[ CAS No. 344591-91-9 ] {[proInfo.proName]}

Name: 344591-91-9|(1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid|97%
Brand: Ambeed
SKU: A153990
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Quality Control of [ 344591-91-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 344591-91-9 ]

SDS Specification

Alternatived Products of [ 344591-91-9 ]

Product Details of [ 344591-91-9 ]

CAS No. :	344591-91-9	MDL No. :	MFCD08701785
Formula :	C₅H₆BF₃N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XPUNXPPXMANQGF-UHFFFAOYSA-N
M.W :	193.92	Pubchem ID :	12056713
Synonyms :

Calculated chemistry of [ 344591-91-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.4
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	38.32
TPSA :	58.28 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.42 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.09
Log Po/w (WLOGP) :	0.27
Log Po/w (MLOGP) :	-0.56
Log Po/w (SILICOS-IT) :	-1.02
Consensus Log Po/w :	-0.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.25
Solubility :	10.9 mg/ml ; 0.056 mol/l
Class :	Very soluble
Log S (Ali) :	-0.87
Solubility :	26.3 mg/ml ; 0.135 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.58
Solubility :	51.2 mg/ml ; 0.264 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.16

Safety of [ 344591-91-9 ]

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

Application In Synthesis of [ 344591-91-9 ]

* 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 [ 344591-91-9 ]
Downstream synthetic route of [ 344591-91-9 ]

[ 344591-91-9 ] Synthesis Path-Upstream 1~4

1
[ 154471-65-5 ]
[ 344591-91-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 3 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane	2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid: 1-methyl-3-trifluoromethyl-1H-pyrazole (1.00 g, 6.66 mmol) was dissolved in THF (25 mL) in an oven-dried round bottom flask and cooled to-78 °C in an acetone/dry ice bath. 2.5 M n-butyl lithium/hexane (3.196 ml, 7.99 mmol) was added drop wise to the stirred solution followed by drop wise addition of triisopropyl borate (5.01 g, 26.64 mmol). The mixture was warmed to room temperature and stirred for three hours. The reaction mixture was adjusted to pH 6 with IN HCl solution followed by the removal of THF under vacuum. The aqueous phase was extracted with EtOAc (3x100 ml). The combined organic phase was washed with brine and dried over anhydrous MgS0(sub>4^{, filtered and evaporated to give 2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid (1.12 g, 5.80 mmol, 87 percent yield) as a white solid: LCMS m/z (percent) = 195 (M+H, 100). %1}H NMR (400 MHz, DMSO-d₆) δ: 8.37-8.40 (m, 2H), 7.57 (dd, J= 4.0 Hz, 1H), 4.06 (s, 3H).

Reference： [1] Patent: WO2005/12254, 2005, A1, . Location in patent: Page/Page column 135-136

2
[ 121-43-7 ]
[ 154471-65-5 ]
[ 344591-91-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: With n-butyllithium In tetrahydrofuran; hexanes; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; hexanes; water at 20℃; for 1.5 h;	Preparation 7[1 -Methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yllboronic acidTo a stirred solution of 1 -methyl-3-(thfluoronnethyl)-1 H-pyrazole (1 .89 g, 12.6 mmol) in anhydrous tetrahydrofuran (20 ml_) under nitrogen cooled to -78°C was added n- butyllithium (8.3 mL, 1 .6 M solution in hexanes, 13.2 mmol) slowly over 5 minutes. The resulting yellow solution was stirred at -78°C for 1 hour and trimethyl borate (1 .56 mL, 13.9 mmol) was then added slowly. The reaction flask was covered in foil and allowed to warm to room temperature for 16 hours. The white solution was quenched with aqueous 1 M hydrogen chloride solution (10 mL) and stirred at room temperature for 1 .5 hours. The mixture was extracted with ethyl acetate (2 x 30 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo to give an off-white foam (2.1 1 g). The foam was triturated with dichloromethane, filtered and dried in vacuo to afford the title compound as a white solid (1 .57 g, 64percent).1H NMR (400 MHz, MeOH-d4): δ 4.04 (s, 3H), 6.89 (s, 1 H).LCMS Rt = 1 .1 1 minutes MS m/z 194 [MH]+ 192 [M-H]-,

Reference： [1] Patent: WO2012/7868, 2012, A2, . Location in patent: Page/Page column 75
[2] Patent: US2002/137633, 2002, A1,
[3] Patent: EP1108720, 2001, A1,

3
[ 497832-99-2 ]
[ 344591-91-9 ]
[ 1138450-30-2 ]

Reference： [1] Patent: WO2009/43883, 2009, A1, . Location in patent: Page/Page column 46-47

4
[ 497832-99-2 ]
[ 344591-91-9 ]
[ 1138450-30-2 ]

Reference： [1] Patent: WO2009/43883, 2009, A1, . Location in patent: Page/Page column 46-47

[ 344591-91-9 ] Synthesis Path-Downstream 1~88

1
[ 344591-91-9 ]
[ 720702-42-1 ]
[ 839714-55-5 ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In Dimethyl ether; water; at 70℃; for 0.166667h;	5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole: Trifluoro-methanesulfonic acid 2-methoxy-5-nitro-phenyl ester (0.10 g, 0.34 mmol), 2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid (0.10 g, 0.52 mmol, 1.5 eq.) and Na2C03 (0.04 g, 0.41 mmol, 1.2 eq.) were dissolved in a mixture of DME (6 mL) and H20 (0.6 ml) in an argon flushed round bottom flask. The mixture was degassed with argon for 5 minutes, followed by the addition of Pd(PPh3)4 (0.04 g, 0.03 mmol, 0.01 eq.). The reaction mixture was degassed under argon for another 5 minutes and stirred at 70C overnight. Once the reaction was complete, the DME was removed under vacuum and the crude reaction mixture was purified by SiO2 column chromatography (Eluent: EtOAc/hexane = 5% to 30%). Final purification was achieved via reverse phase C-18 HPLC to afford 5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.05 g, 0.17 mmol, 49% yield): LCMS m/z (%) = 302 (M+H, 100). 1H NMR (400 MHz, CDCl3) delta: 8.38 (dd, J=10. 0,2. 0 Hz, 1H), 8.19 (d, J= 4.0 Hz, 1H), 7.12 (d, J = 8. 0 Hz, 1H), 6.57 (s, 1H), 3.98 (s, 3H), 3.78 (s, 3H).

