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[ CAS No. 182344-23-6 ] {[proInfo.proName]}

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2D 3D

Chemical Structure| 182344-23-6

Chemical Structure| 182344-23-6

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Quality Control of [ 182344-23-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 182344-23-6 ]

Product Details of [ 182344-23-6 ]

CAS No. :	182344-23-6	MDL No. :	MFCD07363787
Formula :	C₇H₅BF₄O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GUJYFCBXDUPORN-UHFFFAOYSA-N
M.W :	207.92	Pubchem ID :	17750051
Synonyms :

Calculated chemistry of [ 182344-23-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	41.23
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) :	-6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.81
Log Po/w (WLOGP) :	2.1
Log Po/w (MLOGP) :	1.8
Log Po/w (SILICOS-IT) :	0.76
Consensus Log Po/w :	1.29

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.45
Solubility :	0.73 mg/ml ; 0.00351 mol/l
Class :	Soluble
Log S (Ali) :	-2.28
Solubility :	1.09 mg/ml ; 0.00526 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.46
Solubility :	0.721 mg/ml ; 0.00347 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.99

Safety of [ 182344-23-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 182344-23-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 182344-23-6 ]

[ 182344-23-6 ] Synthesis Path-Downstream 1~51

1
[ 106-41-2 ]
[ 182344-23-6 ]
[ 634192-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride In tetrahydrofuran at 60℃; for 18h;

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

2
[ 26307-50-6 ]
[ 182344-23-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride In tetrahydrofuran at 60℃; for 18h;

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

3
[ 18966-67-1 ]
[ 182344-23-6 ]
[ 949147-37-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium fluoride In tetrahydrofuran at 60℃; for 18h;
72%	With potassium fluoride; palladium diacetate; CyJohnPhos In tetrahydrofuran at 50℃;

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]
[2]Rawls, Katherine A.; Grundner, Christoph; Ellman, Jonathan A. [Organic and Biomolecular Chemistry, 2010, vol. 8, # 18, p. 4066 - 4070]

4
[ 182344-23-6 ]
[ 949147-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: KF / palladium acetate; 2-(dicyclohexylphosphino)biphenyl / tetrahydrofuran / 18 h / 60 °C 2.1: phosphorus oxychloride; pyridine / CH₂Cl₂ / 2 h / 0 °C 2.2: H₂O / acetone; CH₂Cl₂

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

5
[ 182344-23-6 ]
[ 949147-38-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 90 percent / KF / palladium acetate; 2-(dicyclohexylphosphino)biphenyl / tetrahydrofuran / 18 h / 60 °C 2: 79 percent / pyridine / 12 h / 0 - 20 °C

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

6
[ 182344-23-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 90 percent / KF / palladium acetate; 2-(dicyclohexylphosphino)biphenyl / tetrahydrofuran / 18 h / 60 °C 2: 79 percent / pyridine / 12 h / 0 - 20 °C 3: DIPEA / Pd(PPh₃)2Cl₂; CuI / dimethylformamide / 48 h / 45 °C

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

7
[ 182344-23-6 ]
[ 949147-39-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 90 percent / KF / palladium acetate; 2-(dicyclohexylphosphino)biphenyl / tetrahydrofuran / 18 h / 60 °C 2: 79 percent / pyridine / 12 h / 0 - 20 °C 3: DIPEA / Pd(PPh₃)2Cl₂; CuI / dimethylformamide / 48 h / 45 °C 4: 1.26 g / aq. NaOH / diethyl ether; methanol / 18 h

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

8
[ 182344-23-6 ]
[ 949147-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 90 percent / KF / palladium acetate; 2-(dicyclohexylphosphino)biphenyl / tetrahydrofuran / 18 h / 60 °C 2: 79 percent / pyridine / 12 h / 0 - 20 °C 3: DIPEA / Pd(PPh₃)2Cl₂; CuI / dimethylformamide / 48 h / 45 °C 4: 1.26 g / aq. NaOH / diethyl ether; methanol / 18 h 5: 8 percent / CuSO₄; sodium ascorbate; KHCO₃ / 2-methyl-propan-2-ol; H₂O / 24 h / 50 °C

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

9
[ 182344-23-6 ]
[ 949147-32-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 90 percent / KF / palladium acetate; 2-(dicyclohexylphosphino)biphenyl / tetrahydrofuran / 18 h / 60 °C 2: 79 percent / pyridine / 12 h / 0 - 20 °C 3: DIPEA / Pd(PPh₃)2Cl₂; CuI / dimethylformamide / 48 h / 45 °C 4: 1.26 g / aq. NaOH / diethyl ether; methanol / 18 h 5: 8 percent / CuSO₄; sodium ascorbate; KHCO₃ / 2-methyl-propan-2-ol; H₂O / 24 h / 50 °C 6: 94 percent / aq. NaOH / tetrahydrofuran / 2 h / 20 °C

Reference： [1]Soellner, Matthew B.; Rawls, Katherine A.; Grundner, Christoph; Alber, Tom; Ellman, Jonathan A. [Journal of the American Chemical Society, 2007, vol. 129, # 31, p. 9613 - 9615]

10
[ 168267-41-2 ]
[ 182344-23-6 ]
[ 923982-33-6 ]

Yield	Reaction Conditions	Operation in experiment
51%	With cesium fluoride In 1,4-dioxane at 20 - 40℃; for 3h;	XI.C C. Synthesis of l-(4-Fluoro-3-trifluoromethylphenyl)-3-azabicyclo[3.1.01hexane Hydrochloride A stirred solution of 3-bromo-l-(3,4-dimethoxybenzyl)maleimide (1.63g,5.0mmol) and 4-fluoro-3-(trifluoromethyl)phenylboronic acid (1.35g, 6.5mmol) in anhydrous dioxane (15mL) under nitrogen was degassed over lOmin with a stream of nitrogen, then treated with cesium fluoride (2.Og, 13.2mmol) and Cl2Pd(dppf). CH2Cl2 (Aldrich, 0.25g, 0.30mmol), stirred Ih at room temperature, then 2h at 4O0C. The mixture was cooled, diluted with methylene chloride (7OmL), stirred a few minutes, filtered through Celite (rinse with methylene chloride), and the filtrate concentrated in vacuo. The residue was dissolved in methylene chloride and loaded onto a silica gel column and the product eluted with methylene chloride to afford product, which was triturated from petroleum ethers to afford the intermediate arylmaleimide (1.05g, 51%) as a yellow solid. NO MS (M+l) peak. 1H NMR (CDCl3) δ 7.69 (m, IH), 7.36 (m, IH), 7.04 (m, IH), 6.92-6.99 (m, 3H), 6.79 (m, IH), 4.68 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H).

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2007/16155, 2007, A2 Location in patent: Page/Page column 125

11
[ 1034296-89-3 ]
[ 182344-23-6 ]
[ 1034296-90-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 0.222222h;	E.14 A degassed solution of 3-(6-amino-5-bromo-pyridin-3-yl)-N-(2-dimethylamino- ethyl)benzamide (40 mg; 0.11 mmol; 0.5 ml of a 0.22 M stock solution in DMF), potassium carbonate (0.5 ml of a 0.725 M stock solution in water), and bis(triphenylphosphine)palladium (II) dichloride (0.5 mL of a 0.011 M stock solution in DMF) was added to 4-fluoro-3-trifluoromethylphenylboronic acid (23 mg; 0.11 mmol) and the mixture heated at 900C on a STEM block for 18 hours. The solvent was removed under vacuum (Genevac) and the residue treated with water (2 mL) and extracted with ethyl acetate (2 mL). The organic phase was separated and the organic phase evaporated (Genevac). The crude product was purified by Prep HPLC using method B to give the title compound as a cream coloured solid. 1H (400MHz, CDCI3) 8.40 (1 H, s), 7.99 (1 H, s), 7.69 (5H, m), 7.65 (1H, t), 7.34 (1 H, t), 6.86 (1 H, bs), 4.61 (2H, bs), 3.55 (2H, q), 2.54 (2H, t), 2.28 (6H, s). LCMS (method B) Rτ 4.28, Ml 447 (M+H+).

