06 mmol), 2-methylpropane-2-sulfinamide (145 mg, 1.2 mmol) and Cs2CO3 (650 mg, 2.0 mmol). The Schlenk tube was evacuated and back-filled with argon. 4-bromo-2-methylbenzonitrile (196 mg, 1.0 mmol) and dioxane (3 ml) were added and the Schlenk tube was then sealed with a Teflon screw cap and placed in a preheated oil bath at 100oC for 15 h. After cooling of the reaction mixture to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by flash chromatography. Yield: 228 mg, 97 % [table-1, entry-5].

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 5625 - 5628

33
[ 1332486-87-9 ]
[ 50488-42-1 ]
[ 1332490-11-5 ]
[ 1332490-25-1 ]

Yield	Reaction Conditions	Operation in experiment
24%; 45%		1.23 ml of a 2.5 M solution of n-butyllithium in toluene are added dropwise to a solution of 695 mg <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> in 10 ml toluene at -80 C. The mixture is stirred for 1 hour and then a solution of 600 mg (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 1 ml toluene is added dropwise. After stirring the mixture for 1 hour at -80 C. the reaction is quenched by addition of a saturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted for three times with ethylacetate. The combined organic phases are dried with magnesium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (pentane/diethylether 100:0 to 70:30).(S)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol:Yield: 186 mg (24% of theory)Mass spectrometry (ESL): m/z=635 [M+H]+ HPLC (Method 11): Retention time=12.61 min.Rf-value: 0.53 (silica gel, pentane/diethylether 4:1)(R)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol:Yield: 350 mg (45% of theory)Mass spectrometry (ESL): m/z=635 [M+H]+ HPLC (Method 11): Retention time=12.92 min.Rf-value: 0.35 (silica gel, pentane/diethylether 4:1)
24%; 45%	With n-butyllithium; In toluene; at -80℃; for 2h;	Example XXIXChiral(S)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8- tetrahvdroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol andChiral(R)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8- tetrahvdroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol1 ,23 ml of a 2,5 M solution of n-butyllithium in toluene are added dropwise to a solution of 695 mg <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> in 10 ml toluene at -80C. The mixture is stirred for 1 hour and then a solution of 600 mg (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7- dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 1 ml toluene is added dropwise. After stirring the mixture for 1 hour at -80C the reaction is quenched by addition of a saturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted for three times with ethylacetate. The combined organic phases are dried with magnesium sulphate and the solvents are evaporated in vacuo. The residue ischromatographed on silica gel (pentane/diethylether 100:0 to 70:30). (S)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5, 6,7,8- tetrahydroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol:Yield: 186 mg (24 % of theory)Mass spectrometry (ESI+): m/z = 635 [M+H]+ HPLC (Method 1 1): Retention time = 12,61 min.Rf-value: 0,53 (silica gel, pentane/diethylether 4:1)(R)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5, 6,7,8- tetrahydroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol:Yield: 350 mg (45 % of theory)Mass spectrometry (ESI+): m/z = 635 [M+H]+ HPLC (Method 1 1): Retention time = 12,92 min.Rf-value: 0,35 (silica gel, pentane/diethylether 4:1)
24%; 45%		1.23 ml of a 2.5 M solution of n-butyllithium in toluene are added dropwise to a solution of 695 mg <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> in 10 ml toluene at -80 C. The mixture is stirred for 1 hour and then a solution of 600 mg (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 1 ml toluene is added dropwise. After stirring the mixture for 1 hour at -80 C. the reaction is quenched by addition of a saturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted for three times with ethylacetate. The combined organic phases are dried with magnesium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (pentane/diethylether 100:0 to 70:30).(S)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol Yield: 186 mg (24% of theory)Mass spectrometry (ESI+): m/z=635 [M+H]+ HPLC (Method 11): Retention time=12.61 min.Rf-value: 0.53 (silica gel, pentane/diethylether 4:1)(R)-((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl)(5-(trifluoromethyl)pyridin-2-yl)methanol Yield: 350 mg (45% of theory)Mass spectrometry (ESI+): m/z=635 [M+H]+ HPLC (Method 11): Retention time=12.92 min.Rf-value: 0.35 (silica gel, pentane/diethylether 4:1)

Reference： [1]Patent: US2012/46304,2012,A1 .Location in patent: Page/Page column 137
[2]Patent: WO2012/110599,2012,A1 .Location in patent: Page/Page column 258-259
[3]Patent: US2013/53404,2013,A1 .Location in patent: Paragraph 2015-2023

34
[ 1394034-58-2 ]
[ 50488-42-1 ]
[ 1394033-54-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate;bis(eta3-allyl-mu-chloropalladium(II)); In 1,4-dioxane; dichloromethane; at 102℃; for 36h;Inert atmosphere;	Step 8. Synthesis of 4-(azetidin-1-yl)-7-methyl-5-{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine 4-(Azetidin-1-yl)-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazine (10.0 g, 37.1 mmol), <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (16.8 g, 74.3 mmol) and ground potassium carbonate (15.4 g, 111 mmol) were combined in a reaction flask, purged with nitrogen, and treated with degassed 1,4-dioxane (600 mL). To this mixture was added allylpalladium(II) chloride dimer (693 mg, 1.86 mmol), and the system was again purged with nitrogen. The reaction was heated to 102 C. for 36 hours, then cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (400 mL) and aqueous hydrochloric acid solution (1 N, 200 mL). The aqueous phase was neutralized with solid sodium bicarbonate and extracted with ethyl acetate (4*50 mL). The combined organic layers were washed with 1 N aqueous citric acid, then with saturated aqueous sodium bicarbonate solution. After treatment with Darco activated carbon, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in a minimal amount of dichloromethane and concentrated under reduced pressure until it became a thick oil. Diethyl ether (100 mL) was added, and upon stirring of the mixture, a solid began to precipitate; stirring was continued for 1 hour at room temperature, and then the white solid was collected by filtration and washed with diethyl ether. Additional product in the mother liquor was isolated by concentrating the filtrate in vacuo and chromatographing the residue on an alumina column (Eluant: 70% ethyl acetate in heptane). The product from the column was recrystallized from warm 20% ethyl acetate in heptane to yield additional product as a white solid. Combined yield: 5.3 g, 12.8 mmol, 35%. This material was combined with the product of a similar reaction (total 15.5 g, 37.4 mmol), and further purified as follows. The material was dissolved in a mixture of ethyl acetate (100 mL) and 2-methyltetrahydrofuran (150 mL) at room temperature. SiliaBond thiol (SiliCycle, 1.35 mmol/g, 15 g) was added, and the mixture was stirred for 20 hours, then filtered through Celite. The filtrate was treated with Darco activated carbon (500 mg) and stirred for 15 minutes before being filtered and concentrated under reduced pressure. The resulting oil was azeotroped with a 1:1 mixture of heptane and ethyl acetate to provide an off-white solid, which was mixed with heptane (100 mL) and stirred at room temperature for 6 hours. Filtration provided the product as a white solid. Purification yield: 14.4 g, 34.7 mmol, 93%. LCMS m/z 415.0 (M+1). 1H NMR (400 MHz, CDCl3) delta 2.17-2.26 (m, 2H), 2.70 (s, 3H), 3.3-3.8 (v br m, 2H), 3.8-4.3 (v br m, 2H), 4.18 (s, 3H), 7.63-7.66 (m, 1H), 7.66 (s, 1H), 7.79-7.83 (m, 2H), 8.95-8.96 (m, 1H).

Reference： [1]Patent: US2012/214791,2012,A1 .Location in patent: Page/Page column 22-29
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018

35
[ 1394034-68-4 ]
[ 50488-42-1 ]
[ 1394034-69-5 ]

Yield	Reaction Conditions	Operation in experiment
50%		Step 2. Synthesis of N-(4-methoxybenzyl)-N,7-dimethyl-5-{1-methyl-5-1-5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine N-(4-Methoxybenzyl)-N,7-dimethyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazin-4-amine (10.0 g, 27.5 mmol), <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (12.4 g, 54.9 mmol) and powdered potassium carbonate (11.4 g, 82.5 mmol) were combined in 1,4-dioxane (90 mL) and heated at reflux for 10 minutes. Allylpalladium chloride dimer (98%, 514 mg, 1.38 mmol) was added, and the reaction was heated for 22 hours at 160 C. in a sealed tube capped with a Q-Tube (Q Labtech). The reaction was cooled to room temperature and concentrated in vacuo. The residue was suspended in ethyl acetate, filtered through Celite and concentrated under reduced pressure. Silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) provided a pale brown foam (7.85 g), which was crystallized from heptane (~100 mL) and ethyl acetate (~5 mL) to provide the product as a pale brown powder. Yield: 7.00 g, 13.8 mmol, 50%. LCMS m/z 509.1 (M+1). 1H NMR (500 MHz, CDCl3) delta 2.54 (s, 3H), 2.72 (s, 3H), 3.75 (s, 3H), 4.14 (s, 3H), 4.34 (br s, 2H), 6.76 (br d, J=8.8 Hz, 2H), 6.94 (br d, J=8.5 Hz, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.76 (dd, J=8.3, 2.2 Hz, 1H), 7.85 (s, 1H), 8.95-8.96 (m, 1H).