Reference： [1]Patent: WO2005/12254,2005,A1 .Location in patent: Page/Page column 136

2
[ 154471-65-5 ]
[ 344591-91-9 ]

Yield	Reaction Conditions	Operation in experiment
87%		2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid: <strong>[154471-65-5]1-methyl-3-trifluoromethyl-1H-pyrazole</strong> (1.00 g, 6.66 mmol) was dissolved in THF (25 mL) in an oven-dried round bottom flask and cooled to-78 C in an acetone/dry ice bath. 2.5 M n-butyl lithium/hexane (3.196 ml, 7.99 mmol) was added drop wise to the stirred solution followed by drop wise addition of triisopropyl borate (5.01 g, 26.64 mmol). The mixture was warmed to room temperature and stirred for three hours. The reaction mixture was adjusted to pH 6 with IN HCl solution followed by the removal of THF under vacuum. The aqueous phase was extracted with EtOAc (3x100 ml). The combined organic phase was washed with brine and dried over anhydrous MgS0(sub>4, filtered and evaporated to give 2-methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid (1.12 g, 5.80 mmol, 87 % yield) as a white solid: LCMS m/z (%) = 195 (M+H, 100). 1H NMR (400 MHz, DMSO-d₆) delta: 8.37-8.40 (m, 2H), 7.57 (dd, J= 4.0 Hz, 1H), 4.06 (s, 3H).

Reference： [1]Patent: WO2005/12254,2005,A1 .Location in patent: Page/Page column 135-136

3
[ 121-43-7 ]
[ 154471-65-5 ]
[ 344591-91-9 ]

Yield	Reaction Conditions	Operation in experiment
64%		Preparation 7[1 -Methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yllboronic acidTo a stirred solution of 1 -methyl-3-(thfluoronnethyl)-1 H-pyrazole (1 .89 g, 12.6 mmol) in anhydrous tetrahydrofuran (20 ml_) under nitrogen cooled to -78C was added n- butyllithium (8.3 mL, 1 .6 M solution in hexanes, 13.2 mmol) slowly over 5 minutes. The resulting yellow solution was stirred at -78C for 1 hour and trimethyl borate (1 .56 mL, 13.9 mmol) was then added slowly. The reaction flask was covered in foil and allowed to warm to room temperature for 16 hours. The white solution was quenched with aqueous 1 M hydrogen chloride solution (10 mL) and stirred at room temperature for 1 .5 hours. The mixture was extracted with ethyl acetate (2 x 30 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo to give an off-white foam (2.1 1 g). The foam was triturated with dichloromethane, filtered and dried in vacuo to afford the title compound as a white solid (1 .57 g, 64%).1H NMR (400 MHz, MeOH-d4): delta 4.04 (s, 3H), 6.89 (s, 1 H).LCMS Rt = 1 .1 1 minutes MS m/z 194 [MH]+ 192 [M-H]-,
	With hydrogenchloride; diisopropylamine; In tetrahydrofuran;	4B Preparation of <strong>[154471-65-5]1-methyl-3-trifluoromethylpyrazol</strong>-5-yl-boronic acid A solution of <strong>[154471-65-5]1-methyl-3-trifluoromethylpyrazol</strong> (2 g) in 10 ml THF is cooled under an inert gas atmosphere to -78 C. A 2 M solution of LDA (9.75 ml) is added dropwise. The mixture is stirred to 10 C. for 1 h and cooled to -75 C. Trimethylborate (5.8 ml) is added and after stirring for 1 h at -75 C. the mixture is stirred overnight at ambient temperature. The resulting reaction solution is added to 10% hydrochloric acid (15 ml). The water phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with water and a saturated sodium chloride solution. The organic phase is dried and evaporated and the residue is crystallized from water. After drying, one obtains the title compound as nearly colorless crystals (1.12 g) of mp. 138 C.
	With hydrogenchloride; diisopropylamine; In tetrahydrofuran;	4B Preparation of <strong>[154471-65-5]1-methyl-3-trifluoromethylpyrazol</strong>-5-yl-boronic acid A solution of <strong>[154471-65-5]l-methyl-3-trifluoromethylpyrazol</strong> (2 g) in 10 ml THF is cooled under an inert gas atmosphere to -78 C. A 2 M solution of LDA (9.75 ml) is added dropwise. The mixture is stirred to 10 C for 1 h and cooled to -75 C. Trimethylborate (5.8 ml) is added and after stirring for 1 h at -75 C the mixture is stirred overnight at ambient temperature. The resulting reaction solution is added to 10 % hydrochloric acid (15 ml). The water phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with water and a saturated sodium chloride solution. The organic phase is dried and evaporated and the residue is crystallized from water. After drying, one obtains the title compound as nearly colorless crystals (1.12 g) of mp. 138C.