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK - WO2008/74997, 2008, A1 Location in patent: Page/Page column 100

12
[ 1093211-87-0 ]
[ 182344-23-6 ]
[ 76-05-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
24%	Stage #1: 4-(3-hydroxy-benzyl)-piperazine-1-carboxylic acid benzo[d]isoxazol-3-ylamide; 4-fluoro-3-(trifluoromethyl)phenylboronic acid With pyridine In dichloromethane at 20℃; for 48h; Molecular sieve; Stage #2: trifluoroacetic acid	28.B A mixture of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (124.7 mg), pyridine (122 μl_), 4 A powdered molecular sieves (181 mg), and Cu(OAc)2 (51.5 mg) in DCM (3 ml_) was stirred, open to air, for 48 h at rt. Additional DCM was added as the mixture dried up. The reaction mixture was filtered through a pad of diatomaceous earth and passed through a pad of silica gel (NH3/MeOH/DCM). The filtrate was concentrated and the residue was purified by reverse-phase HPLC to give 45.1 mg (24%) of the desired product as the TFA salt. MS: 515.2. 1H NMR (CDCI3): 9.75 (s, 1 H), 7.93 (d, J = 8.0, 1 H), 7.51 -7.48 (m, 1 H), 7.35-7.32 (m, 2H)1 7.24 (t, J = 8.0, 1 H)1 7.19-7.17 (m, 1 H), 7.15-7.10 (m, 3H), 7.03 (t, J = 2.0, 1 H), 6.99-6.97 (m, 1 H)1 4.17 (s, 2H), 4.39-3.50 (br s, 4H), 3.45- 2.82 (br s, 4H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2008/153752, 2008, A2 Location in patent: Page/Page column 43-44

13
[ 1191254-15-5 ]
[ 182344-23-6 ]
[ 1191253-90-3 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide; 4-fluoro-3-(trifluoromethyl)phenylboronic acid With pyridine In dichloromethane at 20℃; for 24h; Molecular sieve; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 5h;	4 3-(3,5-Dichloro-4-hydroxyphenyl)-N-(4-(4-fluoro-3-(trifluoromethyl)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (compound 200) 3-(3,5-Dichloro-4-hydroxyphenyl)-N-(4-(4-fluoro-3-(trifluoromethyl)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (compound 200) 3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide (compound G, 60 mg, 0.12 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (50 mg, 0.24 mmol), Cu(OAc)2 (44 mg, 0.24 mmol) and 3 Å powdered molecular sieves (70 mg) were stirred in an open tube in dichloromethane (3 mL). Pyridine (57 mg, 0.72 mmol) was added and the dark green suspension stirred vigorously at room temperature in an open tube for 1 d. The molecular sieves were filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.3 mL) was added. The dark solution was stirred at room temperature for 5 h, then methanol (1 mL) was added and the solution concentrated in vacuo. The residue was purified by preparative HPLC providing the title compound (46 mg, 0.085 mmol, 71%). 1H NMR δ (ppm) (DMSO-d6): 4.53 (2H, d, J=6.20 Hz), 7.06-7.13 (2H, m), 7.36-7.48 (4H, m), 7.53-7.60 (1H, m), 8.01 (2H, s), 10.03 (1H, t, J=6.20 Hz), 11.20 (1H, s). LCMS (10 cm_esci_Bicarb_MeCN) tR 3.48 min; m/z 540/542/544 [M-H]-.
71%	Stage #1: 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide; 4-fluoro-3-(trifluoromethyl)phenylboronic acid With pyridine; copper diacetate In dichloromethane at 20℃; for 24h; Molecular sieve; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 5h;	1.1D 3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide (compound G, 60 mg, 0.12 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (50 mg, 0.24 mmol), Cu(OAc)2 (44 mg, 0.24 mmol) and 3 powdered molecular sieves (70 mg) were stirred in an open tube in dichloromethane (3 mL). Pyridine (57 mg, 0.72 mmol) was added and the dark green suspension stirred vigorously at room temperature in an open tube for 1 d. The molecular sieves were filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.3 mL) was added. The dark solution was stirred at room temperature for 5 h, then methanol (1 mL) was added and the solution concentrated in vacuo. The residue was purified by preparative HPLC providing the title compound (46 mg, 0.085 mmol, 71%). 1H NMR δ (ppm) (DMSO-d6): 4.53 (2H, d, J=6.20 Hz), 7.06-7.13 (2H, m), 7.36-7.48 (4H, m), 7.53-7.60 (1H, m), 8.01 (2H, s), 10.03 (1H, t, J=6.20 Hz), 11.20 (1H, s). LCMS (10 cm_esci_Bicarb_MeCN) tR3.48 min; m/z 540/542/544 [M-H]-.
	Stage #1: 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide; 4-fluoro-3-(trifluoromethyl)phenylboronic acid With pyridine; copper diacetate In dichloromethane at 20℃; for 24h; Molecular sieve; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 5h;	2 Example 2 Preparation of 3-(3,5-Dichloro-4-hydroxyphenyl)- N-(4-(4-fluoro-3- (trifluoromethyl)phenoxy)benzyl)-1,2,4-oxadiazole-5-carboxamide (Compound 23) [0114] 3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-l,2,4- oxadiazole-5-carboxamide (compound D, 60 mg, 0.12 mmol), 4-fluoro-3- (trifluoromethyl)phenylboronic acid (50 mg, 0.24 mmol), Cu(OAc)2 (44 mg, 0.24 mmol) and 3 A powdered molecular sieves (70 mg) are stirred in an open tube in dichloromethane (3 mL). Pyridine (57 mg, 0.72 mmol) is added and the dark green suspension is stirred vigorously at room temperature in an open tube for 1 d. The molecular sieves are filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue is dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.3 mL) is added. The dark solution is stirred at room temperature for 5 h, then methanol (1 mL) is added and the solution concentrated in vacuo. The residue is purified by preparative HPLC providing the title compound.

Reference： [1]Current Patent Assignee: PROGRAM FOR APPROPRIATE TECHNOLOGY IN HEALTH - US2009/264441, 2009, A1 Location in patent: Page/Page column 104
[2]Current Patent Assignee: INSTITUTE FOR ONEWORLD HEALTH - US2009/318429, 2009, A1 Location in patent: Page/Page column 244
[3]Current Patent Assignee: DE HOSTOS, Eugenio L.; NGUYEN, Tue H. - WO2014/47212, 2014, A1 Location in patent: Paragraph 0114

14
[ 853234-57-8 ]
[ 182344-23-6 ]
[ 1104877-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In toluene for 12h; Inert atmosphere; Reflux;	7.1 3.0 g of 3,9-dibromo-indenofluorenedione was mixed with 3.3 g of 4-fluoro-3-(trifluoromethyl)phenylboronic acid, 0.29 g of tetraxis(triphenylenephosphine)palladium (0), 25 ml of 2M sodium carbonate and 160 ml of toluene under argon stream. The mixture was stirred with reflux for 12 hours. After cooling, the reaction liquid was filtered, washed with water and methanol, whereby 3.7 g of a reddish purple solid as an intermediate D was obtained. As a result of mass spectroscopy of the resulting solid, a peak was observed at M/Z=606.

Reference： [1]Current Patent Assignee: IDEMITSU KOSAN CO LTD - US2010/19659, 2010, A1 Location in patent: Page/Page column 31; 32

15
[ 6132-37-2 ]
4-fluoro-3-(trifluoromethyl)phenylboronic acid [ No CAS ]
[ 773138-53-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In benzene; for 5h;Reflux;	To a solution of ethyl 5-broinofuran-2-carboxylate (150ing, 0.69mmol) inDME (5mL) were added 4-fluoro-3-(trifluoromethyDphenylboronic acid (171mg,0.82mmol), 2M Na2CO3 (1.03mL, 2.06mmol), and catalytic amounts of Pd(PPh3)4 (158mg, 0.14mmol). The reaction mixture was refluxed for 5h, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc / n-Hex=l-"5) to give title compound (174 mg, 70 percent) .

Reference： [1]Patent: WO2010/2209,2010,A2 .Location in patent: Page/Page column 143