Reference： [1]Patent: US2012/214791,2012,A1 .Location in patent: Page/Page column 28
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018

36
[ 1394034-71-9 ]
[ 50488-42-1 ]
[ 1394034-69-5 ]

Yield	Reaction Conditions	Operation in experiment
41%		Step 3. Synthesis of N-(4-methoxybenzyl)-N,7-dimethyl-5-{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine A solution of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-N-(4-methoxybenzyl)-N,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-amine (3.35 g, 7.57 mmol) in tetrahydrofuran (75 mL) was cooled to -78 C. and treated over 5 minutes with n-hexyllithium (2.3 M solution in hexane, 3.46 mL, 7.96 mmol). The reaction mixture was stirred for 30 minutes, and then treated in one portion with a -78 C. solution of zinc chloride (99.5%, 1.30 g, 9.49 mmol) in tetrahydrofuran (20 mL). After stirring for 5 minutes at -78 C., the reaction was warmed to room temperature over 30 minutes. After addition of <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (2.57 g, 11.4 mmol), the reaction mixture was heated to 50 C., treated with tetrakis(triphenylphosphine)palladium(0) (99.9%, 87.9 mg, 0.076 mmol), and maintained at reflux for 4 hours. The reaction was cooled and concentrated in vacuo; the residue was dissolved in ethyl acetate and washed sequentially with water, saturated aqueous ammonium chloride solution, and saturated aqueous sodium bicarbonate solution. After drying over magnesium sulfate, the product solution was filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided a pale yellow oil (2.3 g), which was crystallized from heptane to afford the product as a white powder. Yield: 1.58 g, 3.11 mmol, 41%. APCI m/z 509.5 (M+1). 1H NMR (400 MHz, CDCl3) delta 2.54 (s, 3H), 2.72 (s, 3H), 3.76 (s, 3H), 4.14 (s, 3H), 4.34 (br s, 2H), 6.76 (br d, J=8.8 Hz, 2H), 6.94 (br d, J=8.5 Hz, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.76 (dd, J=8.4, 2.2 Hz, 1H), 7.85 (s, 1H), 8.94-8.96 (m, 1H).

Reference： [1]Patent: US2012/214791,2012,A1 .Location in patent: Page/Page column 29

37
[ 50488-42-1 ]
[ 135632-53-0 ]
[ 1093395-71-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In methanol; at 120℃; for 0.5h;Microwave reactor;	In a 5-ml microwave vial equipped was placed potassium carbonate (1.38 g), tert-butyl(piperidin- 4-ylmethyl)carbamate (1.07 g), and <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> (1.13 g) in methanol. This was heated to 120C for 30 min in a microwave reactor. The mixture was cooled and concentrated in vacuo, and the residue was taken up in ethyl acetate. This was filtered through a plug of silica gel, and the eluent was concentrated in vacuo to provide /ert-butyl({l-[5- (trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)carbamate (1.45 g, 81%). This compound was taken up in 15 ml of dichloromethane and 15 ml of trifluoroacetic acid. The resultant mixture was stirred at room temperature for 2 h, and then concentrated and taken up in dichloromethane (20 ml) and saturated aqueous sodium bicarbonate. The mixture was extracted and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1.31 g (87%) of the title compound. Mass spectrum (ESI) 260.1 (M+l).

Reference： [1]Patent: WO2008/156715,2008,A1 .Location in patent: Page/Page column 25

38
[ 50488-42-1 ]
[ 720702-41-0 ]
[ 1356997-31-3 ]

Yield	Reaction Conditions	Operation in experiment
35%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; for 18h;Reflux;	Step 2: Synthesis of 2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine (C13)(1 -Methyl-1 /- -pyrazol-5-yl)boronic acid (C1 ) (1.00 g, 7.94 mmol), 2-bromo-5-(trifluoromethyl)pyridine (1 .79 g, 7.92 mmol), dichlorobis(triphenylphosphine)palladium(ll) (279 mg, 0.397 mmol), and sodium carbonate (3.37 g, 31.8 mmol) were combined in 1 ,2- dimethoxyethane (30 mL) and water (3 mL), and the reaction mixture was heated at reflux for 18 hours. After the reaction had cooled to room temperature, it was concentrated in vacuo, diluted with additional water, and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product. Yield: 630 mg, 2.77 mmol, 35%. H NMR (400 MHz, CD3OD) delta 3.95 (s, 3H), 6.60 (d, J=2.2 Hz, 1 H), 7.58 (d, J=2.0 Hz, 1 H), 7.94 (br d, J=8.2 Hz, 1 H), 8.19-8.23 (m, 1 H), 8.89 (br d, J=2 Hz, 1 H).

Reference： [1]Patent: WO2012/168817,2012,A1 .Location in patent: Page/Page column 52
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 5673 - 5698

39
[ 50488-42-1 ]
[ 201802-67-7 ]
N-[4-(5-trifluoromethylpyridin-2-yl)phenyl]-N,N-diphenylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; potassium carbonate; In ethanol; water; at 80℃;	General procedure: Cyclometalating ligands with a TPA moiety L-1-L-7 were synthesized according to an efficient ligand-free Suzuki reaction [41], which were then used to synthesize new Pt(II) complexes via two distinctive steps as previously reported (Scheme 1) [42]. Synthetic procedure of cyclometalating ligands L-1-L-7: a mixture of 2-pyridyl bromide (0.25 mmol), 1.5 equiv of 4-(diphenylamino) phenylboronic acid (0.375 mmol, 0.108 g), 2 equiv of K2CO3 (0.5 mmol, 0.069 g), Pd(OAc)2 (1.5 mol%, 0.00375 mmol, 0.84 mg), ethanol/water (3 mL/1 mL) was stirred at 80 C in air for indicated time. The reaction mixture was added to brine (15 mL) and extracted four times with ethyl acetate (4×15 mL). The solvent was concentrated and the product was isolated by short-column chromatography. The cyclometalating ligand was reacted with 1.2 equiv K2PtCl4 (0.2 mmol, 83.02 mg) in a mixture of 2-ethoxyethanol and water (6 mL/2 mL) at 80 C for 16-24 h to afford a platinum dimmer, which was subsequently reacted with 5 equiv of the chelating diketone (0.1 mmol, 102.5 muL) and 10 equiv of Na2CO3 (1 mmol, 0.106 g) in 2-ethoxyethanol at 100 C for 18-24 h.
	With palladium diacetate; potassium carbonate; In ethanol; water; at 80℃;	General procedure: A mixture of 2-pyridyl bromide, 1.5 equiv. of arylboronic acid, 2 equiv. of K2CO3, Pd(OAc)2 (1.5 mol%), ethanol/water (3:1 v/v) wasstirred at 80 C in air for indicated time. The reaction mixture was added to brine (15 mL) and extracted with ethyl acetate (4 x 15 mL). The solvent was concentrated under vacuum, and the product was isolated by short-column chromatography on silica gel.
	With palladium diacetate; potassium carbonate; In ethanol; water; at 80℃; for 1h;	Ligand synthesis: In air,To a round bottom flask was added 4-triphenylamine boronic acid (0.375 mmol) in that order,Potassium carbonate (0.5 mmol),Palladium acetate (0.005 mmol),2-Bromo-5-trifluoromethylpyridine (0.25 mmol),then,An ethanol-water mixed solution (4 mL) in a volume ratio of 3: 1 was added,The Suzuki cross-coupling reaction was carried out at 80 C for 60 minutes with magnetic stirring,The progress of the reaction was followed by thin layer chromatography,After completion of the reaction,Saturated brine (15 mL) was added,The reaction product was extracted with ethyl acetate (3 X 15 ml)The organic phases were combined,The filtrate was concentrated,After separation by column chromatography,Analytical N, N-diphenyl-4- (5-trifluoromethylpyridin-2-yl) aniline was prepared.

Reference： [1]RSC Advances,2013,vol. 3,p. 526 - 531
[2]Dyes and Pigments,2014,vol. 101,p. 85 - 92
[3]Dyes and Pigments,2017,vol. 136,p. 641 - 647
[4]Patent: CN103145763,2016,B .Location in patent: Paragraph 0063
[5]Dyes and Pigments,2020,vol. 173

40
[ 1425511-67-6 ]
[ 50488-42-1 ]
[ 1425511-68-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 80℃;Inert atmosphere; Microwave irradiation;	Intermediate 6; 3,4-bis(Benzyloxy)-6-[5-(trifluoromethyl)pyridin-2- yl]ethynyl}pyridazine 3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 530 mg, 1.68 mmol) and 2- bromo-5-(trifluoromethyl)pyridine (379 mg, 1.68 mmol) were dissolved in tetrahydrofuran (5 ml) to produce an orange solution. The reaction mixture was purged with nitrogen and then triethylamine (1.40 ml, 10.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (58.8 mg, 0.08 mmol) and copper(I) iodide (31.9 mg, 0.17 mmol) were added before it was subjected to microwave irradiation for 1 hour at 80 C. Upon cooling, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated in vacuo and the crude residue was then purified by silica chromatography (eluting with 0-50 % ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-[5-(trifluoromethyl)pyridin-2- yl]ethynyl}pyridazine (460 mg, 0.10 mmol, 60 % yield). ? NMR (400 MHz, DMSO-d6): delta 9.08 (s, 1 H), 8.34 - 8.38 (m, 1 H), 7.96 - 8.01 (m, 1 H), 7.70 (s 1 H), 7.33 - 7.53 (m, 10 H), 5.61 (s, 2 H) and 5.33 (s, 2 H). MS ES+: 462.
60%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 80℃; for 1h;Microwave irradiation; Inert atmosphere;	Intermediate 6: 3,4-bis(Benzyloxy)-6-[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine [0238]3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 530 mg, 1.68 mmol) and <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (379 mg, 1.68 mmol) were dissolved in tetrahydrofuran (5 ml) to produce an orange solution. The reaction mixture was purged with nitrogen and then triethylamine (1.40 ml, 10.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (58.8 mg, 0.08 mmol) and copper(I) iodide (31.9 mg, 0.17 mmol) were added before it was subjected to microwave irradiation for 1 hour at 80 C. Upon cooling, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated in vacuo and the crude residue was then purified by silica chromatography (eluting with 0-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (460 mg, 0.10 mmol, 60% yield).[0239]1H NMR (400 MHz, DMSO-d6): delta 9.08 (s, 1H), 8.34-8.38 (m, 1H), 7.96-8.01 (m, 1H), 7.70 (s 1H), 7.33-7.53 (m, 10H), 5.61 (s, 2H) and 5.33 (s, 2H).[0240]MS ES+: 462.

