[ CAS No. 1052686-67-5 ] {[proInfo.proName]}

Name: 1052686-67-5|2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine|97%
Brand: Ambeed
SKU: A189276
Price: 9.0 USD
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Quality Control of [ 1052686-67-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1052686-67-5 ]

SDS Specification

Alternatived Products of [ 1052686-67-5 ]

Product Details of [ 1052686-67-5 ]

CAS No. :	1052686-67-5	MDL No. :	MFCD12032615
Formula :	C₁₁H₁₇BN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	COBZMDPXIDGRHY-UHFFFAOYSA-N
M.W :	220.08	Pubchem ID :	45787282
Synonyms :

Calculated chemistry of [ 1052686-67-5 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.64
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	63.47
TPSA :	44.24 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 :	Yes
Log Kp (skin permeation) :	-6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.59
Log Po/w (WLOGP) :	1.08
Log Po/w (MLOGP) :	0.14
Log Po/w (SILICOS-IT) :	1.26
Consensus Log Po/w :	0.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.42
Solubility :	0.841 mg/ml ; 0.00382 mol/l
Class :	Soluble
Log S (Ali) :	-2.13
Solubility :	1.63 mg/ml ; 0.00741 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.65
Solubility :	0.0497 mg/ml ; 0.000226 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.89

Safety of [ 1052686-67-5 ]

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 [ 1052686-67-5 ]

* 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 [ 1052686-67-5 ]
Downstream synthetic route of [ 1052686-67-5 ]

[ 1052686-67-5 ] Synthesis Path-Upstream 1~2

1
[ 7752-78-5 ]
[ 73183-34-3 ]
[ 1052686-67-5 ]

Reference： [1] Patent: WO2018/160889, 2018, A1, . Location in patent: Page/Page column 660; 661; 662

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[ 5053-43-0 ]
[ 73183-34-3 ]
[ 1052686-67-5 ]

Reference： [1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299

[ 1052686-67-5 ] Synthesis Path-Downstream 1~88

Yield	Reaction Conditions	Operation in experiment
52%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Step 34b: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 0602-107)[0334]To a solution of compound 0601-107 (2.5 g, 11.6 mmol) and bis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) was added potassium acetate (3.4 g, 35 mmol) and PdCl2(dppf)2 (0.95 g, 1.1 mmol). The mixture was degassed with nitrogen and heated at 85 C. for overnight. The reaction mixture was concentrated under reduced pressure to afford the crude product, which purified by column chromatography (ethyl acetate in petroleum ether, 15% v/v) to give the compound 0602-107 (1.55 g, 51%) as a pink solid. LCMS: 262 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d, J=2.0 Hz 1H), 7.73 (d, J=2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 9.93 (s, 1H).
52%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Compound in dioxane (100mL) 0601-107 (2.5g, 11.6mmol) and a solution of bis (pinacolato) diboron (4.4 g, 17.5 mmol), potassium acetate (3.4 g, 35 mmol) and and PdCl2 (dppf) 2 ( 0.95g, 1.1mmol) was added. The mixture was degassed with nitrogen and heated overnight at 85 C.. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether in ethyl acetate, 15% v / v) to give the compound 0602-107 as a pink solid obtained (1.55 g, 51%).

2
[ 1052686-67-5 ]
[ 1346702-61-1 ]
[ 1346702-73-5 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 0.333333h;Inert atmosphere; Microwave irradiation; Sealed tube;	Example 17l-isopropy]-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-6-(2- methylpyrimidin-5-yl)-lH-indazole-4-carboxamideIn a 25 mL sealable tube under nitrogen were combined 6-bromo-l-(l-methylethyl)-N-[(6-methyl-2- oxo-4-propyl-l,2-dihydro-3-pyridinyl)methyl]-lH-indazole-4-carboxamide (100 mg, 0.23 mmol), 2- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (64.2 mg, 0.29 mmol) in dioxane/water (3 mL: lmL). PdCl2(dppf)-CH2Cl2 adduct (9.2 mg, 0.01 1 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (56.6 mg, 0.67 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 1 10 C for 20 min. The mixture was evaporated, DCM/MeOH (1 : 1) was added, and the contents pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH).The collected product was suspended in acetonitrile along with a few drops of EtOH and some hexanes. The contents were sonicated, and solids that precipitated were filtered and dried to afford the title compound as an off-white solid (44 mg, 42%). H NMR (400 MHz, DMSO-<76) delta ppm 11.55 (s, 1 H) 9.21 (s, 2 H) 8.63 (t, .7=4.80 Hz, 1 H) 8.43 (s, 1 H) 8.32 (s, 1 H) 7.94 - 7.96 (m, 1 H) 5.92 (s, 1 H) 5.17 (quin, .7=6.63 Hz, 1 H) 4.43 (br. s., 1 H) 4.42 (br. s., 1 H) 2.69 (s, 3 H) 2.52 - 2.56 (m, 2 H) 2.14 (s, 3 H) 1.49 - 1.55 (m, 8 H) 0.88 (t, .7=7.33 Hz, 3 H); LC-MS (ES) mix = 459.2

Reference： [1]Patent: WO2011/140325,2011,A1 .Location in patent: Page/Page column 51-52

3
[ 1052686-67-5 ]
[ 1403258-69-4 ]
[ 76-05-1 ]
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(((1r,4r)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5-(2-methylpyrimidin-5-yl)benzamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25.9%		Example 164 N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(((1r,4r)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5-(2-methylpyrimidin-5-yl)benzamide To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(1r,4r)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methylbenzamide (1 eq) and <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (1.5 eq) in dioxane/water mixture, Na2CO3 (3.6 eq) was added and the solution purged with argon for 15 min. Pd (PPh3)4 (0.1 eq) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100 C. for 2 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by chromatography over silica gel then prep HPLC to afford the title compound as a TFA salt (0.08 g, 25.97%). LCMS: 531.65 (M+1)+; HPLC: 99.61% ( 210-370 nm) (Rt; 3.981; Method: Column: YMC ODS-A 150 mm4.6 mm5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL; Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.47 (bs, 1H), 9.46 (bs, 1H), 9.00 (m, 2H), 8.20 (s, 1H), 7.53 (s, 1H), 7.35 (s, 1H), 5.86 (s, 1H), 4.29 (m, 2H), 3.125-3.127 (m, 3H), 2.69-2.50 (m, 10H), 2.25-2.10 (m, 9H), 1.94 (m, 4H), 1.43 (m, 4H), 0.83 (m, 3H).

Reference： [1]Patent: US2012/264734,2012,A1 .Location in patent: Page/Page column 190

4
[ 1052686-67-5 ]
[ 1420628-57-4 ]
[ 1420620-28-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With palladium diacetate; sodium carbonate; XPhos; In 1,4-dioxane; water; at 120℃; for 1h;Sealed tube; Inert atmosphere;	To a solution of (S)-2-(l-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)ethyl)-5-chloro-3- phenylquinazolin-4(3H)-one (30 mg, 0.067 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidine (22 mg, 0.1 mmol) in l,4-dioxane-H20 (4: 1, 2 mL) in a sealed tube, 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (15.6 mg, 0.034 mmol), palladium(II) acetate (3.8 mg, 0.017 mmol), and Na2C03 (21 mg, 0.20 mmol) were added sequentially. The mixture was degassed and backfilled with argon (three cycles), and then stirred at 120 C for 1 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2S04 and iltered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH/DCM) to afford compound 1-91 , (S)-2-( 1 -((2-aminopyrido[3 ,2-d]pyrimidin-4-yl)amino)ethyl)-5-(2-methylpyrimidin-5-yl)-3 - phenylquinazolin-4(3H)-one (17 mg, 50% yield). ESI-MS m/z: 502.2 [M+H]+.

