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[ CAS No. 1423-27-4 ] {[proInfo.proName]}

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2D 3D

Chemical Structure| 1423-27-4

Chemical Structure| 1423-27-4

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Quality Control of [ 1423-27-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1423-27-4 ]

SDS Specification

Alternatived Products of [ 1423-27-4 ]

Product Details of [ 1423-27-4 ]

CAS No. :	1423-27-4	MDL No. :	MFCD00236059
Formula :	C₇H₆BF₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JNSBEPKGFVENFS-UHFFFAOYSA-N
M.W :	189.93	Pubchem ID :	2734387
Synonyms :

Calculated chemistry of [ 1423-27-4 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	41.27
TPSA :	40.46 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.71
Log Po/w (WLOGP) :	1.54
Log Po/w (MLOGP) :	1.37
Log Po/w (SILICOS-IT) :	0.29
Consensus Log Po/w :	0.98

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.3
Solubility :	0.942 mg/ml ; 0.00496 mol/l
Class :	Soluble
Log S (Ali) :	-2.18
Solubility :	1.27 mg/ml ; 0.00668 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.18
Solubility :	1.26 mg/ml ; 0.00665 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.62

Safety of [ 1423-27-4 ]

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

Application In Synthesis of [ 1423-27-4 ]

* 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 [ 1423-27-4 ]
Downstream synthetic route of [ 1423-27-4 ]

[ 1423-27-4 ] Synthesis Path-Upstream 1~8

1
[ 1423-27-4 ]
[ 135364-97-5 ]
[ 727-99-1 ]

Reference： [1] Organic Letters, 2017, vol. 19, # 24, p. 6510 - 6513

2
[ 6562-41-0 ]
[ 7732-18-5 ]
[ 88-16-4 ]
[ 1423-27-4 ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: With iodine; magnesium In tetrahydrofuran at 20 - 30℃; for 2.5 h; Stage #2: With ammonium chloride In tetrahydrofuran at 0℃; for 1 h;	In 250 ml three-mouth reaction flask, add 2.3 g magnesium chips, then heating and drying under the protection of nitrogen. Then 0.1 g iodine, 12.8 g bis(dimethylamino)chloroborane and 30 ml tetrahydrofuran were added to the reaction flask. Then start to drop 2.4 g 2-chloro(trifluoromethyl)benzene and 20 ml tetrahydrofuran mixed solution, stir for half an hour. Continue to drop 12.0 g of 2-chloro(trifluoromethyl)benzene and 100 ml tetrahydrofuran mixed solution. The solution temperature maintained at 20 - 30 degrees. After 2 hours addition completed. Then the mixed solution is cooled to 0 degrees, add 50 ml saturated ammonium chloride solution, continuously stirred for 1 hour. Allow to stand to separate the phases. To the aqueous phase, use 70 ml ethyl acetate to extract. The combined organic layer, for drying of magnesium sulfate, concentrated under reduced pressure. For the residue 80 mL65 °C hot ethyl acetate dissolved, then in 2 hours to cool down to room temperature, and then the 1 hours by adding 300 ml of normal hexane, stirring 3 hours, filtering to obtain 7.9 g white solid 2-trifluoromethylphenylboronic acid, yield 52percent.

Reference： [1] Patent: CN104311587, 2017, B, . Location in patent: Paragraph 0068; 0069; 0070

3
[ 121-43-7 ]
[ 392-83-6 ]
[ 1423-27-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1919 - 1922

4
[ 392-83-6 ]
[ 1423-27-4 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
[2] Patent: US6103737, 2000, A,

5
[ 5419-55-6 ]
[ 392-83-6 ]
[ 1423-27-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane	Part A. Preparation of 2-(trifluoromethyl)phenylboronic acid To a solution of 58.8 g (0.261 mol) of 1-bromo-2-(trifluoromethyl)benzene in 250 mL of THF under Ar was added 110 mL (0.275 mol) of 2.5M n-butyllithium in hexane over 35 minutes, keeping the temperature between 0-5°C. The reaction mixture was allowed to warm to 10°C. Triisopropylborate (95 mL, 0.313 mol) was added, keeping the temperature below 35°C. After 1 hour, the reaction mixture was cooled, 1N HCl (425 mL) was added, and the mixture was stirred overnight. The mixture was extracted with 100 mL of ether three times, and the combined organic extracts were extracted with 100 mL of 1N NaOH three times. The aqueous extracts were acidified to pH 1 with 6N HCl, and then extracted with 100 mL ether three times. The combined ether extracts were dried over MgSO₄, and the solvents evaporated in vacuo to give 46.1 g (93percent) of the desired compound as a light yellow oil. ¹H NMR (CDCl₃) δ: 7.77 (d, 1H); 7.72 (d, 1H); 7.56 (m, 2H); 4.87 (br s, 2H).
93%	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane	Part A. Preparation of 2-(trifluoromethyl)phenylboronic acid To a solution of 58.8 g (0.261 mol) of 1-bromo-2-(trifluoromethyl)benzene in 250 mL of THF under Ar was added 110 mL (0.275 mol) of 2.5M n-butyllithium in hexane over 35 minutes, keeping the temperature between 0-5° C. The reaction mixture was allowed to warm to 10° C. Triisopropylborate (95 mL, 0.313 mol) was added, keeping the temperature below 35° C. After 1 hour, the reaction mixture was cooled, 1N HCl (425 mL) was added, and the mixture was stirred overnight. The mixture was extracted with 100 mL of ether three times, and the combined organic extracts were extracted with 100 mL of 1N NaOH three times. The aqueous extracts were acidified to pH 1 with 6N HCl, and then extracted with 100 mL ether three times. The combined ether extracts were dried over MgSO₄, and the solvents evaporated in vacuo to give 46.1 g (93percent) of the desired compound as a light yellow oil. ¹H NMR (CDCl₃) δ: 7.77 (d, 1H); 7.72 (d, 1H); 7.56 (m, 2H); 4.87 (br s, 2H).

Reference： [1] Patent: EP946528, 2003, B1,
[2] Patent: US6187797, 2001, B1,

6
[ 392-83-6 ]
[ 1423-27-4 ]

Reference： [1] Journal of the American Chemical Society, 2006, vol. 128, # 5, p. 1434 - 1435

7
[ 1423-27-4 ]
[ 1122-91-4 ]
[ 198205-95-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 2975 - 2990
[2] Patent: WO2005/118542, 2005, A1, . Location in patent: Page/Page column 59

8
[ 3132-99-8 ]
[ 1423-27-4 ]
[ 675596-31-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 2975 - 2990

[ 1423-27-4 ] Synthesis Path-Downstream 1~88

1
[ 13162-43-1 ]
[ 1423-27-4 ]
[ 199728-08-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1063 - 1066

2
[ 1423-27-4 ]
[ 342777-09-7 ]
[ 939-57-1 ]
(E)-3-[2-(2-Trifluoromethyl-benzyl)-phenyl]-acrylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 747 - 749

3
[ 955124-75-1 ]
[ 1423-27-4 ]
[ 955124-76-2 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium carbonate;dichlorobis(tri-O-tolylphosphine)palladium; In 1,4-dioxane; water; at 90℃; for 3h;	Example 20; [002291 Preparation of (2lambda)-2-(Bro-iioinethyl)-6-fluoro-8-{2- trifluoromethyl)phenyl- chroman (R-Ib).; [00230] To a solution of (lambda)-8-bromo-2-(bromomethyl)-6-fluorochroman (0.16 g, 0.49 mmol) and 2- trifluorobenzene boronic acid (0.4 g, 2 mmol) in dioxane- water (4/1) was added dichlorobis(fr/- o- tolyphosphine)-palladium (0.2 g, 0.02 mmol) and potassium carbonate (0.17 g, 1.2 mmol) at 9O0C. The mixture was heated at 900C for 3 hours. The mixture was filtered through a pad of celite and concentrated under vacuum. ISCO CombiFlash chromatography with 0-40% ethyl acetate in hexanes afforded 0.1 1 g (57%) of the title product as a colorless oil. MS APPI m/z 388 M+.

Reference： [1]Patent: WO2007/123941,2007,A2 .Location in patent: Page/Page column 77

4
[ 101066-87-9 ]
[ 1423-27-4 ]
EM-4034 [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5529 - 5532

5
[ 947513-65-7 ]
[ 1423-27-4 ]
C₂₇H₂₀NO₄F₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With potassium fluoride;bis(tri-t-butylphosphine)palladium(0); In 1-methyl-pyrrolidin-2-one; at 80℃; for 24h;	Example 157; This example concerns the synthesis of Triaryl 53: To a pressure vessel containing 30 (36.2 mg, 0.0980 mmol), was sequentially added KF (51.2 mg, 0.880 mmol), 0-CF3-C6H4-B(OH)2 (74.5 mg, 0.390 mmol), (J-Bu3P)2Pd (2.5 mg, 0.0050 <n="211"/>mmol), and NMP (0.98 mL). The solution was sealed under Ar and heated to 80C. After 24 h, the reaction was quenched with sat. aq. NH4Cl (5 mL), diluted with EtOAc (15 mL), and washed with H2O (10 mL) and sat. aq. NaCl (10 mL). The dried extract (MgSO4) was concentrated in vacuo and purified by chromatography over silica gel, eluting with 3-5% EtOAc / Hexanes followed by recrystallization with Et2O / Hexanes (2:1) to give 55 (10.1 mg, 0.0210 mmol, 22%) as a yellow crystalline solid. MP 102-1040C; IR (neat) 3063, 2933, 1530 cnT1; 1H NMR (300 MHz, CDCl3) delta 7.78 (dd, J= 2.4, 7.2 Hz, IH), 7.57-7.52 (m, 2H), 7.47 (dd, J= 1.8, 7.8 Hz, IH), 7.34-7.28 (m, 5H), 7.24 (d, J= 8.4 Hz, IH), 6.59 (dd, J= 2.4, 8.4 Hz, IH), 6.55 (d, J= 2.4 Hz, IH), 5.01 (s, 2H), 3.82 (s, 3H); 13C NMR (100 MHz,CDCl3) delta 161.2, 156.6, 150.1, 136.7, 135.4, 132.3, 132.1, 131.3, 131.2, 131.1, 130.9, 129.9, 129.8, 129.3, 128.5, 128.4, 127.6, 126.9, 126.4, 126.3, 1 19.0, 105.4, 100.5, 70.5, 55.4; HRMS (EI+) calcd. for C27H20F3NO4 (M+) 479.1344, found 479.1323.

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 9857 - 9865
[2]Patent: WO2008/156656,2008,A2 .Location in patent: Page/Page column 69-71; 209-210

6
[ 22717-55-1 ]
[ 1423-27-4 ]
[ 1261822-70-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; CyJohnPhos;palladium diacetate; In toluene; at 80℃; for 12h;	1. 3-HYDROXY-2'-TRIFLUOROMETHYL-BIPHENYL-4-CARBOXYLIC ACID METHYL ESTER To a solution of 2- (trifluoromethyl)-phenylboronic acid (5.4 g, 0.03 mol), 2- (dicyclohexylphosphino) biphenyl (133 mg, 0.38 mmol), and potassium phosphate (8.1 g, 0.038 mmol) in toluene, add palladium (II) acetate (43 mg, 0.190 mmol). Purge the reaction mixture for 10 minutes with dry nitrogen and then add 4-chloro-2-hydroxybenzoic acid methyl ester. Heat the stirring reaction mixture overnight at 80C, cool the mixture and filter through celite using ethyl acetate. Concentrate under reduced pressure, take up in fresh ethyl acetate and wash the solution with NAHC03 (saturated aqueous). Dry the solution (NA2SO4), concentrate under reduced pressure and then filter through a pad of silica gel using ethyl acetate as eluent. Removal of solvent under reduced pressure gives 3-hydroxy-2'- TRIFLUOROMETHYL-BIPHENYL-4-CARBOXYLIC acid methyl ester as an oil.

Reference： [1]Patent: WO2004/56774,2004,A2 .Location in patent: Page 57

7
[ 651780-27-7 ]
[ 1423-27-4 ]
[ 668970-58-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 35h;	Toluene (40 mL) was added to a flask containing ethyl [6-BROM-1,] 2-benzisoxazole-3-carboxylate (3.15 g, 11.7 mmol), tetrakis (triphenylphosphine) palladium [(0)] (835 mg, 0.723 mmol, Strem), cesium carbonate (4.12 g, 12.6 mmol, Aldrich), and 2- (trifluoromethyl) phenylboronic acid (2. [38] g, 12.5 mmol, Aldrich) under argon. This mixture was heated in a 100 C oil bath for 35 hours. The mixture was diluted with EtOAc (250 mL) and washed with 4: 1 water: brine (250 [ML)] followed by brine (250 mL). The organics were filtered through a [1"PLUG] of silica gel and evaporated. Product was split in two, adsorbed onto silica gel, and purified on Biotage Flash 40 M+ silica cartridges using 20% EtOAc in heptane. Yield was 2.08 g of orange solid. ['H] NMR (400 MHz, DMSO-d6) [5] ppm 1.42 (t, [J=7.] 15 Hz, 3 H) 4.51 (q, [J=7.] 05 Hz, 2 H) 7.52 (d, J=7. 46 Hz, [1] H) 7.51 (d, [J=8.] 09 Hz, 1 H) 7.71 (t, J=7. 57 Hz, [1] H) 7.79 (t, [J=7.] 36 Hz, 1 H) 7.91 (d, [J=7.] 67 Hz, [1] [H)] 7.93 (s, 1 H) 8.14 (d, J=8. 09 Hz, 1 H).

