[ CAS No. 552846-17-0 ] {[proInfo.proName]}

Name: 552846-17-0|tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate|98%
Brand: Ambeed
SKU: A109224
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Quality Control of [ 552846-17-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 552846-17-0 ]

Product Details of [ 552846-17-0 ]

CAS No. :	552846-17-0	MDL No. :	MFCD05663873
Formula :	C₁₄H₂₃BN₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IPISOFJLWYBCAV-UHFFFAOYSA-N
M.W :	294.15	Pubchem ID :	16217654
Synonyms :

Calculated chemistry of [ 552846-17-0 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.71
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	80.91
TPSA :	62.58 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.33 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.49
Log Po/w (WLOGP) :	1.97
Log Po/w (MLOGP) :	1.16
Log Po/w (SILICOS-IT) :	0.52
Consensus Log Po/w :	1.23

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.14
Solubility :	0.211 mg/ml ; 0.000717 mol/l
Class :	Soluble
Log S (Ali) :	-3.45
Solubility :	0.105 mg/ml ; 0.000355 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.9
Solubility :	0.369 mg/ml ; 0.00126 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.47

Safety of [ 552846-17-0 ]

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

Application In Synthesis of [ 552846-17-0 ]

* 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 [ 552846-17-0 ]
Downstream synthetic route of [ 552846-17-0 ]

[ 552846-17-0 ] Synthesis Path-Upstream 1~5

1
[ 552846-17-0 ]
[ 269410-08-4 ]

Reference： [1] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9199 - 9201

2
[ 269410-08-4 ]
[ 24424-99-5 ]
[ 552846-17-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With dmap In dichloromethane at 20℃; for 4 h;	4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1H-pyrazole (1.16 g, 6.0mmol) in methylene chloride (40 mL) was added di-tert-butyl dicarbonate (1.58 g, 7.2 mmol), was added a catalytic amount of 4-dimethylaminopyridine (102 mg, 0.84 mmol), reaction at room temperature for 4 hours.Water was added to the system, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, the organic Xiangde removed by rotary evaporation the crude product (1.5 g, 85percent yield).
76%	at 20℃; for 12 h;	Di-tert-butyl dicarbonate (7.2 molar equivalent), 4-(dimethylamino)pyridine (0.84 molar equivalent) were added to a solution of 4,4,5,5-tetramethyl-2-(1H-pyrazole-4-yl)-1,3,2-dioxaborolane (6 mmol) in 40 mL of DMF. The reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrate was evaporated to give a brown yellow oil residue as compound 21-1 (1.32 g; 4.56 mmol; 76percent). 1H NMR (400 MHz, chloroform-D) δ ppm 1.32 (s, 12H) 1.63 (s, 9H) 7.91 (s, 1H) 8.37 (s, 1H). The residue was used for the next step reaction without further purification.
64%	With dmap In acetonitrile at 20℃; for 18 h;	To a mixture of 4-pyrazoleboronic acid pinacol ester (0.485 g, 2.5mmol) and DMAP (0.153 g, 1.25 mmol) in MeCN (12.5 ml) was added di-tert-butyldicarbonate (0.709 g, 3.25 mmol). The resulting mixture was stirred at rt for 18 h before itwas concentrated under reduced pressure. The obtained residue was purified by flashcolumn chromatography (silica gel, 0-10percent EtOAc in petroleum ether) to afford the titlecompound (0.473 g, 64percent yield) as a white solid. 1H NMR (400 MHz, CDCb) o 8.38 (s, 1 H),7.92 (s, 1H), 1.64 (s, 9H), 1.33 (s, 12H).

57%

With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 48 h;

To a solution of 33a (l .Og, 5.15mmol) in CH₂Cl₂ (3OmL) was added DIEA (2.0g, 15.5mmol), followed by (Boc)₂O (1.55g, 7.4mmol) drop-wise at O⁰C. The resulting mixture was stirred at room temperature for 2 days. After the reaction was complete detected by TLC, the mixture was evaporated and the residue was purified by silica column chromatography (PE:EA=4:1) to provide 35a (0.86g, 57percent yield).

Reference： [1] Patent: CN103936728, 2016, B, . Location in patent: Paragraph 0177; 0203; 0204; 0205
[2] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 68
[3] Patent: WO2018/154466, 2018, A1, . Location in patent: Paragraph 001162; 001164; 001165
[4] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 58
[5] Patent: WO2004/56727, 2004, A2, . Location in patent: Page 97
[6] Patent: WO2013/107291, 2013, A1, . Location in patent: Page/Page column 66
[7] Patent: WO2013/166015, 2013, A1, . Location in patent: Paragraph 0108 - 0110
[8] Patent: WO2015/6100, 2015, A1, . Location in patent: Page/Page column 185
[9] Patent: WO2015/10626, 2015, A1, . Location in patent: Page/Page column 67
[10] Patent: WO2015/10297, 2015, A1, . Location in patent: Page/Page column 66
[11] Patent: WO2016/73652, 2016, A1, . Location in patent: Page/Page column 76
[12] Patent: WO2017/107089, 2017, A1, . Location in patent: Page/Page column 43; 44

3
[ 25015-63-8 ]
[ 219580-32-2 ]
[ 552846-17-0 ]

Reference： [1] Journal of Organic Chemistry, 2009, vol. 74, # 23, p. 9199 - 9201

4
[ 269410-08-4 ]
[ 552846-17-0 ]

Reference： [1] Patent: US2013/190249, 2013, A1, . Location in patent: Page/Page column
[2] Patent: US2015/31627, 2015, A1, . Location in patent: Page/Page column

5
[ 73183-34-3 ]
[ 552846-17-0 ]

Reference： [1] Patent: WO2017/107089, 2017, A1,

[ 552846-17-0 ] Synthesis Path-Downstream 1~88

1
[ 552846-17-0 ]
[ 906092-45-3 ]
[ 952521-75-4 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium acetate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.166667h;Microwave irradiation;	Example 4; Preparation of Pyrazolyl-Pyrrolo[2,3- rf]Pyrimidines of the Invention; [ 0246] 4-(l/y-pyrazo-4-yl)-7-tosyl-7J-pyrtauolo [2,3-rf]pyrimidine (13'); The reaction mixture of 4-iodo-7-tosyl-7H-pyrrolo[2,3-rf]pyrimidine (12', 0.800 g, 2 mmol), terf-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-H-pyrazole-l- carboxylate, 3.5ml 2M KOAc, 0.12g (O.lmmol) Palladium tetrakistriphenylphosphine and 10 ml 1,4-dioxane was deoxygenated by bubbling N2 for 20 min. The reaction mixture was heated at 140 0C on microwave synthesizer for 10 min. Work up: The reaction mixture was cooled to room temperature and filtered. The filtration cake is 2.0 g 95% pure title product, yield 50%.

Reference： [1]Patent: WO2007/117494,2007,A1 .Location in patent: Page/Page column 69-70

2
[ 891785-28-7 ]
[ 552846-17-0 ]
[ 956100-49-5 ]

Yield	Reaction Conditions	Operation in experiment
98.4%	With water; caesium carbonate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; at 84 - 86℃; for 0.416667h;Product distribution / selectivity;	To a 3-necked flask equipped with stirrer, nitrogen inlet and internal thermometer was charged with 3-amino, 6-bromoisoquinoline (6.0 g, 20.0 mmol), 2-(2', 6'-dimethoxybiphenyl)dicyclohexylphosphine (S-Phos) (2.0 g ,3.0 mmol), thoroughly freshly degassed DME (200 mL), water (40 mL), and Cs2CO3 (46.2 g, 142.0 mmol). The suspension was placed under nitrogen in a pre-heated oil bath at 860C. Meanwhile, a solution of 1-BOC-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazole ( 10.8 g, 36.0 mmol) in degassed DME (30 mL) was prepared and stored under nitrogen. When the internal temperature of the suspension had reached 840C, the Pd2(dba)3 (2.8 g, 3.0 mmol) was added, and quiclky followed by dropwise addition of the pyrazole boronate solution (Wa syringe over 5 min). The resulting bi-phasic dark orange solution was stirred at 840C for 20 mins. The flask was then placed in an ice bath to cool rapidly. Once at ambient temperature, the mixture was filtered to remove inorganic substance, washed with water (2 x 25 mL). Upon reduction of the the solution volume via evaporation the solid product was filtered and collected. The light yellow product was washed with ethyl ether 3 time (20 ml) to give a pale yellow solid product. Yield: 6.1 g, 98.4%.
11%	With methanol; caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 80℃; for 16h;Heating / reflux;Product distribution / selectivity;	A 3-L, three-necked rbf, equipped with a condenser, thermometer and large stirrer bar was charged withDME (1 L) and a 2M Cs2CO3 (1 L, 10 eq). The two-phased system purged with nitrogen under vigorous stirring for 45 min, followed by the addition of <strong>[891785-28-7]6-bromoisoquinolin-3-amine</strong> (44 g, 64 w% purity, 126 mmol), the commercially available boronate (50 g, 170 mmol), and PdCI2(dppf), CH2CI2 complex (10.6 g, 14.2 mmol, Strem) and MeOH (2 mL). The nitrogen purge was discontinued and replaced by a nitrogen in/outlet on top of the condenser. The reaction mixture was heated to rfx (internal temperature 8O0C) for a period of 16 h and allowed to cool to room temperature. The cooled reaction mixture appeared as a two- layer system with a virtually colorless, aqueous layer and a dark organic layer in which a light brown precipitate had formed. The reaction mixture was filtered over a short path of Celite (pre-wetted with MeOH) and the Celite was subsequently washed with DME (110 mL). Removal of the solids improved visibility and the water layer could be readily separated. The organic layer was further diluted with ethyl acetate (700 mL) resulting in the separation of more solids which were remove by short-path filtration over a fresh batch of Celite (pre-wetted with MeOH). The filtrate was concentrated to a volume of 30 mL and the formed solids were isolated by filtration and washed with diethyl ether (40 mL) to give 4.8 g (11 %) of the desired product as a yellow solid.

Reference： [1]Patent: WO2007/125405,2007,A2 .Location in patent: Page/Page column 37
[2]Patent: WO2007/125405,2007,A2 .Location in patent: Page/Page column 36-37

3
[ 552846-17-0 ]
[ 956907-14-5 ]
6-((6-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-methyl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With cesium fluoride;[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex; In 1,2-dimethoxyethane; water; at 80℃; for 16h;	Method 7 6-((6-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline: A mixture of DME (3.0 mL) and 1 M aqueous CsF (0.88 mL) was degassed by bubbling in Argon for 10 minutes. The mixture was transferred via syringe to a vial containing 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (100 mg, 0.29 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (95 mg, 0.32 mmol) and Pd(dppf)2Cl2.CH2Cl2 (6.1 mg, 0.01 mmol). The vial was capped and heated to 80 C. for 16 hours. Water (5 mL) was added to the crude reaction mixture and the resulting suspension was filtered. The precipitate was washed with water and air dried. The precipitate was purified by column chromatography using gradient elution with methanol and dichloromethane to afford 6-((6-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (60 mg, 62%).

Reference： [1]Patent: US2007/265272,2007,A1 .Location in patent: Page/Page column 19-20; 51

4
[ 552846-17-0 ]
[ 956907-27-0 ]
7-fluoro-6-[6-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With cesium fluoride;[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex; In 1,2-dimethoxyethane; water; at 20 - 85℃; for 16h;	Preparation of 7-fluoro-6-[6-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}-quinoline To a suspension of 6-[(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl]-7-fluoroquinoline (250 mg, 0.696 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (225 mg, 0.766 mmol) in dimethoxyethane (8.0 ml) was added CsF (317 mg, 2.09 mmol) and water (1.05 ml) at R.T. After degassed several times, to the suspension, 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium (11) 1:1 complex with CH2Cl2 (25.5 mg, 0.04 mmol) was added and the reaction mixture was degassed again. After stirring at 85 C. for 16 h, the reaction mixture was cooled down to R.T. diluted with water (10 ml) and filtered. The aqueous layer was extracted with CH2Cl2 (250 ml) EtOAc (110 ml). The combined the organic layer was dried with K2CO3 filtered and combined this with the solid filtered initially, and concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 0-7% CH2Cl2:MeOH to give the desired product (220 mg 91%). 1H NMR (400 MHz, DMSO-d6) delta ppm 6.18 (s, 2H) 7.53 (dd, J=8.21, 4.17 Hz, 2H) 7.84 (d, J=11.37 Hz, 1H) 8.17 (d, J=8.59 Hz, 1H) 8.29 (s, 1H) 8.41-8.46 (m, 1H) 8.70 (s, 1H) 8.92 (dd, J=4.29, 1.77 Hz, 1H) 9.25 (s, 1H).

Reference： [1]Patent: US2007/265272,2007,A1 .Location in patent: Page/Page column 36

5
[ 552846-17-0 ]
[ 934495-31-5 ]
[ 1013098-90-2 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;	Example 5. Preparation of 2-amino-8-cvclopentyl-6-(1 H-pyrazol-4-yl)-4-methylpyridof2,3-Qipyrimidin- 7(8H)-one (Compound 101 ); <n="38"/>To a solution of 2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-c(lpyrimidin-7(8/-/)-one (100 mg, 0.31 mmol), terf-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1-carboxy late ( 110 mg, 1.2 equiv), dichlorobis(triphenylphosphine)palladium(ll) (6.5 mg, 009 mmol), DMF (2 ml_) in a 10 mL microwave vial was added potassium carbonate (3 M, 0.8 ml_). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 10 min at 120 0C. Once complete, the reaction was diluted with 1 N NaOH (10 mL) and EtOAc (50 mL). The EtOAc layer was washed with 3N HCI, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was submitted for chromatography purification, the title compound was obtained in (62.5 mg, 65% yield). LRMS: 311 (M+H)+.1H NMR (DMSO-CC6, 400 MHz): 8.26 (2H, bs), 8.13 (1 H, s), 7.09 (2H, bs), 6.04-5.99 (1 H, m), 2.59 (3H, s), 2.27-2.23 (2H1 bm), 2.04 (2H, bm), 1.77-1.74 (2H, bm), 1.62 (2H, bm).

Reference： [1]Patent: WO2008/32162,2008,A1 .Location in patent: Page/Page column 36-37

6
[ 269410-08-4 ]
[ 24424-99-5 ]
[ 552846-17-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With dmap; In N,N-dimethyl-formamide; at 0 - 20℃;	To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 25.8 mmol) and DMAP (3.8 g, 31.1 mmol) in DMF (30 mL) was added (Boc)2O (8.4 g, 38.5 mmol) at 0 C. The mixture was stirred at room temperature overnight. The reaction was diluted with NH4Cl (150 mL) and extracted with DCM (200 mL). The organic layer was washed with aqueous 1N HCl, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (7.4 g, 25.2 mmol, 99%) as a white solid. 1H NMR (CD3OD, 400 MHz) delta 8.36 (s, 1H), 7.87 (s, 1H), 1.58 (s, 9H), 1.27 (s, 12H).
99.68%	With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Compound Reg-1-16-a (4.5 g, 2.58 mmol) and dichloromethane (200 mL) were added to a 100 mL flask, diisopropylethylamine (5.99 g, 46.38 mmol) and 4-dimethylaminopyridine (424 mg, 3.48 mmol) were added, followed by slow dropwise addition of Boc2O (7.59 g, 34.79 mmol). The reaction was performed overnight at room temperature. Thin layer chromatography (petroleum ether : ethyl acetate=3:1) indicated the reaction was complete. The reaction solution was concentrated to give a crude product, which was dissolved in dichloromethane (100 mL), and the organic phase was then washed three times with 0.5M dilute hydrochloric acid. The organic phase was further washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain Reg-1-16-b (6.8 g, colorless oil, yield: 99.68%). MS m/z (ESI): 195.2 [M-Boc+H].
85%	With dmap; In dichloromethane; at 20℃; for 4h;	4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1H-pyrazole (1.16 g, 6.0mmol) in methylene chloride (40 mL) was added di-tert-butyl dicarbonate (1.58 g, 7.2 mmol), was added a catalytic amount of 4-dimethylaminopyridine (102 mg, 0.84 mmol), reaction at room temperature for 4 hours.Water was added to the system, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, the organic Xiangde removed by rotary evaporation the crude product (1.5 g, 85% yield).