Reference： [1]Patent: WO2013/27000,2013,A1 .Location in patent: Page/Page column 41
[2]Patent: US2013/52281,2013,A1 .Location in patent: Paragraph 0237-0240

41
[ 1204603-42-8 ]
[ 50488-42-1 ]
[ 1429200-40-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 3h;	Example 226A[1376] tert-butyl (7R,8a5)-7-[5-(trifluoromethyl)pyridin-2-yl]oxy}hexahydro- pyrrolo[l,2-a]pyrazine-2(lH)-carboxylate[1377] To a solution of the product from Example 202A (0.20 g, 0.825 mmol) in anhydrous tetrahydrofuran (8 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.825 mL, 0.825 mmol), followed by 2-bromo-5- (trifluoromethyl)pyridine. The resulting mixture was stirred at room temperature for 3 hours, and then it was partitioned between water and ethyl acetate (3x). The organic extracts were combined and dried over Na2S04. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% CH3OH in CH2Cl2to give the title compound as a colorless solid (0.28 g, 88%).

Reference： [1]Patent: WO2013/49174,2013,A1 .Location in patent: Paragraph 1376-1377

42
[ 1429200-28-1 ]
[ 50488-42-1 ]
[ 1429199-63-2 ]

Yield	Reaction Conditions	Operation in experiment
68%		Example 217C[1337] 2- { [3 -(trifluoromethyl)phenyl]sulfonyl} -7- { [5-(trifluoromethyl)pyridin-2-yl]- oxy}hexahydropyrrolo[l,2-a]pyrazin-6(2H)-one[1338] To a solution of the product from Example 217B (23 mg, 0.063 mmol) in anhydrous N,N-dimethylformamide (0.6 mL) at 0 C was added sodium hydride (60% suspension in mineral oil, 2.78 mg, 0.069 mmol). The resulting mixture was stirred at 0 C for 10 minutes, and <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (21 mg, 0.095 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was partitioned between water and ethyl acetate (3 x), and the combined organic layers were concentrated in vacuo and purified on CI 8 silica gel using a solvent gradient of 0-100% acetonitrile in water (0.1% trifluoroacetic acid). The title compound was obtained as a colorless solid (22 mg, 68%). ¾ NMR (300 MHz, CDC13) delta ppm 1.58 - 1.68 (m, 0.5 H) 2.03 - 2.49 (m, 3 H) 2.88 - 3.21 (m, 1.5 H) 3.72 - 4.08 (m, 3 H) 4.21 (dd, J=13.39, 3.22 Hz, 1 H) 5.50 - 5.74 (m, 1 H) 6.88 (t, J=8.82 Hz, 1 H) 7.69 - 7.85 (m, 2 H) 7.88 - 8.00 (m, 2 H) 8.02 (s, 1 H) 8.26 - 8.43 (m, 1 H); MS (ESI) m/z 510 (M+H)+.

Reference： [1]Patent: WO2013/49174,2013,A1 .Location in patent: Paragraph 1337-1338

43
[ 50488-42-1 ]
[ 31181-84-7 ]

Reference： [1]Patent: WO2013/166621,2013,A1

44
[ 201230-82-2 ]
[ 50488-42-1 ]
[ 124236-37-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; at 80℃; under 11251.1 Torr;	III. methyl 5-trifluoromethyl-pyridine-2-carboxylate A mixture of 2-bromo-5-trifluoromethyl-pyridine (10 g, 44.25 mmol), TEA (17.9 g, 177 mmol) and Pd(dppf)Cl2 (3.24 g, 4.42 mmol) was stirred at 80C under an average pressure of 1.5 MPa with CO gas. The reaction mixture was filtered and the filtrate was concentrated. The residue was extracted between EA (100 mL) and H20 (100 mL). The EA layer was washed with saturated aqueous NaHC03 (2 X 100 mL), brine (1 X 100 mL), dried, concentrated and purified by column chromatography on silica gel to give the title compound as a white solid (6 g, 66% yield): 1H NMR (400 MHz, CDC13) delta ppm 8.97-8.98 (m, 1H), 8.23-8.25 (m, 1H), 8.07-8.09 (m, 1H), 4.03 (s, 3H); ES-LCMS m/z 206 ( +H)+.

Reference： [1]Patent: WO2013/166621,2013,A1 .Location in patent: Page/Page column 48

45
[ 3003-84-7 ]
[ 50488-42-1 ]
[ 1558056-05-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Sodium thiosulfate pentahydrate; caesium carbonate; In ethylene glycol; dimethyl sulfoxide; at 120℃;Inert atmosphere;	Under a nitrogen atmosphere, in 25 ml substrate is added into the test tube reactor 3akm (0.2mmol, 45.0 mg), 2 - (chloromethyl) tetrahydrofuran (3.0mmol, 360.0 mg), PdCl2(dppf) (0.02mmol, 14.6 mg), DPPF (0.01mmol, 5.6 mg), Cs2CO3(0.3mmol, 195.0 mg), Na2S2O35H2O (0.5mmol, 248.0 mg), DMSO (4.0 ml) and glycol (0.1 ml). Heating the reaction system to 120 C for reaction. TLC detection after the reaction is ended, the system is cooled to room temperature. Hydrosolvent quenching reaction with saturated ammonium chloride, extracted with ethyl acetate (3*10 ml), column chromatography purification to obtain the product 3ak (75%).

Reference： [1]Organic Letters,2014,vol. 16,p. 1212 - 1215
[2]Patent: CN103848767,2016,B .Location in patent: Paragraph 0155-0158

46
[ 89031-81-2 ]
[ 50488-42-1 ]
[ 1558056-06-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Sodium thiosulfate pentahydrate; caesium carbonate; In ethylene glycol; dimethyl sulfoxide; at 120℃;Inert atmosphere;	Under a nitrogen atmosphere, in 25 ml substrate is added into the test tube reactor 3amm (0.2mmol, 45.0 mg), tert-butyl (2-chloroethoxy)dimethyl silane (3.0mmol, 582.0 mg), PdCl2(dppf) (0.02mmol, 14.6 mg), DPPF (0.01mmol, 5.6 mg), Cs2CO3(0.3mmol, 195.0 mg), Na2S2O35H2O (0.5mmol, 248.0 mg), DMSO (4.0 ml) and glycol (0.1 ml). Heating the reaction system to 120 C for reaction. TLC detection after the reaction is ended, the system is cooled to room temperature. Hydrosolvent quenching reaction with saturated ammonium chloride, extracted with ethyl acetate (3*10 ml), column chromatography purification to obtain the product 3am (98%).

Reference： [1]Organic Letters,2014,vol. 16,p. 1212 - 1215
[2]Patent: CN103848767,2016,B .Location in patent: Paragraph 0163-0166

47
[ 107-07-3 ]
[ 50488-42-1 ]
2-<5-(trifluoromethyl)pyridin-2-ylsulfanyl>ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Sodium thiosulfate pentahydrate; caesium carbonate; In ethylene glycol; dimethyl sulfoxide; at 120℃;Inert atmosphere;	Under a nitrogen atmosphere, in 25 ml substrate is added into the test tube reactor 3alm (0.2mmol, 45.0 mg), 2-chloro ethanol (3.0mmol, 240.0 mg), PdCl2(dppf) (0.02mmol, 14.6 mg), DPPF (0.01mmol, 5.6 mg), Cs2CO3(0.3mmol, 195.0 mg), Na2S2O35H2O (0.5mmol, 248.0 mg), DMSO (4.0 ml) and glycol (0.1 ml). Heating the reaction system to 120 C for reaction. TLC detection after the reaction is ended, the system is cooled to room temperature. Hydrosolvent quenching reaction with saturated ammonium chloride, extracted with ethyl acetate (3*10 ml), column chromatography purification to obtain the product 3al (62%).

Reference： [1]Organic Letters,2014,vol. 16,p. 1212 - 1215
[2]Patent: CN103848767,2016,B .Location in patent: Paragraph 0159-0162

48
[ 6270-06-0 ]
[ 50488-42-1 ]
[ 1386635-98-8 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Sodium thiosulfate pentahydrate; caesium carbonate; In ethylene glycol; dimethyl sulfoxide; at 120℃;Inert atmosphere;	Under a nitrogen atmosphere, in 25 ml substrate is added into the test tube reactor 3dcm (0.2mmol, 45.0 mg), 3dcm' (1.0mmol, 209.0 mg), PdCl2(dppf) (0.02mmol, 14.6 mg), DPPF (0.0l mmol, 5.6 mg), Cs2CO3(0.3mmol, 195.0 mg), Na2S2O35H2O (0.5mmol, 248.0 mg), DMSO (4.0 ml) and glycol (0.1 ml). Heating the reaction system to 120 C for reaction. TLC detection after the reaction is ended, the system is cooled to room temperature. Hydrosolvent quenching reaction with saturated ammonium chloride, extracted with ethyl acetate (3*10 ml), column chromatography purification to obtain the product 3dc (61%).

