[ CAS No. 148839-33-2 ] {[proInfo.proName]}

Name: 148839-33-2|(5-Chloro-2-methylphenyl)boronic acid|97%
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SKU: A111489
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Quality Control of [ 148839-33-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 148839-33-2 ]

SDS Specification

Alternatived Products of [ 148839-33-2 ]

Product Details of [ 148839-33-2 ]

CAS No. :	148839-33-2	MDL No. :	MFCD03411939
Formula :	C₇H₈BClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QWTHTSAWMJFMOV-UHFFFAOYSA-N
M.W :	170.40	Pubchem ID :	2773336
Synonyms :

Calculated chemistry of [ 148839-33-2 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	46.24
TPSA :	40.46 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) :	-6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.82
Log Po/w (WLOGP) :	0.33
Log Po/w (MLOGP) :	1.21
Log Po/w (SILICOS-IT) :	0.34
Consensus Log Po/w :	0.74

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.38
Solubility :	0.709 mg/ml ; 0.00416 mol/l
Class :	Soluble
Log S (Ali) :	-2.29
Solubility :	0.875 mg/ml ; 0.00513 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.29
Solubility :	0.882 mg/ml ; 0.00518 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 148839-33-2 ]

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 [ 148839-33-2 ]

* 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 [ 148839-33-2 ]
Downstream synthetic route of [ 148839-33-2 ]

[ 148839-33-2 ] Synthesis Path-Upstream 1~2

1
[ 148839-33-2 ]
[ 452-75-5 ]

Reference： [1] Angewandte Chemie - International Edition, 2008, vol. 47, # 32, p. 5993 - 5996

2
[ 121-43-7 ]
[ 33184-48-4 ]
[ 148839-33-2 ]

Yield	Reaction Conditions	Operation in experiment
26%	With hydrogenchloride; iodine In tetrahydrofuran	Example 26 6-(5-Chloro-2-methyl-phenyl)-N4-p-tolyl-pyrimidine-2,4-diamine Magnesium turnings (0.346 g, 14.25 mmol) were activated by heating in an oven at 120° C. for 16 hours. Using oven-dried glassware, anhydrous tetrahydrofuran (50 ml) and a crystal of iodine were added to the magnesium. 4-Chloro-2-iodotoluene was added by syringe and air was removed. Maintaining a positive flow of argon, the reaction was heated under reflux for 5.5 hours. After cooling to -78° C. (dry ice-acetone), a solution of trimethyl borate (2.47 g, 23.76 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise. After slowly warming to room temperature, the mixture was stirred for 16 hours. After careful addition of 1 M hydrochloric acid (20 ml), the mixture was extracted with ether (350 ml). The combined extracts were washed with water (350 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to yield 5-chloro-2-methyl-phenyl boronic acid (0.537 g, 26percent yield) as a white powder.

Reference： [1] Patent: US2004/204386, 2004, A1,

[ 148839-33-2 ] Synthesis Path-Downstream 1~85

1
[ 148839-33-2 ]
[ 148839-37-6 ]
2-(5-Chloro-2-methyl-phenyl)-furan-3-carboxylic acid diethylamide [ No CAS ]

Reference： [1]Tetrahedron Letters,1993,vol. 34,p. 2437 - 2440

2
[ 148839-33-2 ]
[ 148839-38-7 ]
[ 148839-44-5 ]

Reference： [1]Tetrahedron Letters,1993,vol. 34,p. 2437 - 2440

3
[ 13195-76-1 ]
5-chloro-2-methyl-phenyl magnesium bromide [ No CAS ]
[ 148839-33-2 ]
bis-(5-chloro-2-methyl-phenyl)-hydroxy-borane [ No CAS ]

Reference： [1]Zhurnal Obshchei Khimii,1938,vol. 8,p. 1768,1772
Chemisches Zentralblatt,1939,vol. 110,p. 4933

4
[ 56-05-3 ]
[ 148839-33-2 ]
[ 774608-11-6 ]