76%	dmap; In N,N-dimethyl-formamide; at 20℃; for 12h;	Di-tert-butyl dicarbonate (7.2 molar equivalent), 4-(dimethylamino)pyridine (0.84 molar equivalent) were added to a solution of 4,4,5,5-tetramethyl-2-(1H-pyrazole-4-yl)-1,3,2-dioxaborolane (6 mmol) in 40 mL of DMF. The reaction mixture was stirred at room temperature for 12 h. Water was added to the reaction mixture to quench the reaction. EtOAc was then added to extract the aqueous solution. Dry EtOAc layer over Na2SO4. The Na2SO4 was filtered off and the filtrate was evaporated to give a brown yellow oil residue as compound 21-1 (1.32 g; 4.56 mmol; 76%). 1H NMR (400 MHz, chloroform-D) delta ppm 1.32 (s, 12H) 1.63 (s, 9H) 7.91 (s, 1H) 8.37 (s, 1H). The residue was used for the next step reaction without further purification.
65%	With dmap; In N,N-dimethyl-formamide; at 0 - 25℃; for 16h;Inert atmosphere;	To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-1H-pyrazole 125-5a (100 g, 515 mmol) inN N-dimethylformamide (500 mL, 5V) was added 4-dimethylaminopyridine (8.8 g, 72 mmol) followed by BOC anhydride (118 mL,515 mmol) drop wise at 0 C. The reaction mixture was stirred for 16 h at 25 C. The reaction mixture was quenched with chilled water (2.5 L). The solid precipitate was collected by filtration and dried under vacuum to give ester 125-5 as a white solid 99 g (65%).
64%	With dmap; In acetonitrile; at 20℃; for 18h;	To a mixture of 4-pyrazoleboronic acid pinacol ester (0.485 g, 2.5mmol) and DMAP (0.153 g, 1.25 mmol) in MeCN (12.5 ml) was added di-tert-butyldicarbonate (0.709 g, 3.25 mmol). The resulting mixture was stirred at rt for 18 h before itwas concentrated under reduced pressure. The obtained residue was purified by flashcolumn chromatography (silica gel, 0-10% EtOAc in petroleum ether) to afford the titlecompound (0.473 g, 64% yield) as a white solid. 1H NMR (400 MHz, CDCb) o 8.38 (s, 1 H),7.92 (s, 1H), 1.64 (s, 9H), 1.33 (s, 12H).
57%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 48h;	To a solution of 33a (l .Og, 5.15mmol) in CH2Cl2 (3OmL) was added DIEA (2.0g, 15.5mmol), followed by (Boc)2O (1.55g, 7.4mmol) drop-wise at O0C. The resulting mixture was stirred at room temperature for 2 days. After the reaction was complete detected by TLC, the mixture was evaporated and the residue was purified by silica column chromatography (PE:EA=4:1) to provide 35a (0.86g, 57% yield).
	In dichloromethane; at 20℃;	A solution of 4-(4, 4,5, 5-tetramethyl- [1, 3,2] DIOXABOROLAN-2-YL)-LH-PYRAZOLE (0.33g, 1.70 mmol) and di-tert-butyl dicarbonate (0. 51G, 2.34 mmol) in dichloromethane (10 mL) was allowed to stir overnight at ambient temperature. The solution was then washed with saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, and concentrated. The crude product of 4-(4, 4,5, 5- tetramethyl- [1, 3,2] DIOXABOROLAN-2-YL)-PYRAZOLE-1-CARBOXYLIC acid ter-butyl ester (0. 61G) was used in next step without further purification.
	With dmap; In N,N-dimethyl-formamide; at 20℃;	General procedures for the preparation of 3-(lH-pyrazol-4-yl)aniline Step A: Tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate. To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (500 mg, 2.57 mmol) and (Boc)20 (672 mg, 3.08 mmol) in DMF (1.0 mL) was added DMAP (63 mg, 0.52 mmol) in one portion. The mixture was stirred at room temperature overnight, and then partitioned between EtOAc and saturated aq. NH4CI. The organic layer was separated, washed with brine, dried over anhydrous Na2S04, and concentrated to afford the crude product.
		To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,9 (2.0 g, 10 mmol) in DMF (50 mL) was added DMAP (3.14 g, 25 mmol), the mixture wascooled to 0 C and stirred for 10 min. (Boc)20 (2.9 mL, 13 mmol) was added dropwise andthe mixture was stirred for 15 min at same temperature. The resulting reaction mixture was allowed to warm to RT and stir overnight. The progress of the reaction was monitored by TLC (TLC system: 50 % EtOAc/Pet ether, Rf value: 0.8) After completion of the reaction, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified over silica gel (100-200 mesh) column chromatography eluting with 10 % EtOAc/Pet ether to give tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, 10 as a white solid.
	With triethylamine; In dichloromethane; at 20℃; for 24h;	To a stirred solution of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H- pyrazole (1.00 g, 5.15 mmol) and Boc2O (1.436 mL, 6.18 mmol) in dichioromethane(15 mL) was added triethylamine (1.077 mL, 7.73 mmol) at room temperature and the reaction mixture was stirred for 24 h. After completion of the reaction, as determined by TLC (10% ethyl acetate in hexane), water was added and the aqueous layer was extracted with dichloromethane (50 mL). The organic layer was washed with water, concentrated under reduced pressure to afford tert-butyl 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole- 1 -carboxylate (1.5 g, 99% yield), which was used in the next step without purification. LCMS (ESI) rn/c 194.7 (corresponding to de-boc mass under analytical condition) [(M+H-BOC), calcd for C9H15BN202, 194.1]; LC/MS retention time (method C): tp. = 1.92 mm.
	With dmap; In N,N-dimethyl-formamide; at 20℃;	To a solution of 4-(4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (500mg, 2.57 mmol) and (Boc)20 (672 mg, 3.08 mmol) in DMF (1.0 mL)was addedDMAP (63 mg, 0.52 mmol)in one portion. The mixture was stirred at room temperature overnight, and then partitioned between EtOAc and saturated aq. NH4C1. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the crude product.
	With dmap; In N,N-dimethyl-formamide; at 20℃;	Step A: Tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate. To a solution of 4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)- l H-pyrazole (500 mg, 2.57 mmol) and (Boc)20 (672 mg, 3.08 mmol) in DMF (1 .0 mL) was added DMAP (63 mg, 0.52 mmol) in one portion. The mixture was stirred at room temperature overnight, and then partitioned between EtOAc and saturated aq. NH4CI. The organic layer was separated, washed with brine, dried over anhydrous a2S04, and concentrated to afford the crude product.
	With dmap; triethylamine; In dichloromethane; at 20℃; for 4h;	:3 (250 mg, 1.28 mmol), DCM (5 ml), TEA (3.0 eq), (Boc)20 (1.2 eq) DMAP (Cat.), RT. After 4 h, one major non-polar product was observed by TLC. The reaction was quenched with ice-cold water (10 mL) and extracted with DCM (20 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 300 mg of 4 as thick syrup. Repeat preparatin with 3 (500 mg, 2.56 mmol), DCM (10 ml), TEA (3.0 eq), (Boc)20 (1.2 eq) DMAP (cat.). RT. After 4 h, one major non-polar product was observed by TLC, The reaction was quenched with ice-cold water (10 mL) and extracted with DCM (20 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 500 mg of 4 as thick symp. The obtained crude materials were used for next step without further purification.
	With dmap; In N,N-dimethyl-formamide; at 20℃; for 7h;	Boc2O (96 g,0.48 mol) and dmAP (64 g,0.64 mol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in dmf (1 L). The reaction mixture was stined at room temperature for 7 h before the mixture was poured into water and EtOAc. Theorganic layer was separated and washed with water and brine,and dried over anhydrous Na2504 before concentrating to dryness. The resulting residue was purified by silica gel column (10:1 petroleum ether:EtOAc) to give the title compound.
4.58 g	With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.166667h;	Compound TDI01245-1 (5.0 g, 25.77 mmol) was dissolved in dichloromethane (100 ml), diisopropylethylamine(13.30 g, 100.08 mmol) and 4-dimethylaminopyridine (1.57 g, 12.88 mmol) were added, and di-tert-butyl dicarbonate(11.24 g, 51.55 mmol) was added after the reaction was stirred at room temperature for 10 minutes. Thin layer chromatography(petroleum ether : ethyl acetate=3:1) indicated the reaction was complete. The reaction solution was dissolvedin dichloromethane (400 ml), and successively washed with water (500 ml * 2) and saturated brine (500 ml). The organicphase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleumether : ethyl acetate= 1:0 to 10:1), to afford compound TDI01245-2 (4.58 g, white solid).1H NMR (400 MHz, CDCl3) delta 8.42 - 8.34 (m, 1H), 7.93 (s, 1H), 1.65 (s, 9H), 1.34 (s, 12H).
	With dmap; In N,N-dimethyl-formamide; at 20℃; for 7h;	Boc2O (96 g, 0.48 mol) and DMAP (64 g, 0.64 mol) were added to a solution of 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in DMF (1 L). The reaction mixture was stirred atroom temperature for 7 hours before the mixture was poured into water and EtOAc. The organic layer was separated and washed with water and brine, and dried over anhydrous Na2504 before concentrating to dryness. The resulting residue was purified by silica gel column (10:1 petroleum ether:EtOAc) to give the title compound.
	With dmap; In N,N-dimethyl-formamide; at 20℃; for 7h;	Boc20 (96 g, 0.48 mol) and DMAP (64 g, 0.64 mol) were added to a solution of 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole in DMF (1 L). The reaction mixture was stirred at room temperature for 7 hours before the mixture was poured into water and EtO Ac. The organic layer was separated and washed with water and brine, and dried over anhydrous Na2S04 before concentrating to dryness. The resulting residue was purified by silica gel column (10: 1 petroleum ethenEtOAc) to give the title compound.

Reference： [1]Patent: US2018/296543,2018,A1 .Location in patent: Paragraph 0671; 0672
[2]Patent: EP3421464,2019,A1 .Location in patent: Paragraph 0109; 0110; 0187; 0188
[3]Patent: CN103936728,2016,B .Location in patent: Paragraph 0177; 0203; 0204; 0205
[4]Patent: US2006/46991,2006,A1 .Location in patent: Page/Page column 68
[5]Patent: WO2018/175922,2018,A1 .Location in patent: Page/Page column 245; 324
[6]Patent: WO2018/154466,2018,A1 .Location in patent: Paragraph 001162; 001164; 001165
[7]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 58
[8]Patent: WO2004/56727,2004,A2 .Location in patent: Page 97
[9]Patent: WO2013/107291,2013,A1 .Location in patent: Page/Page column 66
[10]Patent: WO2013/166015,2013,A1 .Location in patent: Paragraph 0108 - 0110
[11]Patent: WO2015/6100,2015,A1 .Location in patent: Page/Page column 185
[12]Patent: WO2015/10626,2015,A1 .Location in patent: Page/Page column 67
[13]Patent: WO2015/10297,2015,A1 .Location in patent: Page/Page column 66
[14]Patent: WO2016/73652,2016,A1 .Location in patent: Page/Page column 76
[15]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 43; 44
[16]Patent: EP3421465,2019,A1 .Location in patent: Paragraph 0111; 0112; 0233; 0234
[17]Patent: WO2019/5588,2019,A1 .Location in patent: Page/Page column 33; 34
[18]Patent: WO2019/5587,2019,A1 .Location in patent: Page/Page column 47; 48

7
[ 552846-17-0 ]
[ 130333-46-9 ]
4-(5-formyl-2,4-DIMETHOXYPHENYL)PYRAZOLE-1-CARBOXYLIC acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium fluoride;bis(tri-t-butylphosphine)palladium(0); In tetrahydrofuran; water; at 60℃;	To a mixture OF 2, 4-DIMETHOXY-5-BROMO-BENZALDEHYE (0. 2SG, 1.13 MMOL), 4- (4,4, 5, 5-TETRAMETHYL- [1, 3,2] DIOXABOROLAN-2-YL)-PYRAZOLE-1-CARBOXYLIC acid tert-butyl ester (Ex-36A, 0.61g, 1.70 MMOL), bis (TRI-TE7-T-BUTYLPHOSPHINE) PALLADIUM (43 mg, 0. 085 mmol) and potassium fluoride (0. 24G, 4.08 mmol) was added degassed tetrahydrofuran (15 mL). The reaction mixture was heated at 60 C for one day. Additional potassium fluoride (0.24g, 4.08 mmol) and water (20 muL) were added. The reaction mixture continued to stir at 60 C for another 8 hours. The reaction was then quenched by water. The aqueous solution was extracted with ethyl acetate. The solution of ethyl acetate was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (50%, v/v, in hexane) afforded 4- (5- formyl-2, 4-DIMETHOXY-PHENYL)-PYRAZOLE-1-CARBOXYLIC acid tert-butyl ester (0. 15g, 40%) as white SOLID.'H NMR (CDC13) 8 10. 35 (s, 1H), 8.43 (s, 1H), 8. 09 (s, 1H), 8.02 (s, 1H), 6.52 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.68 (s, 9H). MS m/z = 333 ( [M + H] +, 100%).

Reference： [1]Patent: WO2004/56727,2004,A2 .Location in patent: Page 98

8
[ 552846-17-0 ]
[ 850363-05-2 ]
[ 850363-30-3 ]

Yield	Reaction Conditions	Operation in experiment
81%		(Example 27) Synthesis of 5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-4-(pyrazol-4-yl)-2-(tetrahydropyran-2-yl)-2H-indazole (compound 27-1) 1-tert-Butoxycarbonyl-4-(4,4,5,5-tetramethyl[1,3,2] dioxaborolanyl)pyrazole (312 mg, 1.06 mmol), 123 mg (0.106 mmol) of tetrakistriphenylphosphine palladium, 5 ml of 1,2-dimethoxyethane and 2 ml of 2M aqueous solution of sodium carbonate were added to 310 mg (0.531 mmol) of 5-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-(tetrahydropyran-2-yl)-4-trifluoromethanesulfonyloxy-2H-indazole (compound 17-2) and the mixture was heated to reflux in an argon stream for 30 minutes with stirring. After the mixture was cooled down to room temperature, 5 ml of methanol and 1 ml of 1N sodium hydroxide solution were added thereto and the mixture was stirred at room temperature for 30 minutes. After the reaction was finished, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to a silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 1:1 (v/v)) and the fraction containing the aimed product was concentrated in vacuo to give 215 mg of the title compound as slightly yellow powder (yield: 81%). Rf value: 0.20 (n-hexane: ethyl acetate = 1:2 (v/v)) Mass spectrum (CI, m/z): 502 (M+ + 1) 1H-NMR spectrum (CDCl3, delta ppm): 1.38 (brs, 9H), 1.64-1.83 (m, 9H), 2.04-2.25 (m, 3H), 3.74-3.83 (m, 1H), 4.11-4.16 (m, 1H), 4.95 (brs, 1H), 5.66-5.71 (m, 1H), 7.17-7.22 (m, 2H), 7.30-7.35 (m, 3H), 7.40-7.42 (m, 2H), 7.69 (dd, J1 = 8.9Hz, J2 = 1.1Hz, 1H), 8.20-8.21 (m, 1H)

Reference： [1]Patent: EP1679308,2006,A1 .Location in patent: Page/Page column 90

9
[ 552846-17-0 ]
[ 897375-66-5 ]
[ 897373-59-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 80℃;	A solution of 1-(3-bromophenyl)-3-t-butyl-1H-pyrazol- 5-amine hydrochloride (0.253 g, 0.77 mmol, available from Example 54), t-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole-1-carboxylate (0.28 g, 0.95 mmol, commercially available) and Cs2CO3 (1.0 g, 3.1 mmol) in DMF (5 mL) and H2O (2 mL) was placed under Ar for 15 min. Palladium tetrakis(triphenylphosphine) was added and the reaction mixture was heated at 80 C overnight. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (2x30 mL). The extracts were washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4) concentrated and purified via column chromatography to yield 1-(3-(lH-pyrazol-4- yl)phenyl)-3-t-butyl-lH-pyrazol-5-amine (163 mg, 76% yield).

Reference： [1]Patent: WO2006/71940,2006,A2 .Location in patent: Page/Page column 375

10
[ 141-30-0 ]
[ 552846-17-0 ]
4-(6-chloropyridazin-3-yl)pyrazole-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; In 1,4-dioxane; water; at 70℃; for 4.5h;	mixture of 3,6-dichloro-pyridazine (1.06 g, 6.98 mmol) and 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)~pyrazole-l-carboxylic acid tert-butyl ester (1.47 g, 5.0 mmol) in 2.0 M potassium carbonate (10 mL, 20 mmol) and 1,4-dioxane (40 mL) was degassed by house vacuum for 15 min followed by bubbling with argon for ~ 10 min, Peppsi-ipr (340 mg, 0.5 mmol) was them added. After flushing with argon for another - 10 min, the mixture was heated at 70 0C for 4 h and allowed to cool to room temperature. The solid was removed by filtration through Celite, and the filtrate was <n="151"/>separated. The aqueous solution was extracted with CH2CI2 and the combined organic phases were dried over Na2SC^ , concentrated, and purified by column to provide o.65 g desired product (46%). 1H NMR(DMSO) delta 9.08(s, IH), 8.47 (s, IH), 8.31 (d, /= 9.0 Hz, IH), 8.01 (d, J= 9.0 Hz, IH), 1.59 (s, 3H); MS (ES) m/z 280.8(M+H+).

Reference： [1]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 149-150

11
[ 552846-17-0 ]
[ 2033-46-7 ]
[ 944994-08-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium fluoride;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In methanol; water; toluene; at 70℃;	N-(5-iodo-4-methyl-l,3-thiazol-2-yl)acetamide (Intermediate 1) (282 mg; 1 mmol; 1 eq.), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-pyrazole-l-carboxylic acid tert-butyl ester (441 mg; 1.5 mmol; 1.5 eq.), potassium fluoride (174 mg; 3 mmol; 3 eq.) palladium(II) acetate (22 mg; 0.1 mmol; 0.1 eq.) and 2-dicyclohexylphosphino-2',6'-dimethoxy-l,r- biphenyl (41 mg; 0.1 mmol; 0.1 eq.) were mixed in a flask kept under argon. Toluene (5 ml), MeOH (5 ml) and water (11 mul) were added. The resulting mixture was flushed with argon and stirred at 700C overnight. Solvents were evaporated and the crude mixture was suspended in EtOAc. The desired product was extracted with HCl 1 N aqueous solution, which was neutralized with NaOH 5N solution. The resulting aqueous phase was extracted with 2 fractions of EtOAc. Combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting crude yellow product was suspended in Et2O, filtered and washed with Et2O, affording compound (3) as a white-off solid (103 mg; 46 %). HPLC, Rt: 2.17 min (purity: 96%).

Reference： [1]Patent: WO2007/82956,2007,A1 .Location in patent: Page/Page column 50

12
[ 552846-17-0 ]
[ 879014-17-2 ]
6,7-dimethoxy-4-(1H-pyrazol-4-yl)cinnoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 140℃; for 0.166667h;Microwave irradiation;	Step 1[00169] Into a microwave tube was added 4-bromo-6,7-dimethoxycinnoline (200 mg,0.8 mmol, prepared as described in Example 1 above), bis(triphenylphosphine) palladium(II) <n="56"/>chloride (95.6 mg, 0.136 mmol), tert-butyl-4,-(4,4,5,5-te1iamethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole-1-carboxylate (200 mg, 0.0008 mol), aqueous sodium carbonate (2.00 M, 0.28 mL) and a mixture of dimethoxyethane:water:ethanol (5 mL, 7:3:2). The resulting suspension was subjected to microwave radiation at 1400C for 600 seconds. The reaction was filtered through celite, which was washed with methanol. Concentration, followed by ISCO chromatographic purification (using a gradient of 50 % ethyl acetate:hexanes to 100% ethyl acetate, followed by elution with a 70:30:1 mixture of ethyl acetate:methanol:ammonia afforded 140 mg (70% yield) of 6,7-dimethoxy-4-(lH-pyrazol-4-yl)cinnoline as a yellow solid.

Reference： [1]Patent: WO2007/98169,2007,A1 .Location in patent: Page/Page column 54-55

13
[ 552846-17-0 ]
[ 1023885-03-1 ]
C₂₅H₂₆ClN₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.3%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 85℃; for 12h;	<strong>[552846-17-0]4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester</strong> (287 mg, 0.98 mmol) was added to a solution of the compound obtained in Example 3 (473 mg, 0.98 mmol) in 6 mL of DME. The mixture was purged with N2 several times. Tetrakis (Triphenylphosphine) palladium (113 mg, 0.1 mmol) was added then Na2CO3 (1.5 mL, 2M) was added to the mixture. The mixture was heated and stirred at 85 0C for 12 hours. H2O (20 mL) was added to the reaction mixture. EtOAc (2 x 100 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to give a brown yellow oil (504 mg, 90.3% yield).