Reference： [1]Patent: WO2004/18428,2004,A1 .Location in patent: Page 153-154

8
[ 786654-97-5 ]
[ 1423-27-4 ]
ethyl 2-[2'-(trifluoromethyl)-1,1'-biphenyl-3-yl]-1,3-thiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 85℃; for 16h;	To a solution OF 3-BROMOBENZAMIDE (0. 81g, 4 mmol) in tetrahydrofuran (5 ML) was added Lawesson's reagent (1.79 g, 4.4 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified by column chromatography using 10 % EtOAc in hexanes to give 3-BROMOTHIOBENZAMIDE (0. 625 g, 71 % yield) as a yellow solid. To a solution of the THIOAMIDE (0.50 g, 2.31 mmol) in dioxane (4 ml) was added ethyl bromopyruvate (0.587 g, 3. 01 mmol). The mixture refluxed for 16 hours, then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate and water, then dried over sodium sulfate, filtered and concentrated. Purification of the crude by column chromatography using 10 % EtOAc in hexanes yielded (0.45 g, 62 % ) of the ethyl 2- (3-BROMOPHENYL)-1, 3-thiazole-4-carboxylate as a syrup. To a solution of the above ester (0.149 g, 0.4 mmol) in toluene (1.5 ML) were added 2- TRIFLUROMETHYLPHENYLBORONIC acid (0.135 g, 0.71 mmol), tetrakis (triphenylphosphine) palladium (0. 01 g) and 2M potassium carbonate (0.48 ml, 0. 95 mmol). The reaction was heated at 85 C for 16 hours in a sealed tube, then cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification of the crude by column chromatography using 10 % EtOAc in hexanes gave ethyl 2- [2 - (TRIFLUOROMETHYL)-1, 1 -BIPHENYL-3-YL]-1, 3-thiazole-4-carboxylate (0.14 g, 89%) as a syrup. 'HNMR (CDCL3) (8, ppm) : 8. 19 (S, 1H), 8.03 (d, 1H), 8. 01 (s, 1H), 7.79 (d, 1HO, 7. 61 (t, 1H), 7.60-7. 52 (m, 2H), 7.45 (d, 1H), 7.41 (d, 1 H), 4.47 (q, 2 H), 1.45 (t, 1H). MS (ESI) : 378.0 (MA

Reference： [1]Patent: WO2004/94395,2004,A2 .Location in patent: Page 38, 39

9
[ 1423-27-4 ]
[ 148547-19-7 ]
[ 473264-00-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 3h;Heating / reflux;	A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 3 g; 13.10 mmol; 1 eq.), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (Aldrich 393606; 2.74 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.51 g; <n="63"/>1.31 mmol; 0.10 eq.) in toluene (15 ml_) and water (15 ml_) was refluxed for 3 hours. The resulting mixture was filtered through a short pad of Celite, which was further washed with toluene. After evaporation of the solvent, the residue was taken up in ethyl acetate and washed successively with sat. aq. NaHCC>3, water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (3.7 g, 96%) as a brown oil. HPLC (Method A) : Rt 5.34 min (purity 70.9%). LC/MS : 294.9 (M+H)+.
	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In ethanol; hexane; dichloromethane; water; toluene;	Step B. (2-Methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)carboxylic acid methyl ester A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL: 25 mL: 25 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol) the reaction was heated at 100 C. overnight. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous. sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient of 25% to 50% dichloromethane in hexane provided 2.0 g of the title compound as a colorless oil. 1H NMR (DMSO-d6, 400 MHz): delta2.03 (s, 3H), 3.88 (s, 3H), 7.26 (d, 1H), 7.34 (d, 1H), 7.66 (t, 1H), 7.75 (t, 1H), 7.81-7.83 (m, 1H), 7.86-7.88 (m, 1H), 7.90-7.91 (m, 1H). MS [(+)ESI, m/z]: 312[M+NH4]+. Anal. Calcd. for C16H13F3O2: C, 65.31, H, 4.45. Found: C, 64.92, H, 4.54.
	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In ethanol; hexane; dichloromethane; water; toluene;	Step B. 2-Methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-carboxylic Acid Methyl Ester A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol, the reaction was heated at 100 C. overnight. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient of 25% to 50% dichloromethane in hexane provided 2.0 g of the title compound as a colorless oil. 1H NMR (DMSO-d6, 400 MHz): delta 2.03 (s, 3H), 3.88 (s, 3H), 7.26 (d, 1H), 7.34 (d, 1H), 7.66 (t, 1H), 7.75 (t, 1H), 7.81-7.83 (m, 1H), 7.86-7.88 (m, 1H), 7.90-7.91 (m, 1H). MS [(+)ESI, m/z]: 312 [M+NH4]+. Anal. Calcd. for C16H13F3O2: C 65.31, H 4.45. Found: C 64.92, H 4.54.

	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In ethanol; hexane; dichloromethane; water; toluene;	Step B. (2-Methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)-carboxylic acid methyl ester A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol) the reaction was heated at 100 C. overnight. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient of 25% to 50% dichloromethane in hexane provided 2.0 g of the title compound as a colorless oil. 1H NMR (DMSO-d6, 400 MHz): delta2.03 (s, 3H), 3.88 (s, 3H), 7.26 (d, 1H), 7.34 (d, 1H), 7.66 (t, 1H), 7.75 (t, 1H), 7.81-7.83 (m, 1H), 7.86-7.88 (m, 1H), 7.90-7.91 (m, 1H) MS [ESI, m/z]: 312 [M+NH4]+. Anal. Calcd. for C16H13F3O2: C, 65.31; H, 4.45. Found: C, 64.92; H, 4.54.
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 3h;Heating / reflux;	Methyl 4-bromo-3-methylbenzoate (ABCR. 3 g; 13.10 mmol; 1 eq.), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (2.736 g; 14.41 mmol; 1 .10 eq.), potassium carbonate (9.049 g; 65.48 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) were mixed in Toluene (15 ml_) and water (15 ml_) under N2 atmosphere. The reaction mixture was degassed with N2for 10 min and was heated under reflux for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (500 ml_). The filtrate was concentrated under vacuum to afford brown oil. It was taken in EtOAc (500 ml_). The organic layer was washed with a saturated aqueous solution of NaHCO3 (200 ml_), water (200 ml.) and brine (200 ml_). It was dried over MgSO4, filtered off and concentrated under vacuum giving a brown oil (3.7 g, 96%). It was used in the next step without further purification. LC/MS (Method A): 294.5 (M+H)+. HPLC (Method A) Rt 5.34 min.
5.61 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;	Reference Example 11 [0605] [0606] A mixture of methyl 4-bromo-3-methylbenzoate (4.58 g), [1,1?-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (1.46 g), potassium carbonate (11.0 g) and <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (7.60 g) was stirred in DMF (100 mL) at 80 C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with a mixed solvent of ethyl acetate-toluene (1:1) and filtered. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 11-1 (5.61 g). N-Bromosuccinimide (2.06 g) and benzoyl peroxide (133 mg) were added to a solution of compound 11-1 (3.07 g) in carbon tetrachloride (47 mL) and the mixture was heated to reflux for 6 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 11-2 (4.05 g) as a crude product. The crude product (3.78 g) of compound 11-2 was dissolved in acetic acid (73 mL), sodium acetate (4.17 g) was added thereto, and the mixture was heated to reflux for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to give a residue, to which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 11-3 (2.39 g). Compound 11-3 (2.04 g) was dissolved in a mixed solvent of tetrahydrofuran-methanol (1:1) (40 mL), 1N aqueous solution of sodium hydroxide (23 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 25 hours. The reaction solution was acidified by addition of 2N aqueous solution of hydrochloric acid, concentrated under reduced pressure and ethyl acetate and 1N aqueous solution of hydrochloric acid were added. The organic layer was extracted, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue, which was azeotropically distilled with toluene to give compound 11-4 (1.69 g). Compound 11-5 (89 mg) was prepared from compound 11-4 (94 mg) in the same manner as the second step of Reference Example 9. Compound 11-1: 1H-NMR (CDCl3) delta 2.08 (s, 3H), 3.94 (s, 3H), 7.22 (d, J=8.1 Hz, 2H), 7.50 (t-like, J=7.6 Hz, 1H), 7.59 (t-like, J=7.1 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.88 (md, J=7.9 Hz, 1H), 7.94 (m, 1H). Compound 11-2: 1H-NMR (CDCl3) delta 3.96 (s, 3H), 4.04 (d, J=10.4 Hz, 1H), 4.40 (d, J=10.4 Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.52-7.64 (m, 2H), 7.79 (d, J=7.3 Hz, 1H), 7.99 (dd, J=8.0, 1.7 Hz, 1H), 8.21 (d, J=1.7 Hz, 1H). Compound 11-3: 1H-NMR (CDCl3) delta 2.00 (s, 3H), 3.94 (s, 3H), 4.81 (AB q, JAB=22.8 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 7.48-7.59 (m, 2H), 7.76 (d, J=7.2 Hz, 1H), 8.00 (dd, J=8.0, 1.7 Hz, 1H), 8.14 (d, J=1.3 Hz, 1H). Compound 11-4: 1H-NMR (CDCl3) delta 4.42 (AB q, JAB=23.0 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.50-7.61 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 8.05 (dd, J=8.0, 1.6 Hz, 1H), 8.34 (s, 1H). [0607] Compound 11-5: 1H-NMR (CDCl3) delta 4.83 (AB q, JAB=20.4 Hz, 2H), 7.27 (d, J=7.5 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.50-7.61 (m, 2H), 7.77 (d, J=7.2 Hz, 1H), 8.08 (dd, J=7.9, 1.8 Hz, 1H), 8.21 (d, J=1.7 Hz, 1H).

Reference： [1]Patent: WO2009/43890,2009,A1 .Location in patent: Page/Page column 61-62
[2]Patent: US2003/8863,2003,A1
[3]Patent: US2003/18026,2003,A1
[4]Patent: US2003/55047,2003,A1
[5]Patent: WO2009/43889,2009,A2 .Location in patent: Page/Page column 114
[6]Patent: US2013/116227,2013,A1 .Location in patent: Paragraph 0605; 0606; 0607
[7]ChemMedChem,2015,vol. 10,p. 688 - 714
[8]Journal of Medicinal Chemistry,2016,vol. 59,p. 1800 - 1817

10
[ 626-05-1 ]
1,2-diamino-2-methlypropane [ No CAS ]
[ 1423-27-4 ]
[ 207557-35-5 ]
[ 521268-21-3 ]

Yield	Reaction Conditions	Operation in experiment
	In tert-butyl methyl ether;	Example 138 (2S)-1-({1,1-Dimethyl-2-[6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamino]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, Methansolfonic Acid Salt This compound was obtained in analogy to example 36, steps A] to C] starting from 2,6-dibromopyridine, 1,2-diamino-2-methlypropane, 2-trifluoromethyl-phenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in tert-butyl methyl ether and precipitated by treatment with methanesulfonic acid yielding a white powder. MS (ISP): 446.4 (MH+).

Reference： [1]Patent: US2003/130281,2003,A1

11
[ 624-28-2 ]
1,2-diamino-2-methlypropane [ No CAS ]
[ 1423-27-4 ]
[ 207557-35-5 ]
[ 521267-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	In tert-butyl methyl ether;	Example 121 (2S)-1-({1,1-Dimethyl-2-[5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamino]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, Methansolfonic Acid Salt This compound was obtained in analogy to example 36, steps A] to C] starting from 2,5-dibromopyridine, 1,2-diamino-2-methlypropane, 2-(trifluoromethyl)-phenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in tert-butyl methyl ether and precipitated by treatment with methanesulfonic acid yielding a white powder. MS (ISP): 446.3 (MH+).

Reference： [1]Patent: US2003/130281,2003,A1

12
[ 328918-33-8 ]
[ 1423-27-4 ]
[ 247940-06-3 ]
[ 328918-90-7 ]
[ 328919-12-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride;palladium diacetate; In tetrahydrofuran;	A. 2-Methyl-2-(4-{2-[5-methyl-2-(2'-trifluoromethyl-biphenyl-4-yl)-oxazol-4-yl]-ethoxy}-phenoxy)propionic acid ethyl ester A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2-trifluoromethylphenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 mumol), and 2-(dicyclohexylphosphino)biphenyl (12.3 mumol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.47 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) delta7.98 (d, J=8.4 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 6.80-6.73 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 554.1 (M+H)+.

Reference： [1]Patent: US6417212,2002,B1

13
[ 13162-43-1 ]
[ 1423-27-4 ]
[ 497-19-8 ]
[ 199728-08-0 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In ethyl acetate; benzene;	Part A: To a solution of <strong>[13162-43-1]4,6-dichloro-2-methyl-5-nitropyrimidine</strong> (3.12 g, 15 mmol, J. Chem. Soc 3832 (1954); ibid 677 (1944)) and 2-(trifluoromethyl)phenylboronic acid (3.42 g, 18 mmol) in benzene (50 ml) was added 1M aqueous sodium carbonate (20 ml) and 500 mg of tetrakis(triphenylphosphine)palladium. This mixture was refluxed for 4.5 hours, then was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (10% then 20% ethylacetate in hexanes) afforded 4-Chloro-2-methyl-5-nitro-6-(2-(trifluoromethyl)phenyl)-pyrimidine (1.90 g) as a pale yellow solid. CI Mass Spec. (M+H)+ =318.0.

Reference： [1]Patent: US6103737,2000,A

14
[ 1423-27-4 ]
[ 84358-13-4 ]
[ 881391-42-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	With water; dimethyl dicarbonate;palladium diacetate; P(p-CH3OC6H4)3; In tetrahydrofuran; at 20℃;	PREPARATION 8; SYNTHESIS OF PIPERIDIN-4-YL-(2-TRIFLUOROMETHYLPHENYL)METHANONEA.; To a 50-mL flask was charged with Lambda/-Boc-isonipecotic acid (0.916 g, 4.000 mmol), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (0.835 g, 4.400 mmol), palladium acetate (0.030 g, 0.12 mmol) and tris-(4-methoxyphenyl)phosphane (0.100 g, 0.280 mmol). THF (16 mL), dimethyl dicarbonate (DMDC) (1.600 g, 12 mmol) and water (190 muL, 10 mmol) were added by syringe. The reaction mixture was purged with nitrogen and stirred at ambient temperature overnight, then concentrated in vacuo. The product was isolated by column chromatography. Yield 0.812 g, 57%.

Reference： [1]Patent: WO2006/34338,2006,A1 .Location in patent: Page/Page column 48

15
[ 942411-15-6 ]
[ 1423-27-4 ]
(RS)-N-(ethoxycarbonyl)-S-(4-[4-[(R)-2-hydroxy-1-methylethyl]amino}-5-(2-trifluoromethylphenyl)pyrimindin-2-yl]amino}phenyl)-S-methylsulfoximide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 0.25h;Microwave irradiation;	Example 4.2; (RS)-N-(ethoxycarbonyl)-S-(4-[4-[(R)-2-(hydroxy-1-methylethyl]amino}-5-(2- trifluormethylphenyl)pyrimindin-2-yl]amino}phenyl)-S-methylsulfoximide; <n="224"/>(RS)-N-(ethoxycarbonyl)-S-(4-[4-[(R)-2-(hydroxy-1-methylethyl]amino}-5-iodo- pyrimindin-2-yl]amino}phenyl)-S-methylsulfoximide (80 mg, 0.15 mmol), 2-tri- fluorophenylboronic acid (41.6 mg, 0.22 mmol), toluene (1.6 ml), ethanol(1.6 ml), palladium tetrakistriphenylphosphine (10.7 mg, 0.01 mmol) and sodium carbonate (0.3 ml, 1 M) are filled into a microwave tube and reacted under nitrogen for 15 mins at 120 0C. For the work-up, the reaction mixture is poured into dilute sodium carbonate solution and extracted with ethyl acetate (3x). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated under vacuum. After chromatographic purification, 34 mg (41 %) of the desired product are obtained.1H-NMR (DMSO): 9.76 (bs, 1 H), 8.03 (d, 2H), 7.83 (d, 1 H), 7.77 (d, 2H), 7.72 (t, 1 H), 7.62 (m, 2H), 7.39 (t, 1 H), 5.62 (dd, 1H), 4.66 (q, 1H), 4.25 (m, 2H), 3.88 (m, 2H), 3.38 (s, 3H), 3.28 (m, 2H), 1.06 (m, 6H). MS: 538 (MH+).
41%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 120℃; for 0.25h;Microwave irradiation;	(RS)-N-(ethoxycarbonyl)-S-(4-[4-[(R)-2-(hydroxy-1-methylethyl]amino}-5-iodo-pyrimindin-2-yl]amino}phenyl)-S-methylsulfoximide (80 mg, 0.15 mmol), 2-tri-fluorophenylboronic acid (41.6 mg, 0.22 mmol), toluene (1.6 ml), ethanol (1.6 ml), palladium tetrakistriphenylphosphine (10.7 mg, 0.01 mmol) and sodium carbonate (0.3 ml, 1 M) are filled into a microwave tube and reacted under nitrogen for 15 mins at 120 C. For the work-up, the reaction mixture is poured into dilute sodium carbonate solution and extracted with ethyl acetate (3×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated under vacuum. After chromatographic purification, 34 mg (41%) of the desired product are obtained. 1H-NMR (DMSO): 9.76 (bs, 1H), 8.03 (d, 2H), 7.83 (d, 1H), 7.77 (d, 2H), 7.72 (t, 1H), 7.62 (m, 2H), 7.39 (t, 1H), 5.62 (dd, 1H), 4.66 (q, 1H), 4.25 (m, 2H), 3.88 (m, 2H), 3.38 (s, 3H), 3.28 (m, 2H), 1.06 (m, 6H). MS: 538 (MH+).