Reference： [1]Patent: WO2013/12915,2013,A1 .Location in patent: Paragraph 00814

5
[ 1052686-67-5 ]
[ 1420620-43-4 ]
[ 1420620-49-0 ]

Yield	Reaction Conditions	Operation in experiment
110 mg	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	A mixture of compound 1-96 (100 mg, 0.219 mmol, 1 equiv.), 2-Methylpyrimidine-5-pinacol boronate (96mg, 0.438 mmol, 2 equiv.), sodium carbonate (116 mg, 1.094 mmol, 5 equiv.), and Pd-AMPHOS catalyst (31.0 mg, 0.044 mmol, 0.2 equiv.) in 2.9 mL degassed 4: 1 dioxane-water was sparged with argon for 2 min. The mixture was sealed and heated at 100 C for lh, cooled, diluted with 10 mL each of DCM and water. The organic layer was collected, the aqueous layer was extracted with DCM (3x10 mL), the combined DCM layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate and the solvents were removed in vacuo. The residue was purified on silica gel (12 g, ISCO) using 0-10% methanol in 1 : 1 DCM-EtOAc to provide 110 mg of compound 1-98 as a light yellow solid. ESI-MS m/z 515.3 [M+H]+.

Reference： [1]Patent: WO2013/12915,2013,A1 .Location in patent: Paragraph 00821

6
[ 1052686-67-5 ]
[ 1425042-25-6 ]
[ 1425042-29-0 ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; sodium carbonate; ruphos; In 1,4-dioxane; water; at 120℃; for 1h;Sealed tube; Inert atmosphere;	Example 47 Compound 63 was prepared from 59 according to the following procedure: To a mixture of (S)-2-amino-4-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 59 (50 mg, 0.12 mmol) and <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (40 mg, 0.18 mmol) in a 4:1 mixture of 1,4-dioxane and water (4 mL) in a sealed tube, Na2CO3 (38 mg, 0.36 mmol), RuPhos (28 mg, 0.06 mmol) and Pd(OAc)2 (6.8 mg, 0.03 mmol) were added. The mixture was degassed and back-filled with argon (three cycles) and then stirred at 120 C. for 1 h. The reaction mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-2-amino-4-((1-(5-(2-methylpyrimidin-5-yl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 63. ESI-MS m/z: 476.2 [M+H]+.

Reference： [1]Patent: US2013/53362,2013,A1 .Location in patent: Paragraph 0785; 0786; 0787

7
[ 1052686-67-5 ]
[ 1427853-78-8 ]
[ 1427853-74-4 ]

Yield	Reaction Conditions	Operation in experiment
23 mg	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; 1,2-dichloro-ethane; at 140℃; for 0.166667h;Microwave irradiation; Inert atmosphere;	e) l-cyclopropyl- V-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3- methyl-6-(2-methyl-5-pyrimidinyl)-lH-pyrazolo[3,4-6]pyridine-4- carboxamideA mixture of 6-chloro- l-cyclopropyl-N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3- pyridinyl)methyl]-3-methyl-lH-pyrazolo[3,4-b]pyridine-4-carboxamide (85 mg, 0.220 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (58.2 mg,0.264 mmol), sodium carbonate (0.330 mL, 0.661 mmol), 1 ,2-Dimethoxyethane (DME)(3 mL) and Water (1 mL) were added to a microwave vial and degassed for 10 minutes.Next added 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14.39 mg, 0.018 mmol). The contents were irradiated at 140C for 10 minutes. Water was added and insoluble material was filtered off. This insoluble material was dissolved in acetonitrile and purified by silica gel chromatography(eluent: 0% to 20% (MeOH:NH40H/9: l):DCM). The product was collected as 23mg. 1HNMR (400 MHz, DMSO-d6) delta ppm 1.00 - 1.34 (m, 4 H), 2.12 (s, 3 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 2.72 (s, 3 H), 3.99 (dt, J=7.26, 3.57 Hz, 1 H), 4.39 (d, J=5.05 Hz, 2 H), 5.89 (s, 1 H), 7.86 (s, 1 H), 8.74 (s, 1 H), 9.47 (s, 1 H), 11.53 (br. s., 1 H). LCMS(ES) [M+H] 444.2

Reference： [1]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 198-199

8
[ 1052686-67-5 ]
[ 1339925-58-4 ]
[ 1339925-78-8 ]

Yield	Reaction Conditions	Operation in experiment
89.8%	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In ethanol; water; toluene; at 120℃; for 5h;Inert atmosphere;	Step 102a: Ethyl 5-(tert-butoxycarbonyl(2-(2-methylpyrimidin-5-yl)-4-morpholino-thieno[3,2-d]pyrimidin-6-yl)amino)pentanoate (Compound 1103-229)[0659]A mixture of 1102-226 (300 mg, 0.619 mmol), 2-methyl-5-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0602-229) (681 mg, 3.10 mmol), NaHCO3 (155 mg, 1.854 mmol) and Pd(PPh3)2Cl2 (50 mg) in toluene/EtOH/H2O (5.0 mL/3.2 mL/1.4 mL) was stirred at 120 C. for 5 h under N2. The reaction mixture was concentrated. The residue was purified by column chromatography to afford the titled compound as an off-white solid (300 mg, yield 89.8%).

Reference： [1]Patent: US2013/102595,2013,A1 .Location in patent: Paragraph 0658; 0659

9
[ 1052686-67-5 ]
[ 1476071-49-4 ]

Reference： [1]Patent: US2013/281431,2013,A1

10
[ 1193-21-1 ]
[ 1052686-67-5 ]
[ 1476076-32-0 ]

Yield	Reaction Conditions	Operation in experiment
68%		As shown in step 9-i of Scheme 9, to 4,6-dichloropyrimidine (265.3 g, 1.781 mol) in 1.68 L DME was added CsF (241.5 g, 1.59 mol) and 700 mL water. The mixture was flushed with nitrogen gas for 30 minutes and Pd(PPh3)4 (22.05 g 19.08 mmol) was added. The resulting light yellow solution was flushed with nitrogen gas for an additional 40 minutes, heated to reflux, and a nitrogen-flushed solution of <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (140 g, 636.1 mmol in 420 mL DME) was added dropwise over 1.6 hours. The resulting dark red solution was refluxed under an atmosphere of nitrogen for 16 hours. After this time the mixture was cooled to RT and 300 mL of water was added. The mixture was then cooled to 5 C. and stirred for 40 minutes. The resulting precipitate (6-chloro-2'-methyl-4,5'-bipyrimidine, compound 2039) was collected by filtration, washed with 50 mL water, followed by washing with 150 mL EtOAc. The filtrate was separated into two layers and the aqueous layer extracted with EtOAc (21 L). The combined organics were dried over Na2SO4, concentrated under reduced pressure, diluted with 300 mL of DCM, and purified by medium pressure silica gel chromatography (0-100% EtOAc/DCM). Fractions containing pure product were concentrated under reduced pressure and the concentrate treated with 400 mL of hexanes to produce compound 2039 as a solid. This material was combined with the solid product previously collected and treated with 400 mL of 1:1 THF/DCM. The resulting suspension was heated and transferred to a filtration funnel containing a plug of Florisil. The plug was washed with additional 1:1 THF/DCM to dissolve any remaining solid material and then washed with 4:1 EtOAc/DCM (21 L). The combined filtrates were concentrated under reduced pressure to produce a pink solid which was triturated with 500 mL hexanes, collected by filtration, and dried under reduced pressure to provide 6-chloro-2'-methyl-4,5'-bipyrimidine (compound 2039, 88.8 g, 68% yield): LC-MS=207.01 (M+H); 1H NMR (300 MHz, CDCl3) delta 9.30 (s, 2H), 9.10 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 2.85 (s, 3H).