Reference： [1]Patent: WO2008/53319,2008,A1 .Location in patent: Page/Page column 47

14
[ 552846-17-0 ]
[ 89891-65-6 ]
[ 1083326-12-8 ]

Yield	Reaction Conditions	Operation in experiment
45%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 21.5h;	Intermediate 13; Preparation of 7-bromo-2-(1H-pyrazol-4-yl)quinoxaline; To a 100 mL high pressure vessel was added 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.208 g, 4.11 mmol), 7-bromo-2-chloroquinoxaline (1 g, 4.11 mmol), PdCl2(dppf).CH2Cl2 (0.168 g, 0.205 mmol), 1,4-dioxane (20.53 ml) and 2M aqueous potassium carbonate (10.27 ml, 20.53 mmol). The vessel was sealed and the reaction mixture heated at 100 C. overnight (21.5 hrs). LCMS showed 60% desired product (M+H=276.9) with no Boc group. The organic layer was separated and purified directly on a silica gel column, eluting with 50% ethyl acetate to 100% ethyl acetate in hexanes. The desired fractions were concentrated in vacuo to give a tan solid which was triturated with ethyl acetate, the insolubles collected by suction filtration and dried in vacuo to provide the title compound as a tan powder (508 mg, 45%). ESMS m/e 276.9 [M+H]+.

Reference： [1]Patent: US2008/293706,2008,A1 .Location in patent: Page/Page column 88

15
[ 552846-17-0 ]
[ 1040376-44-0 ]
[ 1040377-19-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃;	To the stirred mixture of D (400mg, l .Ommol) and 35a (467mg, 1.59mmol) in DMF (35mL), was added Pd(PPh3)2Cl2 (74mg, 0.1 lmmol), followed by IN Na2CO3 (4.7mL) aq. slowly. The reaction mixture was degassed and heated at 8O0C overnight. After the reaction was complete, DMF was evaporated and the residue was purified by column chromatography (PE: EA=I : 1 ) to give 35b (267mg, 70%).

Reference： [1]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 58-59

16
[ 552846-17-0 ]
[ 88770-19-8 ]
[ 1187468-01-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; industrial methylated spirit; water; at 110.0℃; for 6h;Inert atmosphere;	5-Bromo-thiophene-3-carboxylic acid methyl ester (6 g, 27 mmol) was dissolved in a mixture of DME (75 mL), IMS (25 mL) and water (12.5 mL). Caesium carbonate (13.2 g, 40 mmol) and 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazole-1 -carboxylic acid tert-butyl ester (9.2 g, 31 mmol) were added and the mixture stirred under argon.Palladium tetrakis-(triphenylphosphine) (3.1 g, 2.7 mmol) was then added and the mixture heated at 110C for 6 hours. The mixture was allowed to cool to room temperature and then diluted with water. The product was extracted into DCM and washed with brine, then dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was triturated with diethyl ether to give the title compound as a pale yellow solid (3.01 g). LCMS m/z 209.1 [M+H]+. R.T. = 3.72 min (Analytical Method 4). 1H NMR (400 MHz, d6-DMSO): delta 8.2 (s, 1 H), 8.15 (s, 1 H), 7.85 (s, 1H), 7.5 (s, 1 H), 3.8 (s, 3H).
	With water; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; industrial methylated spirit; at 140.0℃; for 0.333333h;Microwave irradiation;	Synthesis 45; 5-(1 H-Pyrazol-4-yl)-thiophene-3-carboxylic acid; IMS, delta-Bromo-thiophene-S-carboxylic acid methyl ester (1.29 g, 5.84 mmol) was dissolved in DME (13.5 mL), IMS (4.5 mL) and water (2 ml_) and ), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.89 g, 6.43 mmol) and caesium carbonate (2.85 g, 8.77 mmol) were added followed by palladium tetrakis(triphenylphosphine) (0.675 g, 5.84 mmol). The reaction mixture was heated by microwave irradiation at 1400C for 20 minutes and then diluted with water and extracted with DCM (x 3). The organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by chromatography on a silica Il cartridge, eluting with 10 to 50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give 5-(1H-pyrazol-4-yl)-thiophene-3- carboxylic acid methyl ester as a white, flocculent solid (0.728 g).This material (0.725 g, 3.49 mmol) was dissolved in methanol (10 mL) and sodium hydroxide (1 M aqueous, 8.7 mL) was added. The reaction mixture was stirred for 3 hours at room temperature then a further 0.25 eq. of sodium hydroxide was added and the mixture stirred for 20 minutes. HCI (1 N, 7mL) was added and the mixture was concentrated. The residue was taken up in water and acidified (pH 2) and the resultant white precipitate was collected by filtration to afford the title compound as a white solid (0.5 g). LCMS m/z 236.30 (M + MeCN+H+). RT. = 2.31 min (Analytical Method 6).

Reference： [1]Patent: WO2011/33255,2011,A1 .Location in patent: Page/Page column 72
[2]Patent: WO2009/112845,2009,A1 .Location in patent: Page/Page column 119

17
[ 25015-63-8 ]
[ 219580-32-2 ]
[ 552846-17-0 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 9199 - 9201

18
[ 552846-17-0 ]
[ 1206800-24-9 ]
[ 1206800-43-2 ]
[ 1206800-42-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis(di-tertbutylphosphino)ferrocene; In 1,4-dioxane; water; at 60℃;Inert atmosphere;	Preparation 101 tert-Butyl 4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylateTo a 12 L round bottom flask equipped with overhead agitation, a thermocouple, heating mantle, condenser, and subsurface nitrogen sparge is added 1,4-dioxane (7.44 L) and water (1.67 L). The solution is purged with N2 (inlet tube). Next <strong>[1206800-24-9]6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole</strong> (595 g, 1.63 mol) is added and the solution is purged with N2 again. tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (717.02 g, 2.44 mol), potassium phosphate tribasic N-hydrate (689.8 g, 3.25 mol), and 1,1'-Bis(di-tert-butylphosphino)ferrocene (7.71 g, 16.25 mmol) are added. Finally, Pd2(dba)3 (7.44 g, 8.13 mmol) is added. The solution is purged for 15 min and then heated at 60 C. for 12 hours. The reaction is not complete and more Pd2(dba)3 (7.44 g, 8.13 mmol) is added. The solution is again heated at 60 C. for 3 additional hours and the reaction is complete. 1,4-Dioxane is then removed (Buchi bath temp 60 C.) and the residue is re-dissolved in 10 volumes (6 L) of DCM. Water (3 L) is added and then the layers are separated. The organic solution is dried over Na2SO4, filtered and concentrated to a dark oil (835 g). The material is not purified and is forward processed to the next step. The material is about 60% desired product and about 40% 5-(2-fluoro-4-nitrophenoxy)-1-methyl-6-(1H-pyrazol-4-yl)-1H-indazole. The crude obtained is reprotected in the next step. It is assumed that 50% of the crude product is the 5-(2-fluoro-4-nitrophenoxy)-1-methyl-6-(1H-pyrazol-4-yl)-1H-indazole.To a 22 L round bottom flask with overhead agitation, thermocouple, 1 L addition funnel, N2 purge, and cooling bath is added a solution of crude 5-(2-fluoro-4-nitro-phenoxy)-1-methyl-6-(1H-pyrazol-4-yl)- 1H-indazole (835 g, 1. 18 mol) in DCM (6 L) of. phenoxy)-1-methyl-6-(1H-pyrazol-4-yl)-1H-indazole (835 g, 1.18 mol) in DCM (6 L) of di-tert-butyldicarbonate (283.69 g, 1.30 mol) dissolved in DCM (350 mL) of is added to an addition funnel. The solution is added dropwise over 48 min. After the reaction is complete, DCM is removed by rotary evaporation to give a dark oil. To the dark oil is added MTBE (2.5 L) and the oily solution is cooled to about 0-5 C. The solution is seeded with material obtained in Preparation 98. After seeding, crystallization is observed and the resulting slurry is stirred for 30-40 min. The pale yellow slurry is filtered over a polypropylene pad and the cake is washed with cold (0-5 C.) MTBE (1.5 L). The solids are dried in a 40 C. vacuum oven overnight to give the desired product (443 g, 60% crude yield). MS (m/z): 354.0 (M+H). The material is shown to be about 93-95% pure by HPLC and is therefore forward processed.

Reference： [1]Patent: US2010/22529,2010,A1 .Location in patent: Page/Page column 14

19
[ 552846-17-0 ]
[ 1001070-33-2 ]
[ 1147998-27-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1.08h;	EXAMPLE 2; Compound 2-1; 3-r6-(piperidin-4-yloxy)rhoyrazin-2-yll-5-(lH-pyrazol-4-yl)-lH-pyrrolor2,3-blPvridine; )h 1 -(phenylsulfonylV5-(lH-pwazol-4-vD-lH-pyrrolor2, 3-fr\|pyridine; To a degassed (sparging with argon for 5 minutes), stirred solution of 4-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2yl)-pyrazole-l-carboxylic acid tert-butyl ester (1.31 g, 4.45 mmol) and 5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3->]pyridine (1.00 g, 2.97 mmol) in dioxane (12.0 ml) was added Pd(Ph3P)4 (0.171 g, 0.148 mmol), followed by a degassed aqueous <n="51"/>solution of sodium carbonate (4.45 ml, 8.90 mmol). The reaction mixture was stirred under nitrogen at 100 0C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and saturated aqueous ammonium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 1 - (phenylsulfonyl)-5-(l/-/-pyrazol-4-yl)-lH-pyrrolo[2, 3-£]pyridine as a yellow solid. LRMS (ESI) calculated for C16HnN4O2S [M+H]+, 325.1; found 325.0.

Reference： [1]Patent: WO2009/54941,2009,A1 .Location in patent: Page/Page column 49-50

20
[ 552846-17-0 ]
[ 62224-16-2 ]
[ 1239576-68-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 85℃; for 6h;Sealed flask;	Example 2; Preparation of Lambda/-{(1 S)-2-amino-1-[(3,4-difluorophenyl)methyl1ethyl}-5-chloro-4-(1 /-/- pyrazol-4-yl)-2-thiophenecarboxamide; a) 1 ,1-dimethylethyl 4-{5-[(methyloxy)carbonyl]-3-thienyl}-1 H-pyrazole-1-carboxylate; To a 75 ml. sealed flask was added <strong>[62224-16-2]methyl 4-bromo-2-thiophenecarboxylate</strong> (1.144 g, 5.17 mmol) [prepared according to the procedure of Example 1], potassium carbonate (2.31 g, 16.71 mmol), 1 ,1-dimethylethyl 4-(4,4, 5, 5-tetramethyl-1 , 3,2- dioxaborolan-2-yl)-1 H-pyrazole-1-carboxylate (1.656 g, 5.63 mmol) and bis(tri-t- butylphosphine)palladium(O) (35.1 mg, 0.069 mmol) in 1 ,4-dioxane (20 ml.) and H2O (4 ml_). After stirring for 6 hours at 85 0C, the reaction solution was diluted with CHCI3 (75 ml.) and washed with H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was adsorbed onto silica gel and eluted with [Hexanes/EtOAc, 2:1 ] to give the product [774 mg, quant.] as a yellow oil: LCMS (ES) m/z 309 (M+H)+.

Reference： [1]Patent: WO2010/93885,2010,A1 .Location in patent: Page/Page column 40-41

21
[ 552846-17-0 ]
[ 62224-19-5 ]
[ 1239577-07-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With water; caesium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; at 80℃; for 1h;Sealed flask;	b) methyl 5-(1 /-/-pyrazol-4-yl)-2-thiophenecarboxylate; To a solution of methyl 5-bromo-2-thiophenecarboxylate (442 mg, 2.0 mmol), 1 ,1- dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1 -carboxylate (588 mg, 1.999 mmol) and cesium carbonate (651 mg, 1.999 mmol) in 1 ,4-Dioxane (16 ml.) and Water (4.00 ml.) was added bis(tri-t-butylphosphine)palladium(0) (102 mg, 0.200 mmol). The mixture was sealed and heated at 80 0C for 1 hr. The mixture was cooled down to room temperature and filtered through a celite pad. The filtered solution was concentrated and partitioned between water and DCM. The DCM layer was washed with brine and concentrated to afford a yellow solid as the desired product which was used without any further purification [251.1 mg, 60%]: LC-MS (ES) m/z 209 (M+H) +.

Reference： [1]Patent: WO2010/93885,2010,A1 .Location in patent: Page/Page column 63

22
[ 552846-17-0 ]
trans-4-[4-[(6-bromo-1,3-benzothiazol-2-yl)amino]-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanol [ No CAS ]
trans-4-[(4-(phenylmethyl)-6-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]amino}-2-pyrimidinyl)amino]cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		Example 168: trans-4-[(4-(phenylmethyl)-6-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]amino}-2-pyrimidinyl)amino]cyclohexanolA mixture of 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (192mg, 0.652mmol), trans-4-[4-[(6-bromo-1,3-benzothiazol-2-yl)amino]-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanol (131 mg, 0.257mmol), caesium carbonate (251 mg, 0.770mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(ll)dichloride dichloromethane adduct (10.48mg, 0.013mmol) was sealed and heated in a Biotage "Initiator" microwave at 15O0C for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (15mg, 0.013mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (192mg,0.652mmol) and water (0.6mL) were added and the reaction mixture was heated at 15O0C for a further 30 minutes. More tetrakis(triphenylphosphine)palladium(0) (15mg, 0.013mmol) and 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (192mg, 0.652mmol) were added and the reaction mixture heated for a further 1 hour at 15O0C. The reaction mixture was then partitioned between water (2OmL) and ethyl acetate (2OmL). The aqueous phase was extracted with ethyl acetate (2OmL) and the combined ethyl acetate extracts were evaporated to dryness. The product was purified by mass-directed automated preparative HPLC (ammonium bicarbonate modifier) to afford the title compound (46mg, 0.09mmol, 36%). LCMS (Method B): Rt 2.48minutes; m/z 498 (MH+).

Reference： [1]Patent: WO2010/106016,2010,A1 .Location in patent: Page/Page column 185-186

23
[ 552846-17-0 ]
[ 1244027-95-9 ]
[ 1244027-12-0 ]

Yield	Reaction Conditions	Operation in experiment
47%	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;	A mixture of 6-bromo-l,2, 2, 7-tetramethyl-2, 3- dihydrothieno [3, 2-d] pyrimidin-4 (IH) -one (145 mg, 0.50 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - pyrazole-1-carboxylate (441 mg, 1.50 mmol), cesium carbonate (815 mg, 2.50 mmol), 1, 2-dimethoxyethane (5 mL) and water (1.25 mL) was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 900C overnight. The mixture was poured into water (100 mL) and EtOAc (100 mL) . The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 80:20 EtOAc/MeOH) , then triturated with EtOAc/hexane . The solid was collected by filtration to afford the title compound (65.2 mg, 47%) as a white solid: 1H NMR (300 MHz, DMSO-d6) 6 1.39 (6H, s) , 2.15 (3H, s) , 2.57 (3H, s), 7.70 (IH, s), 7.76 (IH, br s) , 8.09 (IH, br s) , 13.21 (IH, br s) .

Reference： [1]Patent: WO2010/101302,2010,A1 .Location in patent: Page/Page column 225

24
[ 552846-17-0 ]
[ 1257089-99-8 ]
[ 1257090-00-8 ]

Yield	Reaction Conditions	Operation in experiment
35%	With caesium carbonate;bis(tri-tert-butylphosphine)palladium(0); potassium iodide; In 1,4-dioxane; at 108℃; for 3h;Inert atmosphere; microwave irradiation;	A mixture of (6-Bromo-quinoxalin-2-yl)-(4-fluoro-3-trifluoromethyl-benzyl)-methyl-amine (0.35 g, 1 eq, 0.84 mmol), 1-Boc-4-pyrazole boronic acid pinacol ester (0.3 g, 1.2 eq, 1.01 mmol), caesium carbonate (1.1 g, 4.0 eq, 3.3 mmol) and potassium iodide (0.014 g, 0.1 eq, 0.84 mmol) in 1 ,4-dioxane (15 mL) was degassed at RT under vacuum and then placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert-butylphosphine)palladium(O)) (0.02 g, 0.05 eq, 0.04 mmol) was added at room temperature. The reaction mixture was heated at 1080C in a microwave reactor for 180 min. After completion of the reaction (confirmed by TLC), the organic mixture was diluted with ethyl acetate (325 mL) and washed with water (100 mL x 3) followed by brine (100 mL). The organic solvent was dried and concentrated to give a solid residue.For final purification, column chromatography was used on neutral silica gel of 60-120 mesh size employing a gradient of 1-2% methanol in DCM to elute the title compound (0.15g, 35%).

Reference： [1]Patent: WO2010/136755,2010,A1 .Location in patent: Page/Page column 55; 56

25
[ 552846-17-0 ]
[ 1257090-01-9 ]
[ 1257090-02-0 ]

Yield	Reaction Conditions	Operation in experiment
47%	With caesium carbonate;bis(tri-tert-butylphosphine)palladium(0); potassium iodide; In 1,4-dioxane; at 108℃; for 3h;Inert atmosphere; microwave irradiation;	A mixture of (6-Bromo-quinoxalin-2-yl)-((fi)-1-phenyl-ethyl)-amine (0.42 g, 1 eq, 1.28 mmol), 1-boc-4-pyrazole boronic acid pinacol ester (0.45 g, 1.2 eq, 1.53 mmol), caesium carbonate (1.66 g, 4.0 eq, 5.1 mmol) and potassium iodide (0.021 g, 0.1 eq, 0.13 mmol) in 1 ,4-dioxane (20 mL) was degassed at RT under vacuum and then placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert- butylphosphine)palladium(O)) (0.033 g, 0.05 eq, 0.06 mmol) was added at room temperature. The reaction mixture was heated at 1080C in a microwave reactor for 180 minutes. After completion of the reaction (confirmed by TLC), the reaction mixture was diluted with ethyl acetate (200 mL) and then washed with water (50 mL x 3) and brine (50 mL). The organic layer was dried and concentrated to give the crude product.For final purification, column chromatography was used on neutral silica gel of 60-120 mesh size employing a gradient of 1-3% methanol in DCM to elute the title compound (0.25g, 47%).

Reference： [1]Patent: WO2010/136755,2010,A1 .Location in patent: Page/Page column 59; 60

26
[ 552846-17-0 ]
[ 75-75-2 ]
[ 1261284-28-9 ]
2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine methanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		Example 66Synthesis of 2-(Difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-4-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamineThe compound was synthesized according to Method B.Similarly to Example 50, reaction of tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (WO 2006/021881) gave a mixture of tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-4-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate and tert-butyl 4-[4-[6-[(tert-butoxycarbonyl)amino]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-pyrazole-1-carboxylate. Deprotection of the mixture with CH2Cl2/TFA for 20 hrs at 20 C. gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1H-pyrazol-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylamine, which was treated with methanesulfonic acid in MeOH, to give the methanesulfonate salt in 50% overall yield: mp (MeOH/EtOAc)>300 C.; 1H NMR (DMSO-d6) delta 8.48 (s, 2H), 7.88 (br s, 1H), 7.79 (t, Jj=52.9 Hz, 1H), 6.76 (br d, J=1.3 Hz, 1H), 4.01 (m, 2H), 3.99 (s, 3H), 3.87 (m, 2H), 3.76 (m, 4H), 2.34 (s, 3H); Anal. Calcd. for C20H23F2N9O5S: C, 44.5; H, 4.3; N, 23.4. Found: C, 44.5: H, 4.5; N, 23.1%.