16
[ 182344-23-6 ]
[ 1198180-98-1 ]
[ 1198181-53-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium carbonate In ISOPROPYLAMIDE for 16h; Inert atmosphere;	88 Reference Example 88 ethyl (2E)-3-{5-[4-fluoro-3-(trifluoromethyl)phenyl]furan-2-yl}prop-2-enoate; A solution of ethyl (2E)-3-(5-bromofuran-2-yl)prop-2-enoate (0.65 g, 2.64 mmol) obtained in Reference Example 31, [4-fluoro-3-(trifluoromethyl)phenyl]boronic acid (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0.28 g, 0.24 mmol) and 2M sodium carbonate solution (6.56 mL, 13.1 mmol) in N,N-dimethylacetamide (25 mL) was stirred under an argon atmosphere for 16 hr. After cooling the reaction solution to room temperature, the solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 98:2 - 95:5) to give the title compound (0.60 g, yield 76%) as a yellow solid. 1H-NMR (300 MHz, CDCl3)δ: 1.34 (t, J = 7.2 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 6.42 (d, J = 15.9 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 7.24 (t, J = 9.3 Hz, 1H), 7.43 (d, J = 15.9 Hz, 1H), 7.83 - 7.92 (m, 2H).
76%	With sodium carbonate In ISOPROPYLAMIDE for 16h; Inert atmosphere;	88 A solution of ethyl (2E)-3-(5-bromofuran-2-yl)prop-2-enoate (0.65 g, 2.64 mmol) obtained in Reference Example 31, [4-fluoro-3-(trifluoromethyl)phenyl]boronic acid (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0.28 g, 0.24 mmol) and 2M sodium carbonate solution (6.56 ml, 13.1 mmol) in N,N-dimethylacetamide (25 ml) was stirred under an argon atmosphere for 16 hr. After cooling the reaction solution to room temperature, the solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 98:2-95:5) to give the title compound (0.60 g, yield 76%) as a yellow solid.1H-NMR (300 MHz, CDCl3) δ: 1.34 (t, J=7.2 Hz, 3H), 4.27 (q, J=7.2 Hz, 2H), 6.42 (d, J=15.9 Hz, 1H), 6.69 (d, J=3.6 Hz, 1H), 6.74 (d, J=3.6 Hz, 1H), 7.24 (t, J=9.3 Hz, 1H), 7.43 (d, J=15.9 Hz, 1H), 7.83-7.92 (m, 2H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2295406, 2011, A1 Location in patent: Page/Page column 73
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2011/251187, 2011, A1 Location in patent: Page/Page column 53

17
[ 1262132-97-7 ]
[ 182344-23-6 ]
[ 1262132-98-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium phosphate In 1,2-dimethoxyethane at 80℃; for 1h;	1.1-8 Step 1-8 The compound (60 g) obtained in step 1-7, 4-fluoro-3-(trifluoromethyl)phenylboronic acid (29 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (5.4 g), potassium phosphate (113 g) and 1,2-dimethoxyethane (600 ml) were mixed, and the mixture was stirred at 80° C. for 1 hr. 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 magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform/ethyl acetate=10/1) to give a crude product of the compound described in the above-mentioned scheme. This was slurried in diisopropyl ether/hexane=1/1 (500 ml) to give the compound described in the above-mentioned scheme (45 g, 70%).1H-NMR (CDCl3) δ: 1.61 (9H, s), 5.33 (2H, s), 6.88 (1H, s), 7.35-7.48 (6H, m), 8.04 (1H, dd, J=6.7, 2.1 Hz), 8.11-8.15 (1H, m), 8.31 (1H, s).

Reference： [1]Current Patent Assignee: JAPAN TOBACCO INC - US2011/77267, 2011, A1 Location in patent: Page/Page column 29

18
[ 19235-89-3 ]
[ 182344-23-6 ]
[ 1219454-49-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1,4-dioxane at 90℃; for 15h;	38 Reference Production Example 38; To 8 ml of 1,4-dioxane was added 0.6 g of 4-chloropyridine-2-carbonitrile, 1.44 g of potassium carbonate, 0.15 g of tetrakis(triphenylphosphinepalladium) and 1.1 g of 3-trifluoromethyl-4-fluorophenylboronic acid, and the mixture was stirred at 90°C for 15 hours. Thereafter, the resultant reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate three times. The organic layers obtained by extraction were combined and washed with saturated saline, dried over anhydrous magnesium sulfate, then, concentrated. The resultant residue was subjected to silica gel column chromatography to obtain 0.4 g of 4-(3-trifluoromethyl-4-fluorophenyl)pyridine-2-carbonitrile. [Show Image] 1H-NMR:7.40(t,1H),7.70(dd,1H),7.81-7.89(m,3H),8.81(dd,1H)

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP2332936, 2011, A1 Location in patent: Page/Page column 46

19
[ 1228673-56-0 ]
[ 182344-23-6 ]
[ 1228673-57-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In toluene for 8h; Reflux; Inert atmosphere;	6 EXAMPLE 6 Synthesis of Indenofluorenedione Derivative (A-64) The synthesis was conducted according to the following scheme. [Show Image] A mixture of 10 g of 1,5-diiodo-2,4-dimethylbenzene, 5.7 g of 4-trifluoromethoxyphenylboronic acid, 1.29 g of tetrakis(triphenylphosphine)palladium(0), 43 ml of 2 M sodium carbonate, and 70 ml of toluene was refluxed under stirring in argon stream for 6 h. After cooling, the reaction product solution was filtered, washed with water and then methanol, and purified on a silica gel column (developer: hexane), to obtain 3.0 g of white solids. Mass spectrometric measurement on the obtained white solids showed a peak at M/Z = 392. Next, a mixture of 2.9 g of the white solids, 1.8 g of 4-bromophenylboronic acid, 0.35 g of tetrakis(triphenylphosphine)palladium(0), 17 ml of 2 M sodium carbonate, and 19 ml of toluene was refluxed under stirring in argon stream for 6 h. After cooling, the reaction product solution was filtered, washed with water and then methanol, and purified on a silica gel column (developer: hexane), to obtain 1.6 g of white solids. Mass spectrometric measurement on the obtained white solids showed a peak at M/Z = 421. Next, a mixture of 1.6 g of white solids, 1.0 g of potassium permanganate, 6 ml of pyridine, and 10 ml of water was heated under stirring at 100 °C. Thereafter, 1.5-g portions of potassium permanganate were added to the mixture every 30 min in a total amount of 13 g. After heating under stirring for 8 h from starting the reaction, the solid matter was removed by hot filtration and the filtrate was neutralized by adding a 1 N hydrochloric acid dropwise. The precipitated white solids collected by filtration was washed with a diluted hydrochloric acid and then ion exchanged water and dried, to obtain 1.5 g of white solids. Then, a mixture of the white solids and 20 ml of a concentrated sulfuric acid was heated under stirring at 50 °C for 12 h. The reaction product solution was allowed to cool and then poured into iced water. The orange solids were collected by filtration, washed with ion exchanged water, and dried, to obtain 0.9 g of solids. Mass spectrometric measurement on the obtained solids showed a peak at M/Z = 445. A mixture of 0.8 g of the diquinone compound thus obtained, 0.5 g of 4-fluoro-3-trifluoromethylphenylboronic acid, 0.08 g of tetrakis(triphenylphosphine)palladium(0), 3 ml of 2 M sodium carbonate, and 4 ml of toluene was refluxed under stirring in argon stream for 8 h. After cooling, the reaction product solution was filtered to collect the solids which were washed with water, methanol, and then toluene, to obtain 0.7 g of range solids (intermediate A). Mass spectrometric measurement on the obtained solids showed a peak at M/Z = 528. Finally, a mixture of 0.7 g of the diquinone compound thus synthesized, 0.5 g of malononitrile, and 30 ml of pyridine was heated under stirring at 50 °C for 8 h. After allowing the mixture to cool, the solids were collected by filtration, washed with water, methanol, and then toluene, and vacuum-dried. The solids were then purified by sublimation at 320 °C, to obtain 1.5 g of purple crystals. Through IR measurement of the obtained compound, it was found that the absorption at 1725 cm-1 attributable to carbonyl group disappeared and the absorption attributable to cyano group appeared at 2220 cm-1. Mass spectrometric measurement showed a peak at M/Z = 624. The obtained compound was measured for the reduction potential by cyclic voltammetry in the same manner as in Example 1. The reduction potential of the compound (A-3) on the basis of the first oxidation potential of the standard ferrocene (Fc) was -0.85 V (vs Fc+/Fc).

Reference： [1]Current Patent Assignee: IDEMITSU KOSAN CO LTD - EP2371812, 2011, A1 Location in patent: Page/Page column 39

20
[ CAS Unavailable ]
[ 182344-23-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
34%	Stage #1: C₁₄H₁₃BrClNO₃; 4-fluoro-3-(trifluoromethyl)phenylboronic acid With sodium carbonate In water at 144℃; for 0.333333h; Microwave irradiation; Stage #2: With hydrogenchloride In water	I-1-a-24 Example I-1-a-24Process C 0.717 g of the compound according to Ex. I-1'-a-1, 0.448 g of 4-fluoro-3-trifluoromethylphenylboronic acid and 0.8 g of sodium carbonate are initially charged in 15 ml of water, 0.05 g of palladium(II) nitrate dihydrate are added and the mixture is stirred at 144° C. in a microwave oven for 20 min. After cooling, the mixture is acidified with dilute hydrochloric acid and filtered off with suction.This is followed by an MPLC separation on silica gel using a mobile phase gradient of cyclohexane+50-80% ethyl acetate.Yield: 0.31 g (34% of theory), m.p. 257° C.