Reference： [1]Patent: US2013/281431,2013,A1 .Location in patent: Paragraph 0265

11
[ 1052686-67-5 ]
(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide [ No CAS ]
(R)-6-(3-hydroxypyrrolidin-1-yl)-5-(2-methylpyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 2h;Microwave irradiation; Sealed tube; Inert atmosphere;	[00328] (R)-5-Bromo-6-(3-hydroxypyrrolidin-l-yl)-N-(4- (trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 60 mg, 0.134 mmol), 2-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (44.4 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol) and Na2C03 (42.8 mg, 0.403 mmol) were added to a MW vial and treated with DME (570 muKappa), EtOH (81 mu) and water (163 mu). The vial was sealed, evacuated / purged with argon, and subjected to MW irradiation at 80C with stirring for 2 h, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 52.9 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 20% for 0.2 min then 20% to 50% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR = 1.82 min, m/z = 458.2 [M+H]+, m/z = 443.2 [M-H]"; -NuMuRho (400 MHz, DMSO-d6) delta ppm 1.69 - 1.80 (m, 1 H) 1.79 - 1.92 (m, 1 H) 2.69 (s, 3 H) 2.91 (d, J = 11.00 Hz, 1 H) 3.14 - 3.49 (m, 3 H) 4.13 - 4.28 (m, 1 H) 4.83 (br. s, 1 H) 7.34 (d, J = 8.56 Hz, 2 H) 7.80 - 7.91 (m, 2 H) 8.05 (d, J = 2.45 Hz, 1 H) 8.75 (s, 2 H) 8.78 (d, J = 2.20 Hz, 1 H) 10.14 (s, 1 H).

Reference： [1]Patent: WO2013/171640,2013,A1 .Location in patent: Paragraph 00328

12
[ 5053-43-0 ]
[ 73183-34-3 ]
[ 1052686-67-5 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4287 - 4299

13
[ 906099-50-1 ]
[ 1052686-67-5 ]
[ 1610354-67-0 ]

Yield	Reaction Conditions	Operation in experiment
62%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;	1006681 Step D: Preparation of 2-(2-methylpyrimidin-5-yl)-4-phenylthiazole-5- carboxylic acid: 2-Bromo-4-phenylthiazole-5-carboxylic acid (300 mg, 1.06 mmol), 2-methyl- 5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (465 mg, 2.11 mmol), K2C03 (584 mg, 4.22 mmol) and Pd(PPh3)4 (122 mg, 0.11 mmol) were combined in toluene (2 mL), water (1 mL) and EtOH (0.5 mL) and warmed to 95 C in a sealed vessel for 16 hours. The cooled mixture was filtered through GF paper and the filtrate partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc and then adjusted to pH 5 with iN HC1. The resulting solids were filtered, washed with water and Et20 and then dried under vacuum to afford 2-(2-methylpyrimidin-5-yl)-4-phenylthiazole-5-carboxylic acid (195 mg, 62% yield) as a cream solid. MS (apci) mlz = 298.1 (M+H).

Reference： [1]Patent: WO2014/78378,2014,A1 .Location in patent: Paragraph 00668

14
[ 1052686-67-5 ]
[ 1414578-42-9 ]
[ 1610346-16-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube;	Intermediate 12 4-methyl-3-(2-methylpyrimidin-5-yl)- 1 -phenyl- 1 H-pyrazol-5-amine1006731 5-Amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl trifluoromethanesulfonate (900 mg, 2.8 mmol), 2-methyl-5-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidine (925 mg, 4.2 mmol), K2C03 (1.55 g, 11.2 mmol) and Pd(PPh3)4 (324 mg, 0.28 mmol) were combined in toluene (10 mL), water (5 mL) and EtOll (2.5 mL) and warmed to 95 C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% MeOHJDCM to afford the title compound (533 mg, 72% yield) as a pink solid. MS (apci) mlz = 266.1 (M+H).
72%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 95℃; for 16h;Sealed tube;	5 -Amino-4-methyl-l -phenyl- lH-pyrazol-3-yl trifluoromethane sulfonate (900 mg, 2.8 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (925 mg, 4.2 mmol), K2C03 (1.55 g, 11.2 mmol) and Pd(PPh3)4 (324 mg, 0.28 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic phases were washed with brine (30 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (533 mg, 72% yield) as a pink solid. MS (apci) m/z = 266.1 (M+H).
72%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube;	pyrazol-5-amine: 5-Amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl trifluoromethane sulfonate (900 mg, 2.8 nimol), 2-methyl-5-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidine (925 mg, 4.2 mmol), K2C03 (1.55 g, 11.2 mmol) and Pd(PPh3)4 (324 mg, 0.28 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica column chromatography, eluting with 2% MeOH/DCM, to afford the title compound (533 mg, 72% yield) as a pink solid. MS (apci) mlz 266.1 (M+H).

Reference： [1]Patent: WO2014/78331,2014,A1 .Location in patent: Paragraph 00673
[2]Patent: WO2014/78454,2014,A1 .Location in patent: Paragraph 00814
[3]Patent: WO2015/175788,2015,A1 .Location in patent: Paragraph 00227

15
[ 1052686-67-5 ]
[ 1575608-93-3 ]
[ 1575609-62-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3687 - 3706

16
[ 1052686-67-5 ]
[ 1575608-59-1 ]
[ 1575608-85-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 3687 - 3706

17
[ 1052686-67-5 ]
[ 1033202-10-6 ]
[ 1611001-63-8 ]

Yield	Reaction Conditions	Operation in experiment
17.28%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 4h;Inert atmosphere;	The compound of example 1 50 (5.0 g, 29.3 mmol)was treated with 2-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (9.68 g, 44.0 mmol) in DMF (50 ml) in presence of tetrakis(triphenylphosphine)palladium(0) (1 .01 6 g, 0.879 mmol) and sodium carbonate (6.21 g, 58.6 mmol) solution (in 10 mLwater) at 1 20 C for 4 hr according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 1 .2 g (1 7.28 %). 1 H NMR (DMSO-d6, 300 MHz): delta 2.68 (s, 3H, CH3), 7.71 (d, 2H, J = 1 3.5 Hz, Ar), 8.1 0 (s, 1 H, Ar), 8.99 (s, 1 H, Ar), 9.08 (s, 2H, Ar); MS (ES+): m/e 229.1 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 90

18
[ 1052686-67-5 ]
[ 1417334-55-4 ]
[ 1611001-77-4 ]

Yield	Reaction Conditions	Operation in experiment
49.5%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 1 72 (5 g, 1 8.87 mmol) was treated with 2-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (6.23 g, 28.3 mmol) in the presence of [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(l l) complex with dichloromethane (0.308 g, 0.377 mmol) and sodium carbonate (3.00 g, 28.3 mmol) in dry dimethylformamide (25 mL) according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 2.65 g (49.5 %) ; 1 H NMR (DMSO-de, 300 MHz) : delta 2.69 (s, 3H, CH3), 7.77 (s, 1 H, Ar), 8.14 (d, 2H, J =6.0 Hz, Ar), 9.1 3 (s, 2H, Ar), 9.34 (s, 1 H, Ar); MS (ES+) : m/e 279.5 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 102

19
[ 474708-88-8 ]
[ 1052686-67-5 ]
[ 1611002-21-1 ]