Reference： [1]Patent: WO2007/71455,2007,A1 .Location in patent: Page/Page column 222-223
[2]Patent: US2007/232632,2007,A1 .Location in patent: Page/Page column 90; 91

16
[ 1423-27-4 ]
[ 589-15-1 ]
2-phenyl-4-(2'-trifluoromethyl-biphenyl-4-ylmethyl)-thiomorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃;	2-Phenyl-4-(2'-trifluoromethyl-biphenyl-4-ylmethyl)-thiomorpholine; <n="42"/>1 OOmg of 105mg of 4-Bromobenzyl bromide was combined with 82mg of 2-(Trifluoromethyl)phenyl boronic acid, 33mg of tetrakis(triphenylphosphine)palladium(0), 0.96ImL of 2M sodium carbonate solution, 2.6mL toluene and 1.3mL ethanol. The reaction mixture was heated in a sealed tube at 120C overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 414, 75% yield.

Reference： [1]Patent: WO2007/70760,2007,A2 .Location in patent: Page/Page column 40-41

17
1-(4-bromo-benzyl)-3-phenyl-piperidine [ No CAS ]
[ 1423-27-4 ]
3-phenyl-1-(2'-trifluoromethyl-biphenyl-4-ylmethyl)-piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃;	3 -Phenyl- 1 -(2'-trifluoromethyl-bipheny l-4-ylmethyl)-piperidine; lOOmg of l-(4-Bromo-benzyl)-3-phenyl-piperidine was combined with 862mg of 2- (Trifluoromethyl)phenyl boronic acid, 35mg of tetrakis(triphenylphosphine)palladium(0), 1.015mL of 2M sodium carbonate solution, 2.7mL toluene and 1.4mL ethanol. The reaction mixture was heated in a sealed tube at 120C overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 396, 100% yield

Reference： [1]Patent: WO2007/70760,2007,A2 .Location in patent: Page/Page column 43

18
(4-bromophenyl)-(2-phenyl-morpholin-4-yl)-methanone [ No CAS ]
[ 1423-27-4 ]
(2-phenyl-morpholin-4-yl)-(2'-trifluoromethyl-biphenyl-4-yl)-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃;	(2-Phenyl-morpholin-4-yl)-(2'-trifluoromethyl-biphenyl-4-yl)-methanone ;<n="46"/>lOOmg of (4-Bromo-phenyl)-(2-phenyl-morpholin-4-yl)-methanone was combined with 82mg of 2-(Trifluoromethyl)phenyl boronic acid, 33mg of tetrakis(triphenylphosphine)palladium(0), 0.968mL of 2M sodium carbonate solution, 2.6mL toluene and 1.3mL ethanol. The reaction mixture was heated in a sealed tube at 1200C overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 412, 97% yield.

Reference： [1]Patent: WO2007/70760,2007,A2 .Location in patent: Page/Page column 44-45

19
[ 1064137-50-3 ]
[ 1423-27-4 ]
[ 1064136-95-3 ]

Yield	Reaction Conditions	Operation in experiment
73.7%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 100℃; for 5h;	A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.9948 g, 8.8243 mmol), 2- (trifluoromethyl)phenylboronic acid (1.8436 g, 9.7067 mmol), tetrakis(triphenyl- phosphine)palladium (0.50985 g, 0.44121 mmol), and sodium carbonate anhydrous (4.6763 g, 44.121 mmol) in 88 mL Of CH3CN-H2O (3:1) was stirred at 100 0C. After 5 hr, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL x 2), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 30 min as eluent to give 5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 10.01 (1 H, s), 9.19 (1 H, d, J=LO Hz), 8.08 - 8.14 (1 H, m), 7.97 - 8.03 (2 H, m), 7.89 - 7.95 (1 H, m), 7.73 - 7.84 (2 H, m), 7.55 - 7.61 (1 H, m); LC-MS (ESI) m/z 336.1 [M+H]+.

Reference： [1]Patent: WO2008/118454,2008,A2 .Location in patent: Page/Page column 82

20
[ 1065483-00-2 ]
[ 1423-27-4 ]
[ 1065483-37-5 ]

Yield	Reaction Conditions	Operation in experiment
85.61%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 100℃; for 13.5h;	5-Chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline; A mixture of 3,5-dichloro-2-methylquinoxaline (1.1209 g, 5.261 mmol),2- (trifluoromethyl)phenylboronic acid (1.099 g, 5.787 mmol), tetrakis(triphenyl- phosphine)palladium (0.3040 g, 0.2630 mmol), and sodium carbonate anhydrous (2.788 g, 26.30 mmol) in 53 mL of CH3CN-H2O (3:1) was stirred at 1000C.After 13.5 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 20 min as eluent to give 5-chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline as a red solid: 1H NMR (400 MHz, DMSO-(I6) delta ppm 8.09 (1 H, dd, J=8.4, 1.4 Hz), 8.02 (1 H, dd, J=7.6, 1.2 Hz), 7.98 (1 H, d, J=7.8 Hz), 7.73 - 7.92 (4 H, m), 2.47 (3 H, s); LC-MS (ESI) m/z 323.0 [M+H]+.

Reference： [1]Patent: WO2008/118468,2008,A1 .Location in patent: Page/Page column 143

21
[ 1021860-50-3 ]
[ 1423-27-4 ]
[ 1021860-52-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate;dichlorobis(tri-O-tolylphosphine)palladium; In 1,4-dioxane; water; at 90℃; for 0.75h;	To a solution of 3-(azidomethyl)-5-bromo-7-chloro-3,4-dihydro-2H-l,4- benzoxazine or 3-(azidomethyl)-5-bromo-7-fluoro-3,4-dihydro-2H-l,4-benzoxazine (1.0 eq) and substituted benzene boronic acid (2-4 eq) in dioxane-water (4/1) was added dichlorobis(£?-O-tolylphosphine)-palladium (II) (0.05 eq) and potassium carbonate (2.5 eq). The reaction mixture was heated at 900C for 45 min. The mixture was filtered through a pad of celite. The filtrate was then extracted with ethyl acetate, the organic extract washed once with water, treated with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. ISCO CombiFlash chromatography with (9:1) hexanes-ethyl acetate afforded the title product as an oil; 3-(Azidomethyl)-7-chloro-5-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-l,4- benzoxazine Starting with 3-(azidomethyl)-5-bromo-7-chloro-3,4-dihydro-2H-l,4- benzoxazine (0.094 g, 0.31 mmol) and 2-(trifluoromethyl)phenyl boronic acid (0.246 g, 1.3 mmol), 0.085 g (74%) of the title product was obtained as an oil. MS (ES) m/z 367.0 [M-H]".

Reference： [1]Patent: WO2008/52075,2008,A2 .Location in patent: Page/Page column 99

22
[ 1060673-22-4 ]
[ 1423-27-4 ]
[ 1060673-23-5 ]

Yield	Reaction Conditions	Operation in experiment
39%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 72h;	Example 5 3-({7-[2-(trifluoromethyl)phenyl]imidazo[1,2-a]quinoxalin-4-yl}amino) propan-1-ol Tetrakis(triphenylphosphine)palladium (11 mg, 0.009 mmol, 0.1 eq), 3-(7-Bromo-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (30 mg, 0.093 mmol, 1 eq), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (19 mg, 0.102 mmol, 1.1 eq), potassium carbonate (51 mg, 0.372 mmol, 4 eq) are stirred under argon in a mixture of degassed water / 1,2-dimethoxyethane (1 mL / 1 mL) at 80c for 3 days. Evaporation of 1,2-dimethoxyethane, partition (water / ethyl acetate), extraction of the aqueous phase (two times ethyl acetate), reunion of the organic phases, drying over magnesium sulfate and purification over silicagel on prep TLC (eluent: dichloromethane / methanol 90:10) affords the title compound as an off-white solid (14 mg, 0.036 mmol, 39%). 1H NMR (CD3OD), delta (ppm): 8.46 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.69-7.62 (m, 4H), 7.51 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1 H), 3.84 (t, J = 6.7 Hz, 2H), 3.78 (t, J = 6.1 Hz, 2H), 2.02 (qt, J = 6.4 Hz, 2H) ESI-MS m/z 387 (M+H)+

Reference： [1]Patent: EP1972629,2008,A1 .Location in patent: Page/Page column 20-21

23
[ 1052271-60-9 ]
[ 1423-27-4 ]
[ 1059098-47-3 ]

Yield	Reaction Conditions	Operation in experiment
7%	With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 24.0h;Heating / reflux;	Example 11; 8-(2-(trifluoromethyl)phenyl)H-imidazo[1,5-a]pyridine8-bromo-H-imidazo[1,5-a]pyridine (example 12) (0.1 g, 0.5 mmol, 1 eq) was dissolved in 10 mL of DME and kept under an argon atmosphere. To that solution [Pd(PPh3)4] (0.025 mmol, 0.05 eq), 2-(trifluoromethyl)phenyl)boronic acid (0.142 g, 0.75 mmol, 1.5 eq) and an aqueous NaOH solution (0.2M, 5 mL) were added under stirring. The resulting mixture was refluxed for 24 h. After cooling, the mixture was diluted with water and the aqueous layer was extracted with CHCl3. The organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. Semi-preparative HPLC-chromatography afforded the pure product.Yield: 0.009 g (7%), 1H-NMR, 500 MHz, CDCl3: delta 6.97-6.98 (m, 1H); 7.05 (bs, 1H); 7.27 (bs, 1H); 7.41-7.42 (m, 1H); 7.61-7.67 (2H); 7.84-7.85 (m, 1H) 8.41 (bs, 1H); 9.55 (bs, 1H) MS: m/z 263.2 [M+H]+; HPLC: Method [B]. (214 nm), rt: 6.80 min (86.6%)

Reference： [1]Patent: US2008/234313,2008,A1 .Location in patent: Page/Page column 29

24
[ 1055880-27-7 ]
[ 1423-27-4 ]
[ 1055880-33-5 ]

Yield	Reaction Conditions	Operation in experiment
84.0%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 95℃; for 12h;Inert atmosphere;	Example 12; 9-[2-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride; (1) tert-butyl 9-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate; A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-trifluoromethylphenylboronic acid (173 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95C for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (200 mg, 84.0%) as an oil. 1H-NMR (CDCl3) delta; 1.43 (9H, s), 3.71-3.74 (2H, m), 3.83-3.85 (2H, m), 4.46-4.52 (2H, m), 7.00-7.56 (6H, m), 7.73 (1H, d, J = 8.1 Hz).

Reference： [1]Patent: EP2123644,2009,A1 .Location in patent: Page/Page column 50-51

25
[ 1423-27-4 ]
[ 157026-18-1 ]
[ 1221349-85-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃; for 18h;Inert atmosphere;	D. 5-Nitro-3,2'-bis-trifluoromethyl-biphenyl-4-ylamine4-Bromo-2-nitro-6-trifluoromethyl-phenylamine (10.0 g, 35.2 mmol, as prepared in the previous step), 2-trifluoromethylphenylboronic acid (8.70 g, 45.8 mmol), and (dppf)PdCl2 DCM (1.44 g, 1.76 mmol) were placed in a 500 mL round-bottom flask equipped with a magnetic stir bar and reflux condenser. The flask was evacuated and backflushed with Ar. DME (150 mL) and 2M aq Na2CO3 (50.0 mL, 100 mmol) were added via cannula. The mixture was stirred at 90 0C for 18 h. The mixture was cooled to RT, diluted with EtOAc (100 mL), then washed with water (100 mL) and brine (100 mL). The combined aqueous layers were extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified on an 80-g pre-packed SiO2 column eluting with EtOAc/hexanes, 0: 1 to 1 :4, v/v over 30 min, yielding 11.3 g (92 %) of the title compound. 1H-NMR (400 MHz, CDCl3) delta: 8.35 (d, J = 2.0 Hz, IH), 7.78 (d, J = 7.8 Hz, IH), 7.74 (s, IH), 7.61 (t, J = 7.2 Hz, IH), 7.53 (t, J = 7.6 Hz, IH), 7.33 (d, J = 7.6 Hz, IH), 6.75 (br. s., 2H).