Reference： [1]Organic Letters,2014,vol. 16,p. 1212 - 1215
[2]Patent: CN103848767,2016,B .Location in patent: Paragraph 0230-0233

49
[ 1613630-17-3 ]
[ 50488-42-1 ]
[ 1613630-18-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium carbonate; In dimethyl sulfoxide; at 100℃;	A mixture of (8R,9aS)-8-hydroxyoctahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (90 mg, 0.435 mmol, Part A), <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (148 mg, 0.635 mmol) and sodium carbonate (138 mg, 1.306 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 100 C. overnight. The mixture was purified by chromatography on silica gel (ethyl acetate/methanol=15:1) to give 135 mg (98% yield) of the titled compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.77 (m, 1H), 2.09 (m, 1H), 2.50-2.66 (m, 2H), 3.08 (m, 1H), 3.35 (m, 2H), 3.50 (m, 1H), 3.98 (m, 2H), 4.20 (m, 1H), 4.44 (m, 1H), 4.55 (m, 1H), 4.88 (br s, 1H), 7.01 (d, J=8 Hz, 1H), 7.81 (d, J=8 Hz, 1H), 8.43 (s, 1H); MS (ESI) m/z 316.0 (M+H)+

Reference： [1]Patent: US2014/171423,2014,A1 .Location in patent: Paragraph 0913

50
[ 2516-34-9 ]
[ 50488-42-1 ]
N-cyclobutyl-5-(trifluoromethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;Sealed tube;	To a solution of <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (10.0 g, 44.24 mmol), K2003 (8.3 g, 60.05 mmol) in DMSO (50 mL) was added cyclobutylamine (4.51 mL, 52.82 mmol) and maintained at 100 C for 16 h in sealed tube. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water, brine solution, dried over an hydrous Na2SO4 and concentrated. The crude product was purified by column chromatography over silica gel (100 - 200 mesh) using a solvent gradient of 20 % ethyl acetate in pet-ether to afford 8.0 g (84 %) of N-cyclobutyl-5- (trifluoromethyl)pyridin-2-amine 160-1 as a white solid. 1H-NMR (400 MHz, DMSO-d6): c5 8.26 (5, 1H), 7.55-7.63 (m, 2H), 6.50 (d, J= 11.6 Hz, 1H), 4.30-4.33 (m, 1H), 2.23-2.31 (m, 2H), 1.82-1.93 (m, 2H), 1.64-1.72 (m, 2H). ESI-LC/MS: m/z217.06 (M+H); R = 2.85 mm [Waters Acquity UPLC with SOD; Waters Acquity UPLC BEH 018, 1.7 pm, 2.1 X 50 mm column; gradient of 98:02 H20 (0.1% H000H): CH3CN (0.1% H000H) hold for 0.8 mm and to 45:55 H2Q (0.1% H000H):CH3CN (0.1% H000H) in 2.0 mm and hold for 1.0 mm and to 0:100 H2Q (0.1% H000H):CH3CN (0.1% H000H) in 0.5 mm and hold for 1.5 mm with flow rate of 0.4 mLlmin].

Reference： [1]Patent: WO2014/78802,2014,A1 .Location in patent: Page/Page column 247

51
[ 419536-33-7 ]
[ 50488-42-1 ]
[ 1617519-03-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With palladium diacetate; potassium carbonate; In ethanol; water; at 80℃;	General procedure: A mixture of the N-heteroaryl halide (1.0mmol), 4-(9H-carbazol-9-yl)-phenylboronic acid (1.5mmol), K2CO3 (2.0mmol), Pd(OAc)2 (1.5mol%), ethanol (6mL) and distilled water (2mL) was stirred at 80C in air for indicated time (<30min). The reaction was monitored by TLC. The reaction mixture was added to brine (30mL) and extracted four times with ethyl acetate (4×30mL). The solvent was concentrated under vacuum, and the product was isolated by short-column chromatography on silica gel (200-300 mesh).

Reference： [1]Dyes and Pigments,2014,vol. 109,p. 13 - 20
[2]ACS Catalysis,2018,vol. 8,p. 5313 - 5322

52
tert-butyl (9aS)-8-hydroxy-7-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate [ No CAS ]
[ 50488-42-1 ]
tert-butyl (8R,9aS)-7-oxo-8-[5-(trifluoromethyl)pyridin-2-yl]oxy}hexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 4h;Inert atmosphere;	To a solution of the product from Example 21, Part G (0.10 g, 0.370 mmol) in anhydrous N,N-dimethylformamide (4 mL) at 0 C. under N2 was added sodium hydride (60% suspension in mineral oil) (0.016 g, 0.407 mmol), followed by <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (0.125 g, 0.555 mmol). The resulting mixture was stirred at room temperature for four hours, and then it was partitioned between water and ethyl acetate. The organic extract were dried over Na2SO4, the drying agent was removed by filtration, and the solution was concentrated in vacuo to give a crude product that was purified by column chromatography on silica gel using a solvent gradient of 0-5% methanol in dichloromethane. The title compound was obtained as a colorless solid (0.113 g, 74%)

Reference： [1]Patent: US2014/171423,2014,A1 .Location in patent: Paragraph 0834

53
[ 17623-96-0 ]
[ 50488-42-1 ]
2-(2,3-dihydro-1H-inden-2-yl)-5-(trifluoromethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With pyridine; tetrabutylammomium bromide; 4,4'-di-tert-butyl-2,2'-bipyridine; magnesium chloride; nickel dibromide; zinc; In N,N-dimethyl acetamide; at 30℃;Schlenk technique; Inert atmosphere; Glovebox;	General procedure: To a flame-dried Schlenk tube equipped with a magnetic stir bar was loaded alkyl bromide (0.15 mmol, 100 mol%, solid), halogenated pyridine (0.30 mmol, 300 mol%, solid), ligand (0.015 mmol, 10 mol%), zinc powder (0.45 mmol, 300 mol%). The tube was capped with a rubber septum and moved to a dry glove box, at which NiBr2 (0.015 mmol, 10 mol%), MgCl2 (0.15 mmol, 100 mol%) and Bu4NBr (0.075 mmol, 50 mol%) were added. Then the tube was moved out of the glove box. Alkyl bromide (0.15 mmol, 100 mol%, liquid), halogenated pyridine (0.30 mmol, 300 mol%, liquid), pyridine (0.15 mmol, 100 mol%) and DMA(1.0 mL) were added via syringe. After the reaction mixture was allowed to stir overnight under N2 atmosphere at 30 C, it was directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of DCM or eluent. Flash column chromatography provided the product as solid or oil.

Reference： [1]Synthetic Communications,2014,vol. 44,p. 2999 - 3007

54
[ 1072951-54-2 ]
[ 50488-42-1 ]
2,6-dichloro-4-[5-(trifluoromethyl)pyridin-2-yl]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 12h;Inert atmosphere;	A mixture of 2-bromo-5-(trifluoromethyl)pyridine (800.00 mg, 3.54 mmol, 1.00 equiv), (2,6- dichloropyridin-4-yl)boronic acid (1 g, 5.21 mmol, 1.00 equiv), Pd(dppf)C12.CH2C12 (290 mg, 0.36 mmol, 0.10 equiv), and potassium carbonate (1.96 g, 14.18 mmol, 4.00 equiv) in 1,4-dioxane (40 mL) /water(2 mL) was stuffed for 12 h at 120C under nitrogen. The resulting solution was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:100). This resulted in the title compound (680 mg, 66%) as a white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 0775; 0776

55
[ 741709-62-6 ]
[ 50488-42-1 ]
4-[5-(trifluoromethyl)pyridin-2-yl]pyridine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100.0℃; for 12.0h;Inert atmosphere;	A mixture of 4-(tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (1.6 g, 6.95 mmol, 3.10 equiv), 2-bromo-5-(trifluoromethyl)pyridine (500 mg, 2.21 mmol, 1.00 equiv), Pd(dppf)C12 (170 mg, 0.23 mmol, 0.10 equiv), and potassium carbonate (921 mg, 6.66 mmol, 3.00 equiv) in dioxane (40 mL)/water (2 mL) was stuffed for 12 h at 100C under nitrogen. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:20) to afford the title compound (380 mg, 69%) as a white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01607; 01608

56
potassium (2,4-difluorophenyl)trifluoroborate [ No CAS ]
[ 50488-42-1 ]
[ 387827-64-7 ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 2195 - 2198
[2]Organic Letters,2015,vol. 17,p. 3294 - 3297

57
[ 50488-42-1 ]
[ 33252-63-0 ]

Yield	Reaction Conditions	Operation in experiment
69%		General procedure: In a dry Schlenk tube 2-bromo-6-methylpyridine (5.98 g, 35.0 mmol) was dissolved in 100 mL oft-AmylOH and KOt-Bu (39.3 g , 350.0 mmol) was added. The mixture was stirred at 100 C for 40 h. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL of HCO2H. The solution was stirred for 24 h at rt, then the pH was set to about 6 using 3N aq. KOH solution. The extraction was performed using CHCl3 (3×) and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was transferred to a column chromatography (8%MeOH in DCM) to afford 1 (white solid), 2.75 g (72%).