Reference： [1]Patent: US2011/9405,2011,A1 .Location in patent: Page/Page column 66

27
8-(6-iodo-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-isopropylamino-propyl)adenine [ No CAS ]
[ 552846-17-0 ]
[ 1289543-86-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	With water; sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere;	8-(6-(lH-pyrazol-4-yl)benzo [d] [1,3] dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H- purin-6-amine [DZ3-30].; l-Boc-pyrazole-4-boronic acid pinacol ester (25.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHC03 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then ¾0 (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 2:2:1 :0.5) to give 13.7 mg (53%) of DZ3-30. 1H NMR (500 MHz, CDCl3/MeOH-<¾ delta 8.17 (s, IH), 7.58 (s, 2H), 7.10 (s, IH), 6.95 (s, IH), 6.06 (s, 2H), 4.08 (t, J= 6.9 Hz, 2H), 2.89 (septet, J= 6.4 Hz, IH), 2.57 (t, J= 7.2 Hz, 2H), 1.91 (m, 2H), 1.14 (d, J = 6.4 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-<¾ delta 154.0, 152.1, 151.2, 149.7, 148.9, 147.5, 133.6, 132.0, 119.8, 119.1, 117.9, 115.3, 110.9, 102.1, 49.2, 42.9, 40.8, 28.3, 21.3; HRMS (ESI) m/z [M+H]+ calcd. for C2iH25N802S, 453.1821; found 453.1819; HPLC: method A Rt = 5.60, method B Rt = 4.87.

Reference： [1]Patent: WO2011/44394,2011,A1 .Location in patent: Page/Page column 84-85
[2]Heterocycles,2013,vol. 87,p. 91 - 113

28
PU-DZ₁₃ [ No CAS ]
[ 552846-17-0 ]
[ 1289544-00-8 ]

Yield	Reaction Conditions	Operation in experiment
40%	With water; sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;	8-((6-(lH-pyrazol-4-yl)benzo[d\|[l,3]dioxol-5-yl)methyl)-2-nuoro-9-(2- (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-32].; l-Boc-pyrazole-4-boronic acid pinacol ester (25.8 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHC03 (14.7 mg, 0.1755 mmol). DMF (1.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.15 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH-NH3 (7N), 2:2:1 :0.5) to give 10.6 mg (40%) of DZ3-32. 1H NMR (500 MHz, CDCl3/MeOH-^) delta 7.50 (s, 2H), 6.83 (s, lH), 6.69 (s, 1H), 5.98 (s, 2H), 4.18 (s, 2H), 4.01 (t, J= 6.6 Hz, 2H), 2.78 (t, J= 6.6 Hz, 2H), 2.40 (d, J= 7.0 Hz, 2H), 1.71 (m, 1H), 0.88 (d, J= 6.7 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-<¾ delta 158.6 (d, J= 208.3 Hz), 156.3 (d, J= 19.6 Hz), 152.3, 152.1 (d, J= 21.2 Hz), 147.3, 147.1, 126.4, 126.2, 120.1, 115.8, 110.7, 109.9, 101.4, 56.3, 47.3, 40.8, 31.9, 27.0, 20.0; HRMS (ESI) m/z [M+H]+ calcd. for C22H26FN802, 453.2163; found 453.2162; HPLC: method A Rt = 6.23, method B Rt = 6.55.

Reference： [1]Patent: WO2011/44394,2011,A1 .Location in patent: Page/Page column 92-93

29
[ 552846-17-0 ]
[ 1121058-16-9 ]
[ 1121057-56-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 0.333333h;Inert atmosphere;	DMF (155 mL) was added under argon to a mixture of methyl 6-bromo-8- (trifluoromethyl)imidazo[1 ,2-a]pyndine-2-carboxylate {5 g, 15.47 mmol), 4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazole-1 -carboxylic acid tert-butyl ester (22.75 g, 77.40 mmol), tetrakis(triphenylphosphine)palladium(0) (1.79 g, 1.55 mmol), and cesium carbonate (50.4 g, 155 mmol). The reaction was heated to 80 C for 20 minutes. After cooling in a water bath, the solvent was removed in~vacuo. To the resulting residue was added H20 and diethyl ether and the mixture was sonicated for 30 minutes. The precipitate was filtered and washed successively with H20 and diethyl ether, and then air dried to obtain the title compound (5.61 g, 90%) as a beige solid. ES-LCMS m/z: 410.9 (M+1 ).

Reference： [1]Patent: WO2011/41713,2011,A2 .Location in patent: Page/Page column 143

30
[ 552846-17-0 ]
[ 1334167-41-7 ]
[ 1334167-18-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; triphenylphosphine;palladium diacetate; In 1,4-dioxane; water; at 80℃; for 18h;Inert atmosphere;	Palladium (II) acetate (0.026 g, 0.011 mmol) and a 1.5 M solution of potassium carbonate (4.2 ml, 6.31 mmol) were added to a stirred solution of intermediate 27 (0.5 g, 1.68 mmol), commercially available 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- pyrazole-l-carboxylic acid tert-butyl ester (0.99 g, 3.37 mmol) and triphenylphosphine (44 mg, 0.17 mmol) in 1,4-dioxane (9 ml). The mixture was stirred at 80 C for 18 h. under nitrogen and the solid formed was filtered off and the filtrate evaporated. The crude product was purified by flash column chromatography (silica; EtOAc). The desired fractions were collected, evaporated in vacuo and combined with the solid previously obtained to yield compound 142 (0.39 g, 81%) as a solid.
81%	With potassium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; at 80℃; for 18h;Inert atmosphere;	Example B142 2-Methyl-8-morpholin-4-yl-3-(1H-pyrazol-4-yl)-imidazo[1,2-a]pyrazine Palladium (II) acetate (0.026 g, 0.011 mmol) and a 1.5 M solution of potassium carbonate (4.2 ml, 6.31 mmol) were added to a stirred solution of intermediate 27 (0.5 g, 1.68 mmol), commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (0.99 g, 3.37 mmol) and triphenylphosphine (44 mg, 0.17 mmol) in 1,4-dioxane (9 ml). The mixture was stirred at 80 C. for 18 h. under nitrogen and the solid formed was filtered off and the filtrate evaporated. The crude product was purified by flash column chromatography (silica; EtOAc). The desired fractions were collected, evaporated in vacuo and combined with the solid previously obtained to yield compound 142 (0.39 g, 81%) as a solid.

Reference： [1]Patent: WO2011/110545,2011,A1 .Location in patent: Page/Page column 119
[2]Patent: US2012/329792,2012,A1 .Location in patent: Page/Page column 59
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 4196 - 4212

31
[ 552846-17-0 ]
trans-4-({6-[(6-bromo-1,3-benzothiazol-2-yl)amino]-4-[(2-methyl-1H-imidazol-1-yl)methyl]-2-pyridinyl}amino)cyclohexanol [ No CAS ]
trans-4-[(4-[(2-methyl-1H-imidazol-1-yl)methyl]-6-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]amino}-2-pyridinyl)amino]cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With water; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 130℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 83:trans-4-[(4-[(2-methyl-1 H-imidazol-1 -yl)methyl]-6-[6-(1 H-pyrazol-4-yl)-1 ,3- benzothiazol-2-yl]amino}-2-pyridinyl)amino]cyclohexanolA mixture of trans-4-({6-[(6-bromo-1 ,3-benzothiazol-2-yl)amino]-4-[(2-methyl-1 H-imidazol-1-yl)methyl]-2-pyridinyl}amino)cyclohexanol [example 79] (100mg, 0.20mmol), tetrakis(triphenylphosphine)palladium(0) (67.5mg, 0.06mmol), caesium carbonate(190mg, 0.58mmol) and 1 ,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole-1-carboxylate (143mg, 0.49mmol) in a mixture of DMF (4ml_) and water (1.3ml_) was sealed and heated in a Biotage "Initiator" microwave at 130C for 30 minutes. The reaction mixture was added to a mixture of dichloromethane (50ml_) and water (50ml_). After stirring for 15 minutes, the mixture was filtered and the recovered solid was washed with water and dried. The solid was dissolved in DMSO (2ml_) and the product was subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (98mg, 0.20mmol, 79% yield). LCMS (Method A): Rt 0.58 minutes; m/z 501 (MH+)

Reference： [1]Patent: WO2011/110575,2011,A1 .Location in patent: Page/Page column 118

32
[ 552846-17-0 ]
trans-4-[6-[(6-bromo-1,3-benzothiazol-2-yl)amino]-4-(hydroxymethyl)-2-pyridinyl]amino}cyclohexanol [ No CAS ]
trans-4-[(4-(hydroxymethyl)-6-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]amino}-2-pyridinyl)amino]cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With water; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 105:frans-4-[(4-(hydroxymethyl)-6-[6-(1 H-pyrazol-4-yl)-1 ,3-benzothiazol-2-yl]amino}-2- pyridinyl)amino]cyclohexanolA mixture of 1 ,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole-1-carboxylate (380mg, 1.29mmol), trans-4-[6-[(6-bromo-1 ,3-benzothiazol-2- yl)amino]-4-(hydroxymethyl)-2-pyridinyl]amino}cyclohexanol [example 104] (580mg, 1.29mmol), caesium carbonate (1 .26g, 3.87mmol) and tetrakis(triphenylphosphine)- palladium(O) (447mg, 0.387mmol) in Nu,Nu-dimethylformamide (6mL) and water (2ml_) was sealed and heated in a Biotage "Initiator" microwave at 150C for 30 minutes. The cooled reaction mixture was taken up in water (20ml_) and ethyl acetate (20ml_) and filtered. The filtrate was separated and the aqueous phase was extracted with ethyl acetate (50ml_). The organic extracts were combined and evaporated to dryness and the residue was subjected to purification by mass directed automated preparative HPLC (formic acid modifier) to afford the title compound (273mg, 0.63mmol, 49% yield). LCMS (Method A): Rt 0.60 minutes; m/z 437 (MH+).

Reference： [1]Patent: WO2011/110575,2011,A1 .Location in patent: Page/Page column 128-129

33
[ 552846-17-0 ]
trans-4-({6-[(6-bromo-1,3-benzothiazol-2-yl)amino]-2-pyridinyl}amino)cyclohexanol [ No CAS ]
trans-4-[(6-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]amino}-2-pyridinyl)amino]cyclohexanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With water; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 140 - 150℃; for 2.25h;Sealed tube; Microwave irradiation;	Example 8:trans-4-[(6-[6-(1 H-pyrazol-4-yl)-1 ,3-benzothiazol-2-yl]amino}-2- pyridinyl)amino]cyclohexanolA mixture of trans-4-({6-[(6-bromo-1 ,3-benzothiazol-2-yl)amino]-2- pyridinyl}amino)cyclohexanol [example 3] (162mg, 0.39mmol), 1 ,1-dimethylethyl 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1-carboxylate (250mg, 0.85mmol), tetrakis(triphenylphosphine)palladium(0) (22.8mg, 0.02mmol) and caesium carbonate (335mg, 1 .028mmol) in 1 ,4-dioxane (2.4mL) and water (0.6mL) was sealed and heated in a Biotage "Initiator" microwave at 140C for 1 hour. Additional 1 ,1 -dimethylethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1 -carboxylate (200mg) and tetrakis(triphenylphosphine)palladium(0) (10mg) were added and the mixture was heated at 150C for a further 75 minutes. The reaction mixture was then added to a mixture of dichloromethane (+10% methanol) (50mL) and water (30mL). The organic phase was collected, evaporated to dryness and the residue was subjected to purification by mass- directed automated preparative HPLC (formic acid modifier) to afford the title compound (69mg, 0.17mmol, 44% yield). LCMS (Method A): Rt 0.69 minutes; m/z 407 (MH+)

Reference： [1]Patent: WO2011/110575,2011,A1 .Location in patent: Page/Page column 91

34
[ 552846-17-0 ]
[ 1346245-20-2 ]
[ 1346245-21-3 ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	A mixture of intermediate 19 (3g; 8.1 mmol), 1 -Boc-pyrazole-4-boronic acid pinacol ester (2.86g; 9.7mmol), potassium phosphate (3.44g; 16.2mmol), 2-dicyclohexylphosphino- 2',6'-dimethoxybiphenyl (0.33g; 0.81 1 mmol) in dioxane (60ml_) and H20 (6mL) was stirred at room temperature under N2 flow. After 10 minutes,tris(dibenzylideneacetone)dipalladium (0.3g; 0.41 mmol) was added portionwise at room temperature and the mixture was heated at 80C overnight .The reaction mixture was cooled to room temperature and poured out into ice water. EtOAc was added and the mixture was filtered through a layer of celite. The celite was washed with EtOAc, then the filtrate was extracted with EtOAc, washed with brine, dried (MgS04), filtered and the solvent was evaporated. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-40muGammaeta , 300g MERCK; mobile phase 0.05% NH4OH, 99% DCM, 1 % iPrOH). The pure fractions were collected and evaporated to dryness, yielding 1 .48g (36%) of intermediate 20.

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 202

35
[ 552846-17-0 ]
[ 1351166-16-9 ]
[ 1351166-43-2 ]

Yield	Reaction Conditions	Operation in experiment
42%	With water; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃;Inert atmosphere; Sealed tube;	Example 31(S)-l-(l-(5-(l H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)-3 -(2-fluoro-4- (methylsulfonyl)phenylamino)pyrrolidin-2-one[00410] (S)-l-(l -(5-Bromopyrimidin-2-yl)piperidin-4-yl)-3 -(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (Example 7; 0.090 g, 0.17 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (0.057 g, 0.19 mmol), Pd(PPh3)4 (0.020 g, 0.018 mmol) and Na2C03 (0.44 mL, 0.88 mmol) were suspended in dioxane in a sealed tube and stirred at 110 C overnight. The material was cooled and filtered through silica gel (10% MeOH/EtOAc). The material was purified by reverse phase HPLC purification (5 to 95% acetonitrile in water) to give (S)-l-(l-(5-(lH-pyrazol-4- yl)pyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2- one (0.037 g, 42% yield) as a white solid. Mass spectrum (apci) m/z = 500.3 (M+H).

Reference： [1]Patent: WO2011/146335,2011,A1 .Location in patent: Page/Page column 76-77

36
[ 552846-17-0 ]
[ 1350426-11-7 ]
[ 1350426-12-8 ]

Yield	Reaction Conditions	Operation in experiment
97%		To a solution of intermediate 30 (0.20 g, 0.608 mmol) and 1-tert- butoxycarbonyl- lH-pyrazole-4-boronic acid pinacol ester (0.229 g, 0.778 mmol) in dioxane (4 ml), potassium carbonate (0.279 g, 2.02 mmol) and water (0.8 ml) were added and degassed for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.047 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and to the residue water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford the crude pyrazole compound as a yellow solid (0.219 g). To a solution of this intermediate in cone. HC1 (3 ml), stannous chloride (0.750 g, 18.13 mmol) was added at RT and stirred for 5h. The reaction mixture was poured into ice water and pH adjusted to 7-8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated to afford the title compound as yellow solid (0.194 g, 97% ) which was used as such for the next step.

Reference： [1]Patent: WO2011/145035,2011,A1 .Location in patent: Page/Page column 118-119

37
[ 233770-01-9 ]
[ 552846-17-0 ]
[ 1086066-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	With water; sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;	5 g of <strong>[233770-01-9]3-bromo-5-iodopyridine</strong> and 5.4 g of 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxa- borolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester is added to 1.78 g of sodium bicarbonate in 300 ml of DMF and 150 ml of water. The mixture is heated under nitrogen to 80C and then 1.11 g of bis(triphenylphosphin)-palladium(ll)-chloride is added. The mixture is stirred over night. After cooling the reaction mixture is evaporated. The residue is partitioned between ethyl acetate and water. The organic phase is dried, filtrated and evaporated. The product is purified by chromatography. 2.55 g of 3-bromo-5-(1 H-pyrazol-4-yl)-pyridine is obtained;HPLC- S: 1.63 min, [M+H] 226
2.55 g	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 80℃;Inert atmosphere;	1. 1.5 g of <strong>[233770-01-9]3-bromo-5-iodopyridine</strong> and 5.4 g of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester is added to 1.78 g of sodium bicarbonate in 300 ml of DMF and 150 ml of water. The mixture is heated under nitrogen to 80 C. and then 1.11 g of bis(triphenylphosphin)-palladium(II)-chloride is added. The mixture is stirred over night. After cooling the reaction mixture is evaporated. The residue is partitioned between ethyl acetate and water. The organic phase is dried, filtrated and evaporated. The product is purified by chromatography. 2.55 g of 3-bromo-5-(1H-pyrazol-4-yl)-pyridine is obtained; HPLC-MS: 1.63 min, [M+H] 226

Reference： [1]Patent: WO2012/3912,2012,A1 .Location in patent: Page/Page column 67
[2]Patent: US2013/102608,2013,A1 .Location in patent: Paragraph 0.314; 0315

38
[ 552846-17-0 ]
[ 1211533-83-3 ]
[ 1375711-74-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Sealed tube;	Example 56a tert-Butyl 4-(6-amino-2-methoxy-3-pyridyl)pyrazole-1-carboxylate PdCl2(PPh3)2 (0.18 g, 0.25 mmol) was added to a degassed mixture of 5-bromo-6-methoxy-pyridin-2-ylamine (Example 7b, 1.0 g, 4.02 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (CAS 552846-17-0, 2.17 g, 7.39 mmol) and K2CO3 (1.02 g, 7.39 mmol) in a mixture of DME and water (6:2, 140 mL). The reaction mixture was heated in a sealed tube at 90 C. overnight, cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography using a gradient of 0 to 50% EtOAc in hexane to afford 1.2 g (84%) of the title compound. 1H NMR (400 MHz, CDCl3) delta ppm 1.24 (s, 9H) 3.97 (s, 3H) 4.36 (br. s., 2H) 6.14 (d, 1H) 7.59 (d, 1H) 8.01 (s, 1H) 8.37 (s, 1H).