Yield	Reaction Conditions	Operation in experiment
48.5%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 245 (4 g, 17.28 mmol) was treated with 2-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (5.70 g, 25.9 mmol) in the presence of [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(ll) complex with dichloromethane (0.282 g, 0.346 mmol) and sodium carbonate (2.75 g, 25.9 mmol)in dry dimethylformamide (25 mL) according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 2.05 g (48.5 %); 1H NMR (DMSO-de, 300 MHz): delta 2.68 (s, 3H, CH3), 7.69 (s, 1 H, Ar), 7.93 (s, 1 H, Ar), 8.09 (s, 1 H, Ar), 9.06 (s, 3H, Ar); MS (ES+): m/e 245.1 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 126

20
[ 1052686-67-5 ]
[ 217435-65-9 ]
[ 1611001-05-8 ]

Yield	Reaction Conditions	Operation in experiment
70.6%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;	The compound of example 30 (2.0 g, 9.48 mmol) was treated with 2-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (2.085 g, 9.48 mmol) in the presence of [1 ,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(ll)complex with dichloromethane (0.124 g, 0.152 mmol) and sodium carbonate (1.50 g, 14.21 mmol) in dry dimethylformamide according to the procedure for the preparation of the compound of example 2 to afford the title compound. Yield: 1.5 g (70.6 %); 1H NMR (DMSO-d6, 300 MHz): delta 2.58 (s, 3H, CH3), 2.68 (s, 3H, CH3), 7.69 (s, 1 H, Ar), 7.77 (s, 1 H, Ar), 8.05 (s, 1 H, Ar), 9.02 (s, 1 H, Ar), 9.07 (s, 2H, Ar); MS (ES+): m/e 225 (M+1 ).

Reference： [1]Patent: WO2014/80241,2014,A1 .Location in patent: Page/Page column 45

21
[ 1052686-67-5 ]
6-[(5-cyano-1,3-thiazol-2-yl)amino]-5-methoxy-2-[(2S)-2-( 4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl trifluoromethanesulfonate [ No CAS ]
2-({5-methoxy-2'-methyl-2-[(2S)-2-(4-methylphenyl)pyrrolidin-1-yl]-4,5'-bipyrimidin-6-yl}amino)-1,3-thiazole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
220 mg	With 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 0.666667h;Inert atmosphere;	Example 60 2-({5-Methoxy-2'-methyl-2-[(2S)-2-(4-methylphenyl)pyrroli din-1-yl]-4,5'-bipyrimidin-6-yl}amino)-1,3-thiazole-5-car bonitrile [0288] 250 mg of 6-[(5-cyano-1,3-thiazol-2-yl)amino]-5-methoxy-2-[(2S)-2-( 4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl trifluoromethanesulfonate, 200 mg of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p yrimidine, 130 mg of potassium carbonate and 38 mg of [PdCl2(dppf)2]CH2Cl2 are added sequentially to a degassed mixed solvent of 4 mL of 1,4-dioxane and 1 mL of water, and the mixture was stirred at 100C for 40 minutes under an argon atmosphere. The reaction solution was diluted with ethyl acetate, and the obtained organic layer was washed with water and brine sequentially, and then was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to obtain 220 mg of the objective compound as a yellow powder. [0289] MS (ESI) m/z 485 (M+H)+

Reference： [1]Patent: EP2857398,2015,A1 .Location in patent: Paragraph 0288-0289

22
[ 5751-83-7 ]
[ 1052686-67-5 ]
5-(2-methylpyrimidin-5-yl)thiophene-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/161928,2015,A1

23
[ 5751-83-7 ]
[ 1052686-67-5 ]
ethyl 5-(2-methylpyrimidin-5-yl)thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 1h;Inert atmosphere;	Synthesis of ethyl 5-(2-methylyrimidin-5-yl)thiophene-2-carboxylate2-Methylpyrimidine-5-boronic acid pinacol ester (0.920 g, 4.18 mmol), ethyl 5-bromothiophene-2- carboxylate (0.568 mL, 3.80 mmol) and Na2CO3 (1 .21 g, 11 .4 mmol) were mixed in DME (30 mL) and water (7.5 mL) and degassed with Ar. Then PdCI2(dppf) (0.133 g, 0.190 mmol) was added and the mixture was stirred at 100 C for 1 h. Water (20 mL) was added and the mixture was extracted with EtOAc (3x 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2504 andconcentrated in vacuo. FC (EtOAc/heptane 0:1 -> 1:0) afforded ethyl 5-(2-methylpyrimidin-5-yl)thiophene-2-carboxylate (0.740 g, 2.98 mmol, 78%). LCMS: caic. for [M+HJ = 249.07, found 249.1.
78%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 1h;Inert atmosphere;	2-Methylpyrimidine-5-boronic acid pinacol ester (0.920 g, 4.18 mmol), <strong>[5751-83-7]ethyl 5-bromothiophene-2-carboxylate</strong> (0.568 mL, 3.80 mmol) and Na2CO3 (1.21 g, 11.4 mmol) were mixed in DME (30 mL) andwater (7.5 mL) and degassed with Ar. Then PdCI2(dppf) (0.133 g, 0.190 mmol) was added and themixture was stirred at 100 C for 1 h. Water (20 mL) was added and the mixture was extracted with EtOAc (3x 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2504 and concentrated in vacuo. FC (EtOAc/heptane 0:1 -* 1:0) afforded ethyl 5-(2-methylpyrimidin-5-yl)thiophene- 2-carboxylate (0.740 g, 2.98 mmol, 78%). LCMS: cal for [M+H} = 249.07, fd 249.1.

Reference： [1]Patent: WO2015/161928,2015,A1 .Location in patent: Page/Page column 52
[2]Patent: WO2015/161924,2015,A1 .Location in patent: Page/Page column 29

24
[ 1052686-67-5 ]
tert-butyl 5-bromothiazole-2-carboxylate [ No CAS ]
tert-butyl 5-(2-methylpyrimidin-5-yl)thiazole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere;	Synthesis of tert-butyl 5-(2-methylpyrimidin-5-yl)thiazole-2-carboxylateA solution of 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (0.156 g, 0.708 mmol),tert-butyl 5-bromothiazole-2-carboxylate (0.170 g, 0.644 mmol) and Na2CO3 (0.205 g, 1.93 mmol) indioxane (10 mL) and water (3 mL) was degassed with Ar. Tetrakis(triphenylphosphine)palladium (0.037 g,0.032 mmol) was added and the mixture was heated at 90 C for 1 h. The mixture was poured intosaturated aqueous NH4CI (30 mL) and extracted with EtOAc (2x 20 mL). The combined organic layer was washed with water (20 mL) and brine (10 mL), dried on Na2SO4 and concentrated under reduced pressure. Purification by FC (EtOAc/heptane 1:9 -> 1:0) afforded tert-butyl 5-(2-methylpyrimidin-5-yl)-thiazole-2-carboxylate (0.156 g, 0.562 mmol, 87%) as a white solid. LCMS: calc. for [M+H] = 278.09, found 278.2.
87%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere;	A solution of 2-methyi-5-(4,4, 5, 5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)pyrimidine (0.156 g, 0.708 mmol), tertbutyl 5-bromothiazole-2-carboxylate (0.170 g, 0.644 mmol) and Na2CO3 (0.205 g, 1.93 mmol) in dioxane (10 mL) and water (3 mL) was degassed with Ar. Tetrakis(triphenylphosphine)palladium (0.037 g, 0.032 mmol) was added and the mixture was heated at 90 C for I h. The mixture was poured into saturated aqueous NH4CI (30 mL) and extracted with EtOAc (2x 20 mL). The combined organic layer waswashed with water (20 mL) and brine (10 mL), dried on Na2504 and concentrated under reduced pressure. Purification by FC (EtOAc/heptane 1:9 -* 1:0) afforded tert-butyl 5-(2-rnethylpyrimidin-5-yl)- thiazole-2-carboxylate (0.156 g, 0.562 mmol, 87%) as a white solid. LCMS: cal for [M+H] = 278.09, fd278.2.