Reference： [1]Patent: WO2012/7868,2012,A2 .Location in patent: Page/Page column 75
[2]Patent: US2002/137633,2002,A1
[3]Patent: EP1108720,2001,A1

4
[ 952402-39-0 ]
[ 344591-91-9 ]
[ 1138450-30-2 ]
[ 1138449-66-7 ]
[ 1138449-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.25h;Microwave irradiation;	5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)- 2,4(1 H,3H)-pyrimidinedione (PrepiO, 148 mg, 0.293 mmol), [1-methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl]boronic acid and [1-methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]boronic acid (Prep11 , 71 mg, 0.366 mmol), and tetrakis(triphenyphosphine)palladium (0) (42.3 mg, 0.037 mmol) were stirred in 1 ,2-Dimethoxyethane (DME) (4 ml) until dissolution of reagents. Sodium carbonate 1 M solution (1.098 ml, 1.098 mmol) was added and the mixture heated in a microwave apparatus at 15O0C for 15 min. DCM/water (5 + 5 ml.) were added and organic phase separated by phase separation tube. Organic layer was loaded on SCX cartridge (1 g), washed by MeOH (2 ml.) and products eluted by 2M methanolic ammonia. Ammonia phase was concentrated to give a crude that was purified twice by fraction lynx obtaining: Realphaioisomer 1 (ED: 5-[1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl]-1-(3-{(1 S,5R)-1-[4- (trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1 H,3H)-pyrimidinedione (1.4 mg).Regioisomer 2 (E2): 5-[1-methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]-1-(3-{(1 S,5R)-1-[4- (trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1 H,3H)-pyrimidinedione (2.3 mg). Example 1 :1H NMR (CHLOROFORM-d) delta ppm 8.24 (br. s., 1 H) 7.92 (s, 1 H) 7.53 (d, 2 H) 7.45 (s, 1 H) 7.20 (d, 2 H) 3.97 (s, 3 H) 3.87 (t, 2 H) 3.28 - 3.38 (m, 1 H) 3.03 - 3.14 (m, 1 H) 2.42 - <n="74"/>2.62 (m, 4 H) 1.81 - 2.00 (m, 2 H) 1.72 - 1.80 (m, 1 H) 1.39 - 1.47 (m, 1 H) 0.79 - 0.91 (m,1 H)Example 2:1H NMR (CHLOROFORM-d) delta ppm 7.53 (d, 2 H) 7.46 (s, 1 H) 7.20 (d, 2 H) 6.48 (s, 1 H)3.74 - 3.98 (m, 5 H) 3.31 (d, 1 H) 3.06 (d, 1 H) 2.43 - 2.66 (m, 4 H) 1.85 - 1.97 (m, 2 H)1.73 - 1.85 (m, 1 H) 1.27 - 1.42 (m, 1 H) 0.79 - 0.92 (m, 1 H)

Reference： [1]Patent: WO2009/43883,2009,A1 .Location in patent: Page/Page column 72-73

5
[ 497832-99-2 ]
[ 344591-91-9 ]
[ 1138450-30-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 4-bromo-1-methyl-3-(trifluoromethyl)-1 H-pyrazole (100 mg, 0.437 mmol) in Tetrahydrofuran (THF) at -780C, a solution of BuLi 1.6M in hexane (328 mul, 0.524 mmol) was added drop wise. Mixture was stirred at -780C for 1 h, then 4,4,5,5- tetramethyl-2-[(1-methylethyl)oxy]-1 ,3,2-dioxaborolane (134 mul, 0.655 mmol) was added maintaining the temperature below -750C. Mixture was allowed to warm slowly to r.t. within overnight. Half of the mixture was concentrated under reduced pressure. THF was removed form the remaining half of the mixture under reduced pressure, the residue was diluted by DCM/water (5 + 5 ml_), the organic layer separated by separation tube and solvent removed under reduced pressure.The two batches obtained were combined to give title compound as a mixture of stereoisomers. Crude was used without any further purification in the following step. <n="48"/>MS (ES) (m/z): 195.2[MH]+.

Reference： [1]Patent: WO2009/43883,2009,A1 .Location in patent: Page/Page column 46-47

6
[ 344591-91-9 ]
[ 1210043-72-3 ]
[ 1210043-71-2 ]

Yield	Reaction Conditions	Operation in experiment
24%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃; for 3h;	To a degassed solution of triflate 9 (100 mg, 210 mmol), boronic acid 10 (40.3 mg, 210 mmol) and Na2CO3 (88 mg, 830 mmol) in ethanol : water : toluene (2: 1: 1, 780 muL) was added Pd(PPh3)4 (12 mg, 10 mmol). The solution was sealed and heated at 85 0C for 3 hours. The mixture was filtered through celite and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50 % ethyl acetate in hexane) provided 11 (24.4 mg, 24%) as a solid: LRESIMS m/z 482 [M+Eta]+, calcd. for C22H22F3N3O4Si 482.1.

Reference： [1]Patent: WO2010/25295,2010,A2 .Location in patent: Page/Page column 124

7
[ 344591-91-9 ]
[ 1210043-62-1 ]
[ 1210043-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.5h;Mirowave irradiation;	A mixture of 2 (450 mg, 1 mmol), l-methyl-S-trifluoromethylpyrazole-S-boronic acid (193 mg, 1 mmol), Pd(PPh3)4 ( 115 mg, 10% mol eq.) and sodium carbonate (318 mg, 3 eq) in 6 ml of DME/EtOH/H2O (4: 1 : 1) was heat with microwave for 30 min at 110 0C. Silica gel column purification furnished 160 mg 3 as light oil.