Yield	Reaction Conditions	Operation in experiment
42%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;	Intermediate 40 -chloro-6-(5-chloro-2-methylphenyl)pyrimidin-2-amine. To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1 eq) in dioxane/H20 (5 mL, 4: 1) was added <strong>[148839-33-2](5-chloro-2-methylphenyl)boronic acid</strong> (155 mg, 0.91 mmol, 1 eq) followed by potassium carbonate (253 mg, 1.83 mmol, 2 eq) and Pd(PPh3)4 (26 mg, 0.02 mmol, 0.025 eq). The resulting mixture was stirred at 90 C for 12 hrs. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford the desired product as an off-white solid (98 mg, 42%). LCMS [M+H]+ 254; 1 H NMR (400 MHz, CDCI3) delta ppm 7.35 (1 H, d, J = 2.0 Hz), 7.28 (1 H, dd, J = 8.4 and 2.4 Hz), 7.18 (1 H, d, J = 8.4 Hz), 6.72 (1 H, s), 5.30 (2H, br s), 2.34 (3H, s).

Reference： [1]Patent: WO2015/187089,2015,A1 .Location in patent: Page/Page column 80
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2303 - 2308

5
[ 852110-52-2 ]
[ 148839-33-2 ]
[ 852114-81-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 168 (+-)-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine The title compound was prepared (0.68 g, 31%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (+-)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmol) and <strong>[148839-33-2](5-chloro-2-methylphenyl)boronic acid</strong> (0.334 g, 1.96 mmol). mp 146-150 C.

Reference： [1]Patent: US2005/261347,2005,A1

6
[ 2527-99-3 ]
[ 148839-33-2 ]
C₁₃H₁₁ClO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3258 - 3261

7
[ 148839-33-2 ]
C₁₂H₉ClO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3258 - 3261

8
[ 148839-33-2 ]
C₁₂H₈Cl₂O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3258 - 3261

9
[ 148839-33-2 ]
C₁₈H₂₁ClN₄O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3258 - 3261

10
[ 148839-33-2 ]
6-(5-chloro-2-methyl-phenyl)-N⁴-(4-chloro-phenyl)-pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2303 - 2308

11
[ 148839-33-2 ]
N⁴-(3-bromo-phenyl)-6-(5-chloro-2-methyl-phenyl)-pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2303 - 2308

12
[ 148839-33-2 ]
N⁴-(4-bromo-phenyl)-6-(5-chloro-2-methyl-phenyl)-pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2303 - 2308

13
[ 148839-33-2 ]
6-(5-chloro-2-methyl-phenyl)-N⁴-(4-trifluoromethyl-phenyl)-pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2303 - 2308

14
[ 148839-33-2 ]
8-Chloro-naphtho[1,2-b]thiophene-4,5-dione [ No CAS ]

Reference： [1]Tetrahedron Letters,1993,vol. 34,p. 2437 - 2440

15
[ 889848-64-0 ]
[ 148839-33-2 ]
(4-bromo-2-methyl-2H-pyrazol-3-yl)-(5'-chloro-2'-methyl-biphenyl-4-yl)-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.9%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃;	Example 1.46; Preparation of (4-Bromo-2-methyl-2H-pyrazol-3-yl)-(5'-chloro-2'-methyl-biphenyI-4-yl)- amine (Compound 32).A 20-mL scintillation vial was charged with (4-bromo-2-methyl-2H-pyrazol-3-yl)-(4- iodo-phenyl)-amine (80.0 mg, 0.21 mmol), 5-chloro-2-methylphenyl boronic acid (54.1 mg, 0.32 mmol), cesium carbonate (137.9 mg, 0.42 mmol), 1,2-dimethoxyethane (1.5 mL) and water (0.2 mL). The reaction mixture was purged with argon, tetrakis(triphenylphosphine) palladium(O) (24.5 mg, 0.02 mmol) was added then the reaction vessel purged with argon again. The reaction mixture was heated at 800C overnight. Then, it was allowed to cool to ambient temperature, filtered and subjected to a purification by prep EtaPLC (0.05% TFA). The corresponding fractions were collected and lyophilized to afford Compound 32 as a white solid. Yield: 29.2 mg (36.9 %). LCMS m/z (%) =376 (MH-H79Br35Cl, 80), 378 (MH-H81Br35Cl, 100), 380 (MH-H81Br37Cl, 25). 1H NMR (400MHz, CDCl3): delta 2.25 (s, 3H), 3.75 (s, 3H), 5.29 (s, IH), 6.63 (dd, J=7.6, 3.6 Hz, 2H), 7.13 (d, J=4.0 Hz, 2H), 7.25-7.11 (m, 3H), 7.53 (s, IH).