Reference： [1]Patent: US2012/122843,2012,A1 .Location in patent: Page/Page column 55-56

39
[ 552846-17-0 ]
[ 1222791-66-3 ]
[ 1222886-16-9 ]

Yield	Reaction Conditions	Operation in experiment
21%	With water; sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 80℃; under 760.051 Torr;	b. EXAMPLE 2: 2-((1-(3-(1H-PYRAZOL-4-YL)BENZYL)-4,6-DIFLUORO-1H- INDOL-3-YL)SULFONYL)- -(5-METHYLISOXAZOL-3-YL)ACETAMIDE; [00437] Step E. 2-((l-(3-(lH-pvrazol-4-vl)benzvl)-4,6-difluoro-lH-indol-3-vl)sulfonyl)-N- (5-methylisoxazol-3-yl)acetamide. In a 5 mL microwave vial, 2-((l-(3-bromobenzyl)-4,6- difluoro-lH-indol-3-yl)sulfonyl)-N-(5-methyl-isoxazol-3-yl)acetamide ( 20 mg, 0.38 mmol), prepared in Example 1, was dissolved in DMF (2 mL). PdCl2(PPh3)2 (1.0 mg, 0.001 mmol), l-Boc-pyrazole-4-boronic acid pinacol ester (20 mg, 0.68 mmol), and 2 N aqueous sodium carbonate (1 mL) were added and stirred at 80 C overnight. The reaction was cooled to ambient temperature. Water (2 mL) was added and the mixture was extracted with ethyl acetate (2x3mL). The organics were combined, dried over magnesium sulfate andconcentrated in vacuo to give an oily residue which was purified on a Gilson Prep HPLC system (5-95% acetonitrile: water (0.1% TFA) over 6 min) to afford the title compound (4.0 mg, 0.008 mmol, 21% yield) as a white solid. LCMS >98% 220 nm, RT = 0.79 min, m/z = 512 (m+1). 1H NMR (400 MHz, DMSOD6) 12.97 (s, 1H), 11.33 (s, 1H), 8.38 (s, 1H), 8.16, (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.49-7.55 (m, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 10.8 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.48 (s, 1H), 5.52 (s, 2H), 4.48 (s, 2H), 2.35 (s, 3H).

Reference： [1]Patent: WO2011/163280,2011,A1 .Location in patent: Page/Page column 244

40
[ 552846-17-0 ]
[ 1330595-61-3 ]
[ 1400874-20-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; for 18h;	a solution of 48 (500mg, 1.61mmol) in degassed dioxane (10mL) was treated with PdCl2(dppf) (0.2equiv, 0.32mmol, 263mg), 1-N-Boc-pyrazole-4-boronic acid pinacol ester (3equiv, 4.84mmol, 1.42g) and Cs2CO3 (4equiv, 6.45mmol, 2.10g) and stirred at 90C for 18h. Concentration in vacuo directly onto silica and flash column chromatography (2-22% 2M NH3/MeOH in CH2Cl2) gave intermediate 15 (R=Me) (378mg, 79%) as a pale brown gum; 1H NMR (400MHz, DMSO-d6) 8.34 (br s, 1H), 8.13 (br s, 1H), 7.69 (s, 1H), 7.68 (d, J=9.6Hz, 1H), 6.96 (d, J=6.9Hz, 1H), 6.61 (d, J=9.6Hz, 1H), 3.70-3.60 (m, 1H), 2.83-2.77 (m, 2H), 2.21 (s, 3H), 2.12-2.04 (m, 4H), 1.55-1.45 (m, 2H); LC-MS (ES+APCI) 298 ([M+H]+, 100%); a solution of this intermediate (62mg, 0.21mmol) in anhydrous DMF (1mL) containing 1-fluoro-3-iodobenzene (1.1equiv, 0.23mmol, 0.027mL), CuI (0.3equiv, 0.065mmol, 12mg) and Cs2CO3 (2.5equiv, 0.52mmol, 170mg) was stirred under nitrogen at 120C for 18h. The solvent was removed in vacuo and the residue passed through a metal removal cartridge (PolymerLabs, PL-Thiol, 500mg), eluting with 3 column volumes of methanol. Concentration in vacuo and purification by preparative LC-MS gave 17 (30mg, 36%) as an off-white solid;
71%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90℃; for 18h;	a) /V-(1-Methylpiperidin-4-yl)-3- 1H-pyrazol-4-y.)imidazo[1 ,2-b]pyridazin-6-amineA solution of intermediate 6 (1.21 g, 3.92 mmol), PdCI2(dppf) (640 mg, 0.78 mmol, 0.2 eq), 1-boc-pyrazole-4-boronic acid pinacol ester (3.44 g, 11.7 mmol, 3 eq) and Cs2C03 (5.08 g, 15.6 mmol, 4 eq) in degassed dioxane (20 mL) was stirred at 90C for 18 h. Concentration in vacuo directly onto silica and purification by chromatography on silica gel (2-22% 2M NH3/MeOH in EtOAc) afforded a pale brown solid (821 mg, 71 %); 1H NMR (400 MHz, DMSO-d6) delta ppm 8.34 (br. s, 1 H), 8.13 (br. s, 1 H), 7.69 (s, 1 H), 7.68 (d, J=9.6 Hz, 1 H), 6.95 (br. d, J=6.9 Hz, 1 H), 6.61 (d, J=9.6 Hz, 1 H), 3.69-3.60 (m, 1 H), 2.82-2.77 (m, 2H), 2.22 (s, 3H), 2.13-2.05 (m, 4H), 1.55-1.46 (m, 2H); m/z (ES+APCIf : 298 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6019 - 6024
[2]Patent: WO2012/127212,2012,A1 .Location in patent: Page/Page column 129-130

41
[ 552846-17-0 ]
[ 26340-49-8 ]
[ 1416576-73-2 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 123 - 149

42
[ 552846-17-0 ]
[ 1427594-89-5 ]
[ 1427594-90-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With bis(tri-t-butylphosphine)palladium(0); caesium carbonate; In 1,4-dioxane; water; at 50℃;	A mixture of Intermediate (55.1 ) (280.00 mg; 0.51 mmol; 1 .00 eq.), 4-(4,4,5,5- Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazole-1 -carboxylic acid tert-butyl ester (226.93 mg; 0.77 mmol; 1 .50 eq.) and cesium carbonate (335 mg, 1 .03 mmol, 2.0 eq.) in dioxane (3 ml) and water (0.25 ml) was degas, and then bis(tri-t- butylphosphine)palladium(O) (39.43 mg; 0.08 mmol; 0.15 eq.) added. The resulting mixture was stirred at 50 C overnight. The reaction mixture was worked up and purified by SNAP column, eluated with 0-10% mthanol in DCM to give tert-butyl 4-(4- amino-6-(4-(2-((tert-butoxycarbonyl)amino)-1 -(4-(trifluoromethyl)phenyl)ethyl)piperidin-1 -yl)pyrimidin-5-yl)-1 H-pyrazole-1 -carboxylate (280mg, yield 86%), which was added 4 ml of methanol and 3ml of 4.0M HCI in dioxane and stirred at RT for 3hr. The reaction mixture was concentrated to afford the title compound in quantitative yield. LC-MS: (M+1 =432, obsd. = 432).

Reference： [1]Patent: WO2013/40044,2013,A1 .Location in patent: Page/Page column 55

43
[ 552846-17-0 ]
[ 1187932-25-7 ]
[ 1466528-30-2 ]

Yield	Reaction Conditions	Operation in experiment
74.5%		To a degassed solution of Intermediate 1 1A (3.00 g, 9.99 mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (4.410 g, 14.99 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in dioxane (20 mL)/water (8 mL) was added Tetrakis (0.577 g, 0.500 mmol). The vial was purged with argon, sealed and stirred at 90 C for 16 h. Another 20% of tetrakis and boronic ester were added and the reaction mixture was degassed and heated at 90 C for 24 h. The reaction was cooled down to rt and NaOH (14.99 mL, 14.99 mmol) was added and the reaction was stirred at 50 C for 5 h. The mixture was partitioned between EtOAc and water. The organic layer was separated. The aqueous phase was extracted with EtOAc, and the combined organic layers were dried over MgS04 and concentrated in vacuo. The crude material was purified by flash chromatography over 120 g of silica gel (15 min gradient, with 0-100% ethyl acetate in hexanes) to afford Intermediate 1 IB (2.14 g, 7.45 mmol, 74.5% yield) as a white solid. LCMS = 1.86 min [M+l] = 288.2 (Method B).

Reference： [1]Patent: WO2013/151923,2013,A1 .Location in patent: Paragraph 00190

44
[ 552846-17-0 ]
[ 41404-58-4 ]
[ 1381971-92-1 ]

Yield	Reaction Conditions	Operation in experiment
56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 20 - 90℃; for 48h;	A 2 mol/L aqueous Na2CO3 solution (45.2 g, 426.2 mmol) andPd(PPh3)4 (4.93 g, 4.26 mmol) were added to a solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (46.0 g, 156.3 mmol) and 2-bromo-5-fluoropyridine(25.0 g, 142.1 mmol) in 1,4-dioxane (284 mL). The mixture wasthen stirred in an oil bath with a temperature of 90 C for 4 h. Next,the mixture was stirred at room temperature for 2 days. Brine wasadded to the reaction mixture, followed by extraction with EtOAc.The organic layer was dried over Na2SO4, and the desiccant was filteredoff. Then, the solvent was distilled off under reduced pressure.EtOAc was added to the obtained residue, and the deposited solidwas collected by filtration to obtain the title compound 11 as a colorlesspowder (13.0 g, 56%).
0.66 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 20 - 90℃;	Reference Example 5 5-Fluoro-2-(1H-pyrazol-4-yl)pyridine A 2 mol/L aqueous Na2CO3 solution (8.5 mL, 17.1 mmol) and Pd(PPh3)4 (0.20 g, 0.17 mmol) were added to a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.8 g, 6.3 mmol) and 2-bromo-5-fluoropyridine (1.0 g, 5.7 mmol) in 1,4-dioxane (11 mL), and the mixture was stirred in an oil bath with a temperature of 90 C. for 4 hours. Then, the mixture was stirred at room temperature for 2 days. Brine was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was dried over Na2SO4, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. EtOAc was added to the obtained residue, and the deposited solid was collected by filtration to obtain the title compound (0.66 g) (colorless solid). MS (ESI pos.) m/z: 164 [M+H]+
4.9 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 20 - 100℃; for 75h;	To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (15.4 g,52.5 mmol) and 2-bromo-5-fluoropyridine (8.40 g, 47.7 mmol) in 1,4-dioxane (100 mL), Pd(PPh3)4 (5.52 g, 4.77 mmol)and a 2M aqueous solution of Na2CO3 (71.6 mL, 143.2 mmol) were added, then the resulting mixture was stirred at100C for 3 hours and then at room temperature for 72 hours. Water was added to the reaction mixture, followed byextraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, then the drying agent was filteredoff, and then the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the obtainedresidue and the resulting mixture was filtered out and dried to obtain the title compound (4.9 g) (colorless solid).MS (ESI pos.) m/z: 164 [M+H]+

4.9 g

With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 20 - 100℃; for 75h;

Reference Example 11: 5-Fluoro-2-(1H-pyrazol-4-yl)pyridine To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (15.4 g, 52.5 mmol) and 2-bromo-5-fluoropyridine (8.4 g, 47.7 mmol) in 1,4-dioxane (100 mL), Pd(PPh3)4 (5.5 g, 4.77 mmol) and a 2M aqueous solution of Na2CO3 (71.6 mL, 0.14 mol) were added, then the resulting mixture was stirred at 100C for 3 hours and then at room temperature for 72 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the obtained residue and the resulting mixture was filtered out and dried to obtain the title compound (4.9 g) (colorless solid). MS (ESI pos.) m/z: 164 [M+H]+

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 1260 - 1275
[2]Patent: US2013/281465,2013,A1 .Location in patent: Paragraph 0138; 0139; 0140
[3]Patent: EP2862855,2015,A1 .Location in patent: Paragraph 0063; 0064
[4]Patent: EP2862860,2015,A1 .Location in patent: Paragraph 0060; 0061

45
[ 552846-17-0 ]
4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide [ No CAS ]
3-chloro-4-(2-cyano-3-(1H-pyrazol-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With tetrakis(triphenylphosphine) palladium(0); water; sodium carbonate; In 1,4-dioxane; at 90℃; for 12h;Inert atmosphere;	3-chloro-4-(2-cyano-3- ( lH-pyrazol-4-yl)phenoxy)-N- ( (2-hydroxy-4, 6-dimethyl pyridin-3-yl)methyl)benzamide. (Compound 1-5). To a solution of 4-(3-bromo-2-cyanophenoxy)- 3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl) methyl)benzamide (500 mg, 1.03 mmol), tert- butyl4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (323 mg, 1.1 mmol), sodium carbonate (425 mg, 3.07 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1 mmol). The reaction mixture was stirred at 90C under nitrogen atmosphere for 12 hours. After the reaction, it was allowed to cool to room temperature, and concentrated in vacuo, then diluted with ethyl acetate, washed with water. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol = 20: 1) to give the pure product 3-chloro- 4-(2-cyano-3-(lH-pyrazol-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3- yl)methyl)benzamide (331 mg, 68 %). LRMS (M + H+) m/z: calcd 473.13; found 473. 1H NMR (300 MHz, /-DMSO): delta 13.33 (s, IH), 11.48 (s, IH), 8.53 (t, J= 4.8 Hz, IH), 8.35 (s, IH), 8.15 (s, IH), 8.07 (s, IH), 7.90 (d, J= 6.9 Hz, IH), 7.61 (t, J= 8.1 Hz, IH), 7.51 (d, J= 7.8 Hz, IH), 7.32 (d, J= 8.4 Hz, IH), 6.74 (d, J= 8.1 Hz, IH), 5.86 (s, IH), 4.29 (d, J= 4.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).
68%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 12h;Inert atmosphere;	To a solution of 4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (500 mg, 1.03 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (323 mg, 1.1 mmol), sodium carbonate (425 mg, 3.07 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1 mmol). The reaction mixture was stirred at 90 C. under nitrogen atmosphere for 12 hours. After the reaction, it was allowed to cool to room temperature, and concentrated in vacuo, then diluted with ethyl acetate, washed with water. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give the pure product 3-chloro-4-(2-cyano-3-(1H-pyrazol-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (331 mg, 68%). LRMS (M+H+) m/z: calcd 473.13. found 473. 1H NMR (300 MHz, d6-DMSO): delta 13.33 (s, 1H), 11.48 (s, 1H), 8.53 (t, J=4.8 Hz, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.90 (d, J=6.9 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 5.86 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H).

Reference： [1]Patent: WO2013/75083,2013,A1 .Location in patent: Paragraph 00193; 00195
[2]Patent: US9206128,2015,B2 .Location in patent: Page/Page column 111; 112

46
[ 552846-17-0 ]
[ 52488-28-5 ]
4-(3-methyl-5-nitrophenyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;	Preparative Example 1.47 3-Methyl-5-(l-(2-methylallyl)-lH-pyrazol-4-yl)aniline Step 1 : tert-Butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l- carboxylate (8.17 g, 27.8 mmol), te?raHs(triphenylphosphine)palladium(0) (2.67 g, 2.31 mmol) and potassium carbonate (12.8 g, 93.0 mmol) were added to a solution of l-bromo-3-methyl-5- nitrobenzene (5.0 g, 23.1 mmol) in dioxane (7.5 mL). The mixture was degassed with nitrogen for 5 minutes and stirred at 100C for 18 h. The mixture was passed through CELITE, washed with methanol and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/Hexane) to afford 4-(3-methyl-5-nitrophenyl)-lH- pyrazole. MS ESI calc'd. for CioH10 302 [M+H]+ 204, found 204.

Reference： [1]Patent: WO2013/192125,2013,A1 .Location in patent: Page/Page column 95

47
[ 630125-49-4 ]
[ 552846-17-0 ]
[ 1529769-65-0 ]

Yield	Reaction Conditions	Operation in experiment
80.9%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;	Add l-bromo-3-nitro-5-(trifluoromethyl)benzene (0.165 g, 0.61 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-l-carboxylate (0.18 g, 0.61 mmol), sodium acetate (0.1 g, 1.2 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (22 mg, 0.03 mmol) to 1 ,4-dioxane (15 mL) and water (2 mL). Stir the mixture at 100C under N2 for 6 hrs. TLC (EtOAc:PE=l : l) shows that the reaction is complete. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=l :1) affords the title compound (0.17 g, 80.9%). MS: (M+l): 358.2.
80.9%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium acetate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;	Add <strong>[630125-49-4]1-bromo-3-nitro-5-(trifluoromethyl)benzene</strong> (0.165 g, 0.61 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (0.18 g, 0.61 mmol), sodium acetate (0.1 g, 1.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (22 mg, 0.03 mmol) to 1,4-dioxane (15 mL) and water (2 mL). Stir the mixture at 100 C. under N2 for 6 hrs. TLC (EtOAc:PE=1:1) shows that the reaction is complete. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (0.17 g, 80.9%). MS: (M+1): 358.2.

Reference： [1]Patent: WO2014/418,2014,A1 .Location in patent: Page/Page column 70; 71
[2]Patent: US2015/197511,2015,A1 .Location in patent: Paragraph 0332

48
[ 552846-17-0 ]
[ 1206800-24-9 ]
[ 1206800-42-1 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 501 - 510

49
[ 552846-17-0 ]
[ 77337-82-7 ]
[ 1610875-70-1 ]

Yield	Reaction Conditions	Operation in experiment
99.41%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;	To a solution of <strong>[77337-82-7]1-bromo-2-methoxy-4-nitro-benzene</strong> (200 mg, 0.86 mmol) in dioxane (160 ml) and H20 (40 ml) were added K2C03 (35?7.4 mg, 2.58 mmol) and the reaction mixture was purgedwith argon for 10 min. [1-(tert-Butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid pinacol ester (380 mg, 1.29 mmol) and Pd(dppf)2C12*DCM (323mg, 0.39mmol) were added to the reaction mixture and purged agam with argon for l0min. The reaction mixture was heated at 80 C for 16 h. Solyent was eyaporated off under reduced pressure, and the resulting crude mass was diluted with water (60 ml), and extracted with DCM (2x80 ml). The combined organie layers were driedoyer anhydrous Na2SO4, filtered, and eyaporated off in yacuo. The resulting crude mass was purified by column chromatography oyer silica gel (50-60% EtOAclhexane) to get 4-(2- methoxy-4-nitro-phenyl)-1H-pyrazole (1.86g, 99.41%) as a green solid (l3Omg, 68. %). MS (mle) = 220.0 (M+H).