Reference： [1]Patent: WO2010/45166,2010,A1 .Location in patent: Page/Page column 50-51
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 233 - 247

26
[ 875-51-4 ]
[ 1423-27-4 ]
[ 1221349-90-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃; for 16h;Inert atmosphere;	Example 6 S-IT-Chloro-S-Cl-trifluoromethylpheny^-lH-benzimidazol-l-ylJ-l-oxa-l-aza- spiro[4.5]dec-2-ene hydrochloride (Cpd 16)A. 3-Nitro-2'-trifluoromethyl-biphenyl-4-ylamine4- Bromo-2-nitroaniline (10.1 g, 46.7 mmol), 2-trifluoromethylphenylboronic acid (1.3 eq., 11.5 g, 60.7 mmol), and (dppf)PdCl2-DCM (0.05 eq., 1.91 g, 2.34 mmol) were placed in a 500 mL round-bottom flask equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and DME (180 mL) and 2M aq Na2CO3 (60 mL) were added via syringe. The flask was capped tightly, and the reaction was stirred at 90 0C for 16 h. The reaction was cooled to RT, diluted with EtOAc, and washed sequentially with water and brine. The organic extract was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was dry-loaded onto 25 g of SiO2 and purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 20 min, yielding 12.8 g (97 %) of the desired compound. 1H-NMR (400 MHz, CDCl3) delta: 8.11 (d, J = 2.0 Hz, IH), 7.75 (d, J = 7.8 Hz, IH), 7.54 - 7.62 (m, J = 7.6 Hz, IH), 7.44 - 7.53 (m, J = 7.8 Hz, IH), 7.36 (dd, J = 8.6, 1.3 Hz, IH), 7.33 (d, J = 7.6 Hz, IH), 6.84 (d, J = 8.6 Hz, IH).
	With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃;Inert atmosphere;	A solution of 4-bromo-2-nitro-phenylamine (5.00 g, 0.0230 mol) in DME(100 ml_) was treated with (2-trifluoromethylphenyl) boronic acid (5.25 g, 0.0277 mol), LiCI (0.976 g, 0.0230 mol), and 2M aqueous Na2CO3 (92.1 ml_, 0.184 mol). The resulting mixture was heated to 800C under a stream of Argon, treated with Pd(PPh3)4 (2.66 g, 0.00230 mol) and heated to 800C overnight. The cooled mixture was diluted with water and extracted thrice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 200-g Sepra Si 50 SPE column (Isco system: flow rate = 40 mL/min; eluting with EtOAc/hexanes, 5:95 v/v, over 10 min, 5:95 to 20:80, v/v over 25 min, and 20:80 to 40:60 v/v over 35 min) to yield 3-nitro-2'-thfluoromethyl-biphenyl-4-ylamine as an orange solid 1H-NMR (400 MHz; CDCI3) delta: 8.1 1 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.31 - 7.39 (m, 2H), 6.85 (d, J = 8.6 Hz, 1 H), 6.16 (br. s., 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For Ci3H9F3N2O2: 283.1 (M + H), Found 283.2.
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃; for 16h;Inert atmosphere;	To a mixture of 4-bromo-2-nitroaniline (1.30 g, 6.00 mmol), 2-trifluoromethylphenylboronic acid (1.48 g, 7.80 mmol), and (dppf)PdCl2.DCM (245 mg, 0.300 mmol) under Ar was added DME (24 mL) and 2 M aqueous Na2CO3 (8.00 mL, 16.0 mmol). The resulting mixture was stirred at 90 C. for 16 h, cooled to room temperature, diluted with EtOAc (25 mL), and washed sequentially with H2O (10 mL) and brine (10 mL). The resulting solution was dried over MgSO4 and filtered. The solvent was removed under reduced pressure, and the residue was chromatographed using a 80-g SiO2 pre-packed column eluting with 0:1 to 2:3 EtOAc-hexanes to yield an orange solid. 1H-NMR (400 MHz, CDCl3) delta: 8.11 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.54-7.62 (m, J=7.6 Hz, 1H), 7.44-7.53 (m, J=7.8 Hz, 1H), 7.36 (dd, J=8.6, 1.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H).

Reference： [1]Patent: WO2010/45166,2010,A1 .Location in patent: Page/Page column 63
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 233 - 247
[3]Patent: WO2010/132247,2010,A1 .Location in patent: Page/Page column 63
[4]Patent: US2012/202856,2012,A1 .Location in patent: Page/Page column 35

27
[ 146015-42-1 ]
[ 1423-27-4 ]
[ 1221350-07-7 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium phosphate;2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl; palladium diacetate; In toluene; at 90℃; for 4h;Inert atmosphere;	Example 17 -(l-Oxa-2-aza-spiro[4.5]dec-2-en-3-yl)-5-(2-trifluoromethyl-phenyl)-lH- imidazo[4,5-b]pyridine hydrochloride (Cpd 56) 3-Nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamineTo a solution of 6-chloro-2-nitro-pyridin-3-ylamine (143 mg, 1.00 mmol), 2- trifluoromethylphenylboronic acid (285 mg, 1.50 mmol) and K3PO4 (424 mg, 2.00 mmol) in toluene (5 mL) were added S-Phos (16.4 mg, 0.040 mmol) and Pd(O Ac)2 (4.49 mg, 0.020 mmol). The resulting mixture was stirred at 90 0C under Ar for 4 h. The reaction mixture was allowed to cool to rt, diluted with EtOAc (20 mL) and filtered through a pad of Celite. The filtrate was concentrated, and the resulting residue was purified on silica (EtOAc/hexanes, 0: 1 to 1 : 1 v/v) to obtain the title compound (130 mg, 46 %). 1H-NMR (400 MHz, CDCl3) delta: 8.39 (d, J = 8.3 Hz, IH), 7.70 (d, J = 7.8 Hz, IH), 7.46 - 7.62 (m, 2H), 7.39 (d, J = 7.6 Hz, IH), 6.76 (d, J = 8.6 Hz, IH).

Reference： [1]Patent: WO2010/45166,2010,A1 .Location in patent: Page/Page column 88-89

28
[ 1227466-99-0 ]
[ 1423-27-4 ]
[ 1227467-10-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium phosphate;monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 20℃; for 48h;	Example 37: 3-(Azetidin-3-yloxy)-2'-trifluoromethyl-biphenyl-4-carboxylic acid diethylamide; Step A: Preparation of 3-(4-Formyl-2'-trifluoromethyl-biphenyl-3-yloxy)- azetidine-1-carboxylic acid tert-butyl ester. To the title compound of Example 1 Step B (0.20 g, 0.56 mmol), 2-trifluoromethylphenylboronic acid (0.16 g, 0.84 mmol), K3PO4 (0.357 g, 1.68 mmol) Pd(dba)2 (0.013 g, 0.022 mmol) and Q-Phos (0.008 g, 0.011 mmol) was added PhCH3. After 48h at rt the reaction was diluted with EtOAc and filtered through a small silica pad. Silica gel chromatography (0-30% EtOAc in hexanes) gave 0.24 g (99% yield) of the title compound. MS (ESI): mass calcd. for C22H22F3NO4, 421.15; m/z found, 336.1 [M-56]+, 444.1 [IvRNa]+. 1H NMR (CDCI3): 10.53 (d, J = 0.7 Hz, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.61 (t, J = 7.3 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 6.59 (s, 1 H), 4.99 (tt, j = 6.4, 4.0 Hz, 1 H), 4.37-4.29 (m, 2H), 4.11 -4.08 (m, 2H), 1.45 (s, 9H).

Reference： [1]Patent: WO2010/59390,2010,A1 .Location in patent: Page/Page column 61-62

29
[ 1227467-01-7 ]
[ 1423-27-4 ]
[ 1227467-02-8 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium phosphate;monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In toluene; at 80℃; for 18h;	Step E: Preparation of 3-(4-Methoxy-2'-trifluoromethyl-biphenyl-3-yloxy)- azetidine-1-carboxylic acid tert-butyl ester. To title compound of Step D (0.106 g, 0.296 mmol), 2-thfluoromethylphenylboronic acid (0.084 g, 0.444 mmol), K3PO4 (0.189 g, 0.888 mmol), Pd(dba)2 (0.007 g, 0.012 mmol) and QPhos (0.004 g, 0.006 mmol) was added PhCH3 (3 ml_) and the reaction was heated to 80 0C for 18h. The reaction was cooled to rt, diluted with EtOAc, filtered through a small silica plug and concentrated. Silica gel chromatography (0- 30% EtOAc in hexanes) gave 0.062 g (49%) of the title compound. MS (ESI): mass calcd. TOr C22H24F3NO4, 423.17; m/z found, 368.1 [M-56]+, 446.2 [IvRNa]+. 1H NMR (CDCI3): 7.73 (d, J = 7.8 Hz, 1 H), 7.55 (t, J = 7.3 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 6.93 (s, 2H), 6.56 (s, 1 H), 4.92-4.83 (m, 1 H), 4.26 (dd, J = 10.5, 6.5 Hz, 2H), 4.10 (dd, J = 10.5, 4.3 Hz, 2H), 3.93 (s, 3H), 1.43 (s, 9H).

Reference： [1]Patent: WO2010/59390,2010,A1 .Location in patent: Page/Page column 44-45

30
[ 201230-82-2 ]
[ 1239679-31-2 ]
[ 1423-27-4 ]
[ 1239673-18-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In toluene; at 80℃;	Step 32-{2 -°x°-5 '-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3 '-indolj-l '(2 'H)- ylfbenzonitrile2-(5'-iodo-2'-oxospiro[l,3-dioxane-2,3'-indol]-l'(2'H)-yl)benzonitrile (16.5Og, 38.18mmol), trans- dichlorobis(triphenylphosphine)palladium(II) (0.803g, 1.15mmol), K2CO3 (15.82g, 114.54mmol), and boronic acid (8.43g, 45.82mmol) were added to a flask fitted with a reflux condenser, a septum inlet, and a magnetic stir bar. The flask was flushed with carbon monoxide and then charged with toluene (20 mL). The mixture was then stirred at 80 C under an atmosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis (hexane:EtOAc::l:l) indicated reaction to be complete, so reaction mixture was diluted with EtOAc, washed with H2O, followed by brine. The organic layer was dried over Na2SO4, concentrated and then purified by flash chromatography on silica gel to afford the product as a white solid (16.8g, 92%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 479.1 (M+H).

Reference： [1]Patent: WO2010/90680,2010,A1 .Location in patent: Page/Page column 45; 52

31
[ 14348-38-0 ]
[ 1423-27-4 ]
[ 1243559-24-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; cesium fluoride;palladium diacetate; In 1,4-dioxane; water; at 90℃;Inert atmosphere of N2;	A mixture of methyl 4-bromo-3-hydroxybenzoate (Combi-Blocks CA-4189, 4.00 g, 17.3 mmol), 2-(trifluoromethyl)phenylboronic acid (3. 95 g, 20.8 mmol), cesium fluoride (7.90 g, 52 mmol), palladium(ll) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (426 mg, 1.05 mmol) was prepared in dioxane (40 ml.) and water (20 ml.) under N2 atmosphere. The reaction mixture was heated at 900C. After 90 minutes, additional amounts of 2-(trifluoromethyl)phenylboronic acid (1.90 g, 10 mmol), palladium(ll) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (426 mg, 1.05 mmol) were added. After 45 additional minutes, additional amounts of 2-(trifluoromethyl)phenylboronic acid (2.7 g, 14.2 mmol), palladium(ll) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (426 mg, 1.05 mmol) were added. After 15 hours, the reaction mixture was cooled at RT, diluted with MTBE (200 ml_), and then washed with water (30 ml.) and brine (50 ml_). The aqueous layers were extracted with MTBE (100 ml_). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc / heptane), the title compound was obtained as a yellow oil (5.03 g containing 12%w/w of DCM). HPLC (Method A), Rt: 3.6 min (purity: 98.8%). UPLC/MS, M+(ESI): 297.0, M-(ESI): 295.0.

Reference： [1]Patent: WO2010/100142,2010,A1 .Location in patent: Page/Page column 65

32
[ 1423-27-4 ]
[ 148547-19-7 ]
[ 473264-01-6 ]

Yield	Reaction Conditions	Operation in experiment
92%		A mixture of methyl 4-bromo-3-methylbenzoate (20.0 g, 87.3 mmol), 2-(trifluoromethyl)benzeneboronic acid (24.9 g, 131.0 mmol), potassium carbonate (24.1 g, 174.6 mmol) and bis(tricyclohexylphosphine)palladium (II) dichloride (64.5 mg, 0.09 mmol) was prepared in dioxane (200 mL) and water (50 mL) under N2 atmosphere. The mixture was heated at 1000C for 3 hours. A 5N aqueous solution of NaOH (100 mL) was added and the reaction mixture was stirred at 1000C for one additional hour. The reaction mixture was cooled at RT and the aqueous layer was removed. The organic layer was filtered through a Celite pad, concentrated until 75 ml under reduced pressure, diluted with water (125 ml) and washed with MTBE (2x200 mL). The aqueous layer was acidified with a 5N aqueous solution of HCI (25 ml, pH~1 ) and extracted with MTBE (2x100 ml). The organic layers were combined, dried (Na2SO4) and filtered through a Celite pad. The solution was concentrated until 100 mL, then heptane was added (200 mL). The mixture was concentrated until 100 mL. The precipitate was filtered off and rinsed twice with heptane, then dried under reduced pressure to give the title compound as a white powder (22.5 g, 92%). HPLC (Method A), Rt 4.4 min (purity: 100%). LC/MS (Method B): 279.0 (M-H)". 1H NMR (DMSO-d6, 300 MHz) delta 13.00 (s, 1 H), 7.87 (m, 2H), 7.80 (dd, J=7.9, 1.6 Hz, 1 H), 7.75 (m, 1 H), 7.64 (m, 1 H), 7.34 (d, J=7.6 Hz, 1 H), 7.23 (d, J=7.9 Hz, 1 H), 2.02 (s, 3H).
92%		Intermediate 4: 2-methyl-2'-(trifluoromethyl)biphenyl-4-carboxylic acidA m i x t u r e o f m e t h y l 4-bromo-3-methylbenzoate (20 g, 87 mmol), 2- (trifluoromethyl)benzeneboronic acid (24.9 g, 1 31 mmol), potassium carbonate (24 g, 1 75 mmol) and bis(tricyclohexylphosphine)palladium (II) dichloride (65 mg, 0.1 mmol) was prepared in dioxane (200 mL) and water (50 mL) under N2 atmosphere. The mixture was heated at 100C for 3 hours. A 5N aqueous solution of NaOH (100 mL) was added and the reaction mixture was stirred at 1 00C for one additional hour. The reaction mixture was cooled at RT and the aqueous layer was removed. The organic layer was filtered through a celite pad, concentrated until 75 mL under reduced pressure, diluted with water (125 mL) and washed with MTBE (2x200 mL). The aqueous layer was acidified to pH 1 with a 5N aqueous solution of HCI (25 mL) and extracted with MTBE (2x100 mL). The organic layers were combined, dried (Na2S04) and filtered through a celite pad. The solution was concentrated until 100 mL, then heptane was added (200 mL). The mixture was concentrated until 100 mL. The precipitate was filtered off and rinsed twice with heptane, then dried under reduced pressure to give the title compound as a white powder (22.5 g, 92%). HPLC (Method A), Rt 4.4 min (purity: 100%). LC/MS (Method B): 279.0 (M-H) 1H NMR (DMSO-d6, 300 MHz) delta 13.0 (s, 1 H), 7.87 (m, 2H), 7.80 (dd, J = 7.9, 1.6 Hz, 1 H), 7.75 (m, 1 H), 7.64 (m, 1 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 2.02 (s, 3H).
92%	With potassium carbonate;(bis(tricyclohexyl)phosphine)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere of nitrogen;	A mixture of methyl 4-bromo-3-methylbenzoate (20.0 g, 87.3 mmol), 2- (trifluoromethyl)benzeneboronic acid (24.9 g, 131.0 mmol), potassium carbonate (24.1 g, 174.6 mmol) and bis(tricyclohexylphosphine)palladium (II) dichloride (64.5 mg, 0.09 mmol) was prepared in dioxane (200 ml.) and water (50 ml.) under N2 atmosphere. The mixture was heated at 1000C for 3 hours. A 5N aqueous solution of NaOH (100 ml.) was added and the reaction mixture was stirred at 1000C for one additional hour. The reaction mixture was cooled at RT and the aqueous layer was removed. The organic layer was filtered through a Celite pad, concentrated until 75 ml under reduced pressure, diluted with water (125 ml) and washed with MTBE (2x200 ml_). The aqueous layer was acidified with a 5N aqueous solution of HCI (25 ml, pH~1 ) and extracted with MTBE (2x100 ml). The organic layers were combined, dried (Na2SO4) and filtered through a Celite pad. The solution was concentrated until 100 ml_, then heptane was added (200 ml_). The mixture was concentrated until 100 ml_. The precipitate was filtered off and rinsed twice with heptane, then dried under reduced pressure to give the title compound as a white powder (22.5 g, 92%). HPLC (Method A), Rt: 4.4 min (purity: 100%). UPLC/MS, M-(ESI): 279.0. 1H NMR (DMSO-d6, 300 MHz) delta 13.00 (s, 1 H), 7.87 (m, 2H), 7.80 (dd, J=7.9, 1.6 Hz, 1 H), 7.75 (m, 1 H), 7.64 (m, 1 H), 7.34 (d, J=7.6 Hz, 1 H), 7.23 (d, J=7.9 Hz, 1 H), 2.02 (s, 3H).