Reference： [1]Patent: WO2015/161928,2015,A1 .Location in patent: Page/Page column 51; 52
[2]Patent: WO2015/161924,2015,A1 .Location in patent: Page/Page column 28

25
[ 1052686-67-5 ]
N-((S)-2-((3R,3aR,6S,6aS)-6-chloro-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)thiophene-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/161924,2015,A1

26
[ 1052686-67-5 ]
N-((S)-2-((3aS,6S,6aS)-6-chloro-3-oxotetrahydro-2H-furo[3,2-b]pyrrol-4(5H)-yl)-1-cyclopentyl-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)thiophene-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/161924,2015,A1

27
[ 1052686-67-5 ]
5-(2-methylpyrimidin-5-yl)thiophene-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/161924,2015,A1

28
[ 1052686-67-5 ]
6-chloro-3,3-dimethyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one [ No CAS ]
3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 5h;Inert atmosphere;	A suspension of 6-chloro-3 ,3-dimethyl- 1 H-pyrrolo [3 ,2-c]pyridin-2(3H)-one (200 mg, prepared according to Woolford et al., WO 2012143726) and <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (336 mg) in 1,4-dioxane (4 ml) and aqueous sodium carbonate solution (2 M, 1 ml) was flushed with argon, then [1,1?-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (37 mg) was added and stirring was continued at 110 C for 5 h. The mixture was evaporated and the residue purified by flash chromatography (silica gel, gradient, 0% to 10% MeOH in dichloromethane) to give the title compound (221 mg, 85%) as a brownsolid. MS (mlz): 255.1 [(M+H)41.

Reference： [1]Patent: WO2015/197567,2015,A1 .Location in patent: Page/Page column 30

29
[ 1052686-67-5 ]
[ 1442120-67-3 ]
[ 1442120-78-6 ]

Yield	Reaction Conditions	Operation in experiment
46 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; for 0.333333h;Reflux;	General procedure: 80 mg of the aryl bromide prepared in Example 316 together with 32 mg of (5-chloropyridin-2-yl)boronic acid was first placed in 1 ml tetrahydrofuran, treated with 17.3 mg of 1,1'-bis(diphenylphosphino)ferrocenodichloropalladium(II) and 0.17 ml of 1M potassium carbonate solution and heated in the microwave for 10 minutes at 120 C. (100 watts). After fresh addition of 11 mg of (5-chloropyridin-2-yl)boronic acid and 17.3 mg of the palladium(II) catalyst, the reaction mixture was again heated in the microwave for 10 minutes at 120 C. (100 watts) until complete conversion. The reaction mixture was concentrated. After HPLC purification, this yielded 15 mg of the title compound. Analogously to Example 317, 46 mg of the title compound was obtained from 125 mg of 316 and 102 mg of <strong>[1052686-67-5](2-methylpyrimidin-5-yl)boronic acid pinacol ester</strong> under reflux. 1H-NMR (400 MHz, DMSO-d6): delta [ppm], 1.16-1.35 (2H), 1.35-1.67 (2H), 2.21-2.42 (1H), 2.54 (3H), 2.67 (3H), 2.71-2.89 (1H), 2.93-3.20 (1H), 3.50-3.73 (1H), 4.07 (2H), 4.37 (3H), 7.20 (1H), 7.40-7.57 (3H), 7.85 (2H), 8.57 (1H), 8.84 (1H), 9.05 (2H).

Reference： [1]Patent: US2016/89364,2016,A1 .Location in patent: Page/Page column 155-156; 159

30
[ 1052686-67-5 ]
[ 1442116-57-5 ]
N-(2-methoxyethyl)-4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzoyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; for 0.333333h;Reflux;	General procedure: 80 mg of the aryl bromide prepared in Example 316 together with 32 mg of (5-chloropyridin-2-yl)boronic acid was first placed in 1 ml tetrahydrofuran, treated with 17.3 mg of 1,1'-bis(diphenylphosphino)ferrocenodichloropalladium(II) and 0.17 ml of 1M potassium carbonate solution and heated in the microwave for 10 minutes at 120 C. (100 watts). After fresh addition of 11 mg of (5-chloropyridin-2-yl)boronic acid and 17.3 mg of the palladium(II) catalyst, the reaction mixture was again heated in the microwave for 10 minutes at 120 C. (100 watts) until complete conversion. The reaction mixture was concentrated. After HPLC purification, this yielded 15 mg of the title compound. Analogously to Example 317, 36 mg of the title compound was obtained from 100 mg of 54 and 64 mg of <strong>[1052686-67-5](2-methylpyrimidin-5-yl)boronic acid pinacol ester</strong> under reflux. 1H-NMR (300 MHz, DMSO-d6): delta [ppm], 1.27 (2H), 1.38-1.70 (2H), 2.21-2.40 (1H), 2.53 (3H), 2.67 (3H), 2.73-3.16 (2H), 3.28 (3H), 3.40 (2H), 3.43-3.50 (2H), 3.53-3.76 (1H), 4.36 (3H), 7.18 (1H), 7.42 (1H), 7.51 (2H), 7.84 (2H), 8.13 (1H), 8.51 (1H), 9.05 (2H).

Reference： [1]Patent: US2016/89364,2016,A1 .Location in patent: Page/Page column 155-156; 181

31
[ 1052686-67-5 ]
methyl 2-(3-acetyl-5-chloro-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate [ No CAS ]
2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
240 mg	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 125℃; for 30h;Inert atmosphere;	Methyl 2-(3-acetyl-5-chloro-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (670 mg, 2.50 mmol), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (609 mg, 2.76 mmol) and K3PO4(1.60 g, 7.50 mmol) are mixed in co-solvent of dioxane (16 ml) and +H2O (4 ml). The mixture was degassed and refilled with argon. To the mixture, Pd(PPh3)4(0.1 eq) was added under Ar. The reaction was heated in an oil bath (125 C.) for 30 hrs. The reaction was cooled to room temperature and the volatiles are evaporated. The remaining materials are purified to afford 240 mg of title product.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1138

32
[ 647857-39-4 ]
[ 593-71-5 ]
[ 1052686-67-5 ]
[ 1360944-30-4 ]
1-(5-bromo-1H-indazol-3-yl)ethan-1-one [ No CAS ]
[ 76-05-1 ]
(2R,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-1-carboxamide [ No CAS ]
(2S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1171; 1172; 1173

33
[ 1052686-67-5 ]
tert-butyl (1R,3S,5R)-3-(2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate [ No CAS ]
tert-butyl (1R,3S,5R)-3-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.225 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 4h;Inert atmosphere;	Into a mixture of tert-butyl (1R,3S,5R)-3-(2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.32 g, 0.69 mmol), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (0.182 g, 0.83 mmol), and Cs2CO3(0.45 g, 1.38 mmol) in DMF-water (7-0.7 mL), add Pd(PPh3)4(40 mg, 0.035 mmol). The mixture was heated at 80 C. under Ar for 4 hr. Cool down to rt, water was added and the mixture was extracted with AcOEt. After washed with brine and dried over anhydrous Na2SO4, solvent was removed by evaporation. The residue was purified on ISCO with MeOH in DCM (0-10%) as eluent to give tert-butyl (1R,3 S,5R)-3-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.225 g) as brown syrup.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1177