Reference： [1]Patent: WO2006/60762,2006,A2 .Location in patent: Page/Page column 83

16
[ 942123-11-7 ]
[ 148839-33-2 ]
(S)-3-benzyl-1-(5'-chloro-2'-methyl-biphenyl-4-ylmethyl)-piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃;	Example 111: (S) 3-Benzyl-l-(5'-chloro-2'-methyl-biphenyl-4-ylmethyl)-piperazine; <n="80"/>O.lg of 3-(S)-ben2yl-l-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 5- cliloro-2-ralphaethylplieuyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85C under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.077g of the title compound. Yield 68%ES MS (+) m/z 391.

Reference： [1]Patent: WO2007/70760,2007,A2 .Location in patent: Page/Page column 78-79

17
[ 121-43-7 ]
[ 33184-48-4 ]
[ 148839-33-2 ]

Yield	Reaction Conditions	Operation in experiment
26%	With hydrogenchloride; iodine; In tetrahydrofuran;	Example 26 6-(5-Chloro-2-methyl-phenyl)-N4-p-tolyl-pyrimidine-2,4-diamine Magnesium turnings (0.346 g, 14.25 mmol) were activated by heating in an oven at 120 C. for 16 hours. Using oven-dried glassware, anhydrous tetrahydrofuran (50 ml) and a crystal of iodine were added to the magnesium. 4-Chloro-2-iodotoluene was added by syringe and air was removed. Maintaining a positive flow of argon, the reaction was heated under reflux for 5.5 hours. After cooling to -78 C. (dry ice-acetone), a solution of trimethyl borate (2.47 g, 23.76 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise. After slowly warming to room temperature, the mixture was stirred for 16 hours. After careful addition of 1 M hydrochloric acid (20 ml), the mixture was extracted with ether (350 ml). The combined extracts were washed with water (350 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to yield 5-chloro-2-methyl-phenyl boronic acid (0.537 g, 26% yield) as a white powder.

Reference： [1]Patent: US2004/204386,2004,A1

18
[ 56-05-3 ]
[ 148839-33-2 ]
[ 3375-31-3 ]
[ 774607-82-8 ]

Yield	Reaction Conditions	Operation in experiment
35%	With hydrogenchloride; sodium carbonate; triphenylphosphine; In 1,4-dioxane; methanol; water; ethyl acetate; acetone;	To a mixture of 4,6-dichloro-2-amino-pyrimidine (0.481 g, 2.93 mmol), <strong>[148839-33-2]5-chloro-2-methyl-phenyl boronic acid</strong> (0.5 g, 2.93 mmol), palladium (II) acetate (0.1 g, 0.44 mmol), and triphenylphosphine (0.23 g, 0.88 mmol) was added a solution of sodium carbonate (1.5 g, 14.6 mmol) in water (5.0 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere for 16 hours. After addition of acetone (15 ml), the mixture was filtered through a pad of celite under suction and the filtrate was concentrated under vacuum. The residual solid was purified by flash chromatography on silica gel eluding with ethyl acetate-hexane (1:9). After concentration under reduced pressure, the solid was dissolved in methanol and a solution of hydrogen chloride in dioxane (4.0 M, 5 ml) was added. After concentration under vacuum, the solid was treated with ethyl acetate (5 ml) and stirred for one hour. Filtration provided the hydrochloride salt of 4-chloro-6-(5-chloro-2-methyl-phenyl) pyrimidin-2-yl-amine (0.30 g, 35% yield) as a white powder.