Reference： [1]Patent: WO2010/112461,2010,A1 .Location in patent: Page/Page column 83; 84
[2]Patent: WO2012/4287,2012,A1 .Location in patent: Page/Page column 67-68
[3]Patent: WO2010/100142,2010,A1 .Location in patent: Page/Page column 64-65

33
[ 1241909-60-3 ]
[ 1423-27-4 ]
[ 1241909-74-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 20h;Inert atmosphere; Reflux; sealed tube;	In a screw cap pressure tube, Lambda/-(3-bromobenzyl)-2-methyl-l,8-naphthyridine- 3-carboxamide or JV-(4-bromobenzyl)-2-methyl- 1 ,8-naphthyridine-3-carboxamide (1.0 eq.) and the corresponding boronic acid (1.4 eq.) were suspended in a mixture of toluene:EtOH (4:1). Na2CO3 (sat) (0.2 ml/ mmol aryl bromide) was added. N2 was bubbled through the mixture for 5 minutes. Pd(PPh3)4 was added. The tube was sealed and the mixture heated to reflux for 20 h. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography. (CH2Cl2/Me0H 95:5)Yield: 82%1H NMR (CDCl3) delta 9.04 (m, IH), 8.11 (s, IH), 8.10 (m, IH), 7.77 (bd, IH), 7.61-7.29 (m, 7H), 6.53 (bt, IH), 4.76 (d, 2H), 2.90 (s, 3H).
82%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 20h;Inert atmosphere; Sealed; Reflux;	General Procedure B for the Coupling of Aryl Bromides with Boronic Acids (See Scheme 10 Above).In a screw cap pressure tube, N-(3-bromobenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide or N-(4-bromobenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide (1.0 eq.) and the corresponding boronic acid (1.4 eq.) were suspended in a mixture of toluene :EtOH (4:1). Na2CO3 (sat) (0.2 ml /mmol aryl bromide) was added. N2 was bubbled through the mixture for 5 minutes. Pd(PPh3)4 was added. The tube was sealed and the mixture heated to reflux for 20 h. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography.The following substances were synthesized following the general procedure B for the coupling of aryl bromides with the corresponding boronic acid. The solvent system used for the purification, the yield and analytical data is given for each compound. Example 39 2-Methyl-N-((2'-(trifluoromethyl)biphenyl-3-yl)methyl)-1,8-naphthyridine-3-carboxamide(CH2Cl2/MeOH 95:5)Yield: 82% 1H NMR (CDCl3) delta 9.04 (m, 1H), 8.11 (s, 1H), 8.10 (m, 1H), 7.77 (bd, 1H), 7.61-7.29 (m, 7H), 6.53 (bt, 1H), 4.76 (d, 2H), 2.90 (s, 3H).

Reference： [1]Patent: WO2010/97410,2010,A1 .Location in patent: Page/Page column 66
[2]Patent: US2012/40942,2012,A1 .Location in patent: Page/Page column 28-29

34
[ 106291-80-9 ]
[ 1423-27-4 ]
[ 1243559-24-1 ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In 1,4-dioxane; water; at 90℃; for 17.25h;	A mixture of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (Combi-Blocks CA-4189, 4.00 g, 17.3 mmol), 2-(trifluoromethyl)phenylboronic acid (3. 95 g, 20.8 mmol), cesium fluoride (7.90 g, 52 mmol), palladium(ll) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (426 mg, 1.05 mmol) was prepared in dioxane (40 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was heated at 900C. After 90 minutes, additional amounts of 2-(trifluoromethyl)phenylboronic acid (1.90 g, 10 mmol), palladium(ll) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (426 mg, 1.05 mmol) were added. After 45 additional minutes, additional amounts of 2-(trifluoromethyl)phenylboronic acid (2.7 g, 14.2 mmol), palladium(ll) acetate (78 mg, 0.35 mmol) and 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (426 mg, 1.05 mmol) were added. After 15 hours, the reaction mixture was cooled to RT, diluted with MTBE (200 mL), and then washed with water (30 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (100 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc / heptane), the title compound was obtained as a yellow oil (5.03 g containing 12%w/w of DCM). HPLC (Method A), Rt 3.6 min (purity: 98.8%). LC/MS (Method B): 297.0 (M+H)+. 295.0 (M-H)".
258 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 18h;	Reference Example 8 [0599] [0600] A mixture of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (500 mg: compound 8-1), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (316 mg), potassium carbonate (1.19 g) and 2-(trifluoromethyl)phenylboronic acid (455 mg) was stirred in a mixed solvent (11 mL) of DMF-water (10:1) at 80 C. for 18 hours. The mixture was cooled to room temperature, and then aqueous solution of ammonium chloride was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to give a residue, which was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 8-2 (258 mg). Sodium hydride (60%, 22.7 mg) was suspended in DMF (2 mL) and the suspension was added dropwise to compound 8-2 (140 mg) in DMF (2 mL) at 0 C. and then the mixture was stirred at 0 C. for 20 minutes. Then, iodomethane (35 muL) was added thereto at 0 C. and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to give a residue, which was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 8-3 (130 mg). Compound 8-3 (130 mg) was dissolved in DMF (12 mL), 5N aqueous solution of sodium hydroxide (12 mL) was added thereto and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was acidified by addition of 2N aqueous solution of hydrochloric acid at 0 C. and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 8-4 (119 mg). Compound 8-2: 1H-NMR (DMSO-d6) delta 3.84 (s, 3H), 7.17 (d, J=7.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.43 (dd, J=7.9, 1.4 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.59 (t-like, J=7.6 Hz, 1H), 7.68 (t-like, J=7.6 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 9.95 (s, 1H). Compound 8-3: 1H-NMR (DMSO-d6) delta 3.74 (s, 3H), 3.88 (s, 3H), 7.27 (d, J=8.0 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.47 (dd, J=8.0, 2.0 Hz, 1H), 7.53-7.62 (m, 2H), 7.68-7.72 (m, 1H), 7.81 (d, J=7.6 Hz, 1H). Compound 8-4: 1H-NMR (DMSO-d6) delta 3.72 (s, 3H), 7.24 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.43-7.45 (m, 1H), 7.53-7.62 (m, 2H), 7.68-7.72 (m, 1H), 7.80 (d, J=7.8 Hz, 1H), 13.05 (bs, 1H).

Reference： [1]Patent: WO2010/112461,2010,A1 .Location in patent: Page/Page column 85; 86
[2]Patent: US2013/116227,2013,A1 .Location in patent: Paragraph 0599; 0600

35
[ 1141473-84-8 ]
[ 1423-27-4 ]
[ 1246527-12-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With cesium fluoride;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;	methyl 2-(methoxymethyl)-2'-(trifluoromethyl)biphenyl-4-carboxylate A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1 Step 2, 8.0 g, 30.8 mmol), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (8.8 g, 46.3 mmol), cesium fluoride (14.0 g, 92.4 mmol), palladium acetate (0.69 g, 3.1 mmol) and 2-dicyclohexylphosphino-2,6- dimethoxybiphenyl (3.16 g, 7.7 mmol) was prepared in a mixture of dioxane (80 ml.) and water (80 ml.) under nitrogen atmosphere and heated at 1000C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc (200 ml_), and then washed with water (100 ml.) and brine (100 ml_). The organic layer was dried (Na2SC>;4) and concentrated under vacuum. After purification by flash chromatography (silica, pet ether /EtOAc), the title compound was obtained as a pale yellow solid (8.0 g, 88%). 1H NMR (CDCI3, 400 MHz) delta 8.22 (1 H, s), 7.99 (1 H, d, J=6.5 Hz), 7.78 (1 H, d, J=7.7 Hz), 7.57 (2H, m), 7.27 (2H, m), 4.19-4.10 (2H, m), 3.95 (3H, s), 3.26 (3H, s).

Reference： [1]Patent: WO2010/112461,2010,A1 .Location in patent: Page/Page column 83
[2]ChemMedChem,2015,vol. 10,p. 688 - 714

36
[ 1423-27-4 ]
[ 118289-16-0 ]
[ 1261819-36-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; toluene; at 80℃; for 5h;Inert atmosphere;	16.5 ml (0.3 mmol) of an aqueous solution of potassium carbonate having a concentration of 2M and 0.4 g (0.1 mmol) of 1,1'- bis (diphenylphosphino) ferrocene palladium ( I I ) dihydro- chloride are added under a stream of nitrogen to a solution containing 2.0 g (0.1 mmol) of 2- bromopyridine-4-methanol and 2.2 g (0.1 mmol) of 2- (trifluoromethyl) phenylboronic acid in 30 ml of toluene. The mixture is stirred at 80C for 5 hours then 20 ml of water are added. After extraction with ethyl acetate, the organic phase is dried over sodium sulphate, filtered and evaporated. The residue obtained is purified by chromatography over silica gel eluted with a 60/40 heptane/ethyl acetate mixture. 2.3 g (85%) of [2- (2-trifluoromethylphenyl) pyridin-4-yl] methanol are obtained in the form of a yellow oil.

Reference： [1]Patent: WO2011/33010,2011,A1 .Location in patent: Page/Page column 43-44

37
[ 116632-24-7 ]
[ 1423-27-4 ]
[ 1332874-95-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 80℃; for 24h;Inert atmosphere;	Step A: 4-Chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine A solution of <strong>[116632-24-7]4,6-dichloro-pyridin-2-ylamine</strong> (1.00 g, 6.14 mmol) in DME (75 mL) and water (50 mL) was treated with Cs2CO3 (6.00 g, 18.4 mmol) and 2-(trifluoromethyl)phenylboronic acid (1.52 g, 7.98 mmol). The resulting mixture was degassed by heating under a stream of Ar. Cl2Pd(dppf).DCM (270 mg, 0.368 mmol) was added, and the mixture was heated to 80 C. for 24 h. The cooled mixture was diluted with EtOAc (70 mL) and washed twice with water (50 mL). The combined aqueous layers were extracted twice with EtOAc (50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE silica column (Flow rate=30 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, 1:19 to 1:3 over 40 min, then 1:3 until product eluted) to yield 4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as an off-white solid. 1H-NMR (400 MHz, CDCl3) delta: 7.74 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 6.77 (d, J=1.5 Hz, 1H), 6.53 (d, J=1.5 Hz, 1H), 4.59 (br. s., 2H). Mass Spectrum (LCMS, ESI pos.): Calculated for C12H8N2ClF3: 273.0 (M+H); Measured: 273.0.

Reference： [1]Patent: US2011/218197,2011,A1 .Location in patent: Page/Page column 49-50

38
[ 1423-27-4 ]
[ 84487-15-0 ]
[ 1332875-74-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 85℃; for 18h;Inert atmosphere;	Step A: 5-Nitro-2-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine 2-Bromo-5-nitropyridin-4-amine (561 mg, 2.57 mmol), Cs2CO3 (2.52 g, 7.72 mmol), (dppf)PdCl2.DCM (113 mg, 0.154 mmol), and 2-(trifluoromethyl)phenylboronic acid (636 mg, 3.35 mmol) were combined and flushed with Ar and anhydrous DME (24 mL) was added. H2O (8 mL) was added via syringe and the resulting mixture was stirred at 85 C. for 18 h. The resulting mixture was cooled to room temperature and diluted with EtOAc (30 mL) and the resulting solution was washed with brine (30 mL). The aqueous phase was extracted with EtOAc (3*25 mL) and the combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was chromatographed on a 40-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/hexanes to yield 5-nitro-2-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) delta: 9.17 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.56 (t, J=7.1 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.00 (br. s., 2H), 6.71 (s, 1H). Mass Spectrum (LCMS, ESI pos.): Calculated for C12H8F3N3O2: 284.1 (M+H); Measured: 284.1.

Reference： [1]Patent: US2011/218197,2011,A1 .Location in patent: Page/Page column 63

39
[ 1346702-51-9 ]
[ 1423-27-4 ]
[ 1346704-20-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 0.25h;Inert atmosphere; Microwave irradiation;	Example 112N- [(4,6-Dimethyl-2-oxo- 1 ,2-dihydro-3-pyridinyl)methyl] - 1 -( 1 -methylethyl)-6-[2- (trifluoromethyl)phenyl]-l/7-indazole-4-carboxamide In a 25 niL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo- l,2-dihydro-3-pyridinyl)methyl]-l-(l-methylethyl)-lH-indazole-4-carboxamide (100 mg, 0.24 mmol) and [2-(trifluoromethyl)phenyl]boronic acid (68.3 mg, 0.36 mmol) in dioxane/water (3 mL: l mL). PdCl2(dppf)-CH2Cl2 (9.78 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added and the insoluble mixture was heated in a microwave at 110 C for 15 min. Water was added and the solids that precipitated were filtered off. DCM/MeOH (1 : 1) was added, it was pre-absorbed on silica gel and purified by S1O2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered and dried to afford the title compound (87 mg, 74%) as an off-white solid. ¾ NMR (400 MHz, DMSO-c¾) delta ppm 1 1.52 (s, 1 H) 8.53 (t, J=4.80 Hz, 1 H) 8.43 (s, 1 H) 7.88 (d, J=7.83 Hz, 1 H) 7.81 (s, 1 H) 7.77 (t, J=7.45 Hz, 1 H) 7.66 (t, J=7.71 Hz, 1 H) 7.53 - 7.57 (m, 2 H) 5.87 (s, 1 H) 5.05 (dt, J=13.14, 6.57 Hz, 1 H) 4.35 (d, J=4.80 Hz, 2 H) 2.19 (s, 3 H) 2.10 (s, 3 H) 1.48 (s, 3 H) 1.47 (s, 3 H). MS(ES) [M+H]+ 483.0.

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 131-132

40
[ 1450-75-5 ]
[ 1423-27-4 ]
[ 893739-66-7 ]

Yield	Reaction Conditions	Operation in experiment
95%		A mixture of 5-bromo-2-hydroxy acetophenone (3.00 g, 13.9 mmol), 2-(trifluoromethyl)benzeneboronic acid (3.97 g, 20.9 mmol), potassium carbonate (3.86 g, 27.9 mmol) and tetrakistriphenylphosphinepalladium (0) (1.61 g, 1.39 mmol) in 1,4-dioxane (90 mL) and water (18.0 mL) was heated to 50 C. over 2 days under an atmosphere of nitrogen. The reaction was allowed to cool to room temperature and poured into a 1M aqueous solution of hydrogen chloride (50 mL). The aqueous layer was then extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown oil. The oil was purified by silica gel column chromatography (10% ethyl acetate in heptane) to afford the title compound as a colourless oil (3.70 g, 95%).1HNMR (CDCl3): delta 2.62 (s, 3H), 7.02 (d, 1H), 7.35 (d, 1H), 7.45 (dd, 1H), 7.49 (t, 1H), 7.59 (t, 1H), 7.72 (d, 1H), 7.77 (d, 1H)LCMS Rt=3.67 minutes MS m/z 279 [M-H]-.