Reference： [1]Patent: WO2010/25295,2010,A2 .Location in patent: Page/Page column 122-123

8
[ 344591-91-9 ]
[ 1188072-92-5 ]
[ 1279103-40-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 6h;Inert atmosphere;	Bromo-2-(2,6-difluoro-phenyl)-1H-indole (270 mg) was added to dry DMF, under nitrogen atmosphere, followed by 1-methyl-3-trifluoromethyl-1H-pyrazol-3-yl boronic acid (203 mg) and Na2CO3 (139.5 mg, 1.5 equiv). The reaction mixture was degassed, and then water (1 mL) was added, followed by Pd(dppf)Cl2*CH2Cl2 (101.26 ug). The reaction mixture was again degassed and then heated to 90 C. for six hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with water and EtOAc. The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% EtOAc in hexanes) to give 2-(2,6-difluoro-phenyl)-5-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-indole, MS (M+H)=378.

Reference： [1]Patent: US2011/71150,2011,A1 .Location in patent: Page/Page column 43

9
[ 344591-91-9 ]
[ 1346665-42-6 ]

Reference： [1]Patent: WO2011/139765,2011,A2

10
[ 344591-91-9 ]
[ 1346665-41-5 ]

Reference： [1]Patent: WO2011/139765,2011,A2

11
[ 344591-91-9 ]
[ 53324-38-2 ]
[ 1346665-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 17h;Inert atmosphere;	Example 9: Preparation of N-(3-amino-4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5- yl)phenyl)benzo[d]oxazole-2-carboxamide (35):; Preparation of N-(4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3- nitrophenyl)benzo[d]oxazole-2-carboxamide (34):; A reaction mixture of l-methyl-3- trifluoromethylpyrazole-5-boronic acid (560 mg, 3 mmol), 4-bromo-3-nitroaniline (14) (720 mg, 3.3 mmol), Pd(PPh3)4 (173 mg ) and sodium carbonate (1.37 g, 12 mmol) in 10 ml toluene, 10 ml EtOH and 5 ml H20 was sparged with Ar and then heated at 100C for 17h. EA/brine work-up furnished crude 33 which was used for next step reaction without further purification.

Reference： [1]Patent: WO2011/139765,2011,A2 .Location in patent: Page/Page column 130

12
[ 344591-91-9 ]
[ 849758-12-9 ]
[ 1346665-28-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate tribasic trihydrate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 85℃; for 15h;Inert atmosphere;	To a solution of 8 (1.5g, 7.69mmol) in 1,4-dioxane was added 2eq. l-methyl-3- trifluoromethylpyrazole-5-boronic acid, Pd(dppf)2C12 (0.5g) and 3eq.K3P04. 3H20. The reaction mixture was sparged with nitrogen for 10 minutes. And the resulting mixture was stirred at 85C for 15 hours under the N2. EA/brine work and followed by prep HPLC purification to give 1.3 g compound 9. l .lg of 10 was obtained after hydrolysis with aq. LiOH.

Reference： [1]Patent: WO2011/139765,2011,A2 .Location in patent: Page/Page column 125

13
[ 344591-91-9 ]
[ 1346665-30-2 ]
[ 1346665-31-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 3h;Inert atmosphere;	A reaction mixture of l-methyl-3-trifluoromethylpyrazole-5-boronic acid (58.2 mg, 0.3 mmol), intermediate 15 (107 mg, 0.3 mmol), Pd(PPh3)4 (17 mg ) and sodium carbonate (127 mg, 1.2 mmol) in 1 ml DME, 1 ml EtOH and 0.5 ml H20 was sparged with Ar and then heated at 80C for 3h. EA/brine work-up and following flash silica gel column purification furnished 58 mg of 16 as yellow solid.

Reference： [1]Patent: WO2011/139765,2011,A2 .Location in patent: Page/Page column 126

14
[ 344591-91-9 ]
[ 1346665-34-6 ]
[ 1346665-36-8 ]

Reference： [1]Patent: WO2011/139765,2011,A2

15
[ 344591-91-9 ]
[ 1346665-34-6 ]
[ 1346665-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 3h;Inert atmosphere;	Example 7: Preparation of 2-chloro-N-(2-hydroxy-4-(l-methyl-3-(trifluoromethyl)-lH- pyrazol-5-yl)phenyl)benzamide (28):; Preparation of 2-chloro-N-(2-methoxy-4-(l-methyl-3-(trifluoromethyl)-lH- pyrazol-5-yl)phenyl)benzamide (27):; Intermediate 26 was prepared in a similar way as intermediate 2 by coupling 4-bromo-2-methoxybenzoic acid (25) and 2-chloroaniline. A reaction mixture of l-methyl-3-trifluoromethylpyrazole-5-boronic acid (100 mg, 0.5 mmol), intermediate 26 (170 mg, 0.5 mmol), Pd(PPh3)4 (60 mg ) and sodium carbonate (212 mg, 2 mmol) in 2 ml DME, 2 ml EtOH and 1 ml H20 was sparged with Ar and then heated at 80C for 3h. EA/brine work-up and following flash silica gel column purification furnished 182 mg of 27 as a white solid.