Reference： [1]Current Patent Assignee: BAYER AG - US2011/306499, 2011, A1 Location in patent: Page/Page column 51

21
[ 170434-06-7 ]
[ 182344-23-6 ]
[ 1268670-26-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1,2-dimethoxyethane; water for 14h; Reflux; Inert atmosphere;	2.1 2.5 g of 2-chloro-5-n-decylpyrimidine, 2.24 g of 4-fluoro-3-(trifluoromethyl)phenylboronic acid, 22 mL of 1,2-dimethoxyethane, and 26 ml of a 2 M aqueous solution of potassium carbonate were placed in a two-neck flask. After argon gas was aerated into this solution for 20 minute, 0.57 g of a tetrakistriphenylphosphine (0) palladium complex was placed therein. This solution was heated to reflux for 14 hours under an argon atmosphere using an oil bath. The organic layer was separated/collected and separated/purified by silica gel chromatography (eluent: a mixed solvent of dichloromethane and hexane) to obtain 2.50 g of compound B. The 1H-NMR data of the compound B is shown below. 1H-NMR (400 MHz/CDCL3): δ 8.73 (d, 1H), 8.61-8.65 (m, 3H), 7.30 (d, 1H), 2.64 (t, 2H), 1.18-1.70 (m, 16H), 0,88 (t, 3H).

Reference： [1]Current Patent Assignee: NATIONAL INSTITUTE OF ADVANCED INDUSTRIAL SCIENCE AND TECHNOLOGY - EP2471800, 2012, A1 Location in patent: Page/Page column 44

22
[ 34160-40-2 ]
[ 182344-23-6 ]
[ 1401165-65-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With caesium carbonate In 1,4-dioxane at 20 - 80℃;	267A 6-(4-fluoro-3-(trifluoromethyl)phenyl)picolinaldehyde Example 267A 6-(4-fluoro-3-(trifluoromethyl)phenyl)picolinaldehyde To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 4-fluoro-3-(trifluoromethyl)phenylboronic acid (1.11 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3* vacuum/purge N2), then heated at 80° C. overnight. After cooling to room temperature the mixture was concentrated and the residue partitioned between water and CH2Cl2. The organic extract was concentrated and purified by chromatography (10% ethyl acetate:hexanes) to provide 1.31 g (91%) of the title compound. MS (DCI+) m/z 270 (M+H).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2012/245124, 2012, A1 Location in patent: Page/Page column 71

23
[ 1415130-58-3 ]
[ 182344-23-6 ]
[ 1415130-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1,4-dioxane; water at 70℃; for 1h;	102.E Ethyl 3-(5-(2-(((3-chloro-4-iodophenyl)amino)methyl)-4,5-difluorophenyl)picolinamido)propanoate (123 mg, 0.21 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (85 mg, 0.41 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol), and K2CO3 (85 mg, 0.62 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.3 mL) and the resulting mixture was heated to 70° C. After 1 h the resulting mixture directly purified via column chromatography to yield the title compound.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2012/302610, 2012, A1 Location in patent: Page/Page column 69

24
[ 1415129-99-5 ]
[ 182344-23-6 ]
[ 1415130-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1,4-dioxane; water at 80℃; for 16h;	31.B Ethyl 3-(5-(2-(((3-chloro-4-iodophenyl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (300 mg, 0.48 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (138 mg, 0.67 mmol), Pd(dppf)Cl2 (39 mg, 0.05 mmol), and K2CO3 (131 mg, 0.95 mmol) were dissolved in 1,4-dioxane (1.6 mL) and water (0.4 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2012/302610, 2012, A1 Location in patent: Page/Page column 38

25
[ 22282-99-1 ]
4-fluoro-3-(trifluoromethyl)phenylboronic acid [ No CAS ]
[ 1434817-74-9 ]

Yield	Reaction Conditions	Operation in experiment
99.4%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In water; toluene; at 88℃; for 23h;Reflux;	To a stirred suspension of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (42.6 g, 205 mmol) in toluene (200 mL) were added <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (34.4 g, 200 mmol) and 2 M aqueous potassium carbonate (200 mL). After the addition of 1,1?-bis(diphenylphosphino)- ferrocene-palladium(II)dichloride ichioromethane complex (81.7 mg, 0.1 mmol), the two-phase, yellowish reaction mixture was stirred under reflux at 88C for 23 h. The resultant brownish reaction mixture was cooled to room temperature and extracted with toluene (200 mL). After washing with 10% brine (200 mL), the toluene layer was dried with Na2SO4 (50 g) and then treated under stirring with charcoal (2 g) for 30 mm. Filtration and evaporation (50C/ 10 mbar) afforded the crude title product (50.7 g, 99.4%) as an off-white, crystalline residue which was used without purification in the next step. 1H NMR (CDC13, 400 MHz) delta 2.64 (s, 3H), 7.25-7.36 (m, 3H), 7.76-7.82 (m, 1H), 7.84 (dd, J1 = 6.7 Hz, J2 = 2.4 Hz, 1H), 8.58 (d, J 5.0 Hz, 1H). ESI-MS (m/z) [M+H] 256.3 (100).
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; toluene; at 88℃; for 23h;	a) 4-(4-Fluoro-3-trifluoromethyl-phenyl)-2-methyl-pyridine To a stirred suspension of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (42.6 g, 205 mmol) in toluene (200 mL) were added <strong>[22282-99-1]4-bromo-2-methylpyridine</strong> (34.4 g, 200 mmol) and 2 M aqueous potassium carbonate (200 mL). After the addition of 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (81.7 mg, 0.1 mmol), the two-phase, yellowish reaction mixture was stirred under reflux at 88 C. for 23 h. The resultant brownish reaction mixture was cooled to room temperature and extracted with toluene (200 mL). After washing with 10% brine (200 mL), the toluene layer was dried with Na2SO4 (50 g) and then treated under stirring with charcoal (2 g) for 30 min. Filtration and evaporation (50 C./?10 mbar) afforded the crude title product (50.7 g, 99.4%) as an off-white, crystalline residue which was used without purification in the next step. 1H NMR (CDCl3, 400 MHz) delta 2.64 (s, 3H), 7.25-7.36 (m, 3H), 7.76-7.82 (m, 1H), 7.84 (dd, J1=6.7 Hz, J2=2.4 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H). ESI-MS (m/z) [M+H]+256.3 (100).

Reference： [1]Patent: WO2013/68434,2013,A1 .Location in patent: Page/Page column 37; 38
[2]Patent: US2013/123512,2013,A1 .Location in patent: Paragraph 0193; 0194

26
[ 1807515-73-6 ]
[ 182344-23-6 ]
[ 1807515-52-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate monohydrate In <i>tert</i>-butyl alcohol at 28℃; for 12h; Schlenk technique; Inert atmosphere; Sealed tube;	3. General procedure for the Suzuki-Miyaura cross-coupling reaction. General procedure: Procedure A: To a Schlenk tube equipped with a magnetic stiring bar and a teflon septum was charged K3PO4.H2O (1.5 mmol, 3 equiv), aryl pentafluorobenzene sulfonate (0.5 mmol, 1.0 equiv), aryl boronic acid (0.75 mmol, 1.5 equiv) and Pd(PPh3)2Cl2 (0.015 mmol, 3 mol%). The tube was then capped with a rubber septum, evacuated and backfilled with nitrogen and this cycle was repeated twice. Under an inertatmosphere, tert - butanol (3 mL) was added via syringe. Under a positive pressure of nitrogen, the rubber septum was replaced with a Teflon screw cap and this was sealed. The Schlenk tube was stirred at room temperature for the time indicated. When the reaction was completed according to TLC or GCMS (FID), thereaction mixture was diluted with EtOAc (5 mL) and filtered through celite bed. The organic layer was concentrated under reduced pressure. The residue was purified through silica gel (230 - 400 mesh) column chromatography using 1-10% ethyl acetate in petroleum ether to afford the product.