Reference： [1]Patent: US2012/10182,2012,A1 .Location in patent: Page/Page column 42

41
[ 1423-27-4 ]
[ 108-98-5 ]
phenyl(2-(trifluoromethyl)phenyl)sulfane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetra(n-butyl)ammonium hydroxide; oxygen; In ethanol; water; at 25℃; for 8h;Schlenk technique; Green chemistry;	General procedure: An oven-dried Schlenk tuble equipped with a magnetic stirring bar was charged with MCM-41-1,10-Phen-CuSO4 (30 mg, 0.025 mmol), arylboronic acid (0.5 mmol), and thiol (0.75 mmol) (if solid). The tube was evacuated and filled with oxygen. Then EtOH (0.5 mL) was added by a syringe under a counter flow of oxygen. After stirring for 5 min, n-Bu4NOH (40% aq) (0.5 mL) was added by a syringe under a counter flow of oxygen. Next, thiol (0.75 mmol) (if liquid) was added by a syringe under a counter flow of oxygen. The resulting reaction mixture was stirred at 25 C for 8-24 h. The reaction mixture was then diluted with EtOAc (20 mL), and filtered. The MCM-41-1,10-Phen-CuSO4 complex was washed with distilled water (2×5 mL) and EtOH (3×5 mL), and reused in the next run. The filtrate was washed with water (2×5 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel.

Reference： [1]Tetrahedron,2016,vol. 72,p. 3335 - 3343
[2]Journal of Organic Chemistry,2012,vol. 77,p. 2878 - 2884

42
[ 1384958-64-8 ]
[ 1423-27-4 ]
[ 1386859-73-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃;Inert atmosphere;	Synthesis of Compound 3126Ethyl 2-amino-7- [2-(trifluoromethyl)phenyl] -3H- 1 -benzazepine-4-carboxylate[000202] 2-Trifluoromethylphenylboronic acid (233 mg, 1.23 mmol), ethyl-2-amino-7- bromo-3H-l-benzazepine-4-carboxylate (269 mg, 0.870 mmol), toluene (5 mL), ethanol (0.5 mL), cesium carbonate (479 mg, 1.47 mmol), and water (1 mL) were combined and the slurry was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.044 mmol) was added, the mixture degassed again, and heated in an oil bath held at 80 C overnight. The yellow slurry became a yellow solution. Assays indicate complete, reasonably clean conversion to the desired product. The reaction was filtered through a pad of magnesol, rinsing with EtOAc. The organic layer was washed with water and sat. aq. NaCI solution and dried over anhydrous Na2S04. After concentration a crude yellow solid was isolated. The solid was dissolved in nearly refluxing EtOAc, then the solution cooled, first to room temperature, then at -10 to 0 C. The filtered slurry was washed with cold EtOAc and dried to isolate 91 mg of the desired product (yield = 28%; purity = 100%). A second crop of 100 mg (yield = 30%; purity = 98%) was isolated from the filtrate after concentration and trituration with MTBE. Combined yield of two crops of desired material was 191 mg (58%). MS (ESI+) consistent for C2oHi7F3N202 (M+H)+: m/z 375.0.

Reference： [1]Patent: WO2012/97173,2012,A2 .Location in patent: Page/Page column 72

43
[ 890148-78-4 ]
[ 1423-27-4 ]
[ 1392515-26-2 ]

Reference： [1]Journal of Materials Chemistry,2012,vol. 22,p. 15620 - 15627

44
[ 109-04-6 ]
[ 1423-27-4 ]
[ 441072-21-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 70℃; for 24h;	General procedure: Tetraphenylimidodiphosphinate acid (Htpip) and potassiumtetraphenylimidodiphosphinate (Ktpip) were prepared accordingto our previous literatures [41-44]. All CF3-substituted ligandsL2L4 with a ppy core were synthesized by the reaction of thecorresponding 2-bromopyridine (21.1 mmol) and arylboronic acids(25.5 mmol) using tetrakis(triphenylphosphine)-palladium(0)(0.63 mmol) as the catalyst in 50 mL of THF. After 30 mL of aqueous2NNa2CO3 was delivered, the reaction mixturewas heated at 70 Cfor 1 day. The cooled mixture was poured into water and extractedwith CH2Cl2 (50 mL x 3). Finally, silica column purification (nhexane:EtOAc 10: 1 as the eluant) gave white solid products. 2.3.2. 2-[2-(Trifluoromethyl)phenyl]pyridine (L2)Yield: 80%. 1H NMR (CDCl3, 500 MHz): delta 7.2-7.6 (m, 4H), 7.49 (d,J 7.2 Hz, 1H), 7.55 (d, J 7.3 Hz, 1H), 7.65-7.8 (m, 1H), 8.60 (m, 1H).ESI-MS (m/z): calcd for C12H8F3N [M+H]+ 224, found 224.

Reference： [1]Inorganic Chemistry,2013,vol. 52,p. 4916 - 4925
[2]Dyes and Pigments,2017,vol. 143,p. 33 - 41
[3]Organometallics,2012,vol. 31,p. 6288 - 6296
[4]Organic Letters,2018,vol. 20,p. 1333 - 1337
[5]Journal of Materials Chemistry C,2019,vol. 7,p. 11606 - 11611

45
[ 108-86-1 ]
[ 1423-27-4 ]
[ 362-59-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; at 60℃; for 12h;	General procedure: A mixture of aryl bromide (1.0 mmol), arylboronic acid (1.5 mmol),potassium carbonate (2.0 mmol), xylene (3 mL) and the MCM-41-2N,S-Pd(0) complex (13 mg, 0.005 mmol of Pd) was stirred at 60 Cunder air for 3-12 h. The mixture was cooled and the MCM-41-2N,SPd(0) complex was filtered off. It was then washed with distilled water(2 × 10 mL), EtOH (2 × 10 mL) and Et2O (2 × 10 mL). The filtrate waspoured into a saturated aqueous NaCl solution (50 mL) and extractedwith CH2Cl2 (2 × 50 mL). The extracts were washed with water(3 × 20 mL) and dried over MgSO4. After removal of the solvent, theresidue was purified by column chromatography on silica gel usinghexane or hexane/ethyl acetate (15:1 to 20:1) as eluent.
97%Chromat.	With potassium carbonate; In 1,4-dioxane; for 1h;Inert atmosphere; Reflux;	General procedure: Under N2 atmosphere, an around-bottomed flask was charged with aryl halide (1.0 mmol), phenylboronic acid (1.2 mmol), K2CO3 (2.0 mmol), dioxane (5 mL), catalyst 3b (Pd 0.05 mol %) and n-Decane (0.9 mmol, the internal standard). The mixture was heated to reflux for the indicated time and the reaction progress was monitored by GC. After the reaction completed, the catalyst was filtered-off from the reacted mixture, washed with water, ethanol and acetone and dried overnight at 60 C in a drying oven for the next cycle.

Reference： [1]Journal of Chemical Research,2017,vol. 41,p. 186 - 191
[2]Chinese Journal of Chemistry,2012,vol. 30,p. 2151 - 2157
[3]Chinese Journal of Chemistry,2016,vol. 34,p. 373 - 380
[4]Journal of Organometallic Chemistry,2014,vol. 768,p. 23 - 27

46
[ 1423-27-4 ]
[ 4983-28-2 ]
N-(2,6-difluorobenzyl)-5-(2-(trifluoromethyl)phenoxy)pyrimidin-2-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With triethylamine;copper diacetate; In 1,4-dioxane; dichloromethane; at 20 - 80℃;Molecular sieve;	Example 66Preparation of N-(2,6-difluorobenzyl)-5-(2-(trifluoromethyl)phenoxy)pyrimidin-2-amine (126)<strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (100 mg, 0.77 mmol), [2-(trifluoromethyl)phenyl]boronic acid (213 mg, 1.12 mmol), copper (II) acetate (140 mg, 0.219 mmol), triethylamine (386 mg, 3.83 mmol) and 4-angstrom molecular sieves (750 mg) were combined in methylene chloride (9 mL) and stirred vigorously at room temperature overnight.Dioxane (5 mL) and approximately 3 equivalents each of [2-(trifluoromethyl)phenyl]boronic acid, copper (II) acetate and triethylamine were added and the mixture was heated to 80° C. for 20 minutes then cooled to room temperature while stirring overnight.The mixture was filtered and concentrated to give 263 mg of a dark brown oil which was purified by silica gel chromatography (0-15percent ethyl acetate:hexane) to afford 125 as a clear colorless oil (19 mg, 9percent). MS (M+H)=275.

Reference： [1]Patent: US2012/316182,2012,A1 .Location in patent: Page/Page column 107

47
[ 1426436-21-6 ]
[ 1423-27-4 ]
[ 1426436-51-2 ]

Yield	Reaction Conditions	Operation in experiment
97%		General procedure: NaN3 (1.2 equiv), CuSO4 (0.1 equiv), and boronic acids (1.2 equiv) in methanol (10 mL) were allowed to react for 1-4 h, followed by addition of water (10 mL), sodium ascorbate (0.5 equiv), and propargylated alpha-desmotroposantonin (1.0 equiv) [34]. The contents were stirred vigorously at room temperature for 2-8 h (as monitored by TLC analysis). After completion of the reaction, the contents diluted with water and extracted with ethyl acetate (3 times). The combined ethyl acetate extract was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure on a rota vapour. The crude product obtained thus subjected was put to column chromatography (silica gel) with EtOAc:Hexane (15:85) mixture as eluent to afford the desired pure products in >97% yields.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 60,p. 365 - 375

48
[ 59557-90-3 ]
[ 1423-27-4 ]
[ 1355680-38-4 ]

Yield	Reaction Conditions	Operation in experiment
51 mg	With tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 100℃; for 32h;	Reference Example 19 [0622] [0623] N-Bromosuccinimide (1.78 g) was added to 3,5-dimethylaniline (1.21 g) in acetonitrile (50 mL) and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure to give a residue, which was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 19-1 (1.78 g). A mixture of compound 19-1 (100 mg), tris(dibenzylideneacetone)dipalladium (0) (23 mg), 2-dicyclohexylphosphino-2?,6-dimethoxybiphenyl (41 mg), potassium phosphate (424 mg) and 2-(trifluoromethyl)phenylboronic acid (190 mg) was stirred in toluene (1.0 mL) at 100 C. for 32 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified with silica gel column chromatography (hexane/ethyl acetate) to give compound 19-2 (51 mg). Compound 19-1: 1H-NMR (CDCl3) delta 2.31 (d, J=0.5 Hz, 6H), 3.53 (bs, 2H), 6.44 (d, J=0.5 Hz, 2H). [0624] Compound 19-2: 1H-NMR (CDCl3) delta 1.85 (s, 6H), 3.59 (bs, 2H), 6.45 (s, 2H), 7.17 (d, J=7.5 Hz, 1H), 7.44 (t-like, J=7.5 Hz, 1H), 7.56 (t-like, J=7.2 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H).

Reference： [1]Patent: US2013/116227,2013,A1 .Location in patent: Paragraph 0622; 0623; 0624

49
[ 26156-48-9 ]
[ 1423-27-4 ]
[ 1261543-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In toluene; at 110℃; for 20h;Inert atmosphere;	Example 58A Methyl 2-[2-(trifluoromethyl)phenyl]isonicotinate Under an atmosphere of argon, 500 mg (2.31 mmol) of <strong>[26156-48-9]methyl 2-bromoisonicotinate</strong> and 694 mg (3.47 mmol) of 2-(trifluoromethyl)phenylboronic acid were dissolved in 10 ml of toluene. 106 mg (0.12 mmol) of tris(dibenzylideneacetone)dipalladium, 91 mg (0.23 mmol) of tri-tert-butylphosphine and 982 mg (4.63 mmol) of potassium phosphate were then added, and under argon the mixture was heated to 110 C. for 20 h. For work-up, the mixture was diluted at RT with 15 ml of ethyl acetate and 15 ml of water, the organic phase was separated off and the aqueous phase was extracted two more times with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1, then 10:1). This gave 498 mg (59% of theory) of the target compound in a purity of 77%. A second product fraction of lower purity was purified further according to Method 19. This gave a further 54 mg (8% of theory) of the target compound. LC/MS [Method 2]: Rt=2.21 min; MS [ESIpos]: m/z=282 (M+H)+.

Reference： [1]Patent: US2013/190330,2013,A1 .Location in patent: Paragraph 0498; 0499; 0500

50
[ 1423-27-4 ]
[ 87808-49-9 ]
[ 1332503-52-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In toluene; at 110℃; for 20.0h;Inert atmosphere;	Example 106A Methyl 5-methyl-2'-(trifluoromethyl)biphenyl-2-carboxylate Under argon, 500 mg (2.18 mmol) of <strong>[87808-49-9]methyl 2-bromo-4-methylbenzoate</strong> together with 655 mg (3.27 mmol) of 2-(trifluoromethyl)phenylboronic acid were dissolved in 10 ml of toluene, and 86 mg (0.22 mmol) of 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 100 mg (0.11 mmol) of tris(dibenzylideneacetone)dipalladium and 927 mg (4.37 mmol) of potassium phosphate were added successively. The mixture was heated to 110 C. and stirred at this temperature for 20 h. For work-up, the reaction mixture was allowed to cool to RT and diluted with 20 ml of ethyl acetate and 20 ml of water. After phase separation, the aqueous phase was extracted two more times with in each case 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: first cyclohexane/ethyl acetate 30:1, then 20:1). This gave 597 mg (86% of theory) of the target compound. GC/MS [Method 20]: Rt=5.55 min; MS [EIpos]: m/z=294 (M)+.

Reference： [1]Patent: US2013/190330,2013,A1 .Location in patent: Paragraph 0646; 0647; 0648

51
[ 1423-27-4 ]
[ 1837-55-4 ]
[ 1426546-06-6 ]
C₁₈H₁₀F₆N₂ [ No CAS ]
[ 1448295-29-1 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 7758 - 7763

52
[ 1423-27-4 ]
[ 1837-55-4 ]
[ 1426546-06-6 ]
[ 1448295-29-1 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 7758 - 7763

53
[ 1124382-72-4 ]
[ 1423-27-4 ]
[ 1262198-08-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4794 - 4800

54
[ 1150566-27-0 ]
[ 1423-27-4 ]
[ 1431653-84-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 130℃;Microwave irradiation;	Dioxane (anhydrous, 30 mL) and CS2CO3 (21.4 g, 65.6 mmol) were added to a mixture of <strong>[1150566-27-0]ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate</strong> (7.4 g, 32.8 mmol) and 2- (trifluoromethyl)phenylboronic acid (8.1 g, 42.6 mmol). The mixture was then added to Pd(Pli3P)4(1.9 g, 1.64 mmol), and the reaction was heated to 130 C in microwave. The mixture was filtered. After cooling to room temp, the filtrate was concentrated, and the residue was purified by column chromatography to give ethyl 6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-3-carboxylate (4.3 g, yield: 58%). MS (ESI) calcd for C16H12F3N302: 335.1.
58%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 130℃;Microwave irradiation;	Dioxane (anhydrous, 30 mL) and Cs2CO3 (21.4 g, 65.6 mmol) were added to a mixture of <strong>[1150566-27-0]ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate</strong> (7.4 g, 32.8 mmol) and 2-(trifluoromethyl)phenylboronic acid (8.1 g, 42.6 mmol). The mixture was then added to Pd(Ph3P)4 (1.9 g, 1.64 mmol), and the reaction was heated to 130 C in microwave. The mixture was filtered. After cooling to room temp, the filtrate was concentrated, and the residue was purified by column chromatography to give ethyl 6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-3-carboxylate (4.3 g, yield: 58%). MS (ESI) calcd for C16H12F3N3O2: 335.1.