Reference： [1]Patent: WO2011/139765,2011,A2 .Location in patent: Page/Page column 128-129

16
[ 344591-91-9 ]
C₂₀H₁₇F₃N₂O₃ [ No CAS ]

Reference： [1]Patent: WO2012/7868,2012,A2

17
[ 344591-91-9 ]
C₁₉H₁₅F₃N₂O₃ [ No CAS ]

Reference： [1]Patent: WO2012/7868,2012,A2

18
[ 344591-91-9 ]
[ 1355631-31-0 ]

Reference： [1]Patent: WO2012/7868,2012,A2

19
[ 344591-91-9 ]
[ 540-38-5 ]
[ 1355636-66-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 90℃; for 4h;	Preparation 64-H -Methyl-3-(trifluoromethyl)-1 -pyrazol-5-yllphenolTo a solution of 4-iodophenol (75 mg, 0.34 mmol) in a mixture of water (1 mL) and 1 ,4- dioxane (2 m L) was added [1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]boronic acid (Preparation 7, 90 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium(ll) (18.3 mg, 0.03 mmol) and cesium carbonate (240 mg, 0.74 mmol). The resulting mixture was heated at 90C in a Reactivial for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and brine (2 x 10 mL). The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude material was purified by flash column chromatography using the ISCO system (12 g column), eluting with 70:30 heptane/ethyl acetate. Fractions containing product were combined and concentrated in vacuo to afford the title compound as a white solid (61 mg, 73%).1H NMR (400 MHz, d6-DMSO): delta 4.90 (s, 3H), 6.75 (s, 1 H), 6.90 (d, 2H), 7.40 (d, 2H), 9.80 (s, 1 H).LCMS: Rt = 1 .41 minutes MS m/z 242 [MH]+

Reference： [1]Patent: WO2012/7868,2012,A2 .Location in patent: Page/Page column 74

20
[ 344591-91-9 ]
5-(2-methyl-5-trifluoromethyl-2<i>H</i>-pyrazol-3-yl)-thiophen-2-ylamine [ No CAS ]

Reference： [1]Patent: US2012/53210,2012,A1

21
[ 344591-91-9 ]
[ 1361380-58-6 ]

Reference： [1]Patent: US2012/53210,2012,A1

22
[ 344591-91-9 ]
[ 1361379-34-1 ]

Reference： [1]Patent: US2012/53210,2012,A1

23
[ 344591-91-9 ]
[ 1361379-76-1 ]

Reference： [1]Patent: US2012/53210,2012,A1

24
[ 344591-91-9 ]
[ 1361379-79-4 ]

Reference： [1]Patent: US2012/53210,2012,A1

25
[ 344591-91-9 ]
[ 1361379-80-7 ]

Reference： [1]Patent: US2012/53210,2012,A1

26
[ 344591-91-9 ]
[ 1361379-82-9 ]

Reference： [1]Patent: US2012/53210,2012,A1

27
[ 13195-50-1 ]
[ 344591-91-9 ]
[ 1361380-64-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	Examples 71-73Preparation of (2-fluorophenyl)-N-{5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl](2-thienyl)}carboxamide (135) 1-Methyl-3-trifluoromethylpyrazole-5-boronic acid (97 mg, 0.5 mmol) and <strong>[13195-50-1]2-bromo-5-nitrothiophene</strong> (104 mg, 0.5 mmol) was dissolved in 2 mL dimethoxyethane and 2 mL EtOH. The 1 mL of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 60 mg, 0.05 mmol). The reaction was heated at 110° C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by flash column and afforded 133 as yellow solid. Following hydrogenation under standard conditions, to a solution of 134 (37 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added 2-fluorobenzoyl chloride, N,N-diisopropylethylamine (DIEA, 0.5 g, 0.7 mL, 4 mmol), and a catalytic amount of DMAP. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 mL) and extracted with EtOAc (20 mL.x.2). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in THF (2 mL) and MeOH (2 mL). 1M NaOH (2 mL) was added and stirred for 0.5 h at room temperature. The reaction mixture was concentrated and worked-up with EtOAc-Brine. The crude product was purified by flash column and compound 135 (2.7 mg, 5percent) was obtained as yellow solid. LC-MS: calcd. for C16H11F4N3OS: 370 (M+1).

Reference： [1]Patent: US2012/53210,2012,A1 .Location in patent: Page/Page column 82-83

28
[ 3034-22-8 ]
[ 344591-91-9 ]
[ 1361380-56-4 ]

Yield	Reaction Conditions	Operation in experiment
1.9%	With potassium phosphate;bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; acetonitrile; at 70℃; for 1h;Inert atmosphere;	Example 28Preparation of (2,6-difluorophenyl)-N-{5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl](1,3-thiazol-2-yl)}carboxamide (64) Preparation of 5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole-2-ylamine (63): A suspension of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (290 mg, 1.5 mmol), 2-amino-5-bromothiazole (1 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (A-Phos) (53 mg) and K3PO4 (212 mg, 1 mmol) in 2 ml ACN, 2 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 70° C. for 1 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. Prep HPLC purification furnished 4.6 mg 5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole-2-ylamine (63) as light yellow solid (yield 1.9percent; purity>95percent).

Reference： [1]Patent: US2012/53210,2012,A1 .Location in patent: Page/Page column 72

29
[ 344591-91-9 ]
[ 3034-48-8 ]
[ 1361380-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	Example 29Preparation of (2-chlorophenyl)-N-{2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl](1,3-thiazol-5-yl)}carboxamide (67) Preparation of 2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-5-nitro-1,3-thiazole (65): A mixture of <strong>[3034-48-8]<strong>[3034-48-8]2-bromo-5-nitrothiazol</strong>e</strong> (209 mg, 1 mmol), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (194 mg, 1 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 57 mg) and sodium carbonate (212 mg) in 3 ml DME, 0.5 ml EtOH and 0.5 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to silica gel flash chromatography (0-30percent B; A: hexane; B: 50percent EA in hexane) to furnish 37.5 mg of 2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-5-nitro-1,3-thiazole (65) as light yellow solid (yield: 13.5percent; purity>90percent).