Reference： [1]Joseph, Jayan T.; Sajith, Ayyiliath M.; Ningegowda, Revanna C.; Nagaraj, Archana; Rangappa; Shashikanth, Sheena [Tetrahedron Letters, 2015, vol. 56, # 36, p. 5106 - 5111]

27
[ 1257647-77-0 ]
[ 182344-23-6 ]
[ 1835721-02-2 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; water In tetrahydrofuran at 90℃; for 4h; Inert atmosphere; Sealed tube; Microwave irradiation;

Reference： [1]Muir, Calum W.; Vantourout, Julien C.; Isidro-Llobet, Albert; Macdonald, Simon J. F.; Watson, Allan J. B. [Organic Letters, 2015, vol. 17, # 24, p. 6030 - 6033]

28
[ 553-94-6 ]
[ 182344-23-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In water; toluene for 72h; Inert atmosphere; Reflux;	2.1 2.2. Synthetic procedures 2.2.1. Preraration of 1,4-dimethyl-2-(4-fluoro-3-trifluoromethylbenzyl) benzene2-bromo-para-xylene (2 g, 10.8 mmol), 4-fluoro-3-trifluoromethylbenzylboronic acid (2.7 g, 12.97 mmol), K2CO3 (2.82 g,0.1 mol) were mixed into 2:1 of toluene and H2O, Pd (PPh3)4(0.14 g, 0.6 mol %) was added as catalyst. N2was bubbled for halfan hour to remove the dissolve oxygen. The reaction mixture wasrefluxed for three days under nitrogen atmosphere. After the completion of the reaction (monitored by TLC) organic layer was separated from the reaction mixture and passed through neutralalumina to remove the dissolved catalyst. The organic layer wasthen dried over anhydrous magnesium sulfate, concentrated underreduced pressure to get a off white solid material. Further purification by silica gel column chromatography (with n-hexane as aneluent) leads to 2.47 g (85%) of white solid material. Anal. Calcd.for C15H12F4(268.08 g/mol): C, 67.16 H, 4.51; Found: C, 66.76; H,4.68;1H NMR (CDCl3, 200 MHz, dppm): 2.20 (s, 3 H) 2.35 (s, 3H) 6.96-7.10 (m, 1 H) 7.10-7.20 (m, 2 H) 7.24 (d,J= 9.22 Hz, 1H) 7.42-7.58 (m, 2 H).13C NMR (CDCl3, 200 MHz, d ppm):157.30, 139.02, 137.55 133.43, 133.26, 130.64, 129.90, 128.39126.79, 126.66, 116.23, 115.82, 31.17, 29.73.

Reference： [1]Chini, Mrinmoy Kumar; Das, Chayanika; Chatterjee, Shyambo [Chemical Physics Letters, 2016, vol. 657, p. 26 - 32]

29
[ 944718-23-4 ]
[ 182344-23-6 ]
[ 1610734-03-6 ]

Yield	Reaction Conditions	Operation in experiment
45%	With bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran at 70℃; for 2h; Inert atmosphere;	46 Synthesis of compound 97 General procedure: The 10g (0.048mol) Compound 1,8.4g (0.048mol) Compound 2,3.36g (0.0048mol) bis (triphenylphosphine) palladium dichloride, 250ml round bottom flask, and purged with argon three times, tetrahydrofuran ( 150ml) and water (10ml), raw materials were dissolved at an external temperature of 70 ° C the reaction 2h, after completion of the reaction, the solvent under reduced pressure to spin, dry over column (PE: EA = 20: 1) to give a pale yellow solid 8g. Yield: 65% . Method of synthesizing example 1, to obtain light yellow solid, yield 45%

Reference： [1]Current Patent Assignee: SICHUAN BAILI PHARMACEUTICAL CO LTD - CN103804312, 2016, B Location in patent: Paragraph 0071; 0207-0209

30
[ 374063-92-0 ]
[ 182344-23-6 ]
[ 1610733-36-2 ]

Yield	Reaction Conditions	Operation in experiment
65%	With bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran at 70℃; for 2h; Inert atmosphere;	1 Synthesis of compound 3 The 10g (0.048mol) Compound 1, 8.4g (0.048mol) Compound 2, 3.36g (0.0048mol) bis (triphenylphosphine) palladium dichloride, 250ml round bottom flask, and purged with argon three times, tetrahydrofuran ( 150ml) and water (10ml), raw materials were dissolved at an external temperature of 70 ° C the reaction 2h, after completion of the reaction, the solvent under reduced pressure to spin, dry over column (PE: EA = 20: 1) to give a pale yellow solid 8g. Yield: 65%

Reference： [1]Current Patent Assignee: SICHUAN BAILI PHARMACEUTICAL CO LTD - CN103804312, 2016, B Location in patent: Paragraph 0069-0071

31
[ 123-75-1 ]
[ 182344-23-6 ]
[ 895543-04-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	at 120℃; for 8h; Sealed tube;	3 500mg of compound 1 was added to 5ml pyrrolidine, the lower sealed tube at 120 ° C external temperature reaction 8h, the reaction was completeAfter the solvent was spin dry method through the column to give an off-white solid 448mg, 72% yield.

Reference： [1]Current Patent Assignee: SICHUAN BAILI PHARMACEUTICAL CO LTD - CN103804312, 2016, B Location in patent: Paragraph 0076; 0077

32
[ 209959-33-1 ]
4-fluoro-3-(trifluoromethyl)phenylboronic acid [ No CAS ]
C₂₁H₂₃F₄N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.4%	With potassium fluoride monohydrate; palladium diacetate; In methanol;Reflux;	Compound 69 (200 mg, 0 . 948mmol), compound 1 (237 mg, 1 . 138mmol), Pd (AcO)2(11 mg, 0 . 0474mmol), KF·H2O (178.47 mg, 1 . 896mmol) and methanol after mixing, heating to reflux. TLC monitoring the reaction is complete, dry mixes the type, column chromatography PE: EA30 : 1 to 200 mg of colorless liquid, yield of 63.4%

Reference： [1]Patent: CN103804312,2016,B .Location in patent: Paragraph 0168-0170

33
[ 695-53-4 ]
4-fluoro-3-(trifluoromethyl)phenylboronic acid [ No CAS ]
3-[4-fluoro-3-(trifluoromethyl)phenyl]-5,5-dimethyloxazolidine-2,4-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 10705 - 10718

34
[ 1124382-72-4 ]
4-fluoro-3-(trifluoromethyl)phenylboronic acid [ No CAS ]
8-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;	a 8-(4-Fluoro-3-trifluoromethyl-phenyl)-ri,2^1triazolori,5-alpyridin-2-ylamine In a 150 ml round-bottomed flask were combined 8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (1 g, 4.69 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (976 mg, 4.69 mmol) and cesium carbonate (3.06 g, 9.39 mmol) with dioxane (50 ml) and water (5 ml) to give a colorless solution. 1 ,l'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (343 mg, 469 mupiiotaomicron) was added. The recti on mixture was stirred for 3 hours at 100C. Chromatography (silica gel, 50 g, ethyl acetate/heptane = 40:60 to 100:0) yielded the title compound as light brown solid (1.24 g, 89%). MS: m/z = 297.1 [M+H]+.

Reference： [1]Patent: WO2017/42114,2017,A1 .Location in patent: Page/Page column 65

35
[ 2099711-53-0 ]
[ 182344-23-6 ]
[ 2099711-54-1 ]

Yield	Reaction Conditions	Operation in experiment
81.35%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In 1,4-dioxane; water at 100℃; for 16h; Inert atmosphere;	321.6 Preparation of 2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxopyrazolo[1,5-a]pyrazin- 5(4H)-yl)acetic acid: Preparation of 2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxopyrazolo[1,5-a]pyrazin- 5(4H)-yl)acetic acid: [00246] To a solution of 2-(3-bromo-4-oxopyrazolo [1, 5-a] pyrazin-5(4H)-yl) acetate (0.5 g, 1.66 mmol) in 1,4-dioxane:water mixture (4:1, 30 mL), potassium carbonate (0.69 g, 4.99 mmol) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (0.52 g, 2.49 mmol) were added and the reaction mixture was purged with argon for 10 min. Then [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2.DCM) (0.14 g, 0.166 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was diluted with water (50 mL) and it was washed with ethyl acetate (2 x 30 mL). The aqueous layer pH was adjusted to acidic by using 1.5N hydrochloric acid solution and extracted with ethyl acetate (2 x100 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude was purified by silica gel column chromatography using 5% methanol in dichloromethane to afford 2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)acetic acid (0.48 g, 81.35% yield) as a off-white solid. Calculated (M+H): 356.06; Found (M+H): 356.0

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2017/100591, 2017, A1 Location in patent: Paragraph 00246

36
[ 1097834-88-2 ]
[ 182344-23-6 ]
[ 2099711-86-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; tetrabutylammomium bromide; potassium carbonate In water; toluene at 110℃; for 18h; Inert atmosphere;	390.4 Step-4: (0850) (0851) Preparation of 1-tert-butyl 2-methyl 3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole- 1,2-dicarboxylate Step-4: (0850) (0851) Preparation of 1-tert-butyl 2-methyl 3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole- 1,2-dicarboxylate: (0852) [00326] To a solution of 1-tert-butyl 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate (2.5 g, 8.21 mmol), (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (3.59 g, 17.26 mmol) and potassium carbonate (9.08 g, 65.75 mmol) in toluene:water mixture (70 mL, 1:1), tetrabutyl ammonium bromide (0.23 g, 0.73 mmol) was added and the reaction mixture was purged with argon for 15 minutes. Then tetrakis(triphenylphosphine)palladium (0) (0.189 g, 0.16 mmol) was added and the reaction mixture was heated at 110 °C for 18 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2 x 50 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 15% ethyl acetate in hexane to afford the title compound 1-tert-butyl 2-methyl 3-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrrole-1,2- dicarboxylate (1.7 g, 53% yield) as a brownish gum.1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.80-7.78 (m, 2H), 7.54 (t, J = 10 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 3.74 (s, 3H), 1.51 (s, 9H).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2017/100591, 2017, A1 Location in patent: Paragraph 00326