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 77
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0251; 0252

55
[ 1431654-24-8 ]
[ 1423-27-4 ]
[ 1431654-25-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 120℃; for 1.5h;Microwave irradiation; Inert atmosphere;	Ethyl 6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate (750.0 mg, 2.96 mmol) and <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (562.0 mg, 2.96 mmol) were weighed into a 5 mL microwave vial. Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (97.0 mg, 0.236 mmol) and K3PO4 (1.88 g, 8.87 mmol) were added, and the mixture was suspended in dioxane (3.6 mL) and water (0.36 mL). The mixture was purged with nitrogen for 5 min., tris(dibenzylideneacetone)dipalladium(0) (108.0 mg, 0.118 mmol) was added, and the mixture purged 5 min more with nitrogen. The vial was sealed and the reaction heated to 120 C in the microwave for 1.5 h. Saturated aqueous NaHCO3(5 mL) was added and the mixture was allowed to stir 10 min, then it was extracted with EtOAc (3x 20 mL). The combined organics were washed with brine, dried with Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc in pentane) gave ethyl 7,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-3-carboxylate (726.0 mg, 68%). MS (ESI) calcd for C18H16F3N302: 363.12; found: 364 [M+H]
68%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 120℃; for 1.5h;Inert atmosphere; Sealed tube; Microwave irradiation;	Ethyl 6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate (750.0 mg, 2.96 mmol) and <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (562.0 mg, 2.96 mmol) were weighed into a 5 mL microwave vial. Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (97.0 mg, 0.236 mmol) and K3PO4 (1.88 g, 8.87 mmol) were added, and the mixture was suspended in dioxane (3.6 mL) and water (0.36 mL). The mixture was purged with nitrogen for 5 min., tris(dibenzylideneacetone)dipalladium(0) (108.0 mg, 0.118 mmol) was added, and the mixture purged 5 min more with nitrogen. The vial was sealed and the reaction heated to 120 C in the microwave for 1.5 h. Saturated aqueous NaHCO3 (5 mL) was added and the mixture was allowed to stir 10 min, then it was extracted with EtOAc (3x 20 mL). The combined organics were washed with brine, dried with Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc in pentane) gave ethyl 7,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo [1,2-b]pyridazine-3-carboxylate (726.0 mg, 68%). MS (ESI) calcd for C18H16F3N3O2: 363.12; found: 364 [M+H].

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 109; 110
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0382; 0383

56
[ 1423-27-4 ]
[ 144294-37-1 ]
[ 1431654-28-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; ethanol; water; at 75℃; for 5h;	Ethyl 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate (7.4 g, 29 mmol), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (6.6 g, 35 mmol), cesium carbonate (19.0 g, 58 mmol), Pd(PPh3)4 (3.3 g, 3 mmol) were dissolved in a mixture of dioxane: water (4:1) plus 10 drops of EtOH. The mixture was heated to 75 C for 5 h, then concentrated. Water (200 mL) was added and this was extracted with CH2Cl2 (300 mL). The organic layer was concentrated and purified on silica gel to give ethyl 2,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-3-carboxylate (8.0 g, 75%). MS (ESI) calcd for C18H16F3N302: 363.12
75%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; ethanol; water; at 75℃; for 5h;	Ethyl 6-chloro-2,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate (7.4 g, 29 mmol), <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (6.6 g, 35 mmol), cesium carbonate (19.0 g, 58 mmol), Pd(PPh3)4 (3.3 g, 3 mmol) were dissolved in a mixture of dioxane: water (4:1) plus 10 drops of EtOH. The mixture was heated to 75 C for 5 h, then concentrated. Water (200 mL) was added and this was extracted with CH2Cl2 (300 mL). The organic layer was concentrated and purified on silica gel to give ethyl 2,8-dimethyl-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-3-carboxylate (8.0 g, 75%). MS (ESI) calcd for C18H16F3N3O2: 363.12.

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 113
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0393; 0394

57
[ 1431654-56-6 ]
[ 1423-27-4 ]
[ 1431654-57-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; at 100℃; for 12h;	A solution of ethyl 2-methyl-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (9.06 g, 37.70 mmol) <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (14.25 g, 75.00 mmol), PddppfCl2 (1.51 g, 2.10 mmol), and K2CO3 (10.35 g, 75.00 mmol) in degassed dimethoxyethane (120 mL) was heated at 100 C for 12 h. The mixture was concentrated and purified by flash chromatography to give ethyl 2-methyl-5-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (11.70 g, 90% yield). MS (ESI) calcd for C17H14F3N3O2 (m/z): 349.10
90%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; at 100℃; for 12h;	A solution of ethyl 2-methyl-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (9.06 g, 37.70 mmol) <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (14.25 g, 75.00 mmol), Pd(dppfCl2 (1.51 g, 2.10 mmol), and K2CO3 (10.35 g, 75.00 mmol) in degassed dimethoxyethane (120 mL) was heated at 100 C for 12 h. The mixture was concentrated and purified by flash chromatography to give ethyl 2-methyl-5-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (11.70 g, 90% yield). MS (ESI) calcd for C17H14F3N3O2 (m/z): 349.10.

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 145
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0520; 0521

58
[ 5469-69-2 ]
[ 1423-27-4 ]
[ 1215072-76-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,3-dioxane; water; at 100℃; for 3h;	6-chloropyridazin-3-amine (10.0 g, 77.2 mmol) and <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (29.3 g, 154.4 mmol) were added to a 250 mL flask. Cs2CO3 (50.3 g, 154.4 mol), Pd2(dba)3 (3.5 g, 3.82 mmol), and XPhos (1.8 g, 3.82 mmol) were added, followed by dioxane (100 mL) and water (20 mL). The reaction was heated to 100 C for 3 h, followed by cooling to room temp. The mixture was concentrated in vacuo, and the residue was resuspended in DCM (500 mL). The organic layer was washed with bicarb (150 mL), then brine (150 mL), dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified via silica gel column chromatography (EtOAc : PE 2:1) to give 6-(2-(trifluoromethyl)phenyl)pyridazin-3-amine (14.0 g, 76%). MS (ESI) calcd for C11H8F3N3: 239.07
76%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 3h;	6-chloropyridazin-3-amine (10.0 g, 77.2 mmol) and <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong> (29.3 g, 154.4 mmol) were added to a 250 mL flask. Cs2CO3 (50.3 g, 154.4 mol), Pd2(dba)3 (3.5 g, 3.82 mmol), and XPhos (1.8 g, 3.82 mmol) were added, followed by dioxane (100 mL) and water (20 mL). The reaction was heated to 100 C for 3 h, followed by cooling to room temp. The mixture was concentrated in vacuo, and the residue was resuspended in DCM (500 mL). The organic layer was washed with bicarb (150 mL), then brine (150 mL), dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified via silica gel column chromatography (EtOAc : PE 2:1) to give 6-(2-(trifluoromethyl)phenyl)pyridazin-3-amine (14.0 g, 76%). MS (ESI) calcd for C11H8F3N3: 239.07

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 115
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0401; 0402

59
[ 3199-50-6 ]
[ 1423-27-4 ]
[ 1157857-87-8 ]

Yield	Reaction Conditions	Operation in experiment
49.6%	With tetrabutylammomium bromide; palladium diacetate; potassium carbonate; In water; at 70℃; for 3.33h;Inert atmosphere;	General procedure: Mixtures of the aryl bromides 24 or 30 (2.65mmol), the boronic acids 23a or 23b (2.23mmol), tetrabutylammonium bromide (796mg, 2.47mmol), and K2CO3 (2.9g, 21mmol) were suspended in distilled water (10mL) under argon for 20min. Then Pd(OAc)2 (9.2mg, 0.04mmol) was added, and the resulting suspensions were heated to 70C and stirred under argon for 3h. After cooling down, the solutions were diluted with distilled water (10mL) and extracted with CH2Cl2 (3×15mL). The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The crude residues were further purified by silica gel column chromatography, eluting with hexane-ethyl acetate 8:2, to provide the products 25a-b or 25d.

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 406 - 418

60
[ 3572-43-8 ]
[ 1423-27-4 ]
[ 1618645-47-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	General procedure: The reaction was carried out in an Ace-pressure tube. To a dioxane suspension (3mL) of 1 (200mg, 0.53mmol), arylboronic acids (1.60mmol), K2CO3 (1M in water, 2mL), Pd(OAc)2 (5mol%) and ligand III (S-Phos, 10mol%) were added under argon atmosphere. The pressure tube was fitted with a Teflon cap and heated at 100C (TLC control). The mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water. After removal of the solvent in vacuum, the coupling products were isolated by column chromatography in hexane/ethyl acetate.
69%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	The reaction was carried out in an Ace-pressure tube. To a dioxane suspension (3 mL) of 1 (200 mg, 0.53 mmol), arylboronic acids (1.60 mmol), K2CO3 (1 M in water, 2 mL), Pd(OAc)2 (5 mol %) and ligand III (S-Phos, 10 mol %) were added under argon atmosphere. The pressure tube was fitted with a Teflon cap and heated at 100C (TLC control). The mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water. After removal of the solvent in vacuum, the coupling products were isolated by column chromatography in hexane/ethyl acetate.

Reference： [1]Tetrahedron,2014,vol. 70,p. 5128 - 5135
[2]Tetrahedron,2014,vol. 70,p. 5128 - 5135

61
[ 1222174-92-6 ]
[ 1423-27-4 ]
[ 1617523-52-0 ]

Yield	Reaction Conditions	Operation in experiment
55%	With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium carbonate; In 1,4-dioxane; at 120.0℃; for 18.0h;	A solution of intermediate 2a (500 mg), 2-(trifluoromethyl)beneneboronic acid (650 mg), PEPPSI-Ipr (77 mg) and potassium carbonate (939 mg) in dioxane (10 mL) were heated to 120 C. for 18 h. The mixture was chilled, filtered and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Interchim cartridge50SiHP/12 g, Cy/EtOAc) to yield the desired compound (55% yield). [0378] LC-MS (Method 2): m/z [M+H]+=285.2 (MW calc.=284.23); Rt=0.83 min
55%	With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium carbonate; In 1,4-dioxane; at 120.0℃; for 18.0h;	A solution of intermediate 2a (500 mg), 2-(trifluoromethyl)beneneboronic acid (650 mg), PEPPSI -Ipr (77 mg) and potassium carbonate (939 mg) in dioxane (10 mL) were heated to 120 C for 18 h. The mixture was chilled, filtered and the volatiles were removed under reduced pressure. The residue was purified by chromatography (Interchim cartridge50SiHP / 12 g, Cy / EtOAc) to yield the desired compound (55% yield). LC-MS (Method 2): mlz [M+H]+ = 285.2 (MW calc. = 284.23); R, = 0.83 min.

Reference： [1]Patent: US2014/194452,2014,A1 .Location in patent: Paragraph 0376-0378
[2]Patent: WO2014/108336,2014,A1 .Location in patent: Page/Page column 50

62
[ 1082041-85-7 ]
[ 1423-27-4 ]
[ 1613505-03-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5129 - 5140

63
[ 1423-27-4 ]
[ 156454-43-2 ]
[ 1613505-05-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5129 - 5140

64
[ 1312008-66-4 ]
[ 1423-27-4 ]
C₁₆H₁₀ClF₃N₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5129 - 5140

65
[ 552331-16-5 ]
[ 1423-27-4 ]
[ 1613505-04-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5129 - 5140

66
(3aS,6aS)-tert-butyl 5-(((trifluoromethyl) sulfonyl)oxy)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ No CAS ]
[ 1423-27-4 ]
(3aR,6aS)-tert-butyl 5-(2-(trifluoromethyl)phenyl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 6h;Inert atmosphere;	Step F: To an degassed mixture of ( 3aS, 6aS) - tert-butyl 5- ( ( ( trifluoromethyl ) sulfonyl ) oxy) -3 , 3a, 6 , 6a-tetrahydrocyclopenta [c] yrrole-2 (1H) -carboxylate (6, 14.79 g, 41.4 mmol), 2- trifluoromethylphenylboronic acid (19.70 g, 104 mmol), and a 2 M aqueous solution of Na2C< (250 mL) in DME (500 mL) was added Pd(PPh3) (4.80 g, 4.16 mmol) . The mixture was heated at 80 C for 6 hours, then cooled to room temperature and diluted with H20 (500 mL) . The aqueous mixture was extracted wit EtOAc (2 x200 mL) and the combined organic extracts were washed with 0 (200 mL) , brine (200 mL) , dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography ( Isco CombiFlash Rf unit, 330 g Redisep column, 0% to 10% EtOAc in hexanas) to give (3ai, 6aS) - tert-butyl 5- (2~ (trifluoromethyl ) henyl ) -3 , 3a, 6 , 6a- tetrahydrocyclopenta[c]pyrrole-2 (IH) -carboxylate (7) as a clear, viscous oil (13.70 g, 94%) : NMR (500 MHz, CDClj) delta 7.65 (m, IH) , 7.47 (m, 2H) , 7.25 (m, IH) , 5.58 s, IH) , 3.85-3.42 (m, 4H) , 3.23 (ra, IH) , 2.98 (m, 2H) , 2.49 (m, IH) , 1.47 (s, 9H) .
94%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl acetamide; water; at 80℃; for 6h;	To an N2 degassed mixture of (3aS,6aS)-tert-butyl 5-)((trifluoromethyl)sulfonyl)oxy) -3, 3a, 6, 6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6, 14.79 g, 41.4 rnmol), 2-trifluoromethyiphenylboronic acid (19.70 g, 104 mrnol), and a 2 Maqueous solution of Na2CO3 (250 mL) in DM14 (500 mL) was addedPd(PPh3)4 (4.80 g, 4.16 mmol(. The mixture was heated at 80 C for 6hours, then cooled to room temperature and diluted with H20 (500mL) . The aqueous mixture was extracted wit EOOAc (2 x200 mL( and the combined organic extracts were washed with H20 (200 mL), brine (200 aD) , dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography(Isco CombiFlash Sf unit, 330 g Redisep column, 0% to 10% EtOAc in hexanes) to give (3aR, 6aS)-tert-butyl 5-(2-(trifluoromethyl)phenyl) - 3,3a,6, 6a-tetrahydrocyclopenta[c]pyrrole-2 (lH( -carboxylate (7) as a clear, viscous oil (13.70 g, 94%): ?S NMR (500 MHz, COd3) 8 7.65 (m, 1H(, 7.47 (rn, 2H(, 7.25 (m, 114), 5.58 (s, 1H), 3.85-3.42 (m, 4H),3.23 (a, 1H(, 2.98 (m, 2H(, 2.49 Cm, lH), 1.47 (s, 914).
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 6h;Inert atmosphere;	Compound 2 (0.04 M) (1 equiv) and the respective boronic acid (2.5 equiv) were stirred in a 1:2 mixture of 2 M aqueous sodium carbonate and 1 , 2-dimethoxyethane . The reaction mixture was evacuated and purqed with argon. Tetrakis ( triphenylphosphine ) palladium ( 0 ) (0.1 equiv) was added, and, the reaction mixture was evacuated and purged with argon. It was heated to and stirred at 80 C for 6 h, after which it was allowed to cool to room temperature. Ethyl acetate was added and the reaction mixture was concentrated in vacuo. An additional volume of ethyl acetate was added. The organic and aqueous layers were separated. The organic layer was washed with brine (2x) and dried with anhydrous sodium sulfate. The solvent was evaporated in vacuo. The resulting crude material was purified via normal phase silica gel column chromatography (hexanes followed by 20 % ethyl acetate in hexanes followed by ethyl acetate) .