34
[ 647857-39-4 ]
[ 593-71-5 ]
[ 1052686-67-5 ]
1-(5-bromo-1H-indazol-3-yl)ethan-1-one [ No CAS ]
tert-butyl (2R,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (2S,4S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1169

35
[ 647857-39-4 ]
[ 593-71-5 ]
[ 1052686-67-5 ]
1-(5-bromo-1H-indazol-3-yl)ethan-1-one [ No CAS ]
[ 76-05-1 ]
2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)-1-((2R,4S)-4-fluoropyrrolidin-2-yl)ethan-1-one trifluoroacetate [ No CAS ]
2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)-1-((2S,4S)-4-fluoropyrrolidin-2-yl)ethan-1-one trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1170

36
[ 152213-66-6 ]
[ 1052686-67-5 ]
2-(6-(2-methylpyrimidin-5-yl)-1H-indol-3-yl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.107 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere;	Into a mixture of 2-(6-bromo-1H-indol-3-yl)acetic acid (0.11 g, 0.43 mmol), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (0.114 g, 0.52 mmol), and Cs2CO3(0.423 g, 1.30 mmol) in DMF-water (5-0.5 mL), add Pd(PPh3)4(25 mg, 0.022 mmol). The mixture was heated at 90 C. under Ar for 2 hr. Cool down to rt, filter and concentrated under reduced pressure. The residue was purified on ISCO with MeOH in DCM (0-20%) as eluent to give 2-(6-(2-methylpyrimidin-5-yl)-1H-indol-3-yl)acetic acid (0.107 g) as yellow solid.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1187

37
[ 1052686-67-5 ]
tert-butyl 5-bromo-6-methoxy-1H-indazole-1-carboxylate [ No CAS ]
tert-butyl 6-methoxy-5-(2-methylpyrimidin-5-yl)-1H-indazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;	Into solution of tert-butyl 5-bromo-6-methoxy-1H-indazole-1-carboxylate and <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (0.95 g, 4.32 mmol) in dioxane-H2O (20 mL-2 mL), K2CO3(1.08 g, 7.86 mmol) and PddppfCl2(0.080 g, 0.098 mmol) were added. The mixture was heated to 90 C. under Ar for 2 hr. The reaction mixture was cooled to rt, filtered, and concentrated. Residue was dissolved in acetonitrile, filtered, and then concentrated to give tert-butyl 6-methoxy-5-(2-methylpyrimidin-5-yl)-1H-indazole-1-carboxylate for next step.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1577

38
[ 1052686-67-5 ]
N-(5-bromo-2-methylthiophen-3-yl)acetamide [ No CAS ]
N-(2-methyl-5-(2-methylpyrimidin-5-yl)thiophen-3-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 95℃; for 3h;Inert atmosphere;	N-(5-bromo-2-methylthiophen-3-yl)acetamide (859 mg, 3.67 mmol), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (888 mg, 4.0 mmol) and Cs2CO3(1.8 g, 5.5 mmol) were mixed in co-solvent of DMF (16 ml) and H2O (4 ml). The mixture was degassed and refilled with argon. To the mixture, Pd(PPh3)4(0.1 eq) was added under Ar. The reaction was heated in an oil bath (95 C.) for 3 hrs. The reaction was cooled to room temperature and the volatiles were evaporated. The residue was treated with water and the resulting solid was collected, washed with water, and dried. The residue (702 mg) was used for next step without further purification.1H NMR (400 MHz, DMSO-d6) delta: 2.04 (s, 3H), 2.33 (s, 3H), 2.63 (s, 3H), 7.61 (s, 1H), 8.87 (s, 2H), 9.56 (s, 1H) ppm. LC (method A): tR=0.76 min. LC/MS (EI) m/z: [M+H]+248.15

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1585

39
[ 1052686-67-5 ]
[ 156454-43-2 ]
7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 0.5 g of bromoindazole (1 equiv), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.782 g, 1.5 equiv), cesium carbonate (2.315 g, 3 equiv) in dioxane (10 mL) and water (1.o mL) was purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium (0) (0.550 g, 0.2 equiv) was then added under argon and the pressure vessel was sealed and heated at 90 C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by ISCO (eluent: 0-3% MeOH in CH2Cl2) to get 0.395 g of the product as white solid.
0.395 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; Sealed tube;	A mixture of 0.5 gof bromoindazole (1 equiv), 2-methyl-5 -(4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidine(0.782 g, 1.5 equiv), cesium carbonate (2.3 15 g, 3 equiv) in dioxane (10 mL) and water (1.0 mL) was purged with argon in a pressure vessel for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.550 g, 0.2 equiv) was then added under argon and the pressure vessel was sealed and heated at 90 C overnight. The reaction mixture was cooled to room temperature and the solvent wasremoved under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 0-3 % MeOH in CH2C12) to afford 0.395 g of the product as a white solid.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1604
[2]Patent: WO2018/160889,2018,A1 .Location in patent: Page/Page column 470

40
[ 1052686-67-5 ]
tert-butyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate [ No CAS ]
tert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate; In water; at 25 - 90℃;Inert atmosphere; Large scale;	Synthesis of Intermediate 9 (0625) (0626) In Scheme 4, Step 2, 5-bromo-2-methylpyrimidine is reacted with te-pinacolatodiborane in 1,4-dioxane in the presence of a palladium catalyst (Pd(dppf)Ch). The reaction is monitored for the conversion of starting materials by HPLC. Intermedaite 6 is added and the coupling reaction is monitored by HPLC for the consumption of intermediate 6 After extraction and carbon treatment, Z-cysteine is added to scavenge palladium. A thiol resin may also be used for scavenging palladium. Once acceptable levels of Pd are achieved, the product mixture is treated with charcoal and the product is precipitated with MTBE and heptane. After isolated by filtration, the wet cake is washed with MTBE and heptane, and then vacuum dried in a vacuum tray dryer. (0627) The process description is as follows: The reactor was charged with 1 ,4-dioxane (20 Vo) and 5-bromo-2 -methyl pyrimidine (1.0 w/w) at 25±5 C'C under nitrogen atmosphere. The reactor was charged with Ws-pinacof atodiborane (1 47 w/w) and potassium acetate (1.7 w/w), and the mass was stirred at 25±5 C for 15 minutes. The reaction mass was degassed using nitrogen for 30 minutes. The reactor was charged with Pd(dppf)Cl2.DCM (0.093 w/w). The mass temperature was raised to 85 C-90±5 C, and the mass was stirred until the starting pyrimidine content was achieved. After completion of the reaction, the mass was cooled to 25±5 C. The vessel was charged with intermediate 6 (1.63 w/w) and K2CO3 (2.39 w/w). The vessel was charged with purified water (1.0 w/w). The reaction mass was stirred at 25±5 C for 15 minutes. The reaction mass was degassed using nitrogen for 30 minutes. The mass temperature was raised to 85 C- 9Q±5 C, and the mass was stirred until the Starting Material content is achieved. After completion of the reaction, the mass was cooled to 25±5 C.
360 mg		A mixture of tert-butyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate (353 mg), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (242 mg), cesium carbonate (652 mg), DMF (4.5 mL), and water (0.5 mL) was purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium (0) (20 mg) was then added under argon and the pressure vessel was sealed and heated at 100 C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The solvent was removed under reduced pressure and the remaining material was purified by silicagel chromatography to afford 360 mg.
135 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 95℃; for 2h;Inert atmosphere;	A mixture of tert-butyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate (scheme 9-4 compound S3, 150 g, 1 equiv), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (112.2 g, 1.2 equiv), cesium carbonate (166.1 g, 1.2 equiv) in DMF (1.5 L) and water (150 mL) was purged with nitrogen gas for 30 min. Tetrakis(triphenylphosphine)palladium(0) (24.5 g, 0.05 equiv) was then added under an atmosphere of nitrogen and the reaction mixture was heated at 95 C for 2 h. The reaction mixture was cooled to room temperature and added slowly to water (15 L). The solid was collected by filtration and dried. The crude residue was purified by column chromatography (silica gel, ethyl acetate/methanol) to afford the title compound as an off-white solid (135 g).