Reference： [1]Synlett,2015,vol. 26,p. 1557 - 1562

58
[ 68-12-2 ]
[ 50488-42-1 ]
[ 31224-82-5 ]

Yield	Reaction Conditions	Operation in experiment
		iPrMgCl (2M in Et20, 750 ml, 1 .5 mol) was added to 2-bromo-5-trifluoromethylpyridine (295 g, 1 .3 mol) in DCM (4 L) at -2C over 3 minutes.After stirring at 0-6C for 40 minutes the mixture was cooled to -20C and DMF(200 ml, 2.6 mol) added in one portion. The mixture was cooled to 0C over 20minutes then quenched by addition of 1 .5 L saturated NaHCO3 in one portion.The mixture was stirred at 12C for 15 minutes then filtered through a celite pad.The layers were separated. The filtered solids were washed with 1 L DCM andthis was then used to re-extract the aqueous layer. The combined organics were dried over MgSO4, filtered through a pad of 1 kg silica, washed with 5 L DCM and evaporated (bath temp 35C). The brown oil was dissolved in 2 L hexane and washed with 2 x 1 L 12% brine to remove DMF. The organics were filteredthrough a pad of MgSO4 and concentrated to low volume. This oil was distilled at35C and 20C in Hg to remove hexane then at 56C and 26C in Hg to afford the title compound as a pale yellow moist crystal (154 g, ?-90% purity, 0.79 mol, 61%): 1H NMR (400MHz, CDCI3) 7.60 (1H, 5), 7.83 (1H, d), 8.85 (1H, d), 9.86 (1H, d).
		To commercially available 2-bromo-5-trifluoromethylpyridine (295 g, 1 .3 mol) in DCM (4L) at -2C was added iPr gCI (2M in Et20, 750 ml, 1 .5 mol) over 3 minutes then stirred at 0-6 C for 40 minutes [jacket at 0 C, mild and gradual exotherm took pot temp to 6 C maximum after about 15 minutes]. The mixture was cooled to -20 C then DMF (200ml, 2.6mol) was added in one portion [exotherm to 6 C]. The mixture was slowly re- cooled to 0C over 20 minutes then quenched by addition of 1 .5L saturated NaHC03 in one portion [temperature to 12 C]. The mixture was stirred at 12 C for 15 minutes then filtered through a celite pad. The layers were separated. The filtered solids were washed with 1 L DCM and this was then used to re-extract the aqueous layer. The combined organics were dried over MgS04, filtered through a pad of 1 kg silica, washed with 5L DCM and evaporated (bath temp 35 C). The brown oil was dissolved in 2L hexane and washed with 2 x 1 L 12% brine to remove DMF. The organics were filtered through a pad of MgS04 and concentrated to low volume. This oil was distilled at 35 C and 20 inches Hg to remove hexane then at 56 C and 26 inches Hg to afford the 5- (trifluoromethyl)-picolinaldehyde product (154 g, about 90% purity, 0.79 mol, 61 %) as a pale yellow moist crystal.

Reference： [1]Patent: WO2015/100232,2015,A2 .Location in patent: Page/Page column 153; 154
[2]Patent: WO2016/209635,2016,A1 .Location in patent: Page/Page column 44

59
2-(pyridin-3-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-4(5H)-one [ No CAS ]
[ 50488-42-1 ]
2-(pyridin-3-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-4(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 6h;Inert atmosphere;	To a solution of Compound F2 (0.050 g, 0.23 mmol) in dioxane (2.3 mL) was added <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (0.063 g, 0.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.0068 g, 0.012 mmol), and cesium carbonate (0.11 g, 0.35 mmol). The reaction was degassed with nitrogen and tris(dibenzylideneacetone)dipalladium (0) (0.0021 g, 0.0023 mmol) was added. The reaction was heated at 120 C. for 6 hours. The reaction was cooled to room temperature, diluted with brine, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using 0-15% methanol/dichloromethane as eluent to provide Compound F37 as a white solid (0.069 g, 82%).

Reference： [1]Patent: US2015/327551,2015,A1 .Location in patent: Paragraph 0301-0302

60
[ 4612-26-4 ]
[ 50488-42-1 ]
1,4-bis(5-trifluoromethylpyridin-2-yl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With C37H45ClN2O3PPd; potassium carbonate; In ethanol; water; at 80℃; for 6h;Inert atmosphere; Schlenk technique;	A 10-mL round-bottom flask was charged with the prescribe damount of catalyst, 1,4-benzenediboronic acid (0.5 mmol), N-heteroaryl halides (1.5 mmol), the selected base (1.5 mmol) and solvent (4 mL). The flask was placed in an oil bath and heated at 80 °C for 6 h, then cooled to room temperature and extracted with CH2Cl2. The crude products obtained from evaporation were purified by flash chromatography on silica gel. The products 5b?c, 5f, 5m [21], 5d [22], 5e [23], 5l [24] were known compounds and characterized by the comparison of data with those in the literature. The products 5a, 5g?k, 5n?o were new compounds and characterized by elemental analysis, IR, MS,1H and 13C NMR.

Reference： [1]Transition Metal Chemistry,2015,vol. 40,p. 501 - 508

61
[ 50488-42-1 ]
[ 124236-37-9 ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 2930 - 2934

62
[ 16156-95-9 ]
[ 50488-42-1 ]
[ 1558056-23-7 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Sodium thiosulfate pentahydrate; caesium carbonate; In ethylene glycol; dimethyl sulfoxide; at 120℃;Inert atmosphere;	Under a nitrogen atmosphere, in 25 ml substrate is added into the test tube reactor 5bm (0.1mmol, 22.5 mg), 5bm (1.5mmol, 283.5 mg), PdCl2(dppf) (0.01mmol, 14.6 mg), DPPF (0.005mmol, 5.6 mg), Cs2CO3(0.15mmol, 97.5 mg), Na2S2O35H2O (0.25mmol, 124.0 mg) DMSO (2.0 ml) and glycol (0.05 ml). Heating the reaction system to 120 C for reaction. TLC detection after the reaction is ended, the system is cooled to room temperature. Hydrosolvent quenching reaction with saturated ammonium chloride, extracted with ethyl acetate (3*10 ml), column chromatography purification to obtain the product 3b (71%).

Reference： [1]Patent: CN103848767,2016,B .Location in patent: Paragraph 0254-0257

63
N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester [ No CAS ]
[ 50488-42-1 ]
methyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Zn (1.35 g), N,N-dimethylformamide (100 mL). This wasfollowed by the addition ofT2 (188.1 mg) in several batches at 50C in 10 mm. To this was addedmethyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-iodopropanoate (6 g, 18.23 mmol, 1.00 equiv) in several batches at 0C in 30 mm. To the mixture was added <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (3.3 g, 14.60 mmol, 0.80 equiv) in several batches at 0C. To the mixture was added Pd(PPh3)2Cl2 (1.04 g, 1.48 mmol, 0.08 equiv) in several batches at 0C. The resulting solution was stirred for 5 h at 50C. The reaction mixture was cooled. The solids were filtered out. The resulting solution was diluted with 50 mL of H20. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The organic phase was washed with6x100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). The collected fractions were combined and concentrated under vacuum. This resulted in 5 g (79%) of methyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5- (trifluoromethyl)pyridin-2-yl]propanoate as yellow oil. MS (ES, m/z): 349 (M+H); ?H NMR (CDC13, 300 IVIHz) : 8.80 (s, 1 H), 7.89-7.86 (m, 1 H), 7.32 (d, J4.5 Hz, 1 H), 5.80-5.60 (m, 1 H), 4.77-4.75 (m, 1 H), 3.73 (s, 3 H), 3.42-3.41 (m, 2 H), 1.43 (s, 9 H).
79%		Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Zn (1.35 g), N,N-dimethylformamide (100 mL). This was followed by the addition of I2 (188.1 mg) in several batches at 50oC in 10 min. To this was added methyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-iodopropanoate (6 g, 18.23 mmol, 1.00 equiv) in several batches at 0oC in 30 min. To the mixture was added <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (3.3 g, 14.60 mmol, 0.80 equiv) in several batches at 0oC. To the mixture was added (1198) Pd(PPh3)2Cl2 (1.04 g, 1.48 mmol, 0.08 equiv) in several batches at 0oC. The resulting solution was stirred for 5 h at 50oC. The reaction mixture was cooled. The solids were filtered out. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The organic phase was washed with 6x100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and (1199) concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). The collected fractions were combined and concentrated under vacuum. This resulted in 5 g (79%) of methyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5- (trifluoromethyl)pyridin-2-yl]propanoate as yellow oil. MS (ES, m/z): 349 (M+H); 1H NMR (CDCl3, 300 MHz) delta: 8.80 (s, 1 H), 7.89-7.86 (m, 1 H), 7.32 (d, J=4.5 Hz, 1 H), 5.80-5.60 (m, 1 H), 4.77-4.75 (m, 1 H), 3.73 (s, 3 H), 3.42-3.41 (m, 2 H), 1.43 (s, 9 H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 238; 239
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 256; 257