Reference： [1]Patent: US2004/204386,2004,A1

19
lead(IV) acetate [ No CAS ]
[ 148839-33-2 ]
[ 1033760-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	With mercury(II) diacetate; In chloroform; at 40℃; for 5h;	To a mixture of lead tetraacetate (2.15 g, 4.85 mmol) and mercuric diacetate (0.15 g, 0.47 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40 0C, and <strong>[148839-33-2]5-chloro-2-methylphenylboronic acid</strong> (0.76 g, 4.46 mmol) is added in one portion, and the suspension is heated at this temperature for 5 hours. After cooling to room temperature the mixture is concentrated to a small volume then triturated with hexanes and filtered to yield crude 5-chloro-2-methylphenyllead triacetate (2.27 g).
	With mercury(II) diacetate; In chloroform; at 40℃; for 5h;	Step 1 : Preparation of 5-chloro-2-methylphenyllead triacetate <n="57"/>To a mixture of lead tetraacetate (2.15 g, 4.85 mmol) and mercuric diacetate (0.15 g, 0.47 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40 0C, and delta-chloro-?-methylphenylboronic acid (0.76 g, 4.46 mmol) is added in one portion, and the suspension is heated at this temperature for 5 hours. After cooling to room temperature the mixture is concentrated to a small volume then triturated with hexanes and filtered to yield crude 5-chloro-2-methylphenyllead triacetate (2.27 g).

Reference： [1]Patent: WO2008/71405,2008,A1 .Location in patent: Page/Page column 53
[2]Patent: WO2008/145336,2008,A1 .Location in patent: Page/Page column 55-56

20
[ 148839-33-2 ]
[ 933-88-0 ]
[ 1062600-61-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 80℃; for 16h;	Preparation 19 Preparation of (5-chloro-2-methylphenyl)(o-tolyl)methanone To a mixture of <strong>[148839-33-2]5-chloro-2-methylphenylboronic acid</strong> (3.00 g, 17.60 mmol), cesium carbonate (11.50 g, 35.20 mmol), tetrakis(triphenylphosphene)palladium(0) (1.02 g, 0.85 mmol) in anhydrous toluene (60 mL) was added o-toluoyl chloride (4.60 mL, 35.20 mmol). The reaction mixture was heated at 80 C. for 16 hours, cooled to ambient temperature and filtered through a pad of celite. The pad was washed with ethyl acetate (50 mL) and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluted with a gradient of 0 to 20% ethyl acetate in hexanes to afford (5-chloro-2-methylphenyl)(o-tolyl)methanone as a colorless oil in 75% yield (3.20 g). 1H NMR (300 MHz, CDCl3) delta 7.42-7.26 (m, 5H), 7.22-7.16 (m, 2H), 2.47 (s, 3H), 2.34 (s, 3H): 13C NMR (75 MHz, CDCl3) delta 199.2, 140.7, 138.7, 137.8, 136.2, 132.7, 131.7, 131.7, 131.3, 130.8, 130.7, 129.5, 125.6, 20.9, 20.0.

Reference： [1]Patent: US2008/234384,2008,A1 .Location in patent: Page/Page column 57-58

21
[ 1063716-38-0 ]
[ 148839-33-2 ]
[ 1063716-83-5 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 5993 - 5996

22
[ 148839-33-2 ]
[ 452-75-5 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 5993 - 5996

23
[ 1156500-66-1 ]
[ 148839-33-2 ]
[ 1156500-67-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;	Examples 134-151 were prepared according to Scheme 12.

Reference： [1]Patent: US2009/143361,2009,A1 .Location in patent: Page/Page column 48-49

24
[ 148839-33-2 ]
(4-halo-3-methoxyphenyl)((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone [ No CAS ]
[ 1238635-48-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 3742 - 3745

25
[ 148839-33-2 ]
[ 1403333-39-0 ]

Reference： [1]Patent: WO2012/139930,2012,A1
[2]Patent: US2014/51708,2014,A1

26
[ 148839-33-2 ]
[ 1403333-46-9 ]

Reference： [1]Patent: WO2012/139930,2012,A1
[2]Patent: US2014/51708,2014,A1

27
[ 148839-33-2 ]
[ 1403332-38-6 ]

Reference： [1]Patent: WO2012/139930,2012,A1
[2]Patent: US2014/51708,2014,A1

28
[ 148839-33-2 ]
ethyl 3-acetyl-1H-pyrazole-5-carboxylate [ No CAS ]
[ 1403333-33-4 ]
[ 1403333-31-2 ]