11.8 kg

With potassium carbonate; In water; at 90℃;Inert atmosphere; Large scale;

Step 4: Synthesis of tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (9): Bispinnacolato diboron (14.67kg) was added to a solution of 4-bromo-2- methylpyrimidine (7, 10 kg) in dioxane (206kg) under an atmosphere of nitrogen followed by the addition of potassium acetate (17kg). The reaction mixture was degassed using nitrogen. Pd(dppf)Ck (0.94 kg) was added and the reaction mixture heated to 90±5C until the pyrimidine was consumed. The reaction mixture was cooled to 25±5C and intermediate 6 (16.33kg) was added followed by potassium carbonate (20.7kg) and water (16.33 kg) and the reaction was degassed using nitrogen. The reaction was again heated to 90±5C until completion. The reaction mixture was cooled to 25±5C and diluted with ethyl acetate (269kg) and water (150 kg) maintaining the temp at 10±5C. Activated charcoal (1kg) was added to the mixture with stirring and then filtered through a bed of celite. The ethyl acetate layer was separated, washed with 5% aqueous sodium chloride followed by 5% L-Cysteine solution to remove palladium related impurities. The ethyl acetate layer was evaporated to dryness. The product (9) was isolated from MTBE/heptane. Yield, 11.8 kg, 56%.

Reference： [1]Patent: WO2020/69024,2020,A1 .Location in patent: Page/Page column 121-122
[2]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1155
[3]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0790
[4]Patent: WO2020/51538,2020,A1 .Location in patent: Page/Page column 77; 78-79

41
[ 1052686-67-5 ]
tert-butyl 2-(3-acetyl-5-bromo-6-methoxy-1H-indol-1-yl)acetate [ No CAS ]
tert-butyl 2-(3-acetyl-6-methoxy-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.85 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;	To a mixture of tert-butyl 2-(3-acetyl-5-bromo-6-methoxy-1H-indol-1-yl)acetate (0.88 g, 2.3 mmol) and <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (0.61 g, 2.76 mmol) in DMF-water (20 mL/2 mL) was added Cs2CO3(1.5 g, 4.6 mmol) and Pd(PPh3)4(0.132 g, 0.115 mmol) in succession. The mixture was stirred at 80 C. under an atmosphere of argon for 3 h. The solvent was removed under reduced pressure and the remaining residue was purified by column chromatography on silica gel (50% EtOAc in hexanes) to give tert-butyl 2-(3-acetyl-6-methoxy-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetate (0.85 g) as a pale yellow solid.
0.85 g	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;	To a mixture of tert-butyl 2-(3-acetyl-5-bromo-6-methoxy-lH-indol-l-yl)acetate (0.88 g, 2.3 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (0.61 g, 2.76 mmol) in DMF-water (20 mL/2 mL) was added Cs2C03 (1.5 g, 4.6 mmol) followed by Pd(PPh3)4 (0.132 g, 0.115 mmol). The mixture was stirred at 80 C under an atmosphere of argon for 3 h. The solvent was removed under reduced pressure and the remaining residue was purified by column chromatography on silica gel (50% EtOAc in hexanes) to give tert-butyl 2-(3-acetyl-6- methoxy-5-(2-methylpyrimidin-5-yl)-lH-indol-l-yl)acetate (0.85 g) as a pale yellow solid.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0619
[2]Patent: WO2017/35361,2017,A1 .Location in patent: Paragraph 0570

42
[ 1052686-67-5 ]
2-(1-acetyl-6-(2-methylpyrimidin-5-yl)-1H-indol-3-yl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1

43
[ 1052686-67-5 ]
(2S,4R)-1-(2-(1-acetyl-6-(2-methylpyrimidin-5-yl)-1H-indol-3-yl)acetyl)-N-(2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1
[2]Patent: WO2017/35353,2017,A1

44
[ 1052686-67-5 ]
(2S,4R)-1-(2-(1-acetyl-6-(2-methylpyrimidin-5-yl)-1H-indol-3-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1

45
[ 1052686-67-5 ]
2-(1-acetyl-6-(2-methylpyrimidin-5-yl)-1H-indol-3-yl)acetylazide [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1

46
[ 1052686-67-5 ]
1-(3-isocyanato-6-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)ethan-1-one [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1

47
[ 1052686-67-5 ]
(2S,4R)-N₁-(1-acetyl-6-(2-methylpyrimidin-5-yl)-1H-indol-3-yl)-N₂-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-1,2-dicarboxamide [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1

48
[ 1052686-67-5 ]
3-bromo-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1
[2]Patent: WO2018/160889,2018,A1

49
[ 1052686-67-5 ]
tert-butyl 2-(3-bromo-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1
[2]Patent: WO2018/160889,2018,A1

50
[ 1052686-67-5 ]
tert-butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1
[2]Patent: WO2018/160889,2018,A1
[3]Patent: WO2020/51538,2020,A1

51
[ 1052686-67-5 ]
(2S,4R)-1-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1

52
[ 1052686-67-5 ]
tert-butyl 2-(5-bromo-3-(N-(4-methoxybenzyl)sulfamoyl)-1H-indol-1-yl)acetate [ No CAS ]
tert-butyl 2-(3-(N-(4-methoxybenzyl)sulfamoyl)-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.4%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 120℃; for 2h;Inert atmosphere;	To a mixture of tert-butyl 2-(5-bromo-3-(N-(4-methoxybenzyl) sulfamoyl)-1H-indol-1-yl) acetate (50 mg, 0.098 mmol), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (20 mg, 0.089 mmol), K2CO3(31 mg, 0.22 mmol) in dioxane/H2O (v/v=9:1) was added tetrakis(triphenylphosphine) palladium(0) (10 mg, 0.0089 mmol) under N2atmosphere. The reaction was stirred at 120 C. for 2 hrs under N2atmosphere. After diluted with EtOAc, the mixture was washed with water and brine, dried over anhydrous Na2SO4and concentrated. The obtained crude product was purified by column chromatography on silica gel eluted with DCM/MeOH (100:1 to 50:1) to give the title compound (40 mg, 78.4% yield) as yellow solid. LCMS: m/z (ES+): 523 [M+H]

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0985

53
[ 1052686-67-5 ]
(5-bromo-1H-indazol-6-yl)methanol [ No CAS ]
(5-(2-methylpyrimidin-5-yl)-1H-indazol-6-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	A mixture of (5-bromo-1H-indazol-6-yl)methanol (0.72 g, 3.17 mmol), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (698 mg, 3.17 mmol), K3PO4(2.02 g, 9.5 mmol) and Pd(dppf)2Cl2(252 mg, 0.31 mmol) in co-solvent of dioxane-H2O (dioxane 15.0 mL, H2o 3.0 mL) was purged with argon in a pressure vessel for 5 min and stirred at 100 C. overnight. The reaction mixture was cooled to rt. The volatiles are removed under reduced pressure and the residue was co-evaporated with toluene (30 mL) twice. The remaining solid was used for next step without further purification.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1092