64
[ 50488-42-1 ]
[ 497147-93-0 ]
5-[5-(trifluoromethyl)-2-pyridyl]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); sodium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 2.0h;	To 390 2-bromo-5-(trifluoromethyl)pyridine (4.0 g, 18 mmol) and 391 <strong>[497147-93-0]5-cyano-3-pyridylboronic acid</strong>(3.1 g, 21 mmol) were added 267 sodium carbonate (3.8 g, 35 mmol) and 244 1,1?-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.66 g, 0.90 mmol), 107 N,N-dimethylformamide(160 mL) and 52 water (40 mL) and the mixture was stirred at 110 C. for 2 hr. The insoluble material wasfiltered off, 57 ethyl acetate was added to the filtrate and the mixture was washed successively with waterand saturated brine, dried over sodium sulfate, and the desiccant was filtered off. The solvent was evaporatedand the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) togive the 392 title compound ( 3.3 g , 13 mmol, 73%). MS (ESI) m/z 250 (M+H)+ 1H NMR (400 MHz, CDCl3) delta 9.44 (s, 1H), 9.03 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.12 (d, J=8.4 Hz,1H) . 7.94 (d, J=8.4 Hz, 1H).
73%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 2.0h;	To 2-bromo-5-(trifluoromethyl)pyridine (4.0 g, 18 mmol), <strong>[497147-93-0]5-cyano-3-pyridylboronic acid</strong> (3.1 g, 21 mmol), sodium carbonate (3.8 g, 35 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.66 g, 0.90 mmol) were added N,N-dimethylformamide (160 mL) and water (40 mL), and the mixture was stirred at 110C for 2 hr. Insoluble material was filtered off, ethyl acetate was added to the filtrate and the mixture was washed successively with water and saturated brine and dried over sodium sulfate. The desiccant was filtered off. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (3.3 g, 13 mmol, 73%). MS (ESI) m/z 250 (M+H)+ 1H NMR (400 MHz, CDCl3) delta 9.44 (s, 1H), 9.03 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H).

Reference： [1]Patent: US2016/332999,2016,A1 .Location in patent: Paragraph 0559; 0560; 0561
[2]Patent: EP3330266,2018,A1 .Location in patent: Paragraph 0147

65
[ 50488-42-1 ]
[ 497147-93-0 ]
[5-[5-(trifluoromethyl)-2-pyridyl]-3-pyridyl]methylamine [ No CAS ]

Reference： [1]Patent: US2016/332999,2016,A1
[2]Patent: EP3330266,2018,A1

66
[ 50488-42-1 ]
[ 612833-37-1 ]
4-methoxy-3-[5-(trifluoromethyl)-2-pyridyl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 2.0h;	To the compound (1.1 g, 6.0 mmol) obtained in step 483 1, 390 2-bromo-5-(trifluoromethyl)pyridine(1.2 g, 5.5 mmol), 267 sodium carbonate (1.2 g, 11 mmol) and 244 1,1?-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.20 g, 0.27 mmol) were added 107 N,N-dimethylformamide (16 mL) and52 water (4 mL) and the mixture was stirred at 100 C. for 2 hr. The insoluble material was filtered off,57 ethyl acetate was added to the filtrate and the mixture was washed successively with water andsaturated brine, dried over sodium sulfate, and the desiccant was filtered off. The solvent was evaporated andthe obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to givethe 485 title compound ( 1.4 g , 5.1 mmol, 92%). MS (ESI) m/z 279 (M+H)+
92%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 2.0h;	To the compound obtained in step 1 (1.1 g, 6.0 mmol), 2-bromo-5-(trifluoromethyl)pyridine (1.2 g, 5.5 mmol), sodium carbonate (1.2 g, 11 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.20 g, 0.27 mmol) were added N,N-dimethylformamide (16 mL) and water (4 mL), and the mixture was stirred at 100C for 2 hr. Insoluble material was filtered off, ethyl acetate was added to the filtrate and the mixture was washed successively with water and saturated brine, and dried over sodium sulfate. The desiccant was filtered off. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (1.4 g, 5.1 mmol, 92%). MS (ESI) m/z 279 (M+H)+

Reference： [1]Patent: US2016/332999,2016,A1 .Location in patent: Paragraph 0652; 0653
[2]Patent: EP3330266,2018,A1 .Location in patent: Paragraph 0170

67
[ 6994-25-8 ]
[ 50488-42-1 ]
C₁₂H₁₁F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 2-bromo-5- (trifluoromethyl)pyridine (2.25 g, 0.01 mol), C52CO3 (6.52 g, 0.02 mol) in DMF (20 mL) was stirred for 1 hour at 100 C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The cmde product was purified via silica gel chromatography (PE-EA) to give desired compound asyellow solid (1.95 g, 65%). ESI MS m/z = 301.2 [M+Hf ?HNMR (300 MHz, DMSO-d6) oe1.31 (m, 3H), 4.14-4.40 (m, 2H), 5.96 (d, J= 4.0 Hz, 2H), 7.86 (m, 1H), 8.36 (m, 1H), 8.74 (d, J = 3.7 Hz, 1H), 8.83 (d, J 2.8 Hz, 1H).
65%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 2-bromo-5- (trifluoromethyl)pyridine (2.25 g, 0.01 mol), Cs2CO3 (6.52 g, 0.02 mol) in DMF (20 mL) was stirred for 1 hour at 100C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give desired compound as yellow solid (1.95 g, 65%). ESI MS m/z = 301.2 [M+H]+.1H NMR (300 MHz, DMSO-d6) delta 1.31 (m, 3H), 4.14- 4.40 (m, 2H), 5.96 (d, J = 4.0 Hz, 2H), 7.86 (m, 1H), 8.36 (m, 1H), 8.74 (d, J = 3.7 Hz, 1H), 8.83 (d, J = 2.8 Hz, 1H).

Reference： [1]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 332; 333
[2]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 302

68
[ 1320747-32-7 ]
[ 50488-42-1 ]
2',5,6'-tris(trifluoromethyl)-2,4'-bipyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In 1,2-dimethoxyethane; at 80℃;Inert atmosphere;	General procedure: In a fume hood, an oven-dried Schlenk flask equipped with magnetic stirring bar was filled with N2 and evacuated (three cycles). Under N2 atmosphere, Pd(OAc)2 (1.1 mg, 0.005 mmol, 1 mol% Pd), SPhos (4.1mg, 0.01 mmol, 2 mol%), K3PO4 (160 mg, 1.5 mmol, 1.5 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trifluoromethyl)pyridine (1, 171 mg, 0.5 mmol, 1 equiv), aryl bromide (0.75 mmol,1.5 equiv), and DME (2 mL) were added in order. The Schlenk flask was closed and the mixture was heated at 80 C in an oil bath for 24-48 h. The progress of reaction was monitored by GC-MS and TLC. Upon completion of reaction, the Schlenk flask was cooled to r.t. and exposed to air. The mixture was extracted into EtOAc, washed with water and brine, and dried (anhyd Na2SO4). The crude product was purified by column chromatography (silica gel). For chloro-substituted bromoarenes (2g, 2h, and 2m), Pd(PPh3)4 (23mg, 0.02 mmol, 4 mol% Pd) was used (for 1-mmol scale reaction) in place of Pd(OAc)2 and SPhos. Unless otherwise noted, reactions were performed on a 0.5-mmol 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trifluoromethyl)pyridine (1) scale.

Reference： [1]Synthesis,2017,vol. 49,p. 1327 - 1334

69
[ 280-57-9 ]
[ 50727-04-3 ]
[ 50488-42-1 ]
5-methoxy-2-(2-(4-(5-trifluoromethylpyrid-2-yl)-1-piperazinyl)-1-ethyl)isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium phosphate; In N,N-dimethyl acetamide; at 120℃; for 24h;	<strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> (224 mg, 1 mmol), triethylene diamine (224 mg, 2 mmol),4-methoxyphthalimide (354 mg, 2 mmol), potassium phosphate (434 mg, 2 mmol),N, N-dimethylacetamide (2 ml) was added to the dry reaction tube and suspended in an oil bath at 120 C for 24 h.After cooling the reaction system, 15 ml of water was added and the aqueous phase was extracted three times with 30 ml of ethyl acetate,The organic phases were combined and the solvent was evaporated under reduced pressure to give 338 mg of a colorless solid, 5-methoxy-2- (2-(4- (5-trifluoromethylpyridyl) 2-piperazinyl) 1-ethyl) isoindole-1,3-dione in a yield of 78%.

Reference： [1]Patent: CN106317021,2017,A .Location in patent: Paragraph 0073; 0074

70
[ 1953-02-2 ]
[ 50488-42-1 ]
C₁₁H₁₁F₃N₂O₃S [ No CAS ]

Reference： [1]Chemical Science,2018,vol. 9,p. 336 - 344

71
[ 128376-64-7 ]
[ 50488-42-1 ]
[ 871252-64-1 ]

Yield	Reaction Conditions	Operation in experiment
69.3%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 5h;Inert atmosphere;	4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzaldehyde 2a (2.32 g, 10.0 mmol),<strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> 3a (2.05 g, 9.10 mmol),Tetratriphenylphosphine palladium (526 mg, 0.445 mmol) and sodium carbonate (2.40 g, 22.6 mmol)Soluble in a mixed solution of 25 mL ethylene glycol dimethyl ether and water (V/V=4/1)The reaction was carried out at 90 C for 5 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (eluent: System A).4-(5-(trifluoromethyl)pyridin-2-yl)benzaldehyde 3b (1.58 g, white solid) was obtained in a yield of 69.3%.