Reference： [1]Patent: WO2014/79850,2014,A1 .Location in patent: Page/Page column 135

50
[ 552846-17-0 ]
[ 586-78-7 ]
[ 114474-26-9 ]

Yield	Reaction Conditions	Operation in experiment
99.41%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;	To a solution of 1-bromo-4-nitro-benzene (2 g, 9.90 mmol) in dioxane (160 ml) and water (40 ml) was added potassium carbonate (4.10 mg, 29.70 mmol), and the reaction mixture was purged with argon for 10 min. [1-(tert-Butoxycarbonyl)-1H-pyrazol-4-yl]boronic acid pinacol ester (4.36 g, 14.85 mmol) and Pd(dppf)2C12*CH2Cl2 (323 mg, 0.39 mmol) were added to the reaction mixture and purged again with argon for 10 min. The reaction mixture was heated to 80 C for 16 h. The solvent was evaporated under reduced pressure, and the resulting crude mass was diluted with water (60 ml), and extracted with dichloromethane (2x80 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated off in vacuo. The resulting crude mass was purified by column chromatography (silica gel, 50-60% ethyl acetate/hexane) to get 4-(4-nitrophenyl)-1H-pyrazole (1.86g, 99.41%) as yellow solid. MS: 190.0 (M+H).
12 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Compound Reg-1-16-b (6.8 g, 23.12 mmol) and 1-bromo-4-nitrobenzene (7.0 g, 34.68 mmol) were dissolvedin a mixture of 1,4-dioxane / water (4:1) (200 mL), followed by addition of potassium carbonate (9.58 g, 69.35 mmol)and Pd(dppf)Cl2 (0.9 g, 1.16 mmol). Purge with argon was performed for 3 times, and the reaction was placed in an oilbath at 80C overnight. LC-MS indicated the reaction was complete. The reaction solution was cooled to room temperature,filtered, and concentrated under reduced pressure to afford compound Reg-1-16-c (12 g, brown solid). The crudewas used directly in the next reaction. MS m/z (ESI): 190.1 [M+H].
	With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;	Compound Reg-1-16-b (6.8 g, 23.12 mmol) and 1-bromo-4-nitrobenzene (7.0 g, 34.68 mmol) were dissolved in a mixture of 1,4-dioxane / water (4:1) (200 mL), followed by addition of potassium carbonate (9.58 g, 69.35 mmol) and Pd(dppf)Cl2 (0.9 g, 1.16 mmol). Purge with argon was performed for 3 times, and the reaction was placed in an oil bath at 80C overnight. LC-MS indicated the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to afford compound Reg-1-16-c (12 g, brown solid). The crude was used directly in the next reaction. MS m/z (ESI): 190.1 [M+H].

Reference： [1]Patent: WO2014/79850,2014,A1 .Location in patent: Page/Page column 99
[2]Patent: EP3421465,2019,A1 .Location in patent: Paragraph 0111; 0113
[3]Patent: EP3421464,2019,A1 .Location in patent: Paragraph 0109; 0111

51
[ 552846-17-0 ]
[ 1610875-56-3 ]
[ 1610875-58-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 1h;	In a 25 m round-bottomed fiask, N-(4-bromo-2-(2-morpholinoethoxy)phenyl)-2-(2- chlorophenyl)acetamide (100 mg, 220 imol), tert-butyl 4-(4,4,5 ?5-tetramethyl- 1,3,2- dioxaborolan-2-yl)- 1 H-pyrazole- 1 -carboxylate (?77 .8 mg, 264 imol) and cesium carbonate (86.2mg. 264 imol) were combined with dioxane (10 ml) and water (1.0 ml). Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (32.3 mg, 44.1 imol) was added and the reaction mixture was stirred at 70 C for 1 hour. The reaction mixture was purified by chromatography (silicagel, methanol / dichloromethane = 0:100 to 10:90) to yield tert-butyl 4-(4- (2-(2-chlorophenyl)acetamido)-3- (2-morpholinoethoxy)phenyl)- 1 H-pyrazole- 1 -carboxylate (104mg, 87%) as brown solid. MS: mle = 541.6 [M+H].

Reference： [1]Patent: WO2014/79850,2014,A1 .Location in patent: Page/Page column 121

52
[ 552846-17-0 ]
[ 17100-63-9 ]
[ 1623119-26-5 ]

Yield	Reaction Conditions	Operation in experiment
69%		Intermediate 1A: methyl 3-methoxy-4-(1H-pyrazol-4-yl)benzoate [0251] To a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) in dioxane (30 mL) and water (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.901 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) and PdCl2(dppf) (0.197 g, 0.269 mmol) at RT. The reaction was stirred under argon at 100 C. for 3 hrs. The reaction mixture was diluted with EtOAc, washed with H2O. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (10 mL) and TFA (5 mL) was added. The reaction was stirred at RT for 1.5 hrs. Solvent was removed. The residue was taken into EtOAc, which was washed with NaHCO3 (3×) and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. Desired product was isolated as white solid (0.86 g, 69% yield). LCMS (ESI) m/z: 233.0 (M+H)+; 1H NMR (400 MHz, CDCl3) delta 8.13 (s, 2H), 7.73-7.66 (m, 1H), 7.66-7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).
69%		To a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) in dioxane (30 mL) and water (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.90 1 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) and PdC12(dppf) (0.197 g, 0.269 mmol) at rt. The reaction was stirred under argon at 100 C for 3 hrs. The reaction mixture was diluted with EtOAc, washed with H20. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (10 mL) and TFA (5 mL) wasadded. The reaction was stirred at rt for 1.5 hrs. Solvent was removed. The residue was taken into EtOAc, which was washed with NaHCO3 (3x) and brine, dried over Na2504, filtered and concentrated. The crude product was purified by normal phase chromatography. Desired product was isolated as white solid (0.86 g, 69% yield).LCMS(ESI) m/z: 233.0 (M+H) ?H NMR (400MHz, CDC13) oe 8.13 (s, 2H), 7.73 - 7.66(m, 1H), 7.66 - 7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).
69%		Intermediate 1A: Methyl 3-methoxy-4-(1H-pyrazol-4-yl)benzoateTo a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) in dioxane (30 mL) and water (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.901 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) and PdCl2(dppf) (0.197 g, 0.269 mmol) at rt. The reaction was stirred under argon at 100 C for 3 h. The reaction mixture was diluted with EtOAc, washed with H2O. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (10 mL) and TFA (5 mL) was added. The reaction was stirred at rt for 1.5 h. The solvent was removed. The residue was taken into EtOAc, which was washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. The desired product was isolated as white solid (0.86g, 69% yield). LCMS(ESI) m/r. 233.0 (M+H)+; 1H NMR (400MHz, CDCl3) delta 8.13 (s, 2H), 7.73 - 7.66 (m, 1H), 7.66 - 7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).

Reference： [1]Patent: US2014/243338,2014,A1 .Location in patent: Paragraph 0250; 0251
[2]Patent: WO2016/10950,2016,A1 .Location in patent: Page/Page column 242
[3]Patent: WO2016/28971,2016,A1 .Location in patent: Page/Page column 57
[4]Patent: WO2017/123860,2017,A1 .Location in patent: Page/Page column 165

53
[ 552846-17-0 ]
[ 923595-58-8 ]
tert-butyl 4-(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 16h;	General procedure: A solution of K3PO4 (3.5 equiv) in water (2 M) was added to a solution of <strong>[923595-58-8]5-chloro-3-iodopyrazolo[1,5-a]pyrimidine</strong> (19) (1 equiv) and the desired boronic acid pinacolester (1.2 equiv) in dioxane (0.1 M). To this was added PdCl2(dppf)*CH2Cl2 (0.5 equiv) and the reaction was heated at 80 C for 16 h. The crude material was adsorbed onto silica and purified by automated flash chromatography on silica gel (generally EtOAc-cyclohexane) to yield the desired product. 4.1.41. tert-Butyl 4-(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)-1H-pyrazole-1-carboxylate (20a) Reaction of <strong>[923595-58-8]5-chloro-3-iodopyrazolo[1,5-a]pyrimidine</strong> (19) (129 mg, 0.462 mmol) with 1-(Boc)-1H-pyrazole-4-boronic acidpinacol ester using method D gave, after chromatography (0-60%EtOAc-cyclohexane) filtration through silica gave 20a as a yellow solid which was used without further purification. LC-MS tR7.05 min; LC254 97.0%; m/z 320.3/322.1 [M+H].

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6280 - 6296

54
[ 552846-17-0 ]
[ 1309774-03-5 ]
2-chloro-7-(1H-pyrazol-4-yl)-1,5-naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,4-dioxane; water; at 110℃; for 5h;Inert atmosphere;	Example 0646 0646-1 A mixture of <strong>[1309774-03-5]7-bromo-2-chloro-1,5-naphthyridine</strong> (5.0 g), 1-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (6.04 g), sodium carbonate (4.4 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (366 mg), 1,4-dioxane (24 mL), and water (2.4 mL) was stirred at 110 C. for 5 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added thereto, and the solid matter was collected by filtration. The obtained solid matter was suspended by the addition of ethyl acetate, and the solid matter was collected by filtration, thereby obtaining 2-chloro-7-(1H-pyrazol-4-yl)-1,5-naphthyridine (2.6 g) as a pale brown solid. MS m/z (M+H): 231.

Reference： [1]Patent: US2015/322063,2015,A1 .Location in patent: Paragraph 2991; 2992; 2993

55
[ 552846-17-0 ]
methyl 4-bromo-3-cyanobenzoate [ No CAS ]
methyl 3-cyano-4-(1H-pyrazol-4-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; at 20 - 90℃; for 2h;	To a solution of Intermediate 1 44A (0.25 g, 1.0 mmol) in dioxane (10 mL) were added tert-butyl 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole- 1- carboxylate (0.37 g, 1.3 mmol), K3P04 (1 M, 3.1 mL, 3.1 mmol) and XPhos-G2-Pd- PreCat (16 mg, 0.02 1 mmol) at rt. The reaction was stirred under argon at 90 C for 2 h.The reaction was cooled to rt. The reaction mixture was diluted with EtOAc, washed with H20 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to give Intermediate 144B (0.22 g, 93%) as white solid. LC-MS(ESI) m/z: 228.1 [M+H] ?H NMR(400MHz, CDC13) oe 11.27 (brs, 1H), 8.37 (d,J1.8 Hz, 1H), 8.27-8.17 (m, 3H),7.70 (d,J=8.1 Hz, 1H), 3.97 (s, 3H).
93%	With potassium phosphate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;	Intermediate 7B: Methyl 3-cyano-4-(1H-pyrazol-4-yl)benzoateTo a solution of Intermediate 7A (0.25 g, 1.0 mmol) in dioxane (10 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.37 g, 1.3 mmol), K3PO4 (1 M, 3.1 ml, 3.1 mmol) and XPhos-G2-Pd- PreCat (16 mg, 0.021 mmol) at rt. The reaction was stirred under argon at 90 C for 2 h. The reaction was cooled to rt. The reaction mixture was diluted with EtOAc, washed with H2O and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to give Intermediate 7B (0.22 g, 93%) as a white solid. LC-MS(ESI) m/z: 228.1 [M+H]+; 1H NMR (400MHz, CDCl3) delta 11.27 (br. s., 1H), 8.37 (d, J=1.8 Hz, 1H), 8.27 - 8.17 (m, 3H), 7.70 (d, J=8.1 Hz, 1H), 3.97 (s, 3H).

Reference： [1]Patent: WO2016/10950,2016,A1 .Location in patent: Page/Page column 243
[2]Patent: WO2016/28971,2016,A1 .Location in patent: Page/Page column 64

56
[ 552846-17-0 ]
[ 849758-12-9 ]
tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)-1H-pyrazole-1-carboxylate [ No CAS ]
methyl 3-fluoro-4-(1H-pyrazol-4-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%; 35%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 20 - 60℃;Inert atmosphere;	To a solution of <strong>[849758-12-9]methyl 4-bromo-3-fluorobenzoate</strong> (526 mg, 2.26 mmol) in dioxane (10 mL) and H20 (2 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)- 1H-pyrazole- 1 -carboxylate (797 mg, 2.71 mmol), K3P04 (958 mg, 4.51 mmol) and XPhos-G2-Pd-preCat (35.5 mg, 0.045 mmol) at rt. The reaction was stirred under N2 at 60 C overnight. The reaction mixture was diluted with EtOAc,washed with H20 and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography to give two products as white solids. Intermediate 151A (463 mg, 64%): ?H NMR (400MHz, CDC13) oe 8.51 (d,J=1.5 Hz, 1H), 8.10 (s, 1H), 7.84 (dd,J=8.1, 1.5 Hz, 1H), 7.79 (dd, J=11.4, 1.5 Hz, 1H), 7.63 (t,J=7.8 Hz, 1H), 3.92 (s, 3H), 1.68 (s, 9H). LC-MS(ESI) m/z:321.0 [M+H]. Intermediate 151B (175 mg, 35%): ?H NMR (400MHz, CDC13)oe 8.06(d, J=1.8 Hz, 2H), 7.85 (dd,J=8.1, 1.8 Hz, 1H), 7.80 (dd,J11.7, 1.5 Hz, 1H), 7.66 (t,J7.7 Hz, 1H), 3.94 (s, 3H). LC-MS(ESI) m/z: 221.0 [M+H].

Reference： [1]Patent: WO2016/10950,2016,A1 .Location in patent: Page/Page column 250; 251

57
[ 552846-17-0 ]
tert-butyl 4-hydroxy-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With water; dihydrogen peroxide; sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 1.08333h;	To <strong>[552846-17-0]tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate</strong> (25 g, 85 mmol) in THF (170 mL) at 0 C. was added sodium hydroxide (85 mL of 2 M, 170 mmol) followed by hydrogen peroxide (19.27 mL of 30% w/v, 170.0 mmol) and the reaction mixture was stirred at 0 C. for 10 min and RT for 45 min. The reaction mixture was cooled to 0 C. and diluted with DCM and 2 M HCl was added till pH 2 was reached. The organics were separated, dried and concentrated under reduced pressure to give tert-butyl 4-hydroxypyrazole-1-carboxylate (15 g 100%) as yellow solid. ESI-MS m/z calc 184.19. found 185.0 (M+1)+; LCMS retention time (3 min run) 0.63 min.

Reference： [1]Patent: US2016/95858,2016,A1 .Location in patent: Paragraph 5334; 5335

58
[ 552846-17-0 ]
((2R)-4-azido-2-(2-fluorophenyl)pyrrolidin-1-yl)(4-bromo-3-methoxyphenyl)methanone [ No CAS ]
((2R)-4-azido-2-(2-fluorophenyl)pyrrolidin-1-yl)(3-methoxy-4-(1H-pyrazo-4-yl)phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium phosphate; methyl 4-bromo-3-methoxybenzoate; In 1,4-dioxane; water; at 20℃; for 1.5h;Inert atmosphere;	Example 106E: ((2R)-4-Azido-2-(2-fluorophenyl)pyrrolidin-1-yl)(3-methoxy-4-(1H-pyrazo-4-yl)phenyl)methanoneTo a solution of Example 106D (43 mg, 0.103 mmol) in dioxane (5 mL) and H2O (1 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (45.3 mg, 0.154 mmol), K3PO4 (65.3 mg, 0.308 mmol) and XPhos-G2-Pd-PreCat (8.07 mg, 10.26 mumomicronl) at rt. The reaction was stirred under N2 at rt for 1.5 h. The reaction mixture was diluted with DCM, washed with H2O and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in DCM (1 mL), and TFA (0.5 mL) was added. After stirred at rt for 30 min, the solvent was removed to afford a crude product of Example 106E (42 mg, 100%). LC-MS(ESI) m/z: 407.0[M+H]+.

Reference： [1]Patent: WO2016/28971,2016,A1 .Location in patent: Page/Page column 139

59
[ 552846-17-0 ]
1-[(6-bromo-imidazo[1,2-a]pyridine-3-sulfonyl)]-6-bromo-1H-pyrazolo[4,3-b]pyridine [ No CAS ]
1-[6-(4-pyrazolyl)-imidazo[1,2-a]pyridine-3-sulfonyl]-6-(4-pyrazolyl)-1H-pyrazolo[4,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		j0499] Into a microwave reaction tube were disposed 80mg 1 -[(6-bromo-imidazo[1 ,2-a]pyridine)-3-sulfonyl] -6-bromo-1 -H-pyrazolo[4,3-b]pyridine, 113 mg 1 -t-butoxycarbonyl1H-pyrazolo-4-boronic acid pinacol ester and 97 mg potassium carbonate, 5 ml dioxane, 2.5 ml ethanol and 2.5 ml water were added into the microwave reaction tube, air was displaced for three times, under a nitrogen atmosphere, 7.2 mg 1,1 ?-bis(diphenylphosphino) ferrocene palladium (II)dichloromethane complex was added into the microwave tube, then the microwave tube was sealed. The microwave tube was placed into a microwave reactor, reaction was conducted at a temperature of 120 C. for 30 minutes, the reaction was completed. The aforementioned reactant liquid was poured into 15 ml water, extracted three times with dichloromethane, the organic layer was dried over anhydrous sodium sulfate then concentrated. The concentrated solid was dissolved in 10 ml dioxane saturated with hydrochloric acid, stirred at room temperature for 3 hours, then evaporated to remove the organic phase, and isolated by flash preparative chromatography to obtain the target compound 104 (m=64 mg, yield:85%). ESI (mlz): 432.0 [M+H].10500] ?H NMR (400 MHz, CDC13) oe 9.25 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.09 (s, 2H), 7.98 (s, 2H), 7.77 (d, J=9.1 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H).Example 105

Reference： [1]Patent: US2016/137640,2016,A1 .Location in patent: Paragraph 0497; 0499; 0500

60
[ 552846-17-0 ]
[ 590371-73-6 ]
4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.35%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;	A microwave vial was charged with 1 ,4-Dioxane (1 OmL) and Water (3ml_) which was degassed with nitrogen for ~10 mins. To this was added 4-lodo-2-(trifluoromethyl)pyridine (500mg, 1 .83mmol), tert- butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole-1 -carboxylate (808mg, 2.75mmol) and potassium carbonate (506mg, 3.66mmol) followed by [1 ,1 - bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (149mg, 0.1800mmol) . The vessel was then sealed, flushed with nitrogen and irradiated for 1 hour at 1 10C. LC-MS after this time showed conversion to the deprotected product and no starting material remaining, so reaction was worked up. The reaction mixture was concentrated to dryness then taken up in MeOH. This was loaded on to a 5g SCX cartridge and washed through with ~10CV of MeOH. The product was then eluted with 1 M ammonia in MeOH (~5CV). The ammonia wash was then concentrated to dryness, but did not yield the desired product. The MeOH washes were then concentrated to dryness and the remaining residue was triturated with chloroform. The resulting suspension was sonicated and then filtered, wasing with a little chloroform, affording 4-(1 H-pyrazol-4-yl)-2-(trifluoromethyl)pyridine (384mg, 1 .80mmol, 98.35% yield) as a beige solid. MS Method 2: RT: 1 .30 min, ES+ m/z 214.0 [M+H]+ H NMR (400MHz, MeOD) delta/ppm: 8.66 (s, 1 H), 8.34-8.38 (m, 2H), 8.08 (s, 1 H), 7.89-7.92 (m, 1 H).