Yield	Reaction Conditions	Operation in experiment
36%; 43%	With pyridine; copper diacetate; In dichloromethane; at 20℃; for 48h;Inert atmosphere;	Preparation HEthyl 3-acetyl-1-(5-chloro-2-methylphenyl)-1 H-pyrazole-5-carboxylate [(IVc) R2"'= 5-chloro-2-methylphenyl, R3 = COOEt] and ethyl 5-acetyl-1-(5-chloro-2-methylphenyl)-1 H-pyrazole-3-carboxylate [(IVc) R2"'= 5-chloro-2-methylphenyl, R3 = COOEt]step 3A mixture of ethyl 3-acety I- 1 H-py razole-5-carboxyl ate (364 mg, 2.0 mmol), <strong>[148839-33-2](5-chloro-2-methylphenyl)boronic acid</strong> (680 mg, 4.0 mmol), copper(ll) acetate (571 mg, 3.0 mmol) and pyridine (0.32 ml_, 4 mmol) in DCM (10 ml_) was stirred at r.t. under an air atmosphere for 48 h. After removal of the insolubles by filtration, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (hexane/AcOEt, 90/10) to obtain ethyl 3-acetyl-1-(5-chloro-2-methylphenyl)-1H-pyrazole-5- carboxylate as a white solid (269 mg, 43%),1H NMR (400 MHz, DMSO-d6) delta ppm 7.58 - 7.59 (m, 1 H) 7.54 - 7.58 (m, 1 H) 7.45 (d, J =8.18 Hz, 1 H) 7.44 (s, 1 H) 4.17 (q, J =7.08 Hz, 2 H) 2.54 (s, 3 H) 1.94 (s, 3 H) 1.12 (t, J =7.08 Hz, 3 H)HRMS (ESI) calcd for C15H16CIN2O3 [M +H]+ 307.0844, found 307.0844;and ethyl 5-acetyl-1-(5-chloro-2-methylphenyl)-1 H-pyrazole-3-carboxylate as an oil (220 mg, 36%)1H NMR (400 MHz, DMSO-d6) delta ppm 7.82 (s, 1 H) 7.56 (dd, J =8.18, 2.32 Hz, 1 H) 7.44 (d, J =2.32 Hz, 1 H) 7.42 (d, J=8.54 Hz, 1 H) 4.34 (q, J =7.12 Hz, 2H) 2.54 (s, 3H) 1.87 (s, 3H) 1.32 (t, J =7.08 Hz, 3H)HRMS (ESI) calcd for C15H16CIN2O3 [M +H]+ 307.0844, found 307.0850.
36%; 43%	With pyridine; copper diacetate; In dichloromethane; at 20℃; for 48h;	Step 3 A mixture of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (364 mg, 2.0 mmol), <strong>[148839-33-2](5-chloro-2-methylphenyl)boronic acid</strong> (680 mg, 4.0 mmol), copper(II) acetate (571 mg, 3.0 mmol) and pyridine (0.32 mL, 4 mmol) in DCM (10 mL) was stirred at r.t. under an air atmosphere for 48 h. After removal of the insolubles by filtration, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (hexane/AcOEt, 90/10) to obtain ethyl 3-acetyl-1-(5-chloro-2-methylphenyl)-1H-pyrazole-5-carboxylate as a white solid (269 mg, 43%), 1H NMR (400 MHz, DMSO-d6) delta ppm 7.58-7.59 (m, 1H) 7.54-7.58 (m, 1H) 7.45 (d, J=8.18 Hz, 1H) 7.44 (s, 1H) 4.17 (q, J=7.08 Hz, 2H) 2.54 (s, 3H) 1.94 (s, 3H) 1.12 (t, J=7.08 Hz, 3H) HRMS (ESI) calcd for C15H16ClN2O3[M+H]+ 307.0844. found 307.0844; and ethyl 5-acetyl-1-(5-chloro-2-methylphenyl)-1H-pyrazole-3-carboxylate as an oil (220 mg, 36%) 1H NMR (400 MHz, DMSO-d6) delta ppm 7.82 (s, 1H) 7.56 (dd, J=8.18, 2.32 Hz, 1H) 7.44 (d, J=2.32 Hz, 1H) 7.42 (d, J=8.54 Hz, 1H) 4.34 (q, J=7.12 Hz, 2H) 2.54 (s, 3H) 1.87 (s, 3H) 1.32 (t, J=7.08 Hz, 3H) HRMS (ESI) calcd for C15H16ClN2O3[M+H]+ 307.0844. found 307.0850.