37
[ 2099712-11-3 ]
[ 182344-23-6 ]
[ 2099712-12-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In 1,4-dioxane; water at 100℃; for 16h; Inert atmosphere;	448.5 Step 5: Preparation of 2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-oxoimidazo[1,2-c]pyrimidin- 6(5H)-yl)acetic acid: Step 5: Preparation of 2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-oxoimidazo[1,2-c]pyrimidin- 6(5H)-yl)acetic acid: (1007) [00373] To a solution of ethyl 2-(3-iodo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)acetate (0.2 g, 0.58 mmol) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid (0.12 g, 0.58 mmol) in 1,4-dioxane:water mixture (5 mL:2 mL) potassium carbonate (0.24 g, 1.73 mmol) was added. The reaction mixture was purged with argon for 10 min. Then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1008) [Pd(dppf)Cl2.DCM] (0.05 g, 0.06 mmol) was added and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was allowed to cool to room temperature, filtered through celite and the filtrate was concentrated. The residue was diluted with water (25 mL) and washed with ethyl acetate (20 mL). The aqueous layer was acidified with concentrated hydrochloric acid (pH~4) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude compound, which was triturated with 50% diethyl ether in n-pentane to afford the title compound2-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)- yl)acetic acid (0.11 g, 55% yield) as pale yellow solid. Calculated (M+H): 356.06; Found (M+H): 356.1.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2017/100591, 2017, A1 Location in patent: Paragraph 00373

38
[ 799293-83-7 ]
4-fluoro-3-(trifluoromethyl)phenylboronic acid [ No CAS ]
3-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 18h;Inert atmosphere;	Ste -1: (0269) (0270) Preparation of 3-(4-fluoro-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one: (0271) [00131] To a solution of <strong>[799293-83-7]3-bromothieno[3,2-c]pyridin-4(5H)-one</strong> (0.55 g, 2.17 mmol) and (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (0.73 g, 3.25 mmol) in 1,4-dioxane:water mixture (20 mL, 4:1), potassium carbonate (0.9 g, 6.51 mmol) was added. The reaction mixture was purged with argon for 15 min and bis(triphenylphosphine)palladium chloride [PdCl2(PPh3)2] (0.15 g, 0.21 mmol) was added. Then the reaction mixture was stirred at 100 C for 18 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 30% ethyl acetate in hexane to afford the title compound 3-(4-chloro-3- (trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one (0.74 g, 94% yield) as off-white solid. Calculated (M+H): 330; Found (M+H): 330.0.

Reference： [1]Patent: WO2017/100591,2017,A1 .Location in patent: Paragraph 00131

39
[ 2237252-52-5 ]
[ 182344-23-6 ]
[ 2237252-53-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In 1,4-dioxane; water at 90℃; for 16h;	6 Ethyl-5-[4-f1uoro-3-(trifluoromethyl)phenyl]-2-(propan-2-yl)pyrazolo[1,5-a]pyridine-3- carboxylate Ethyl-5-iodo-2-(propan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.25 g, 0.69 mmol) and 4- fluoro-3-trifluoromethylphenylboronic acid (0.21 g, 1.03 mmol) were dissolved in dioxane water (4:1, 5 ml_) and treated with K3PO4 (0.44 g, 2.07 mmol). The solution was degassed 20-30 min before addition of PdCl2(dppf).DCM catalyst (57 mg, 0.07 mmol), The reaction mixture was heated to 90 °C for 16h, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by coloumn chromatography (100-200 mesh silica gel, by elution with 10% ethyl acetate in hexane). Fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (240 mg, 85%) UPLC rt 1.94 min MH* 395(3 min run)1H NMR (400 MHz, DMSO-de) δ 8.91(d, J=7.36 Hz, 1H), 8.26 (s, 1 H) 8.20-8.19 (m, 1H), 8.13 (d, J=6.Q4 Hz, 1 H), 7.70 (t, J=10.16 Hz, 1H), 7.52 (dd, =7.2 Hz, 1.02 Hz, 1 H), 4.36-4.30 (m, 2H), 3.77-3.74 (m, 1H), 1.38-1.32 (m, 9 H)
240 mg	Stage #1: ethyl 5-iodo-2-(propan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate; 4-fluoro-3-(trifluoromethyl)phenylboronic acid With potassium phosphate In 1,4-dioxane; water Heating; Stage #2: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In 1,4-dioxane; water for 16h;	6 Ethyl-S-[4-fluoro-3-(trifluoromethyl)phenyl]-2-(propan-2-yl)pyrazolo[1 ,S-a]pyridine-3- carboxylate Ethyl-5-iodo-2-(propan-2-yI)pyrazolo[1 ,5-a]pyridine-3-carboxylate (0.25 g, 0.69 mmcl) and 4-fluoro-3-trifluoromethylphenylboronic acid (0.21 g, 1 .03 mmol) were dissolved indioxane/water (4:1, 5 mL) and treated with K3P04 (0.44 g, 2.07 mmol). The solution wasdegassed 20-30 mm before addition of PdCl2(dppf).DCM catalyst (57 mg, 0.07 mmol), Thereaction mixture was heated to 90 °C for 16h, cooled to room temperature, and partitionedbetween ethyl acetate and water. The organic layer was dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified by coloumnchromatography (100-200 mesh silica gel, by elution with 10% ethyl acetate in hexane).Fractions containing the desired product were combined and evaporated under reducedpressure to give the title compound (240 mg, 85%) UPLC rt 1 .94 mm MH 395(3 mm run)1H NMR (400 MHz, DMSO-d6) 6 8.91(d, J=7.36 Hz, 1H), 8.26 (s, 1H) 8.20-8.19 (m, 1H), 8.13(d, J=6.64 Hz, 1H), 7.70 (t, J=10.16 Hz, 1H), 7.52 (dd, J=7.2 Hz, 1.02 Hz, 1H), 4.36-4.30 (m,2H), 3.77-3.74 (m, 1H), 1.38-1.32 (m, 9 H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2018/130853, 2018, A1 Location in patent: Page/Page column 32; 34; 35
[2]Current Patent Assignee: MERCK KGAA - WO2020/16235, 2020, A1 Location in patent: Page/Page column 36; 38-39

40
[ 1987897-01-7 ]
[ 182344-23-6 ]
[ 2122861-40-7 ]

Yield	Reaction Conditions	Operation in experiment
138 mg	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; water at 140℃; for 0.5h; Inert atmosphere; Microwave irradiation;	50 Preparation of the Compound (50) A mixture of 200 mg (0.67 mmol) of bromide (XI), 141 mg (0.67 mmol) of [4-fluoro-3-(trifluoromethyl)phenyl]boric acid, 3.8 equivalents of sodium carbonate, 0.05 eq. of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride, 0.05 eq. of 1,1′-bis(diphenylphosphino)ferrocene, 2 ml of 1,2-dimethoxyethane and 0.5 ml of water was flushed with argon and then heated in the microwave at 140° C. with stirring for 30 minutes. The mixture was concentrated and partitioned between dichloromethane/water. The organic phase was dried with magnesium sulphate and filtered and the filtrate was concentrated to dryness. The residue obtained in this manner was purified by HPLC. Yield: 138 mg (51% of theory). (0496) 1H-NMR (CD3CN, 400 MHz); δ=3.43 (s, 3H), 3.83 (s, 3H), 6.39 (s, 1H), 7.37-7-45 (m, 2H), 7.71-7.74 (m, 1H), 7.86-7.90 (m, 2H), 8.46-8.49 (m, 2H).