Reference： [1]Patent: WO2016/55786,2016,A1 .Location in patent: Paragraph 00251

61
[ 552846-17-0 ]
[ 586-78-7 ]
[ 209959-25-1 ]

Yield	Reaction Conditions	Operation in experiment
67%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere;	To a solution of 1-bromo-4-nitrobenzene (5.0 g, 24.8 mmol), K2C03 (10.26 g, 74.3 mmol) in dioxane (20 mL) and water (2 mL), the reaction mixture was purged with nitrogen for 10 mm and then was charged with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)- 1H-pyrazole- 1 -carboxylate (8.01 g, 27.2 mmol) and PdC12(dppf)(1.08 g, 1.48 mmol), again purged with nitrogen for 5 mm and heated at 80 C for 3 h. The reaction mixture was cooled to rt and then diluted with ethyl acetate, washed with brine solution, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0-25% EtOAc/Hex gradient) to obtain Intermediate 2a (4.8 g, 67% yield) as a yellow solid. MS(ESI) m/z: 231.0 [M+H-(t-Bu)j; ?H NMR (300 MI-Tz, DMSO10 d6) oe ppm 9.01 (s, 1 H) 8.47 (s, 1 H) 8.26 (d, J=8.92 Hz, 2 H) 8.07 (d, J=8.97 Hz, 2 H)1.62 (s, 9 H).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 70℃;Sealed tube;	The compounds b,N-BOC-pyrazole boronic acid pinacol ester,Cs2CO3, PdCl (dppf),Mixed solvent (1,4-dioxane: water = 10: 1) was added to a 15-well sealed tube,Evacuate the mixture in a vacuum,70 C conditions for 6-8 hours,After completion of the reaction, after removal of the solvent,The crude product was purified by flash chromatography to give compound e.

Reference： [1]Patent: WO2016/144936,2016,A1 .Location in patent: Page/Page column 104; 105
[2]RSC Advances,2016,vol. 6,p. 58516 - 58520
[3]Patent: CN105949180,2016,A .Location in patent: Paragraph 0018-0019

62
[ 552846-17-0 ]
[ 103966-66-1 ]
C₁₅H₁₇N₃O₅ [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 58516 - 58520

63
[ 552846-17-0 ]
[ 185331-69-5 ]
C₁₄H₁₄FN₃O₄ [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 58516 - 58520

64
[ 552846-17-0 ]
methyl 2-bromo-5-(3-((3-methoxyphenyl)amino)-2-oxopyrrolidin 1-yl)benzoate [ No CAS ]
tert-butyl 4-(2-(methoxycarbonyl)-4-(3-((3-methoxyphenyl)amino)-2-oxopyrrolidin-yl)phenyl)-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); In 1,4-dioxane; water; at 75℃; for 2h;Inert atmosphere;	A solution of methyl 2-bromo-5-(3-((3 -methoxyphenyl)amino)-2-oxopyrrolidin-yl)benzoate (0.5 g, 1.19 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.526 g, 1.79 mmol) and potassium phosphate tribasic (0.633 g, 2.98 mmol) in 1,4-dioxane (15 mL) and water (0.2 mL) was degassed with nitrogen. 2nd generation XPhos precatalyst (0.056 g, 0.072 mmol) was added and the reaction mixture heated at 75 C for 2 h. The reaction mixture was cooled to rt, diluted with water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organicextracts were washed with water and brine, dried over Na2SO4 and concentrated to give the crude. The crude product was purified by flash chromatography (eluting with 50-60% EtOAc in hexane) to give tert-butyl 4-(2-(methoxycarbonyl)-4-(3-((3-methoxyphenyl)amino)-2-oxopyrrolidin- 1 -yl)phenyl)- 1H-pyrazole- 1 -carboxylate (0.52 g, 85% yield) as an off-white solid. MS(ESI) m/z: 507.4 (M+H) ?H NMR (300MHz, DMSO-d6) oe ppm 8.39 (d, J = 0.7 Hz, 1 H), 8.19 (d, J = 2.3 Hz, 1 H), 7.91 - 7.85 (m, 2 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.03 - 6.95 (m, 1 H), 6.34 - 6.27 (m, 2 H), 6.20 - 6.15 (m, 1 H), 5.97 (d, J = 7.2Hz, 1 H), 4.47 - 4.37 (m, 1 H), 3.92 - 3.83 (m, 2 H), 3.78 (s, 3 H), 3.68 (s, 3 H), 2.62 -2.55 (m, 1 H), 1.97 - 1.87 (m, 1 H), 1.60 (s, 9 H).

Reference： [1]Patent: WO2016/144936,2016,A1 .Location in patent: Page/Page column 222

65
[ 552846-17-0 ]
(3S,4R)-1-(4-bromophenyl)-4-(hydroxymethyl)-3-((3-methoxyphenyl)amino)pyrrolidin-2-one [ No CAS ]
(3R,4S)-1-(4-(1H-pyrazol-4-yl)phenyl)-4-(hydroxymethyl)-3-((3-methoxyphenyl)amino)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); In 1,4-dioxane; water; at 70℃; for 3h;Inert atmosphere;	To a solution of (3R,4S)- 1 -(4-bromophenyl)-4-(hydroxymethyl)-3-((3-methoxyphenyl)amino)pyrrolidin-2-one (0.060 g, 0.153 mmol) in Dioxane (3 mL), was added 1-Boc-pyrazole-4-boronic acid pinacol ester (0.054 g, 0.184 mmol), potassium phosphate tribasic (0.065 g, 0.3 07 mmol) and water (0.6 mL). The reaction mixture was bubbled with nitrogen for 5 mm. 2nd generation XPhos precatalyst (7.2 mg, 9.2 imol) was added to the reaction mixture and was again bubbled with nitrogen for 5 mm. Thereaction mixture was heated at 70 C for 3 h. Reaction mixture was cooled to rt, diluted with EtOAc, and washed with water and brine, dried over Na2SO4 and concentrated. The crude product was dissolved in DCM (3 mL), and TFA (0.1 mL) was added. The reaction mixture was stirred for overnight at a The solvent was evaporated in vacuo to afford a gummy product which was purified by preparative HPLC to afford (3R,4S)-1-(4-(1H-pyrazol-4-yl)phenyl)-4-(hydroxymethyl)-3 -((3-methoxyphenyl)amino)pyrrolidin-2-one(7.7 mg, 95%). MS(ESI) m/z: 379.2 (M+H) ?H NMR (400 MHz, DMSO-d6) oe ppm12.90 (br. s., 1 H) 8.16 (s, 1 H) 7.90 (br. s., 1 H) 7.68 (d, J=8.80 Hz, 2 H) 7.62 (d, J9.05Hz, 2 H) 6.95 (t, J=7.95 Hz, 1 H) 6.25 - 6.31 (m, 2 H) 6.14 (d, J8.31 Hz, 1 H) 6.00 (d,J=8.56 Hz, 1 H) 4.93 (t, J=4.89 Hz, 1 H) 4.22 (t, J=8.93 Hz, 1 H) 3.87 (t, J9.05 Hz, 1 H)3.65 - 3.69 (m, 1 H) 3.66 (s, 3 H) 3.55 - 3.65 (m, 2 H); 100% ee (RT: 4.03), determinedby chiral SFC analysis, Column: CHIRALCEL OJ-H (250 x 4.6 mm), si?, Mobile Phase: 0.2% DEA in MeOH with Co-solvent C02 40%j; [cx]25?D = +27.2 (c 0.05, DMSO).

Reference： [1]Patent: WO2016/144936,2016,A1 .Location in patent: Page/Page column 228

66
[ 552846-17-0 ]
4-[(6-bromo-pyridine-2-carbonyl)-amino]-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]
4-[6-(1-tert-butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With bis(tri-t-butylphosphine)palladium(0); potassium carbonate; In 1,4-dioxane; water; at 35℃;	4-[6-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (0259) (0260) A reaction mixture of 4-[6-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (5000 mg; 13.37 mmol), <strong>[552846-17-0]4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester</strong> (4770 mg; 16.22 mmol; 1.10 eq.), dipotassium carbonate (2241 mg; 16.22 mmol; 1.10 eq.), 100 mL of dioxane and 10 mL of water was degassed. To it was added palladium; tritert-butylphosphane (376 mg; 0.74 mmol; 0.05 eq.), and the reaction was stirred at 35 C. overnight. The reaction was diluted with EA (100 mL), washed with brine, dried, and concentrated, white solid that precipitated out, filtered, to provide the title compound (5700 mg, yield 90%). LC-MS (M+1): 427.

Reference： [1]Patent: US2016/229856,2016,A1 .Location in patent: Paragraph 0259; 0260

67
[ 552846-17-0 ]
[ 74553-29-0 ]
di-tert-butyl 4,4’-(2-formyl-1,4-phenylene)bis(1H-pyrazole-1-carboxylate) [ No CAS ]

Reference： [1]ChemPlusChem,2016,vol. 81,p. 864 - 871
[2]ChemPhysChem,2017,vol. 18,p. 3245 - 3252

68
[ 552846-17-0 ]
3-cyano-4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridin6-yltrifluoromethane sulfonate [ No CAS ]
4-(4-(4-(3,3-dimethylbutanoyl)piperazin-1-yl)phenyl)-6-(1Hpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		A solution of 3 -cyano-4-(4-(4-(3 ,3 -dimethylbutanoyl)piperazin- 1 -yl)phenyl)pyrazolo[ 1,5 -a]pyridin-6-yl trifluoromethanesulfonate (Intermediate P16; 0.200 g, 0.3639 mmol) in dioxane (15 mL) was treated with tert-butyl 4- (4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole- 1 -carboxylate (0.1606 g, 0.5459 mmol) and 2 M K2C03(aq) (0.3639 mL, 0.7278 mmol). The resulting reaction mixture was purged with nitrogen for 5 mm, and then X-Phos (0.03470 g, 0.07278 mmol) and Pd2(dba)3 (0.01666 g, 0.01820 mmol) were added. The reaction mixture was purged with nitrogen for an additional 5 mm and then heated overnight at 80 C under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and then diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2504, filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (0-50% of 20% MeOHIDCM in EtOAc). The fractions containing the desired mass for tert-butyl 4-(3-cyano-4- (4-(4-(3 , 3 -dimethylbutanoyl)piperazin- 1 -yl)phenyl)pyrazolo[ 1,5 -a]pyridin-6-yl)- 1 H-pyrazole- 1- carboxylate (by LCMS) were combined, concentrated in vacuo, dissolved in 20% MeOH/DCM (25 mL), treated with 4 N HC1 in dioxane (5 mL) and stirred overnight. The reaction mixture was quenched with saturated NaHCO3(aq) and extracted with 10% MeOHIDCM (3 x 50 mL). The organic and aqueous extracts were treated separately. The organic extracts were combined, dried over anhydrous Na2504, filtered and reserved. The aqueous layer was filtered and the insoluble solid collected was separately washed with MeOH (50 mL) and DCM (50 mL). The organic filtrates from both the original extraction and the solid wash were combined and concentrated in vacuo to afford the title compound (0.1663 g, 98% yield). MS (apci) m/z = 468.1 (M+H).10012841

Reference： [1]Patent: WO2017/11776,2017,A1 .Location in patent: Paragraph 001281; 001282; 001283

69
[ 552846-17-0 ]
4-bromomethyl-2,6-(2,5-dimethylpyrrol-1-yl)-pyridine [ No CAS ]
4-((1H-pyrazol-4-yl)methyl)-2,6-bis(2,5-dimethyl-1H-pyrrol-1-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		In a 20 mL vial was added Intermediate 4 (1.00 g, 2.79 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1H-pyrazole- 1 -carboxylate (0.862 g, 2.93mmol), (DtBPF)PdC12 (0.182 g, 0.279 mmol) and 3M K3P04 (2.79 mL, 8.37 mmol). The reaction was purged with argon, and THF (9.30 mL) was added. The reaction mixture was heated at 70 C for 2.5 hours. After cooling to rt, the mixture was transferred to a round bottom flask and methanol (4 mL) and iN NaOH (4 mL) were added, followed byheating at 50 C for 30 mm to cleave the Boc protecting group. The reaction mixture was cooled to rt, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to provide Intermediate 5 (0.73 g, 75%) as a light tan foam which was used without further purification. MS(ESI) m/z 346.2 (M+H)h ?H NMR (400MHz,CDC13) oe 7.48 (s, 2H), 7.05 (s, 2H), 5.87 (s, 4H), 4.02 (s, 2H), 2.12 (s, 12H).
75%		In a 20 mL vial was added the bromide from Step C (1.00 g, 2.79 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.862 g, 2.93 mmol), (DtBPF)PdCl2 (0.182 g, 0.279 mmol) and 3M K3PO4 (2.79 mL, 8.37 mmol). The reaction flask was purged with argon, and THF (9.30 mL) was added. The reaction mixture was heated at 70 C for 2.5 hours. After cooling to rt, the mixture was transferred to a round bottom flask and methanol (4 mL) and 1N NaOH (4 mL) were added, followed by heating at 50 C for 30 min to cleave the Boc protecting group. The reaction mixture was cooled to rt, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to provide 4-((1H-Pyrazol-4-yl)methyl)-2,6- bis(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (0.73 g, 75%) as a light tan foam which was used without further purification. MS(ESI) m/z 346.2 (M+H).1H NMR (400MHz, CDCl3) delta 7.48 (s, 2H), 7.05 (s, 2H), 5.87 (s, 4H), 4.02 (s, 2H), 2.12 (s, 12H).

Reference： [1]Patent: WO2017/40449,2017,A1 .Location in patent: Paragraph 00170
[2]Patent: WO2017/160632,2017,A1 .Location in patent: Page/Page column 65; 66

70
[ 552846-17-0 ]
(2E)-ethyl 3-(4-chloropyridin-3-yl)acrylate [ No CAS ]
(2E)-ethyl 3-(4-(1H-pyrazol-4-yl)pyridin-3-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; at 80℃; for 14h;	The mixture of 6 (2504 mg, 11.83 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (5.23 g, 17.8 mmol), [1,1'-biphenyl]-2-yldicyclohexylphosphine (518 mg, 1.48 mmol), Pd2(dba)3 (542 mg, 0.59 mmol), a solution of 2 M aq. Cs2CO3 solution (17.8 mL, 35.5 mmol) in DME (90 mL) was heated at 80 C for 14 h. The mixture was diluted with EtOAc (50 mL), and the aqueous layer extracted with EtOAc (15 mL × 2). The separated organic layers were combined, washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography (NH silica gel, eluted with 10-100% EtOAc/hexane) to yield 8b (2.13 g, 74%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 1.26 (3H, t, J = 7.1 Hz), 4.21 (2H, q, J = 7.1 Hz), 6.70 (1H, d, J = 16.1 Hz), 7.52 (1H, dd, J = 5.2, 0.6 Hz), 7.78 (1H, d, J = 16.3 Hz), 7.95 (2H, br s), 8.54 (1H, d, J = 5.2 Hz), 8.90 (1H, s), 13.37 (1H, br s). MS (API): m/z 243.9 (M + H)+.
750 mg	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; chloro(2-dicyclohexylphosphino-2?,4?,6?-tri-isopropyl-1,1?-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether; caesium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 1.5h;	A mixture of (2E)-ethyl 3-(4-chloropyridin-3-yl)acrylate (995 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2655 mg), Sphos (185 mg), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-tert-butyl ether complex (343 mg), cesium carbonate (4411 mg), DME (15 mL) and water (3 mL) was stirred at 130 C. for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (750 mg). MS: [M+H]+ 243.9.
750 mg	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; chloro(2-dicyclohexylphosphino-2?,4?,6?-tri-isopropyl-1,1?-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether; caesium carbonate; In 1,2-dimethoxyethane; at 130℃; for 1.5h;	At 130 C, (2E) -3- (4-chloropyridin-3-yl) acrylate (995 mg) 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (2655 mg ), Sphos (185 mg), 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl) T-butyl ether complex (343 mg), Cesium carbonate (4411 mg), DME (15 mL) and water (3 mL) was stirred for 1.5 h. The reaction mixture was filtered through celite and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (750 mg).

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3018 - 3033
[2]Patent: US2017/44132,2017,A1 .Location in patent: Paragraph 0629; 0630
[3]Patent: TW2017/14883,2017,A .Location in patent: Paragraph 0164

71
[ 552846-17-0 ]
[ 1341232-15-2 ]
methyl 5-chloro-6-cyano-2-(1H-pyrazol-4-yl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride; In 1,4-dioxane; water; at 80℃; for 2.33333h;Inert atmosphere;	To a solution of methyl 2,5-dichloro-6-cyanonicotinate (0.80 g, 3.5 mmol, Example 26, Step 3), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2.0 g, 6.9 mmol, Aldrich), and cesium fluoride (1.6 g, 10. mmol) in water (6.08 mL) and 1,4-dioxane (15.8 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.14 g, 0.21 mmol). The mixture was degassed by sparging the solution with nitrogen for 10 minutes. The reaction was heated to 80 C. for 2 hours and 20 minutes. Upon cooling to room temperature, saturated NaHCO3 was added, and the mixture was extracted with EtOAc. The organic extract was dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromatography (0-50% EtOAc in hexanes). Yield: 0.76 g, 90%. LCMS calculated for C11H8ClN4O2 monoisotopic (M+H)+: m/z=263.0; found 263.0.

Reference： [1]Patent: US2017/129899,2017,A1 .Location in patent: Paragraph 0997; 0998; 1063; 1064

72
[ 552846-17-0 ]
[ 78607-36-0 ]
tert-butyl 4-(2-chloropyridin-3-yl)-1H-pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 65℃; for 3h;Inert atmosphere;	<strong>[78607-36-0]2-chloro-3-iodopyridine</strong> (100 g x 2,0.42 mol) and tert-butyl 4-(2-chloropyridin-3-yl)-1H-pyrazole-1-carboxylate (123 g,0.42 mol) was dissolved in dioxane (2 L). The system was placed under N2 and Pd(dppf)c12(15 g,17 mmol) was added to the solution and the reaction was heated to 65C for 3 h. The reaction was cooled to RT and the mixture was poured into water and partitioned with EtOAc. The organic was washed with water and brine, Then dried over anhydrous Na2504 before concentrating to dryness. The title compound was obtained and was usedwithout further purification.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 65℃; for 3h;Inert atmosphere;	2-Chloro-3 -iodopyridine (100 g x 2, 0.42 mol) and tert-butyl 4-(2-chloropyridin-3 -yl)- 1H-pyrazole-1-carboxylate (123 g, 0.42 mol) was dissolved in dioxane (2 L). The system was placed under N2and Pd(dppf)C12 (15 g, 17 mmol) was added to the solution and the reaction was heated to 65 C for3 h. The reaction was cooled to RT and the mixture was poured into water and partitioned withEtOAc. The organic was washed with water and brine, then dried over anhydrous Na2SO4 before concentrating to dryness. The title compound was obtained and was used without further purification.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 65℃; for 3h;Inert atmosphere;	2-Chloro-3-iodopyridine (100 g x 2, 0.42 mol) and tert-butyl 4-(2-chloropyridin-3-yl)-lH-pyrazole- 1-carboxylate (123 g, 0.42 mol) was dissolved in dioxane (2 L). The system was placed under N2 and Pd(dppf)Cl2 (15 g, 17 mmol) was added to the solution and the reaction was heated to 65 C for 3 h. The reaction was cooled to RT and the mixture was poured into water and partitioned with EtO Ac. The organic was washed with water and brine, then dried over anhydrous Na2S04 before concentrating to dryness. The title compound was obtained and was used without further purification.