Reference： [1]Patent: WO2012/139930,2012,A1 .Location in patent: Page/Page column 52-53
[2]Patent: US2014/51708,2014,A1 .Location in patent: Paragraph 0507-0513

29
[ 148839-33-2 ]
[ 29682-15-3 ]
[ 1415129-66-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); In 1,4-dioxane; water; at 80℃; for 16h;	Methyl 5-bromopicolinate (5.0 g, 23.1 mmol), <strong>[148839-33-2](5-chloro-2-methylphenyl)boronic acid</strong> (4.5 g, 26.6 mmol), Pd(dppf)Cl2 (1.9 g, 2.3 mmol), and K2CO3 (6.4 g, 46.3 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 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]Patent: US2012/302610,2012,A1 .Location in patent: Page/Page column 31; 32

30
[ 148839-33-2 ]
[ 1415127-53-5 ]

Reference： [1]Patent: US2012/302610,2012,A1

31
[ 148839-33-2 ]
[ 1415129-69-9 ]

Reference： [1]Patent: US2012/302610,2012,A1

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[ 1415129-72-4 ]

Reference： [1]Patent: US2012/302610,2012,A1

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[ 148839-33-2 ]
[ 1415129-75-7 ]

Reference： [1]Patent: US2012/302610,2012,A1

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[ 1415129-78-0 ]