Reference： [1]Patent: WO2014/152018,2014,A1 .Location in patent: Page/Page column 86-87
[2]Patent: WO2014/151936,2014,A1 .Location in patent: Page/Page column 86
[3]Patent: WO2019/213234,2019,A1 .Location in patent: Page/Page column 54

67
[ 25462-85-5 ]
[ 1423-27-4 ]
2-chloro-6-methyl-4-picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃;Inert atmosphere;	[0063] 1.0g of compound 6 (<strong>[25462-85-5]2-chloro-6-methyl-4-picolinic acid</strong>, from Hangzhou Banghua Imp. &Exp. Co. Ltd.), 2.21gof compound 7 (2-(trifluoromethyl) phenylboronic acid, from Shanghai Yiji Industries Co., Ltd.), K2CO3 and Pd(PPh3)Cl2were added to a reaction flask with N2 protection, followed by sequentially adding H2O, DMF, and heated to 90C,tracked by TLC. After the reaction was completed, the system was filtered. The resulting filter cake was washed withwater. The filtrate was added with water and the aqueous phase was washed with ethyl acetate and adjusted to beacidic with hydrochloric acid to precipitate a yellow solid. The yellow solid was obtained by filtration and recrystallizedwith ethanol to obtain a light yellow solid (compound 8).
	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃;Inert atmosphere;	1.0 g of compound 6 (2-chioro-6-methyl-4-pi- colinic acid, from Hangzhou l3anghua Imp. &Exp. Co. Ltd.), 2.21 g of compound 7 (2-(trifluoromethyl) phenylboronic acid, from Shanghai Yiji Industries Co., Ltd.), K2C03 and Pd(PPh3)C12 were added to a reaction flask with N2 protection, followed by sequentially adding H20, DMF, and heated to 90 C., tracked by TLC. Afier the reaction was completed, the system was filtered. The resulting filter cake was washed with watet The filtrate was added with water and the aqueous phase was washed with ethyl acetate and adjusted to be acidic with hydrochloric acid to precipitate a yellow solid. The yellow solid was obtained by filtration and recrystallized with ethanol to obtain a light yellow solid (compound 8).

Reference： [1]Patent: EP2784065,2014,A1 .Location in patent: Paragraph 0058; 0062
[2]Patent: US2015/133497,2015,A1 .Location in patent: Paragraph 0062; 0067

68
[ 25462-85-5 ]
[ 1423-27-4 ]
C₂₄H₃₀F₃N₃O [ No CAS ]

Reference： [1]Patent: EP2784065,2014,A1

69
4-bromo-9-(2-(pyrrolidin-1-yl)ethoxy)-7H-furo[3,2-g]chromen-7-one [ No CAS ]
[ 1423-27-4 ]
C₂₄H₂₀F₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.4%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 2.5h;	General procedure: A mixture of compound 3, Na2CO3, <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong>, tetrakis(triphenylphosphine)palladium, dioxane and H2O was stirred at 90 C for 2.5 h. After cooling, H2O was added in. The aqueous phase was extracted with ethyl acetate (50 x 4 mL), the combined organic phase was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/Ether (2:1), EtOAc/CH2Cl2 (2:1), and EtOAc/MeOH (10:1).

Reference： [1]Dyes and Pigments,2015,vol. 113,p. 174 - 180

70
4-bromo-9-(2-morpholinoethoxy)-7H-furo[3,2-g]chromen-7-one [ No CAS ]
[ 1423-27-4 ]
C₂₄H₂₀F₃NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.8%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 2.5h;	General procedure: A mixture of compound 3, Na2CO3, <strong>[1423-27-4]2-(trifluoromethyl)phenylboronic acid</strong>, tetrakis(triphenylphosphine)palladium, dioxane and H2O was stirred at 90 C for 2.5 h. After cooling, H2O was added in. The aqueous phase was extracted with ethyl acetate (50 x 4 mL), the combined organic phase was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/Ether (2:1), EtOAc/CH2Cl2 (2:1), and EtOAc/MeOH (10:1).

Reference： [1]Dyes and Pigments,2015,vol. 113,p. 174 - 180

71
[ 1423-27-4 ]
[ 20925-60-4 ]
4-[2-(trifluoromethyl)phenyl]-1H-indazol-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium phosphate; ((2-dicyclohexylphosphino-2',4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate); In ethanol; water; toluene; at 80℃; for 4h;Inert atmosphere;	Under argon, 4-chloro-lH-indazol-3 -amine (0.50 g, 2.98 mmol), 2-trifluoromethylphenylboronic acid (0.85 g, 4.48 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l , l '-biphenyl)[2-(2'-amino-l, - biphenyl)]palladium(II) methanesulfonate (0.07 g, 0.09 mmol) were dissolved in a degassed mixture of ethanol, water, and toluene (1 : 1 : 1 , 20 mL total volume). Potassium phosphate solution (1 M in water, degassed) (6.00 mL, 6.00 mmol) was added and the mixture was stirred at 80 C for 4 h. The mixture was concentrated in vacuo and purified by preparative HPLC (Method 1A) to yield the title compound (0.31 g, 37% of theory). LC-MS (Method IB): Rt = 0.89 min, MS (ESIPos): m/z = 278 [M+H]+
0.31 g	With potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); In ethanol; water; toluene; at 80℃; for 4h;Inert atmosphere;	Example 100A 4-[2-(Trifluoromethyl)phenyl]-1H-indazol-3-amine Under argon, <strong>[20925-60-4]4-chloro-1H-indazol-3-amine</strong> (0.50 g, 2.98 mmol), 2-trifluoromethylphenylboronic acid (0.85 g, 4.48 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.07 g, 0.09 mmol) were dissolved in a degassed mixture of ethanol, water, and toluene (1:1:1, 20 mL total volume). Potassium phosphate solution (1 M in water, degassed) (6.00 mL, 6.00 mmol) was added and the mixture was stirred at 80 C. for 4 h. The mixture was concentrated in vacuo and purified by preparative HPLC (Method 1A) to yield the title compound (0.31 g, 37% of theory). LC-MS (Method 1B): Rt=0.89 min, MS (ESIPos): m/z=278 [M+H]+

Reference： [1]Patent: WO2015/67549,2015,A1 .Location in patent: Page/Page column 117
[2]Patent: US2015/126449,2015,A1 .Location in patent: Paragraph 0646 - 0648

72
[ 1423-27-4 ]
[ 20925-60-4 ]
tert-butyl 4-{2-oxo-10-[2-(trifluoromethyl)phenyl]-1,2-dihydropyrimido[1,2-b]indazol-4-yl}piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/126449,2015,A1

73
[ 25462-85-5 ]
[ 1423-27-4 ]
C₂₄H₃₀F₃N₃O [ No CAS ]

Reference： [1]Patent: US2015/133497,2015,A1

74
[ 22348-32-9 ]
[ 1493-13-6 ]
[ 1423-27-4 ]
C₂₄H₂₁BF₃NO*CHF₃O₃S [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 5936 - 5939

75
[ 126728-20-9 ]
[ 1423-27-4 ]
2-chloro-4-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 6368 - 6371

76
[ 126728-20-9 ]
[ 1423-27-4 ]
C₁₄H₇ClF₃N₃ [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 6368 - 6371

77
[ 1423-27-4 ]
[ 135364-97-5 ]
[ 727-99-1 ]

Reference： [1]Organic Letters,2017,vol. 19,p. 6510 - 6513

78
[ 213745-17-6 ]
[ 1423-27-4 ]
4-chloro-7-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 2037 - 2041

79
[ 213744-81-1 ]
[ 1423-27-4 ]
4-chloro-7-isopropyl-5-(2-(trifluoromethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 2037 - 2041

80
[ 2065-37-4 ]
[ 1423-27-4 ]
2-(2-trifluoromethylphenyl)-1,4-naphthoquinone [ No CAS ]

Reference： [1]Journal of Materials Chemistry A,2018,vol. 6,p. 14761 - 14768

81
[ 1423-27-4 ]
[ 2255-80-3 ]
4-methyl-7-(2-trifluoromethyl-6-acetoxyphenyl)-2,1,3-benzothiadiazole [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 5692 - 5695

82
[ 1423-27-4 ]
[ 2255-80-3 ]
C₁₄H₉F₃N₂S [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 5692 - 5695

83
[ 461-89-2 ]
[ 1423-27-4 ]
2-(2-(trifluoromethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With oxygen; copper diacetate; triethylamine; In N,N-dimethyl-formamide; at 65℃; for 4h;	General procedure: To a solution of <strong>[461-89-2]6-azauracil</strong> (100 mg, 0.88 mmol) inDMF (10.0 mL) was added base (1.76 mmol) and Cu(OAc) 2(159 mg, 0.88 mmol) at room temperature. The resulting reationmixture was degassed with oxygen for 10 min and then addedarylboronic acids (0.96 mmol) at room temperature and stirredat appropriate temperature (Table-1) under oxygen atmosphere.The reaction mixture was diluted with water (15 mL) andextracted with dichloromethane (3 × 15 mL). The organic layerwashed with H 2 O (15 mL), brine solution (15 mL), dried overNa 2 SO 4 and concentrated. The obtained crude product waspurified by column chromatography (0 to 10 % CH 3 OH/CH 2 Cl 2 )to afford the title compounds.

Reference： [1]Asian Journal of Chemistry,2018,vol. 30,p. 2495 - 2501

84
[ 2178-24-7 ]
[ 1423-27-4 ]
C₁₇H₁₅F₃O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 138 - 142

85
[ 1092114-59-4 ]
[ 1423-27-4 ]
3-[2-(trifluoromethyl)phenyl]-1H-indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;	Dioxane : water (2.4:0.6 ml) mixture was added to a round bottom flask containing compound 15 (250 mg). Added the boronic acid (248 mg) and K2C03 (386 mg) to the flask. Allowed it to degas for 15 min. Then added the Palladium catalyst (37 mg) to the reaction mixture. Allowed it to degas again for 5 min. Refluxed the reaction mixture at 1 10C for 2 hrs. Reaction progress was monitored by TLC and LCMS. Once complete, the reaction mixture was filtered through celite. Washed thoroughly with ethyl acetate (EA). Extracted the crude compound with EA from aqueous phase. Washed the ethyl acetate layer with brine solution and dried over Na2S04. Crude material was purified by Yamazen purification system using 15% ethylacetate : heptane mixture as eluent. 180mg of the desired solid compound 16 was obtained. (0555) 1 H NMR (300 MHz, DMSO-d6): ppm delta 1 1.96 (s, 1 H), 7.88 (d, 1 H), 7.73 - 7.78 (m, 2H), 7.52 - 7.66 (m, 4H), 7.50 (d, 1 H).

Reference： [1]Patent: WO2019/57660,2019,A1 .Location in patent: Page/Page column 221

86
[ 918504-27-5 ]
[ 1423-27-4 ]
N-(2,4-difluoro-3-(5-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 0.75h;Microwave irradiation; Inert atmosphere;	N-[3-(5-bromo-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1 - sulfonamide (0.120 g, 0.262 mmol), [2-(trifluoromethyl)phenyl]boronic acid (0.0547 g, 0.288 mmol) and Potassium Carbonate (0.0734 g, 0.524 mmol) were suspended in 1 ,4-dioxane (0.900 mL) and water (0.450 ml_) and degassed with argon for 5 min. XPhos Pd G3 (0.01 1 1 g, 0.0131 mmol) was added and the mixture was heated to 1 10C in a microwave oven for 45min at SOW. The crude was filtered over a pad of Celite, flushed with EtOAc and the filtrate was washed with sat., aq. NH4CI solution. The organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure and the product was purified applying flash chromatography using DCM/MeOH (100/0 v/v to 97/3 v/v) as eluent. Analytical data: 1H NMR (600 MHz, DM80-efe) d 13.07 (s, 1 H), 9.76 (s, 1 H), 8.39 (s, 1 H), 8.35 (d, J = 1.7 Hz, 1 H), 8.29 (d, J = 1 .5 Hz, 1 H), 7.90 (d, J = 7.9 Hz, 1 H), 7.78 (t, J = 7.5 Hz, 1 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.61 - 7.54 (m, 2H), 7.28 (t, J = 8 6 Hz, 1 H), 3.14 - 3.10 (m, 2H), 1.78 - 1.70 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). Calculated exact mass for C24H18F5N303S: 523.1 (molecular weight: 523.48) MS(ESP): 521 .9 for [M-H] .

Reference： [1]Patent: WO2020/16243,2020,A1 .Location in patent: Page/Page column 102; 103

87
[ 307353-32-8 ]
[ 1423-27-4 ]
methyl 5-(hydroxymethyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In ethanol; at 85℃;	2-(Trifluoromethyl)phenyl)boronic acid (114 mg, 0.60 mmol), PdCl2(dppf) (12 mg, 0.016 mmol), Et3N (167 muL, 1.2 mmol) were added to a solution of <strong>[307353-32-8]methyl 3-bromo-5-(hydroxymethyl)benzoate</strong> (97.5 mg, 0.40 mmol) in EtOH (4 mL). The reaction mixture was stirred at 85 C. overnight, diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc=0-60% gradient) to afford the title compound (100 mg, 80%). 1H NMR (400 MHz, CDCl3) delta 8.09 (s, 1H), 7.95 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.56 (m, 3H), 7.33 (d, J=7.6 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H), 3.94 (s, 3H), 1.79 (t, J=6.0 Hz, 1H).

Reference： [1]Patent: US2020/102288,2020,A1 .Location in patent: Paragraph 0393

88
[ 1423-27-4 ]
[ 384-22-5 ]

Reference： [1]Organic Letters,2020

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P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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