Reference： [1]Patent: CN107759522,2018,A .Location in patent: Paragraph 0210; 0212; 0213-0215

72
[ 6746-94-7 ]
[ 50488-42-1 ]
2-(2-cyclopropylethynyl)-5-(trifluoromethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); diisopropylamine; In tetrahydrofuran; at 70℃; for 18h;	A mixture of <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (5 g, 22.1 mmol), cyclopropylacetylene (2.43 mL, 28.7 mmol), CuI (1.89 g, 9.92 mmol), Pd(PPh3)4 (409 mg, 0.354 mmol), and diisopropylamine (5.27 mL, 37.6 mmol) in THF (60 mL) was stirred at 70 C. for 18 h. The reaction mixture was evaporated under reduced pressure. Purification (FCC, SiO2; 100% Et2O) afforded the title compound which was repurified (FCC, SiO2; 50% DCM/hexanes) to give the title compound (3.72, 79%) as a light brown solid. MS (ESI): mass calcd. for C11H8F3N, 211.1; m/z found, 211.8 [M+H]+.

Reference： [1]Patent: US2018/111933,2018,A1 .Location in patent: Paragraph 0315

73
[ 50488-42-1 ]
[ 503309-11-3 ]
2-(2-fluoro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)pyridine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 5369 - 5373
Angew. Chem.,2018,vol. 130,p. 5467 - 5471,5

74
[ 142-08-5 ]
[ 50488-42-1 ]
5'-(trifluoromethyl)-2H-[1,2'-bipyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 120℃; for 2h;Inert atmosphere;	General procedure: Following a reported procedure,1 copper iodide (5 mol %), potassium phosphate tribasic (2.00 equiv), the corresponding 2-hydroxypyridine (1.00 equiv) and the corresponding 2-bromopyridine (2.00 equiv) were suspended in toluene [0.4 M] under N2. N,N?-Dimethylethylenediamine (0.10 equiv) was added and the resulting mixture was stirred 20 h at 120 C. The resulting mixture was allowed to cool to rt and then quenched with water. A small amount of N,N?-dimethylethylenediamine was added to dissolve the residual copper salts into the aqueous phase. The layers were separated and the aqueous layer was extracted three times with EtOAc (20 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. A purification by flash chromatography (eluent DCM/EtOAc 1:1 with 4%vv of NEt3) affordeded the desired product.

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 1208 - 1214

75
[ 667-27-6 ]
[ 50488-42-1 ]
ethyl 2,2-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		To a suspension of copper(O) powder (229 g, 1128 mmol) in DMSO (1.7 L) was added ethyl 2-bromo-2,2-difluoroacetate (47.9 g, 752 mmol) at room temperature. The reaction mixture was stirred for 1 hour and <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (Arborchem, Mechanicsburg, PA, USA) (85 g, 376 mmol) was added portion-wise. The reaction mixture was stirred at room temperature for 12 hours, then quenched with sat'd ammonia chloride (250 mL). The reaction mixture was filtered through a Celite pad and the filtrate was extracted with EtOAc (3 x 350 mL). The combined organic solution was dried over Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 - 2% EtOAc in hexanes) to provide 5a (65 g, 64% yield). MS (ESI, positive ion) m/z: 270.1 (M+l). NMR (400 MHz, Chloroform- ) delta 8.94 (d, J= 1.7 Hz, 1H), 8.14 (dd, J= 8.2, 2.2 Hz, 1H), 7.91 (d, J= 8.3 Hz, 1H), 4.46 - 4.33 (m, 2H), 1.45 - 1.26 (m, 3H).
64%		To a suspension of copper (0) powder (229 g, 1128 mmol) in DMSO (1.7 L) was added ethyl 2-bromo-2,2-difluoroacetate (47.9 g, 752 mmol) at RT. The reaction mixture was stirred at RT for 1 h and <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (Arborchem, Mechanicsburg, PA, USA) (85 g, 376 mmol) was added in portion-wise manner. The reaction mixture was stirred at RT for 12 h, then quenched with sat'd ammonium chloride (250 mL). The reaction mixture was filtered through a celite pad and the filtrate was extracted with ethyl acetate (3 x 350 mL). The combined organic solution was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 - 2% ethyl acetate in hexanes) to provide 5a (65 g, 64% yield). MS (ESI, positive ion) m/z: 270.1 (M+1). 1H NMR (400 MHz, chloroform-d) _ 8.94 (d, J = 1.7 Hz, 1H), 8.14 (dd, J = 8.2, 2.2 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 4.46- 4.33 (m, 2H), 1.45-1.26 (m, 3H).

Reference： [1]Patent: WO2018/112084,2018,A1 .Location in patent: Page/Page column 57
[2]Patent: WO2018/112094,2018,A1 .Location in patent: Page/Page column 74

76
[ 75-07-0 ]
[ 50488-42-1 ]
[ 1345973-17-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	With n-butyllithium; In toluene; at -78℃; for 0.0833333h;	To a solution of n-butyllithium (30.425 mL, 1.60 molL, 48.7 mmol) in toluene (100 mL) at -78C was slowly added a solution of2-bromo-5-(trif1uoromethyl)pyridine (10.0 g, 44.3 mmol) in toluene (50 mL), followed byacetaldehyde (2.73 mL, 48.67 mmol). The resulting mixture was stirred at -78C for 5 min andacetic acid (5.07 mL, 88.5 mmol) was added followed by a sat. solution of sodium bicarbonate(50 mL) and a l 0/o solution of methanol in dichloromethane (100 mL). The aqueous layer was30 saturated with NaCl and extracted with a solution of 10% methanol in dichloromethane (3x50rnL). The combined organic layer was concentrated under reduced pressure. Purification (FCC,Si02, 0-40% 10% methanol in EtOAc;Heptanes) afforded the title compound (5.69 mg, 67%) asa beige oil 1H NMR (400 MHz, DMSO-dG) i5 8.87 (d, I" 1.0 Hz, 1H), 8.20 (dd, J '" 8.4, 2.3 Hz,1H), 7.75 (d, J= 8.3 Hz, 1H), 5.60 (d, J= 4.6 Hz, 1H), 4.77-4.88 (m, 1H), 1.40 (d, J= 6.6 Hz,3 H). [M+H] '" 192.02.

Reference： [1]Patent: WO2018/125810,2018,A1 .Location in patent: Page/Page column 59; 60; 64

77
[ 667-27-6 ]
[ 50488-42-1 ]
ethyl 2,2-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)acetate [ No CAS ]
[ 142946-80-3 ]

Reference： [1]Organic Process Research and Development,2018,vol. 22,p. 1441 - 1447

78
[ 50488-42-1 ]
[ 164341-39-3 ]

Reference： [1]Patent: US2004/157849,2004,A1

79
[ 98437-23-1 ]
[ 50488-42-1 ]
[ 405282-51-1 ]

Yield	Reaction Conditions	Operation in experiment
71.6%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 10h;Inert atmosphere;	General procedure: First, 1.0 g of 2-bromo-5-fluoropyridine (5.68 mmol),1.6 g of potassium carbonate (11.6 mmol)And 1.5 g of 2-boronic acid benzothiophene (8.43 mmol)Add to a 50 mL round bottom flask and then add 15 mL of 1,4-dioxane.Then 0.15 g of catalyst Pd(DPPF)2Cl2 was added.Pumping air immediately,The reaction was then heated to 90 C and stirred under nitrogen for 10 h.After the reaction was completed, the reaction solution was cooled to room temperature.Use thin plate chromatography to check for reaction,The resulting mixed solution was spin-dried using a rotary evaporator.The crude product was mixed with petroleum ether/ethyl acetate in a volume ratio of 100:1.The eluent is separated and purified by silica gel column chromatography.After drying in vacuum,0.46 g of the first intermediate 5-fluoro-2-pyridinebenzothiophene was obtained as a white powder.The yield was 35.4%.

Reference： [1]Patent: CN108997434,2018,A .Location in patent: Paragraph 0036; 0037; 0053

80
[ 941294-54-8 ]
[ 50488-42-1 ]
2-methoxy-5-[5-(trifluoromethyl)-2-pyridyl]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		To 123 5-bromo-2-methoxypyridine-3-carbonitrile (300 mg, 1.41 mmol), 195 bis(pinacolato)diboron (393 mg, 1.55 mmol), 125 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (51.5 mg, 0.0704 mmol) and 196 potassium acetate (415 mg, 4.23 mmol) was added 126 1,4-dioxane (2.4 mL), and the mixture was stirred with heating by using a microwave reactor at 120C for 30 min. To the reaction mixture were added 197 <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (318 mg, 1.41 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (51.5 mg, 0.0704 mmol) and 1 mol/L aqueous sodium carbonate solution (2.4 mL), and the mixture was stirred with heating by using a microwave reactor at 100C for 30 min. To the reaction mixture was added 79 ethyl acetate, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The desiccant was filtered off, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the 198 title compound (370 mg, 1.32 mmol, 94%). MS (ESI) m/z 280 (M+H)+

Reference： [1]Patent: EP3412664,2018,A1 .Location in patent: Paragraph 0176

81
[ 50488-42-1 ]
[ 785762-99-4 ]

Reference： [1]Patent: CN108997202,2018,A

82
[ 50488-42-1 ]
[ 374538-01-9 ]
C₁₃H₇F₄NO [ No CAS ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 5672 - 5676