Reference： [1]Patent: US2012/302610,2012,A1

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ethyl 5-(2-aminopyrimidin-4-yl)-2-bromo-1H-pyrrole-3-carboxylate [ No CAS ]
[ 148839-33-2 ]
[ 1403679-96-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In ethanol; water; toluene; at 100℃; for 5h;	To a solution of ethyl 5-(2-aminopyrimidin-4-yl)-2-bromo-1 H-pyrrole-3-carboxylate (prepared according to WO2007/110344, 2.0 g, 6.43 mmol) dissolved in EtOH (20 mL) and toluene (20 mL), LiCI (408 mg, 9.64 mmol), 1 M aq Na2C03 (17 mmol), <strong>[148839-33-2]5-chloro-2-methylphenylboronic acid</strong> (1.423 g, 8.35 mmol) and Pd(Ph3P)2CI2 (470 mg, 0.67 mmol) were added and the reaction mixture was heated at 100 C for 5 h. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure, dissolved in DCM and washed with water. The organic layer was then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM/EtOAc 50/50) to afford the title compound (1.99 g, 87%).1H NMR (400 MHz, DMSO-de) delta ppm 1.09 (t, J=7.14 Hz, 3 H) 2.11 (s, 3 H) 4.04 (q, J=7.12 Hz, 2 H) 6.41 (s, 2 H) 7.01 (d, J=5.25 Hz, 1 H) 7.25 - 7.36 (m, 3 H) 7.37 - 7.43 (m, 1 H) 8.21 (d, J=5.13 Hz, 1 H) 12.17 (bs, 1 H).
87%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In ethanol; water; toluene; at 100℃; for 5h;Inert atmosphere;	Ethyl cyanoacetate (5.3mL, 50mmol) was added to a suspension of sodium (1.15g, 50mmol) in 150mL of anhydrous EtOH at 0C. After 20min at room temperature, the reaction mixture was concentrated and the resultant solid was added to a solution of 1-(2-aminopyrimidin-4-yl)-2-bromoethanone hydrobromide (35, 14.85g, 50mmol) and N,N-diisopropylethylamine (8.8mL, 50mmol) in anhydrous THF (300mL). The reaction mixture was stirred overnight at room temperature, concentrated and the residue was suspended in water and extracted with DCM. The organic extracts were dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (DCM/MeOH 95:5) to give ethyl 4-(2-aminopyrimidin-4-yl)-2-cyano-4-oxobutanoate (36, 5.16 g, 41%). 1H NMR (400MHz, DMSO-d6) delta 8.52 (d, J=4.9Hz, 1H), 6.97 (d, J=4.9Hz, 1H), 4.56 (t, J=5.6Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 3.74 (d, J=5.6Hz, 2H), 1.21 (t, J=7.1Hz, 3H); LC-MS (ESI): m/z 249 [M+H]+; HRMS (ESI): m/z calcd for C11H12N4O3+H+ 249.0982, found 249.0975. A suspension of 36 (5.0g, 20.14mmol) in DCM (40mL) was added dropwise to 33% HBr in AcOH (40mL) at 0C. The mixture was left at 0C for 30min and then at room temperature until disappearance of the starting material. The solid was filtered, washed with DCM, neutralized with 7N NH3 in MeOH to afford ethyl 5-(2-aminopyrimidin-4-yl)-2-bromo-1H-pyrrole-3-carboxylate (37, 5.5g, 88%). 1H NMR (400MHz, DMSO-d6) delta 12.84 (br s, 1H), 8.22 (d, J=5.4Hz, 1H), 7.23 (s, 1H), 6.99 (d, J=5.1Hz, 1H), 6.42 (br s, 2H), 4.21 (q, J=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H); LC-MS (ESI): m/z 312 [M+H]+; HRMS (ESI): m/z calcd for C11H11BrN4O2+H+ 311.0138, found 311.0139. To a solution of 37 (2.0g, 6.43mmol) dissolved in EtOH (20mL) and toluene (20mL), LiCl (408mg, 9.64mmol), 1M aq Na2CO3 (17mmol), <strong>[148839-33-2]5-chloro-2-methylphenylboronic acid</strong> (1.423g, 8.35mmol) were added. The resulting reaction mixture was degassed three times back filling with argon each time before being charged with Pd(Ph3P)2Cl2 (470mg, 0.67mmol), degassed four times back filling with argon each time and then heated at 100C for 5h. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure, dissolved in DCM and washed with water. The organic layer was then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM/EtOAc 50:50) to afford ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylate (38e, 1.99g, 87%). 1H NMR (400MHz, DMSO-d6) delta 12.18 (br s, 1H), 8.21 (d, J=5.2Hz, 1H), 7.40 (dd, J=8.2, 2.2Hz, 1H), 7.27-7.34 (m, 3H), 7.01 (d, J=5.2Hz, 1H), 6.41 (s, 2H), 4.04 (q, J=7.1Hz, 2H), 2.11 (s, 3H), 1.09 (t, J=7.1Hz, 3H); LC-MS (ESI): m/z 357 [M+H]+; HRMS (ESI): m/z calcd for C18H17ClN4O2+H+ 357.1113, found 357.1115. The intermediate 38e (1.0g, 2.80mmol) was treated with 1.5M KOH in 95% EtOH (37.3mL, 20equiv) under reflux for 20h. After cooling, the residue was concentrated, dissolved in water and washed with DCM. A solution of 2N HCl was added, under agitation, to the aqueous phase cooled to 5C. The resultant precipitate was collected by filtration to give 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylic acid (39e, 0.92g, 95%). 1H NMR (400MHz, DMSO-d6) delta 12.54 (br s, 1H), 12.06 (s, 1H), 8.28 (d, J=6.5Hz, 1H), 7.77 (br s, 1H), 7.59 (d, J=2.6Hz, 1H), 7.40-7.45 (m, 1H), 7.28-7.37 (m, 3H), 2.12 (s, 3H); LC-MS (ESI): m/z 329 [M+H]+; HRMS (ESI): m/z calcd for C16H13ClN4O2+H+ 329.0800, found 329.0799. A solution of 39e (470mg, 1.43mmol) in DMF/ THF (1/1, 5mL) and N,N-diisopropylethylamine (1.02mL, 5.86mmol) was stirred at 0C. EDCI (594mg, 3.1mmol) and HOBT·NH3 (430mg, 2.79mmol) were added and the reaction mixture was stirred for 3h at room temperature. The mixture was dropped into a saturated solution of NaHCO3 and ice and the resulting precipitate was collected by filtration to afford 6 (384mg, 82%). 1H NMR (400MHz, DMSO-d6) delta 11.84 (br s, 1H), 8.19 (d, J=5.2Hz, 1H), 7.32-7.40 (m, 2H), 7.26-7.30 (m, 2H), 7.22 (br s, 1H), 6.93 (d, J=5.2Hz, 1H), 6.73 (br s, 1H), 6.32 (br s, 2H), 2.12 (s, 3H); LC-MS (ESI): m/z 328 [M+H]+; HRMS (ESI): m/z calcd for C16H14ClN5O+H+ 328.0960, found 328.0959. The following compounds 2-5, and 25-34 were prepared according to the method described above using the suitable aryl boronic acid.

Reference： [1]Patent: WO2013/14039,2013,A1 .Location in patent: Page/Page column 50
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 4998 - 5012

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[ 148839-33-2 ]
5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide [ No CAS ]