Reference： [1]Patent: US2012/53210,2012,A1 .Location in patent: Page/Page column 72-73

30
[ 344591-91-9 ]
[ 1361380-60-0 ]
[ 1361380-61-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	The <strong>[344591-91-9](1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid</strong> (29 mg, 0.15 mmol) and 70 (40 mg, 0.12 mmol) was dissolved in 1 mL dimethoxyethane and 1 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 12 mg, 0.01 mmol). The reaction was heated at 110 C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by flash column and afforded 71 as yellow solid.

Reference： [1]Patent: US2012/53210,2012,A1 .Location in patent: Page/Page column 74

31
[ 344591-91-9 ]
[ 1366109-51-4 ]
[ 1366109-54-7 ]

Yield	Reaction Conditions	Operation in experiment
13%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	To a solution of 1 (175 mg, 1 mmol) in acetic acid (2 mL) was added bromine (240 mg, 1.5 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was worked-up with EtOAc extraction and product was used for next step without further purification.The acid 2 was dissolved in CH2Cl2 and 1 drop DMF and oxalyl chloride were added. The mixture was stirred for 1 h and organic volatile was removed in vacuo. The residue was dissolved in CH2Cl2 and DMAP (6 mg, 0.05 mmol), DIEA (520 mg, 0.7 mL, 4 mmol) and 2-fluoroaniline (167 mg, 1.5 mmol) were added in sequence. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The crude product was purified by ISCO columns. Fractions containing pure product were combined and evaporated. The yellow oil 4 (258 mg, 74%) was obtained.The boronic acid 5 (23 mg, 0.12 mmol) and 4 (35 mg, 0.1 mmol) was dissolved in 1 mL dimethoxyethane and 1 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 11 mg, 0.01 mmol). The reaction was heated at 110 C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 6 (5.4 mg, 13%) as white solid. LC-MS: calcd. for C16H11F4N3OSe: 418 (M+1).

Reference： [1]Patent: US2012/71516,2012,A1 .Location in patent: Page/Page column 59-60

32
[ 344591-91-9 ]
[ 1366109-59-2 ]
[ 1366109-61-6 ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	Compound 3 (1 mmol) was dissolved in CH2Cl2 and DMAP (6 mg, 0.05 mmol), DIEA (520 mg, 0.7 mL, 4 mmol) and 3-fluoro-4-pyridylamine (224.2 mg, 2 mmol) were added in sequence. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The crude product was purified by ISCO columns. Fractions containing pure product were combined and evaporated. The yellow solid 9 (249 mg, 72%) was obtained.The boronic acid 5 (23 mg, 0.12 mmol) and 9 (35 mg, 0.1 mmol) was dissolved in 1 mL dimethoxyethane and 1 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 11 mg, 0.01 mmol). The reaction was heated at 110 C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 10 (12.8 mg, 31%) as white solid. LC-MS: calcd. for C15H10F4N4OSe: 419 (M+1).

Reference： [1]Patent: US2012/71516,2012,A1 .Location in patent: Page/Page column 60

33
[ 344591-91-9 ]
[ 1366110-04-4 ]
[ 1366110-06-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	The mixture of selenourea (246 mg, 2 mmol) and chloroacetaldehyde (157 mg, 2 mmol) in EtOH (5 mL) was heated at 80 C. for 48 h. The solvent was removed in vacuo and residue was treated with water and EtOAc. The organic layer was separated and aqueous was extracted with EtOAc. The combined organic layer was dried (Na2SO4) and concentrated in vacuo. The residue solid was mixed with bromine (640 mg, 4 mmol) and carbon tetrachloride (10 mL) and heated at 80 C. for 72 h. The solvent was removed in vacuo and residue was treated with water and EtOAc. The organic layer was separated and aqueous was extracted with EtOAc. The combined organic layer was dried (Na2SO4) and concentrated in vacuo. The crude material 39 was suspended in CH2Cl2 (10 ml) and the 2-fluorobenzoyl chloride (396 mg, 2.5 mmol) and dimethylaminopyridine (DMAP, 24 mg, 0.2 mmol) were added along with N,N-diisopropylethylamine (DIEA, 520 mg, 4 mmol). The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with NaHCO3 and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material 40 was used for next step without further purification.The boronic acid 5 (100 mg, 0.5 mmol) and 40 (168 mg, 0.48 mmol) was dissolved in 2 mL dimethoxyethane and 2 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 23 mg, 0.02 mmol). The reaction was heated at 110 C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 41 (1.9 mg, 1%) as yellow solid. LC-MS: calcd. for C15H10F4N4OSe: 418 (M+1).

Reference： [1]Patent: US2012/71516,2012,A1 .Location in patent: Page/Page column 65-66

34
[ 344591-91-9 ]
[ 1366110-08-8 ]
[ 1366110-10-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	The crude material 39 was suspended in CH2Cl2 (10 ml) and the 2-chlorobenzoyl chloride (438 mg, 2.5 mmol) and dimethylaminopyridine (DMAP, 24 mg, 0.2 mmol) were added along with N,N-diisopropylethylamine (DIEA, 520 mg, 4 mmol). The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with NaHCO3 and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material 42 was used for next step without further purification.The boronic acid 5 (60 mg, 0.3 mmol) and 42 (78 mg, 0.2 mmol) was dissolved in 2 mL dimethoxyethane and 2 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 23 mg, 0.02 mmol). The reaction was heated at 110 C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 43 (1.1 mg, 3%) as white solid. LC-MS: calcd. for C15H10ClF3N4OSe: 435 (M+1).