Reference： [1]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 43; 44
[2]Patent: WO2019/5588,2019,A1 .Location in patent: Page/Page column 34; 35
[3]Patent: WO2019/5587,2019,A1 .Location in patent: Page/Page column 47; 48

73
[ 552846-17-0 ]
[ 808744-34-5 ]
7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; N,N-dimethyl-formamide; for 10h;Inert atmosphere;	Compound 8 (12.20 g, 61.93 mmol), Compound 26 (20.00 g, 68.03 mmol) was dissolved in DMF (220 mL)Stir well with H2O (100 mL), then add K2CO3 (31.80 g, 230.43 mmol), respectively.Pd(dppf)Cl2·DCM (7.60 g, 9.30 mmol), nitrogen was replaced with air three times and stirred under the protection for 10 hours.The reaction solution was concentrated and purified by silica gel column chromatography. The mobile phase was taken from dichloromethane and methanol (DCM:MeOH = 40:1 to 25:1).A brown solid 27 (8.80 g, 70%) was obtained.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 19h;	1.95 g of B, 3.0 g of C, 6.52 g of Cs2C03 (cesium carbonate) and 40 mg of Pd (dppf) Cl2 ([1,1'-bis(diphenylphosphine) ferrocene] was dissolved in 50 mL of a mixture of 1,4-dioxane and water (1,4-dioxane: water = 4: 1).After replacing the nitrogen three times, the mixture was heated to 90 C, Keep the temperature for 19 hours. After completion of the reaction, the solid residue was filtered off with celite and concentrated, and the resulting viscous solid was used directly in the next step.

Reference： [1]Patent: CN110003202,2019,A .Location in patent: Paragraph 0168; 0173-0176
[2]Patent: CN105017245,2017,B .Location in patent: Paragraph 0016; 0024; 0028

74
[ 552846-17-0 ]
(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone [ No CAS ]
(4-(6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With bis(tri-t-butylphosphine)palladium(0); sodium carbonate; In 1,4-dioxane; water; at 85℃; for 12h;Inert atmosphere;	A mixture of tert-butyl 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole- 1- carboxylate (335 mg, 1.14 mmol), (4-(6-bromopyrrolo[ 1 ,2-b]pyridazin-4-yl)piperazin- 1- yl)(cyclopropyl)methanone (400 mg, 1.14 mmol), Na2CO3 (362 mg, 3.42 mmol) and Pd(t-Bu3P)2(116 mg, 0.228 mmol) in dioxane/water (v/v = 3:1, 10 mL) was degassed with N2 three times, and then stirred at 85 C for 12 hours. The reaction mixture was cooled and evaporated in vacuo. The residue was purified by flash column (PE:EA = 3:1 to 1:3) to give the title compound as a yellow solid (340 mg, yield 88%). MS (ES+) C18H20N60 requires: 336, found: 337 [M+H].

Reference： [1]Patent: WO2017/181117,2017,A1 .Location in patent: Page/Page column 240; 241

75
[ 552846-17-0 ]
[ 57381-43-8 ]
C₂₄H₂₈N₄O₆ [ No CAS ]

Reference： [1]ChemPhysChem,2017,vol. 18,p. 3245 - 3252

76
[ 552846-17-0 ]
[ 121554-10-7 ]
C₂₃H₂₅N₅O₄ [ No CAS ]

Reference： [1]ChemPhysChem,2017,vol. 18,p. 3245 - 3252

77
[ 552846-17-0 ]
[ 126728-20-9 ]
C₁₀H₆ClN₅ [ No CAS ]

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

78
[ 552846-17-0 ]
(S)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine [ No CAS ]
(S)-6-(4-chlorophenyl)-1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.5%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95℃; for 2h;Inert atmosphere; Sealed tube;	(S)-8-Bromo-6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepine (63-1) (0.200 g, 0.4978 mmol) tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (146 mg, 0.4978 mmol) and potassium carbonate (137 mg, 0.9956 mmol) were dissolved in dioxane (1.99 mL) and water (995 muL) (Ar was bubbled through solvents for 10 minutes prior). Tetrakis (57.5 mg, 0.04978 mmol) was added and the vial was purged with Ar and sealed. The reaction was stirred at 95C for 2 hours, at which time LCMS showed reaction was complete. Azeotroped reaction onto celite from toluene and purified by isco 0 - 10% MeOH/DCM to give (S)-6-(4-chlorophenyl)-1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (64-1) (165.0 mg, 0.426 mmol, 85.5 %) as a white solid. LCMS (ES+): m/z= 389 [M + H]+

Reference： [1]Patent: WO2017/197056,2017,A1 .Location in patent: Page/Page column 397

79
[ 552846-17-0 ]
[ 688363-79-3 ]
4-(2-(benzyloxy)-3-nitrophenyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.1%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;	To 2-(benzyloxy)-1-bromo-3-nitrobenzene(1.0 g, 3.3 mmol) and ter-butyl 1H-pyrazole-4-boronic acid pinacol ester-1-carbonate(1.0 g, 3.4 mmol) in dioxane(30 mL) was added Pd(dppf)Cl2 (250 mg, 341.7 umol), K2CO3 (1.4 g, 9.8 mmol) and H2O (2.5 mL) under the protection of nitrogen. The mixture was stirred at 100C for reacting for 12 hours. Both TLC(PE:EA=1:1) and LC-MS detected and showed that the reaction was completed. The reaction mixture was diluted with water(20 mL), and extracted with ethyl acetate(20 mL*3). The organic phase was combined, washed with saturated salt water(5 mL), dried with anhydrous sodium sulfate, and filtered and spun dry. The residue was separated and purified through column chromatography (PE:EA=1:1) to give 4-(2-(benzyloxy)-3-nitrophenyl)-1H-pyrazole (900 mg, 89.1% yield) as a yellow oil product. 1H NMR (400 MHz, CDCl3) delta = 8.03 (s, 2 H), 7.70 - 7.78 (m, 2 H), 7.33 - 7.39 (m, 5 H), 7.28 - 7.32 (m, 1 H), 4.87 (s, 2 H). MS (ESI) Calcd. for C16H13N3O3 [M+H]+ 296, Found 296.

Reference： [1]Patent: EP3290418,2018,A1 .Location in patent: Paragraph 0163; 0165

80
[ 7461-50-9 ]
[ 552846-17-0 ]
tert-butyl 4-(4-aminopyrimidinyl-2-yl)pyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.49%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;	<strong>[7461-50-9]2-chloro-4-aminopyrimidine</strong>(3.0 g, 23.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazol-1-carboxylic ester(8.2 g, 27.8 mmol), and potassium carbonate(9.6 g, 69.5 mmol) were dissolved in the mixed solvent of dioxane(30 mL) and water(5 mL). Then Pd(dppf)Cl2(1.7 g, 2.3 mmol) was added. It was evacuated and replaced with nitrogen. The reaction mixture was stirred at 80C in an oil bath for 2 hours under the protection of nitrogen, and the complete reaction was tracked and determined by TLC. After cooling, the mixture was filtered through diatomaceous earth and filter cake washed with ethyl acetate (100 mL) and tetrahydrofuran(100 mL). The filtrate was dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by using silica gel column chromatography(eluting with petroleum ether/ethyl acetate=2/1?1/1) to give tert-butyl 4-(4-amidopyrimidinyl-2-yl) pyrazole-1-carboxylate(4.50 g, 59.49% yield) as a pale yellow oil. 1H NMR (400MHz, DMSO-d6) delta = 8.50 (s, 1H), 8.17 (s, 1H), 8.07 (d, J=5.8 Hz, 1H), 6.92 (br. s., 2H), 6.30 (d, J=5.8 Hz, 1H), 1.58 (s, 9H). MS (ESI). Calcd. for C12H15N5O2 [M + H]+262, Found 262.

Reference： [1]Patent: EP3290418,2018,A1 .Location in patent: Paragraph 0068

81
[ 552846-17-0 ]
tert-butyl 6-bromo-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]
tert-butyl 6-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium phosphate; In N,N-dimethyl-d6-formamide; at 50℃; for 16h;Inert atmosphere;	Solution LLL TP-12 (50 mg, 0.15 mmol) under N2 atmosphere4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-tert-Butyl pyrazole-1-carboxylate(67 mg, 0.23 mmol), K3 PO4 (97 mg,0.46 mmol) andXPhos-Ring PalladiumComplexes(13 mg, 0.015 mmol)Add to vial. DMF (1.60 mL) was added and the reaction solution was heated in a microwave to 50 C for 16 hours. EtOAc and H2O were added to dilute the reaction solution. The aqueous layer was extracted with EtOAc (3 mL x 2). Separate the organic layer,Dry and evaporate to produce crude product by preparative TLC(petroleum ether/EtOAc = 1/1) was purified to give the desired compound TP-23 (33 mg, 90%) as a colorless oil.

Reference： [1]Patent: TW2018/2074,2018,A .Location in patent: Page/Page column 286

82
[ 552846-17-0 ]
[ 876343-82-7 ]
C₁₀H₇ClN₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.25h;	General procedure: To 6 (150 mg, 0.65 mmol) was added crude solution of 126 (166 mg, 0.648 mmol) in DME (3 mL) followed by the addition of 2M sodiumcarbonate (0.75 mL, 1.5 mmol) and [1,1?-bis(diphenylphosphino) ferrocene]dichloropalladium(II)·DCM (52.9 mg, 0.065 mmol). The reactionmixture was heated in microwave at 120 C for 15 min. The crudereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, dried over sodium sulfate, filtered andconcentrated. The crude was tried to dissolved in CH2Cl2. The solidobserved was filtered and dried to give 13 (100 mg; 55% yield).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3197 - 3201

83
[ 552846-17-0 ]
[ 1007-15-4 ]
t-butyl 4-(5-acetyl-2-fluorophenyl)-1H-pyazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
960 mg	With potassium phosphate; XPhos; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere;	After dissolving <strong>[1007-15-4]1-(3-bromo-4-fluorophenyl)ethan-1-one</strong> (1.0 g, 4.6 mmol) in 1,4-dioxane (20 mL) and water (4 mL), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole-1-carboxylate (2.0 g, 6.9 mmol), tripotassium phosphate (2.0 g, 9.2 mmol) and XPhos (156 mg, 0.2 mmol) were added thereto under nitrogen, and the result was heated under reflux for 5 hours at 100C. The result was cooled to room temperature, then extracted with ethyl acetate, dried and concentrated. The result was purified using column chromatography to obtain a target compound (960 mg). 1H NMR (300 MHz, CDCl3) delta 8.51 (s, 1H), 8.21 (d, 1H), 8.14 (s, 1H), 7.23 (d, 1H), 2.64 (s, 3H), 1.70 (s, 9H). MS (ESI+): [M+H]+ m/z 305

Reference： [1]Patent: EP3480193,2019,A1 .Location in patent: Paragraph 0070; 0071

84
[ 552846-17-0 ]
[ 808744-34-5 ]
tert-butyl 4-imidazo[1,2-a]pyridin-7-ylpyrazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; at 70℃; for 3h;Inert atmosphere;	A degassed solution of fert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole-l- carboxylate (CAS 552846-17-0; 1.50 g, 4.99 mmol, 1.10 eq,), potassium phosphate, K3PO4 (2.91 g, 3.0 eq.), 7-bromoimidazo[l,2-a]pyridine (CAS 808744-34-5; 920 mg, 1.0 eq.) and Pd(dppf)Cl2-DCM complex (190 mg, 0.23 mmol, 0.05 eq.) in dry THF (18 mL) is placed under argon atmosphere and stirred at 70 C for 3 h. The mixture is cooled to RT and diluted with 100 mL of EtOAc. The organic layer is then washed with 200 mL of water followed by 100 mL of brine. After drying over Na2S04 and filtration, the solvent is evaporated. The residue is purified by flash chromatography on silica gel (eluting 0 to 50% (10% MeOH in EtOAc) in EtOAc) to afford fert-butyl 4-imidazo[l,2-a]pyridin-7-ylpyrazole-l- carboxylate.LCMS: MW (calcd): 284.3; m/z MW (obsd): 285.6

Reference： [1]Patent: WO2019/105886,2019,A1 .Location in patent: Paragraph 0555

85
[ 95-89-6 ]
[ 552846-17-0 ]
2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	A 3-necked flask equipped with reflux condenser and thermometer was charged with <strong>[95-89-6]3-chloro-2,5-dimethyl-pyrazine</strong> (5 mL, 40 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole-1-carboxylate (10 g, 34 mmol) and 1,4-dioxane (100 mL). Pd(PPh3)4 (2 g, 2 mmol), and Na2CO3 (60 mL of 2 M, 100 mmol) were added and the solution was evacuated and backfilled with N2 (x 2). The solution was heated at 100 C and stirred for 16 hours. The reaction mixture was cooled to ambient temperature and filtered, washing with diethyl ether. The filtrate was concentrated in vacuo and the residue purified by column chromatography (silica, 0- 100% [EtOAc+2% 2 M methanolic ammonia]-PE gradient elution) to give 2,5-dimethyl-3-(1H- pyrazol-4-yl)pyrazine as a white solid (4.5 g, 64%); MS m/z: 175 (M+H)+
64%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 100℃;Inert atmosphere;	A 3-necked flask equipped with reflux condenser and thermometer was charged with <strong>[95-89-6]3-chloro-2,5-dimethyl-pyrazine</strong> (5 mL, 40 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole-1-carboxylate (10 g, 34 mmol) in 1,4-dioxane (100 mL). Pd(PPh3)4 (2 g, 2 mmol), and Na2CO3 (60 mL of 2M, 100 mmol) were added and the solution was evacuated and backfilled with N2 (x 2). The solution was heated at 100 C and stirred overnight. The reaction mixture was cooled to ambient temperature and filtered, washing with diethyl ether. The filtrate was concentrated in vacuo and the residue purified by chromatography (silica, 0-100% [EtOAc+2% 2M methanolic ammonia]-Petroleum ether gradient elution). The product fractions were combined and concentrated in vacuo to give 2,5-dimethyl-3-(1H-pyrazol-4-yl)pyrazine as a white solid (4.5 g, 64%); MS m/z: 175 (M+H)+.

Reference： [1]Patent: WO2019/148132,2019,A1 .Location in patent: Paragraph 00861; 00862
[2]Patent: WO2019/148136,2019,A1 .Location in patent: Paragraph 00392

86
[ 552846-17-0 ]
[ 746630-34-2 ]
3-hydroxy-5-(1-methyl-1H-pyrazol-4-yl)isobenzofuran-1(3H)-one [ No CAS ]
sodium (E)-2-(3-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3-oxoprop-1-en-1-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzoate [ No CAS ]

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 83 - 9,93

87
[ 552846-17-0 ]
4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine [ No CAS ]
N-(1-methyl-1H-pyrazole-4-yl)-4-(1H-pyrazol-4-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 95℃; for 24h;	Compound 99a, 4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (824 mg, 4.0 mmol), and compound 99b, 4- (4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid tert-butyl ester (2.35g, 8.0mmol), Pd (dppf) Cl2 (292 mg, 0.4 mol), sodium carbonate (292 mg, 0.4 mmol), 1,4-dioxane (42 mL) and water (7 mL) were added to a three-necked flask. The system was pumped to replace nitrogen three times under the conditions of a water pump. The reaction solution was allowed to react at 95 C for 24 hours and then cooled. After completion of the reaction, the crude product was concentrated under reduced pressure and purified by column chromatography (eluent: ethyl acetate / methanol = 1/20) to obtain an off-white solid compound 99c, namely N- (1-methyl-1H-pyrazole- 4-yl) -4- (1H-pyrazol-4-yl) pyrimidin-2-amine (0.8 g, yield 83%)
83%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 95℃; for 24h;Inert atmosphere;	Put compound 99a4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine (824 mg, 4.0 mmol),Compound 99b i.e.4- (4,4,5,5-tetramethyl(-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester(2.35g, 8.0mmol),Pd (dppf) Cl2 (292mg, 0.4mol),Sodium carbonate (292mg, 0.4mmol),1,4-dioxane (42 mL) and water (7 mL) were addedInto a three-necked flask.The system was pumped to replace nitrogen three times under the conditions of a water pump.The reaction solution was allowed to react at 95 C for 24 hours and then cooled.After the reaction was completed, the crude product was concentrated under reduced pressure and purified by column chromatography (eluent: ethyl acetate / methanol = 1/20).Compound 99c was obtained as an off-white solid, i.e.N- (1-methyl-1H-pyrazol-4-yl)4- (1H-pyrazol-4-yl) pyrimidin-2-amine(0.8 g, 83% yield).

Reference： [1]Patent: CN110734428,2020,A .Location in patent: Paragraph 0376; 0377; 0378; 0379
[2]Patent: CN110862376,2020,A .Location in patent: Paragraph 0467; 0468; 0469; 0470

88
[ 1150271-23-0 ]
[ 73183-34-3 ]
[ 552846-17-0 ]

Yield	Reaction Conditions	Operation in experiment
82.3%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In ethanol; for 16.0h;Inert atmosphere; Reflux;	Add <strong>[1150271-23-0]1-Boc-4-bromopyrazole</strong> (24.7 g, 0.1 mol), bis(pinacolato)diboron (25.4 g, 0.1 mol) and catalyst [1,1'-bis (diphenylphosphino) ferrocene ] Palladium dichloride (0.74 g, 0.001 mol), potassium acetate (19.6 g, 0.2 mol), 200 ml of ethanol were added to the reaction bottle, and after removing the oxygen under reduced pressure, the nitrogen was heated to reflux, and the reaction was held for 16 hours. After monitoring the reaction of the raw materials, the filtrate was filtered. The filtrate was distilled off ethanol under reduced pressure. The residue was extracted with petroleum ether and purified to obtain 24.2 g of 1-Boc-4-pyrazoleboronic acid pinacol ester with a yield of 82.3%.

Reference： [1]Patent: CN110698506,2020,A .Location in patent: Paragraph 0020-0023

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Organoboron

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