Reference： [1]Current Patent Assignee: BAYER AG - US2019/47982, 2019, A1 Location in patent: Paragraph 0493-0496

41
[ 1564-64-3 ]
[ 182344-23-6 ]
[ 2489621-94-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 9-Bromoanthracene; 4-fluoro-3-(trifluoromethyl)phenylboronic acid at 85℃; for 1h; Inert atmosphere; Schlenk technique; Stage #2: With bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium carbonate Inert atmosphere; Schlenk technique;	2.2.1. 9-Bromo-10-(4-fluoro-3-(trifluoromethyl)phenyl)anthracene (1) The flask containing a toluene solution (500 ml) of 9-bromoanthracene (10.00 g, 38.89 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (11.32 g, 54.4 mmol) was heated at 85 °C. After being stirred for 60 min at the same temperature, a DI solution (70 mL) of K2CO3 (21.5 g) was added. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium()(Pd) (120 mg, 0.169 mmol) was added to the mixture as catalyst. After completion of the reaction, as indicated by thin layer chromatography (TLC), the reaction mixture was cooled to room temperature and extracted with toluene and saline solution for several times. The collected extracts were dehydrated by anhydrous Na2SO4 and activated carbon followed by a filtration. The filtrate was pumped dry and the residue was washed by THF and dried to afford compound 1 as a light yellow solid (11.8 g, 90%). 1H NMR (400 MHz, DMSO-d6, 298 K) δ 8 8.52 (d, J=8.9 Hz, 2H), 7.89-7.65 (m, 6H),7.57-7.47 (m, 4H). 13C NMR (100 MHz, DMSO-d6, 298 K) δ 160.5, 158.0, 138.3, 135.2, 134.9, 130.9, 130.0, 129.8, 128.3, 127.8, 127.2, 127.0, 123.0, 118.4, 118.2.

Reference： [1]Chen, Li-Yin; Shiu, Yi-Jiun; Wu, Yi-Ju; Huang, Wen-Yao [Organic electronics, 2020, vol. 76]

42
[ 2377398-27-9 ]
[ 182344-23-6 ]
[ 2377398-28-0 ]

Yield	Reaction Conditions	Operation in experiment
37%	With bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); caesium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 50℃; for 2h; Inert atmosphere;	1.5; 2.5 Rac-trans-1-(2,4'-difluoro-5-methoxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazine-6(7H)-sulfonamide To a solution of rac-trans-1-(3'-bromo-2-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(isoxazol-3- yl)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazine-6(7H)-sulfonamide (300 mg, 0.42 mmol), bis(di-tert- butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (59 mg, 0.08 mmol), Cs2CO3 (258 mg, 0.79 mmol) and CuCl (123 mg, 1.25 mmol) in DMF (5 mL) was added (4-fluoro-3- (trifluoromethyl)phenyl)boronic acid (259 mg, 1.25 mmol). The reaction mixture was heated to 50 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (50 mL), extracted with EtOAc (50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 65-95 / 0.225% formic acid in water) to give the title compound (90 mg, 37%) as yellow oil. LCMS (ESI) m/z: 589.0 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2019/191702, 2019, A1 Location in patent: Page/Page column 40; 41; 43; 44

43
[ 2227193-91-9 ]
[ 182344-23-6 ]
[ 2227192-93-8 ]

Yield	Reaction Conditions	Operation in experiment
21%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In N,N-dimethyl acetamide; water for 2h; Inert atmosphere;	1 Synthesis of compound I-1: Add 0.20g of compound 1, 0.13g of 4-fluoro, 3-trifluoromethylphenylboronic acid to a 100ml single-mouth bottle in turn,0.06gPd(dppf)Cl2, 0.22g potassium carbonate, 10ml DMA and 1ml water, react for 2 hours under nitrogen protection,TLC detects that the raw material has reacted completely, stop the reaction, pour the reaction liquid into water,Add 100ml EA for extraction, wash with 50ml*2 saturated sodium chloride, dry with anhydrous sodium sulfate, spin dry under reduced pressure,Column chromatography (ethyl acetate/petroleum ether) gave 50 mg of white solid compound I-1, with a yield of 21%.

Reference： [1]Current Patent Assignee: NANJING HUAWE MEDICAL TECH DEVELOPMENT - CN108017639, 2020, B Location in patent: Paragraph 0108-0109; 0112-0114

44
[ 2227193-95-3 ]
[ 182344-23-6 ]
[ 2227193-97-5 ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; for 2h; Inert atmosphere;	6 Example 6: Synthesis of Compound I-67 Add 0.25g of compound 12 to a 100ml single-mouth bottle one by one,0.18g 4-fluoro-3-trifluoromethylphenylboronic acid, 0.07gPd(dppf)Cl2,0.20g potassium carbonate, 20ml DME and 2ml water, react at 80 for 2 hours under nitrogen protection,TLC detects that the raw material has reacted completely, stop the reaction, pour the reaction liquid into water,Add EA for extraction, wash with saturated sodium chloride, dry by spin-drying, and separate by column chromatography to obtain a colorless and transparent liquid compound 17.Then dissolve compound 17 in THF and add 2ml 4N hydrochloric acid,After stirring at room temperature for three hours, TLC detected that the raw material reaction was complete.Spin off THF, add ammonia water to adjust to weak alkaline, then add EA for extraction,After drying and spin-drying, column chromatography was separated to obtain 50 mg of white solid compound I-67.

Reference： [1]Current Patent Assignee: NANJING HUAWE MEDICAL TECH DEVELOPMENT - CN108017639, 2020, B Location in patent: Paragraph 0138-0140

45
[ 2227193-11-3 ]
[ 182344-23-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
40 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; for 1h; Inert atmosphere;	2 Synthesis of compound I-48: Weigh 0.29g of Intermediate 8 in a 100mL reaction flask, and then weigh 0.28g of 4-fluoro-3-trifluoromethylphenylboronic acid,0.10g Pd(dppf)Cl2 and 0.36g potassium carbonate, and finally add 10mL DME and 1mL water,Replace it with nitrogen three times and place it in an oil bath, and raise it to 80°C for 1 hour.TLC detects that the reaction is complete. It is quenched by adding 100mL of water, and extracted with 50ml*2EA.The organic layers were combined and dried over anhydrous sodium sulfate, spin-dried under reduced pressure, and column chromatography (petroleum ether: ethyl acetate),40 mg of the product is obtained, which is compound I-48.

Reference： [1]Current Patent Assignee: NANJING HUAWE MEDICAL TECH DEVELOPMENT - CN108017639, 2020, B Location in patent: Paragraph 0115-0116; 0119-0120

46
[ 2569045-38-9 ]
[ 182344-23-6 ]
[ 2569047-82-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In 1,4-dioxane at 90℃; Inert atmosphere;	233 1-[(2-Methylpyrimidin-5-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3- b]pyridine trifluoroacetate salt. General procedure: A mixture of 6-bromo-1-((2-methylpyrimidin-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 46, 60 mg, 0.2 mmol), (3-(trifluoromethyl)phenyl)boronic acid (56 mg, 0.3 mmol), Cs2CO3 (129 mg, 0.4 mmol), and [1,1¢-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (10 mg, 0.01 mmol), in 1,4-dioxane (1.8 mL) was heated to 90 °C. After completion, the reaction mixture was concentrated under vacuum and the residue purified by reverse phase HPLC (Method C) to provide title compound (42 mg, 0.09 mmol, 44%). MS (ESI): mass calcd. for C19H14F3N5, 369.1; m/z found, 370.0 [M+H]+.1H NMR (500 MHz, DMSO-d6) d 8.96 (d, J = 2.0 Hz, 1H), 8.80- 8.78 (m, 1H), 8.73 (s, 2H), 8.43- 8.40 (m, 1H), 8.22- 8.16 (m, 2H), 7.87- 7.77 (m, 2H), 5.79 (s, 2H), 2.58 (s, 3H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/249785, 2020, A1 Location in patent: Page/Page column 68; 102; 207

47
[ 2567042-30-0 ]
[ 182344-23-6 ]
[ 2567039-82-9 ]

Yield	Reaction Conditions	Operation in experiment
	With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate In 1,4-dioxane at 90℃;	74 Example 1: 1-[6-(3,5-difluorophenyl)pyrazolo[4,3-bipyridin-1-yl]butan-2-one. General procedure: l-(6-Bromo-lH-pyrazolo[4,3-b]pyridin-l-yl)butan-2-one (Intermediate 11, 30 mg, 0.112 mmol), 3,5-difluorophenylboronic acid (21.2 mg, 0.134 mmol), CS2CO3 (109 mg, 0.336 mmol), Pd(dppf)Cl2 · DCM (8.2 mg, 0.0112 mmol), and 1,4-dioxane (1 mL) were combined and heated, with stirring, to 90 °C overnight. After cooling to rt, the crude material was loaded directly onto a column and purified (FC SiCh, 0 - 100% EtOAc in hexanes) to afford the title compound (37.4 mg, 111%). MS (ESI): mass calcd. for C16H13F2N3O, 301.1; m/z found, 302.0 [M+H]+.
	With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate In 1,4-dioxane at 90℃;	74 Example 1 ;1-[6-(3,5-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one General procedure: 1-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11, 30 mg, 0.112 mmol), 3,5-difluorophenylboronic acid (21.2 mg, 0.134 mmol), Cs2CO3 (109 mg, 0.336 mmol), Pd(dppf)C12.DCM (8.2 mg, 0.0112 mmol), and 1,4-dioxane (1 mL) were combined and heated, with stirring, to 90° C. overnight. After cooling to rt, the crude material was loaded directly onto a column and purified (FCC, SiO2, 0-100% EtOAc in hexanes) to afford the title compound (37.4 mg, 111%). MS (ESI): mass calcd. for C16H13F2N3O, 301.1; m/z found, 302.0 [M+H]+.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/249791, 2020, A1 Location in patent: Page/Page column 65; 99
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2020/392130, 2020, A1 Location in patent: Paragraph 0292-0293; 0440; 0441