Reference： [1]Patent: US2012/71516,2012,A1 .Location in patent: Page/Page column 66

35
[ 344591-91-9 ]
[ 1366110-12-4 ]
[ 1366110-14-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Inert atmosphere; Microwave irradiation;	The crude material 39 was suspended in CH2Cl2 (10 ml) and the 2,6-difluorobenzoyl chloride (438 mg, 2.5 mmol) and dimethylaminopyridine (DMAP, 24 mg, 0.2 mmol) were added along with N,N-diisopropylethylamine (DIEA, 520 mg, 4 mmol). The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with NaHCO3 and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material 44 was used for next step without further purification.The boronic acid 5 (24 mg, 0.12 mmol) and 42 (31 mg, 0.08 mmol) was dissolved in 2 mL dimethoxyethane and 2 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 23 mg, 0.02 mmol). The reaction was heated at 110 C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 45 (1.2 mg, 3%) as white solid. LC-MS: calcd. for C15H9ClF5N4OSe: 437 (M+1).

Reference： [1]Patent: US2012/71516,2012,A1 .Location in patent: Page/Page column 67

36
[ 344591-91-9 ]
[ 1415640-19-5 ]
[ 1415640-21-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium phosphate;bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; acetonitrile; at 85℃; for 3h;Inert atmosphere;	Example 34 Preparation of 5-(2,2-difluoro-6-methylbenzo[d]1,3-dioxolen-5-yl)-2-[2,6-difluorophenyl)methoxy]pyrimidine (63) Argon was bubbled through a mixture of 2-[(2,6-difluorophenyl)methoxy]-5-bromopyrimidine (60) (30 mg, 0.1 mmol), <strong>[344591-91-9]1-methyl-3-trifluoromethylpyrazole-5-boronic acid</strong> (39 mg, 0.2 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (14 mg, 10% mol) and K3PO4 (42 mg) in 1 ml ACN, 1 mL dioxane, 0.5 ml H2O. The reaction mixture was heated at 85 C. for 3 h. After cooling to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4, concentrated and then subjected to silica gel flash chromatography to give 34.1 mg 2-[2,6-difluorophenyl)methoxy]-5-[1-methyl-3-trifluoromethyl)pyrazol-5-yl]pyrimidine (63) (yield: 92%, purity>95%) as an off-white solid.

Reference： [1]Patent: US2012/316182,2012,A1 .Location in patent: Page/Page column 95-96

37
[ 344591-91-9 ]
[ 1415640-22-0 ]
[ 1415640-24-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium phosphate;bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; acetonitrile; at 70℃;Inert atmosphere;	Example 36 Preparation of 2-[2,6-difluorophenyl)methoxy]-5-[1-methyl-3-trifluoromethyl)pyrazol-5-yl]pyridine (67) Argon was bubbled through a mixture of 2-[(2,6-difluorophenyl)methoxy]-5-bromopyridine (65) (30 mg, 0.1 mmol), <strong>[344591-91-9]1-methyl-3-trifluoromethylpyrazole-5-boronic acid</strong> (39 mg, 0.2 mmol), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (14 mg, 10% mol) and K3PO4 (42 mg) in 1 ml ACN, 1 ml dioxane, 0.5 ml H2O. The reaction mixture was heated overnight at 70 C. After cooling to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. The organic phase was dried over Na2SO4, concentrated and then subjected to silica gel flash chromatography to give 36 mg 2-[2,6-difluorophenyl)methoxy]-5-[1-methyl-3-trifluoromethyl)pyrazol-5-yl]pyridine (67) (yield: 98%, purity>90%).

Reference： [1]Patent: US2012/316182,2012,A1 .Location in patent: Page/Page column 97

38
[ 344591-91-9 ]
[ 1415640-50-4 ]
[ 1415640-51-5 ]

Yield	Reaction Conditions	Operation in experiment
20%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Microwave irradiation;	Compound 93 (30 mg, 0.1 mmol) and boronic acid (20 mg, 0.1 mmol) were dissolved in dimethixylethane (DME, 1 mL), EtOH (1 mL). The 0.4 mL 1 M NaHCO3 was added. The mixture was heated to 110 C. using microwave irradiation for 0.5 h. The reaction mixture was allowed to cool to ambient temperature and poured in brine. The product was extracted with EtOAc and purified by flash column. The compound 94 (7.4 mg, 20%) was obtained as white solid. LC-MS: calcd. for C16H12F5N5: 370 (M+1).

Reference： [1]Patent: US2012/316182,2012,A1 .Location in patent: Page/Page column 102

39
[ 344591-91-9 ]
[ 1341766-40-2 ]
[ 1415640-52-6 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; at 110℃; for 0.5h;Microwave irradiation;	Compound 95 (28 mg, 0.1 mmol) and boronic acid (20 mg, 0.1 mmol) were dissolved in dimethixylethane (DME, 1 mL), EtOH (1 mL). The 0.4 mL 1 M NaHCO3 was added. The mixture was heated to 110 C. using microwave irradiation for 0.5 h. The reaction mixture was allowed to cool to ambient temperature and poured in brine. The product was extracted with EtOAc and purified by flash column. The compound 96 (8 mg, 25%) was obtained as white solid. LC-MS: calcd. for C16H13F4N5: 352 (M+1).

Reference： [1]Patent: US2012/316182,2012,A1 .Location in patent: Page/Page column 102

40
[ 344591-91-9 ]
[ 1419171-64-4 ]
C₂₈H₂₂F₆N₄O₄S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; In methanol; toluene; at 80℃; for 0.5h;Inert atmosphere; Sealed tube;	Argon was bubbled through a mixture of intermediate D (55 mg, 0.100 mmol), 1 -methyl-3 - trifluoromethylpyrazole-5-boronic acid (48.4 mg, 0.250 mmol) and KF (29 mg, 0.500 mmol) in toluene (1 ml) and MeOH (1 ml). PEPPSI-iPr (2 mg, 0.003 mmol) was added and the mixture heated at 80 C for 30 min in a sealed tube. Solvents were evaporated and dioxane (1 ml) and 2 M NaOH (1 ml) was added. The mixture was heated at 80 C for 2 h. The product was isolated by prep, hplc using 25-55% MeCN in 50 mM buffer as eluent. Pure fractions were combined, product precipitated by addition of 6 M HCl and isolated by centrifugation. The precipitate was washed several times with water and freeze dried for 2 d. Yield: 27.0 mg (41%); bright yellow solid. Rt = 2.72 mm, 99% at 254 nm, (20-50% MeCN in buffer, XBridge) and Rt = 2.72 mm, 98% at 400 nm (20-50% MeCN in buffer, XBridge). ¾ NMR (400 MHz, OMSO-d6): delta 3.82 (s, 4H), 4.07 (s, 6H), 7.09 (d, J 0.5 Hz, 2H), 7.38 (s, 2H), 7.54 (s, 2H). LC-MS: m/z = 661 (M + 1)
	With potassium fluoride; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; In methanol; toluene; at 80℃; for 0.5h;Inert atmosphere;	Argon was bubbled through a mixture of intermediate D (55 mg, 0.100 mmol), l-methyl-3- trifluoromethylpyrazole-5-boronic acid (48.4 mg, 0.250 mmol) and KF (29 mg, 0.500 mmol) in toluene (1 ml) and MeOH (1 ml). PEPPSI-iPr (2 mg, 0.003 mmol) was added and the mixture heated at 80 C for 30 min in a sealed tube. Solvents were evaporated and dioxane (1 ml) and 2 M NaOH (1 ml) was added. The mixture was heated at 80 C for 2 h. The product was isolated by prep, hplc using 25-55% MeCN in 50 mM buffer as eluent. Pure fractions were combined, product precipitated by addition of 6 M HC1 and isolated by centrifugation. The precipitate was washed several times with water and freeze dried for 2 d. Yield: 27.0 mg (41%); bright yellow solid. Rt = 2.72 min, 99% at 254 nm, (20-50% MeCN in buffer, XBridge) and Rt = 2.72 min, 98% at 400 nm (20-50% MeCN in buffer, XBridge). 1H NMR (400 MHz, DMSO-i¾): delta 3.82 (s, 4H), 4.07 (s, 6H), 7.09 (d, J0.5 Hz, 2H), 7.38 (s, 2H), 7.54 (s, 2H). LC-MS: m/z = 661 (M + 1)

Reference： [1]Patent: WO2013/9259,2013,A1 .Location in patent: Page/Page column 105
[2]Patent: WO2013/36196,2013,A1 .Location in patent: Page/Page column 109-110

41
[ 344591-91-9 ]
[ 1429341-55-8 ]
[ 1429341-05-8 ]

Yield	Reaction Conditions	Operation in experiment
34%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 20 - 85℃; for 16h;	Example 5 3-(2,6-Difluoro-phenyl)-7-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine 3-(2,6-Difluoro-phenyl)-7-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine: To a stirred solution of the 7-bromo-3-(2,6-difluoro-phenyl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.1 g, 0.31 mmol) in 1,4-dioxane (10 mL) was added 1M K2CO3 (0.9 mL), Pd(PPh3)4(0.035 g, 0.31 mmol), SPhos (0.006 g, 0.02 mmol) and <strong>[344591-91-9]1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylboronic acid</strong> (0.60 g, 0.31 mmol) at rt. The mixture was then heated to 85 C. for 16 h (monitoring by TLC; ethyl acetate-hexane=1:9; Rf ?0.2), cooled, and filtered through celite. The filtrate was concentrated under reduced pressure and purified by HPLC to give 3-(2,6-difluoro-phenyl)-7-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.041 g, 34%) as a light brown solid. LC-MS: 396 [M+H].

Reference： [1]Patent: US2013/90333,2013,A1 .Location in patent: Paragraph 0206

42
[ 344591-91-9 ]
[ 1429341-61-6 ]
[ 1429341-34-3 ]

Yield	Reaction Conditions	Operation in experiment
64%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95℃; for 1h;	3-(2-Chlorophenyl)-7-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine: To a mixture of 7-bromo-3-(2-chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 308 mumol, Eq: 1.00), <strong>[344591-91-9]1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylboronic acid</strong> (71.7 mg, 370 mumol, Eq: 1.2), tetrakis(triphenylphosphine)palladium (0) (35.6 mg, 30.8 mumol, Eq: 0.1) and potassium carbonate (128 mg, 924 mumol, Eq: 3) was added dioxane (5.48 ml) and water (1.37 ml). The reaction mixture was then heated to 95 C. for 1 h, before being concentrated under reduced pressure, and purified by column chromatography (EtOAc/Hex gradient) to give 3-(2-chlorophenyl)-7-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (78 mg, 198 mumol, 64% yield) as a yellow solid. MS: 394.1 [M+H].

Reference： [1]Patent: US2013/90333,2013,A1 .Location in patent: Paragraph 0266

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[ 344591-91-9 ]
[ 656-65-5 ]
[ 1431386-72-9 ]