54
[ 1052686-67-5 ]
tert-butyl 2-(5-bromo-3-(methylcarbamoyl)-1H-indazol-1-yl)acetate [ No CAS ]
2-(3-(methylcarbamoyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; at 100℃; for 15.25h;Inert atmosphere;	A mixture of tert-butyl 2-(5-bromo-3-(methylcarbamoyl)-1H-indazol-1-yl)acetate (565 mg), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (405 mg, 1.2 eq), K3PO4(975 mg) and Pd(dppf)2Cl2(0.1 eq) in co-solvent (dioxane 15 mL, H2o 4.0 mL) was purged with argon in a pressure vessel for 5 min and stirred for 15 h at 100 C. The volatiles are removed under reduced pressure and the residue was washed with ethyl acetate twice. The remaining solid was then quenched with citric acid (10%) and the resulting precipitate was collected and dried for next step use without further purification.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1101

55
[ 1052686-67-5 ]
tert-butyl 5-bromo-6-((tert-butoxycarbonyl)oxy)-1H-indazole-1-carboxylate [ No CAS ]
tert-butyl 6-((tert-butoxycarbonyl)oxy)-5-(2-methylpyrimidin-5-yl)-1H-indazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.2 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;	Into a solution of tert-butyl 5-bromo-6-((tert-butoxycarbonyl)oxy)-lH-indazole-l- carboxylate (2.205 g) and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (1.16 g, 5.26 mmol) in dioxane-H20 (25 mL-2.5 mL) K2C03 (1.32 g, 9.56 mmol) and Pddppf k (0.098 g, 0.12 mmol) were added. The mixture was heated at 90 C under Ar for 2 hr. The reaction mixture was cooled to rt, filtered, and concentrated. Residue was purified on ISCO with MeOH in DCM (0-10%) as eluent to give tert-butyl 6-((tert-butoxycarbonyl)oxy)-5-(2-methylpyrimidin-5- yl)-lH-indazole-l-carboxylate (2.2 g) as a light yellow solid.

Reference： [1]Patent: WO2017/35361,2017,A1 .Location in patent: Paragraph 0579

56
[ 1190861-39-2 ]
[ 1052686-67-5 ]
6'-(2-methylpyrimidin-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 110℃; for 24h;Inert atmosphere;	6'-Bromospiro[cyclobutane-l,3'-indolin]-2'-one (120 mg, 476 mupiiotaomicron, Eq: 1), 2-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (157 mg, 714 mupiiotaomicron, Eq: 1.50) and dichlor(l,l '- bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (19.4 mg, 23.8 mupiiotaomicron, Eq: 0.05) were combined with a degassed solution 2M of sodium carbonate (714 mu, 1.43 mmol, Eq: 3.00) and degassed dioxane (4 ml) under nitrogen atmosphere. The reaction mixture was heated to 110 C and stirred for 24h. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (3x). The organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. (0332) The residue was purified by chromatography on silica gel to afford the desired product as a light brown solid (100 mg, 79 %). MS (m/z) = 266.2 [M + H]+
79%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 110℃; for 24h;Inert atmosphere;	6'-bromospiro[cyclobutane-1,3'-indolin]-2'-one (120 mg, 476 mumol, Eq: 1), <strong>[1052686-67-5]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine</strong> (157 mg, 714 mumol, Eq: 1.50) and dichlor(1,1'-bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (19.4 mg, 23.8 mumol, Eq: 0.05) were combined with a degassed solution 2M of sodium carbonate (714 muL, 1.43 mmol, Eq: 3.00) and degassed dioxane (4 mL) under nitrogen atmosphere. The reaction mixture was heated to 110C and stirred for 24h. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (3x). The organic layers were combined and washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the desired product as a light brown solid (100 mg, 79%). MS (m/z)=266.2 [M+H]+;

Reference： [1]Patent: WO2017/76932,2017,A1 .Location in patent: Page/Page column 37-38
[2]Patent: WO2017/76931,2017,A1 .Location in patent: Page/Page column 26; 27

57
[ 1060816-22-9 ]
[ 1052686-67-5 ]
ethyl 2-(2-methylpyrimidin-5-yl)oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With tris-(dibenzylideneacetone)dipalladium(0); 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane; potassium carbonate; In tetrahydrofuran; water; at 65℃; for 16h;	A mixture of <strong>[1060816-22-9]ethyl 2-bromooxazole-5-carboxylate</strong> (0.50 g, 2.3 mmol), 2- methylpyrimidine-5-boronic acid pinacol ester (0.625 g, 2.84 mmol) , (1S,3R,5R,7S)-1,3,5,7- tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.066 g, 0.23 mmol), bis(dibenzylideneacetone)palladium (0) (0.065 g, 0.11 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in a pressure tube was degassed three times with a nitrogen back flush each time. Tetrahydrofuran (7.5 mL) and water (1.5 mL) were added, and the mixture was again degassed three times with a nitrogen back flush each time. The reaction mixture was warmed to 65 C and stirred for 16 hours. The mixture was allowed to cool to ambient temperature, then anhydrous Na2SO4 was added, and the mixture was filtered through diatomaceous earth. The filtrate was then concentrated under reduced pressure. The residue was purified via column chromatography (SiO2, 1-40% ethyl acetate/heptanes) to give the title compound (0.295 g, 1.27 mmol, 56% yield). MS (ESI+) m/z 234 (M+H)+.
56%	With tris-(dibenzylideneacetone)dipalladium(0); (1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane; potassium carbonate; In tetrahydrofuran; water; at 65℃; for 16h;Inert atmosphere; Sealed tube;	A mixture of <strong>[1060816-22-9]ethyl 2-bromooxazole-5-carboxylate</strong> (0.50 g, 2.3 mmol), 2- methylpyrimidine-5-boronic acid pinacol ester (0.625 g, 2.84 mmol) , (15,3R,5R,75)-1 , 3,5,7- tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.066 g, 0.23 mmol), bis(dibenzylideneacetone)palladium (0) (0.065 g, 0.11 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in a pressure tube was degassed three times with a nitrogen back flush each time. Tetrahydrofuran (7.5 mL) and water (1.5 mL) were added, and the mixture was again degassed three times with a nitrogen back flush each time. The reaction mixture was warmed to 65 C and stirred for 16 hours. The mixture was allowed to cool to ambient temperature, then anhydrous Na2SC>4 was added, and the mixture was filtered through diatomaceous earth. The filtrate was then concentrated under reduced pressure. The residue was purified via column chromatography (Si(, 1-40% ethyl acetate/heptanes) to give the title compound (0.295 g, 1.27 mmol, 56% yield). MS (ESI+) m/z 234 (M+H)+.

Reference： [1]Patent: WO2017/193063,2017,A1 .Location in patent: Page/Page column 355
[2]Patent: WO2019/90076,2019,A1 .Location in patent: Page/Page column 289

58
[ 1052686-67-5 ]
2-(2-methylpyrimidin-5-yl)oxazole-5-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2017/193063,2017,A1
[2]Patent: WO2019/90076,2019,A1

59
[ 1052686-67-5 ]
N-{3-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[1.1.1]pentan-1-yl}-2-(2-methylpyrimidin-5-yl)-1,3-oxazole-5-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/193063,2017,A1
[2]Patent: WO2019/90076,2019,A1

60
[ 1052686-67-5 ]
C₂₂H₂₂F₃N₃O₆S [ No CAS ]