48
[ CAS Unavailable ]
[ 182344-23-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-((S)-1-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl trifluoromethanesulfonate; 4-fluoro-3-(trifluoromethyl)phenylboronic acid With potassium phosphate; dichloro[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene]palladium (II) In tetrahydrofuran; water at 20℃; for 16h; Inert atmosphere; Stage #2: With ammonia In tetrahydrofuran; methanol; water for 2h; Inert atmosphere;	19 General Procedure E: General procedure: To 5 mL vial equipped with a stir bar was added a solution of (3P)-3-(4-chloro-l-methyl-3- (methylsulfonamido)-lH-indazol-7-yl)-2-((S)-l-(2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro- 3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamido)-2-(3,5- difluorophenyl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-7-yl trifluoromethanesulfonate (30 mg, 0.031 mmol) in THF (1.0 mL), a solution of K3PO4 (0.025 g, 0.094 mmol) in water (0.25 mL), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (2.377 mg, 3.14 pmol), and the appropriate boronic acid (0.094 mmol). The vial was degassed (the flask was evacuated and the atmosphere replaced with Ar; this process repeated three time) and then maintained under Ar atmosphere. The mixture was stirred at rt for 16 h. To the mixture was added 2 M ammonia in methanol (1 mL). The mixture was stirred for 2 h and then concentrated under reduced pressure. The resulting residue was dissolved in DMF, the solution was filtered, and the filtrate was subjected to prep-HPLC purification to afford the product as indicated.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2021/64571, 2021, A1 Location in patent: Page/Page column 20-21; 72

49
[ 2649241-28-9 ]
[ 182344-23-6 ]
[ 2649898-78-0 ]

Yield	Reaction Conditions	Operation in experiment
38.2%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water; N,N-dimethyl-formamide at 80℃; for 4h;	2 The Synthesis of (S)-2-(3,5-dichloro-4′-fluoro-3′-(trifluoromethyl)biphenyl-4-ylcarboxamido)-3-(2-(3 guanidinobenzamido)acetamido)propanoic acid (SU15210-0105-01) solution of 0096-5 (117 mg, 0.2 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (83.2 mg, 0.4 mmol), Pd(dppf)Cl2 (14.6 mg, 0.02 mmol) and K2CO3 (104 mg, 0.8 mmol) were suspended in DMF (3 mL) and water (0.3 mL). The reaction mixture was heated to 80° C. and stirred for 4 h. After the reaction was finished, 1N HCl was added to adjust pH=2-3, filtrated, the filtrate was purified directly by pre-HPLC to give SU15210-0105-01 (40 mg, yield: 38.20%) as a white solid. Agilent LCMS 105-63314, Column: Waters X-Bridge C18 (50 mm4.6 mm3.5 μm); Column Temperature: 40° C.; F Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water+0.05% TFA] and 5% [CH3CN+0.05% TFA] to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] in 3.0 min, then under this condition for 1.6 min, finally changed to 0% [water+0.05% TFA] and 100% [CH3CN+0.05% TFA] in 0.05 min and under this condition for 1.4 min. Purity: 96.57%. Rt=1.595 min; MS Calcd.: 656.1; MS Found: 657.1 [M+H]+. Agilent HPLC 1200; Column: Waters X-Bridge C18 (150 mm4.6 mm3.5 μm); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water+0.1% TFA] and 5% [CH3CN+0.1% TFA] to 0% [water+0.1% TFA] and 100% [CH3CN+0.1% TFA] in 10 min, then under this condition for 10 min, finally changed to 95% [water+0.1% TFA] and 5% [CH3CN+0.1% TFA] in 0.1 min and under this condition for 5 min. Purity: 95.74%. Rt=7.342 min. (1H NMR (400 MHz, DMSO-d6) δ 11.50 (br s, 1H), 9.01 (s, 1H), 8.13-8.53 (m, 8H), 7.91 (s, 2H), 7.61-7.77 (m, 3H), 7.44 (t, J=7.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.05-4.09 (m, 1H), 3.83-3.85 (m, 2H), 3.71-3.73 (m, 1H), 2.98-3.03 (m, 1H).

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA; TATE & LYLE PUBLIC LIMITED COMPANY - US2021/171455, 2021, A1 Location in patent: Paragraph 0323; 0672-0676

50
[ 1949728-36-2 ]
[ 182344-23-6 ]
[ 1292159-44-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium fluoride; 5,11,17,23-tetra-t-butyl-25,26,27,28-tetrahydroxycalix-4-arene; copper(ll) bromide; magnesium chloride for 8h; Inert atmosphere; Heating;	General procedure for the synthesis of amides 5 by the reaction of 2-bromo-2,2-diuoroacetamides1 with aryl boronic acids 2 General procedure: Under inert atmosphere (glovebox operating with a constant Ar-purge), to an 18 mLACE pressure tube equipped with a stir bar, consequently, an appropriate 2-bromo-2,2-difluoroacetamide (1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg,1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid (1.3 mmol, 1.3 equiv.), the L1 (0.2 mmol,0.2 equiv.), and finally CuBr2 (0.1 mmol, 0.1 equiv.) were placed; then the hexafluoropropanol(0.12 mmol/mL) was added and the reaction vessel was properly capped byTeon stopper. Finally, the reaction vessel was removed from the glovebox and subjectedto heating under vigorous stirring for 8 h. The progress of the reaction was controlled byTLC. After completion, the reaction mixture was evaporated until it reached dryness usinga rotary evaporator, the content of the flask was generously treated with distilled water,filtered, and finally properly dried in vacuum. The resulting crude was directly subjectedto gradient ash chromatography on silica gel using a mixture of hexane/ethyl acetate aseluent to isolate the desired amide derivative.The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide.

Reference： [1]Iaroshenko, Viktor O.; Jakubczyk, Michał; Lanka, Suneel; Mkrtchyan, Satenik; Pittelkow, Michael [Molecules, 2021, vol. 26, # 10]

51
[ 4595-60-2 ]
[ 182344-23-6 ]
[ 2757431-51-7 ]

Yield	Reaction Conditions	Operation in experiment
1 g	With anhydrous sodium carbonate In ethanol; lithium hydroxide monohydrate; toluene at 80℃; for 8h; Inert atmosphere;	90 Synthesis of Compound 1258 (( 2R,3R,4R,5S)-2-(hydroxymethyl)-l-(6-[4 - (pyrimidin-2-yl)-2-(trifluoromethyl)phenyl]amino}hexyl)piperidine-3,4,5-triol) 2-Bromopyrimidine (800 mg), toluene:water:ethanol (1 : 1 : 1; 30 mL), Na2CCh (3.0 eq), 4-fluoro-3-trifluoromethylphenylboronic acid (1 eq) reacted 8 hours at 80°C. The reaction was cooled to room temperature and concentrated, residue was dissolved in EtOAc (100 mL) and washed with water (30 mL). The organic layer was dried over Na2SC>4, filtered, concentrated, and purified on silica [10% EtOAc-hexane] to afford 1 g of 2 as off-white solid.
1 g	With anhydrous sodium carbonate In ethanol; lithium hydroxide monohydrate; toluene at 80℃; for 8h; Inert atmosphere;	90 Synthesis of Compound 1258 (( 2R,3R,4R,5S)-2-(hydroxymethyl)-l-(6-[4 - (pyrimidin-2-yl)-2-(trifluoromethyl)phenyl]amino}hexyl)piperidine-3,4,5-triol) 2-Bromopyrimidine (800 mg), toluene:water:ethanol (1 : 1 : 1; 30 mL), Na2CCh (3.0 eq), 4-fluoro-3-trifluoromethylphenylboronic acid (1 eq) reacted 8 hours at 80°C. The reaction was cooled to room temperature and concentrated, residue was dissolved in EtOAc (100 mL) and washed with water (30 mL). The organic layer was dried over Na2SC>4, filtered, concentrated, and purified on silica [10% EtOAc-hexane] to afford 1 g of 2 as off-white solid.

Reference： [1]Current Patent Assignee: EMERGENT BIOSOLUTIONS INC - WO2022/11211, 2022, A1 Location in patent: Paragraph 1138
[2]Current Patent Assignee: EMERGENT BIOSOLUTIONS INC - WO2022/11211, 2022, A1 Location in patent: Paragraph 1138

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