83
[ 25225-13-2 ]
[ 50488-42-1 ]
N-[2-(adamantan-1-yloxy)ethyl]-5-(trifluoromethyl)pyridin-2-amine [ No CAS ]
N-[2-(adamantan-1-yloxy)ethyl]-5-(trifluoromethyl)-N-[5-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%; 10%	With copper(l) iodide; 2-(2-methyl-1-oxopropyl)cyclohexanone; caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 24h;Schlenk technique;	General procedure: a. Palladium(0)-catalyzed reactions. A Schlenk flask was charged with Pd(dba)2 (1-8 mol %, 2.9-23 mg), phosphine ligand (1.25-9 mol %), and bromopyridine2-8 (0.5 mmol), and 5 mL of dioxane, amine 1 or 21 (0.625 mmol), and sodium tert-butoxide(0.75 mmol, 72 mg) were added. The mixture was refluxed for 12 h with stirring and cooled to room temperature, the organic phase was separated, the precipitate was washed with methylene chloride (5 mL),and the organic phase was combined with the washings and evaporated under reduced pressure. The residue was dissolved in methylene chloride (5 mL), and the solution was washed with water (3 × 5 mL), dried over 4A molecular sieves, and thoroughly evaporated under reduced pressure (1 mm). b. A Schlenk flask was charged with copper(I)iodide (10 or 20 mol %, 9.5 or 19 mg), 2-isobutyrylcyclohexanone(20 or 40 mol %, 17 or 34 mg), and bromopyridine 2-8 (0.5 mmol), and 1 mL of DMF,amine 1 or 21 (0.5 mmol), and cesium carbonate(0.75 mmol, 250 mg) were added. The mixture was heated for 24 h at 140C with stirring and cooled to room temperature, the organic phase was separated,and the residue was washed with methylene chloride(5 mL). The organic phase was combined with the washings and evaporated under reduced pressure, the residue was dissolved in methylene chloride (5 mL),and the solution was washed with water (3 × 5 mL),dried over 4A molecular sieves, and thoroughly evaporated under reduced pressure (1 mm). The spectral parameters of compounds 9, 16 [21], 22, and 29 [26]were consistent with published data
36%; 46%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; In 1,4-dioxane; at 100℃; for 12h;Schlenk technique;	General procedure: a. Palladium(0)-catalyzed reactions. A Schlenk flask was charged with Pd(dba)2 (1-8 mol %, 2.9-23 mg), phosphine ligand (1.25-9 mol %), and bromopyridine2-8 (0.5 mmol), and 5 mL of dioxane, amine 1 or 21 (0.625 mmol), and sodium tert-butoxide(0.75 mmol, 72 mg) were added. The mixture was refluxed for 12 h with stirring and cooled to room temperature, the organic phase was separated, the precipitate was washed with methylene chloride (5 mL),and the organic phase was combined with the washings and evaporated under reduced pressure. The residue was dissolved in methylene chloride (5 mL), and the solution was washed with water (3 × 5 mL), dried over 4A molecular sieves, and thoroughly evaporated under reduced pressure (1 mm). b. A Schlenk flask was charged with copper(I)iodide (10 or 20 mol %, 9.5 or 19 mg), 2-isobutyrylcyclohexanone(20 or 40 mol %, 17 or 34 mg), and bromopyridine 2-8 (0.5 mmol), and 1 mL of DMF,amine 1 or 21 (0.5 mmol), and cesium carbonate(0.75 mmol, 250 mg) were added. The mixture was heated for 24 h at 140C with stirring and cooled to room temperature, the organic phase was separated,and the residue was washed with methylene chloride(5 mL). The organic phase was combined with the washings and evaporated under reduced pressure, the residue was dissolved in methylene chloride (5 mL),and the solution was washed with water (3 × 5 mL),dried over 4A molecular sieves, and thoroughly evaporated under reduced pressure (1 mm). The spectral parameters of compounds 9, 16 [21], 22, and 29 [26]were consistent with published data

Reference： [1]Russian Journal of Organic Chemistry,2019,vol. 55,p. 737 - 747
Zh. Org. Khim.,2019,vol. 55,p. 829 - 840,12
[2]Russian Journal of Organic Chemistry,2019,vol. 55,p. 737 - 747
Zh. Org. Khim.,2019,vol. 55,p. 829 - 840,12

84
[ 112275-50-0 ]
[ 50488-42-1 ]
tert-butyl 4-[5-(trifluoromethyl)pyridin-2-yl]-1,4-diazepane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90℃; for 16h;Sealed tube; Inert atmosphere;	A solution of <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (1 g, 4.42 mmol, 1.00 eq.), /<?/7-butyl l,4-diazepane-l-carboxylate (1.1 g, 5.49 mmol, 1.20 eq.) NaOtBu (1.28 g, 3.00 eq.), BINAP (140 mg, 0.22 mmol, 0.05 eq.), and Pd2(dba)3 (200 mg, 0.22 mmol, 0.05 eq.) in toluene (20 mL) was stirred in a 30-mL sealed tube under N2 for 16 h at 90 C in an oil bath. The reaction mixture was then diluted with water and extracted with 2x50 mL EtOAc. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc / hexane (1/1) to afford 1.2 g (79 %) of the title compound as an off-white solid. LC-MS: (ES, m/z ): 346.15.

Reference： [1]Patent: WO2019/140188,2019,A1 .Location in patent: Paragraph 0150

85
[ 57260-71-6 ]
[ 50488-42-1 ]
4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 12h;	Dissolve <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> (11.25g, 50.0mmol) in 100mL of dry DMF.Triethylamine (10.1 mL, 100.0 mmol) and 1-Boc piperazine (11.2 mg, 60 mmol) were added, and the mixture was stirred and reacted at 80 C for 12 hours.The solvent was distilled off under reduced pressure, and the residue was dissolved in 140 mL of DCM.Washed with 80 mL of water and 50 mL of saturated saline successively.Anhydrous Na2SO4 was dried, and DCM was recovered to obtain 13.74 g of an off-white solid with a yield of 83%.

Reference： [1]Patent: CN110357833,2019,A .Location in patent: Paragraph 0030; 0032-0033

86
[ 113778-69-1 ]
[ 50488-42-1 ]
2-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%		n-Butyllithium (2.5 M in n-hexane, 22.0 mL, 44.4 mmol) was added dropwise to a - 80 C solution of 2-bromo-5-(trifluoromethyl)pyridine (5.0 g, 22.1 mmol) in THF (35 mL), and the resulting solution stirred for 10 minutes. N-methoxy-N-methylisobutyramide (3.49 g, 26.61 mmol) was added at -80 C, and the reaction mixture stirred for 1 h at -80 C. The reaction was then quenched by the addition of 40 mL of saturated aqueous ammonium chloride solution, and the mixture was allowed to warm to room temperature. The resulting solution was extracted with 3x40 mL of ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1 :7 ethyl acetate/petroleum ether) to give 2-methyl-l-(5-(trifluoromethyl)pyridin-2-yl)propan-l-one (550 mg, 8% yield) as a yellow solid. MS (ESI, m/z): 218 [M+H]+.

Reference： [1]Patent: WO2019/204550,2019,A1 .Location in patent: Paragraph 00291

87
{6-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]-2-methylpyridin-3-yl}boronic acid [ No CAS ]
[ 50488-42-1 ]
6'-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]-2'-methyl-5-(trifluoromethyl)-2,3'-bipyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 15h;	General procedure: To a mixture of2-[(5-bromo-3-methylpyridin-2-yl) oxy] methyl}-4-methoxy-3,5-dimethylpyridine (2a; 100 mg, 0.30 mmol) and 1,4-dioxane(3.0 mL) were added (4-fluorophenyl) boronic acid (83 mg,0.59 mmol), 2.0 mol/L Na2CO3 aqueous solution (0.74 mL,1.5 mmol) and PdCl2(PPh3)2 (10 mg, 0.015 mmol). The mixturewas stirred at 90C for 15 h. After cooling to room temperature,the mixture was diluted with H2O and extracted withEtOAc. The organic layer was washed with saturated NaHCO3aqueous solution and brine, dried over MgSO4 and concentratedin vacuo. The residue was purified by column chromatographyon silica gel (hexane/EtOAc) to give the product (100 mg,100%). 1H-NMR (DMSO-d6) delta: 2.19 (3H, s), 2.23 (3H, s), 2.26(3H, s), 3.76 (3H, s), 5.43 (2H, s), 7.24-7.34 (2H, m), 7.66-7.75(2H, m), 7.86-7.92 (1H, m), 8.21 (1H, s), 8.26-8.33 (1H, m);MS m/z: 353 (M + H)+

Reference： [1]Chemical and pharmaceutical bulletin,2020,vol. 68,p. 77 - 90

88
[ 375853-82-0 ]
[ 50488-42-1 ]
tert-butyl 5-(trifluoromethyl)-1,2,3,6-tetrahydro-[2,4-bipyridine]-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.2%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; toluene; at 85℃; for 3h;Sealed tube; Inert atmosphere;	In a 30-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (600 mg, 2.655 mmol, 1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-l-carboxylate(l .5 g, 4.820 mmol, 1.82 eq), Pd(dppf)Cl2 (196 mg, 0.268 mmol, 0.10 eq), Na2C03 (565 mg, 5.331 mmol, 2.01 eq), toluene (4 mL), H20 (0.8 mL). The resulting solution was stirred for 3 h at 85 C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether. This resulted in 800 mg (91.2%) of tert-butyl 5- (trifluoromethyl)-l,2,3,6-tetrahydro-[2,4-bipyridine]-l-carboxylate as an off-white solid.

Reference： [1]Patent: WO2019/241131,2019,A1 .Location in patent: Paragraph 00368; 00398

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P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere