[ CAS No. 940284-98-0 ] {[proInfo.proName]}

Name: 940284-98-0|tert-Butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate|98%
Brand: Ambeed
SKU: A567946
Price: 8.0 USD
Availability: InStock
Rating: 98 (35 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 940284-98-0 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 940284-98-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 940284-98-0 ]

SDS Specification

Alternatived Products of [ 940284-98-0 ]

Product Details of [ 940284-98-0 ]

CAS No. :	940284-98-0	MDL No. :	MFCD07781250
Formula :	C₁₉H₃₁BN₄O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YODSUBUWTUTLAZ-UHFFFAOYSA-N
M.W :	390.28	Pubchem ID :	46739020
Synonyms :

Calculated chemistry of [ 940284-98-0 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.74
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	115.71
TPSA :	77.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.3
Log Po/w (WLOGP) :	1.07
Log Po/w (MLOGP) :	0.75
Log Po/w (SILICOS-IT) :	0.6
Consensus Log Po/w :	0.94

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.54
Solubility :	0.113 mg/ml ; 0.00029 mol/l
Class :	Soluble
Log S (Ali) :	-3.56
Solubility :	0.109 mg/ml ; 0.000278 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.86
Solubility :	0.0535 mg/ml ; 0.000137 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.77

Safety of [ 940284-98-0 ]

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 [ 940284-98-0 ]

* 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 [ 940284-98-0 ]
Downstream synthetic route of [ 940284-98-0 ]

[ 940284-98-0 ] Synthesis Path-Upstream 1~3

1
[ 780705-64-8 ]
[ 73183-34-3 ]
[ 940284-98-0 ]

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

2
[ 374930-88-8 ]
[ 73183-34-3 ]
[ 940284-98-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5361 - 5379

3
[ 57260-71-6 ]
[ 940284-98-0 ]

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

[ 940284-98-0 ] Synthesis Path-Downstream 1~77

2
[ 940284-98-0 ]
[ 1246372-62-2 ]
[ 1246372-67-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 110℃; for 2.5h;	Example 19; 4-{5-[2-(3,4-Dimethoxy-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]- pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1 ,3,4]thiadiazole (0.3 g, 0.775 mmol, 1 eq), PdCI2(Ph3P)2 (0.11 g, 0.155 mmol, 0.2 eq), 2-(4-boc- piperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (0.454 g, 1.16 mmol, 1.5 eq) and Na2CO3 (2M aqueous solution, 1.5 mL) in dioxane (4.5 mL) was heated at 110 ºC for 2.5 h. The reaction was cooled down to rt and solvents were removed under reduced pressure. The residue was treated with water, sonicated and filtered. The solid was washed with water, Et2O and dried to give the desired product (416 mg, 100%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50 ºC): t*= 6.48 min, [M+H]+ m/z 524.2; 1H NMR (300 MHz, DMSO) delta 8.99 (s, 2H), 7.70 (s, 1H), 7.55 (d, J = 8.4 Hz, 1 H), 7.47 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 3.88 (s, 3H), 3.86 (s, 3H), 3.80 (m, 4H), 3.43 (m, 4H), 1.43 (s, 9H).

Reference： [1]Patent: WO2010/112874,2010,A1 .Location in patent: Page/Page column 60

3
[ 374930-88-8 ]
[ 73183-34-3 ]
[ 940284-98-0 ]

Reference： [1]Organic Letters,2019,vol. 21,p. 8158 - 8163
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 665 - 687
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

4
[ 940284-98-0 ]
[ 1272972-51-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

5
[ 940284-98-0 ]
[ 1379522-46-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

6
[ 940284-98-0 ]
[ 1272973-41-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

7
[ 940284-98-0 ]
[ 1272972-59-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

8
[ 940284-98-0 ]
[ 1379522-47-0 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

9
[ 940284-98-0 ]
[ 1272973-82-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

10
[ 940284-98-0 ]
[ 1272972-86-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

11
[ 940284-98-0 ]
[ 1379522-48-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

12
[ 940284-98-0 ]
[ 1379522-49-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

13
[ 940284-98-0 ]
[ 1272973-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; In tetrahydrofuran; water; at 20℃; for 1.5h;	In a vessel, tert-butyl 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)piperazine-l-carboxylate (0.5 g, 1.28 mmol) and 35% aqueous hydrogen peroxide (1.2 mL, 12.8 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture diluted to 40 mL with aqueous saturated sodium thiosulfate solution and then extracted with ethylacetate to give the desired product tert-butyl 4-(5-hydroxypyrimidin-2-yl)piperazine-l-carboxylate as a brown oil. This material was used in Step 2 without further purification.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379
[2]Journal of the American Chemical Society,2014,vol. 136,p. 4287 - 4299
[3]Patent: WO2014/160521,2014,A1 .Location in patent: Page/Page column 22-23

14
[ 940284-98-0 ]
[ 1272972-49-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5361 - 5379

15
[ 940284-98-0 ]
[ 1536390-34-7 ]
[ 1536390-94-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 18h;Inert atmosphere;	Intermediate 7 (250 mg, 0.68 mmol) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine- 1 -carboxylate (319 mg, 0.82 mmol) were dissolved in 1,4-dioxane (3 mL). A 2M aqueous solution of potassium carbonate (1.2 mL) was added and the reaction mixture was degassed with nitrogen for 5 minutes. Bis[3 -(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yl]iron-dichloropalladium-dichloro10 methane complex (28 mg, 0.03 mmol) was added and the reaction mixture was heated at90C in a pressure tube for 18 h. The reaction mixture was diluted with EtOAc, washed with water and brine, then dried over sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography, eluting with 0-10% methanol in DCM, to yield the title compound (324 mg, 86%). oH (500 MHz, DMSO-d6)8.69 (s, 2H), 8.40 (s, 1H), 7.55 (d, J9.3 Hz, 1H), 7.48 (d, J 10.7 Hz, 1H), 7.46-7.10 (m,4H), 7.04 (d, J6.8 Hz, 1H), 4.36 (s, 2H), 3.81-3.74 (m, 4H), 3.47-3.39 (m, 4H), 2.32 (s,3H), 1.43 (s, J3.5 Hz, 9H). Method B HPLC-MS: MH+ m/z 551, RT 1.72 minutes(80%).

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 124

16
[ 940284-98-0 ]
[ 1537169-11-1 ]
[ 1537169-51-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 8.5h;Inert atmosphere; Sealed tube;	Intermediate 6 (100 mg, 0.27 mmol) and tert-bvXy 4-[5-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-l -carboxylate (88 mg, 0.225 mmol) were dissolved in 1,4-dioxane (4 mL) and 2M aqueous potassium carbonate solution (475 mu) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yljiron; dichloromethane; dichloro- palladium (11.1 mg, 0.01 mmol) was added. The reaction was heated at 90C for 8.5 h in a sealed tube under nitrogen. The mixture was diluted with EtOAc (20 mL) and washed with water (15 mL). The aqueous phase was diluted with water (15 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography, eluting with heptanes: ethyl acetate 1 :0 to 1 : 1 , to yield the title compound (81 mg, 50%). deltaEta (250 MHz, CDC13) 9.07 (s, 1H), 8.76 (s, 2H), 7.95 (d, J 1.4 Hz, 1H), 7.31 (d, J 7.4 Hz, 1H), 7.13 (m, 2H), 6.94 (m, 1H), 6.64 (t, J29 Hz, 1H), 4.33 (s, 2H), 3.87 (m, 4H), 3.51 (m, 4H), 2.58 (s, 3H), 1.49 (s, 9H). Method A HPLC-MS: MH+ mlz 552, RT 5.01 minutes
50%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 8.5h;Inert atmosphere; Sealed tube;	Intermediate 6 (100 mg, 0.27 mmol) and <strong>[940284-98-0]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate</strong> (88 mg, 0.225 mmol) were dissolved in 1,4-dioxane (4 mL) and 2M aqueous potassium carbonate solution (475 iut) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (11.1 mg, 0.01 mmol) was added. The reaction was heated at 90 C. for 8.5 h in a sealed tube under nitrogen. The mixture was diluted with EtOAc (20 mL) and washed with water (15 mL). The aqueous phase was diluted with water (15 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography, eluting with heptanes:ethyl acetate 1:0 to 1:1, to yield the title compound (81 mg, 50%). deltaH (250 MHz, CDCl3) 9.07 (s, 1H), 8.76 (s, 2H), 7.95 (d, J 1.4 Hz, 1H), 7.31 (d, J 7.4 Hz, 1H), 7.13 (m, 2H), 6.94 (m, 1H), 6.64 (t, J 29 Hz, 1H), 4.33 (s, 2H), 3.87 (m, 4H), 3.51 (m, 4H), 2.58 (s, 3H), 1.49 (s, 9H). Method A HPLC-MS: MH+ m/z 552, RT 5.01 minutes.

Reference： [1]Patent: WO2014/9296,2014,A1 .Location in patent: Page/Page column 90; 91
[2]Patent: US2015/191482,2015,A1 .Location in patent: Paragraph 0471

17
[ 940284-98-0 ]
[ 1571828-48-2 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128
[2]Chemical Communications,2016,vol. 52,p. 11915 - 11918

18
[ 940284-98-0 ]
[ 1571828-51-7 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128

19
[ 940284-98-0 ]
[ 1571828-31-3 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128

20
[ 940284-98-0 ]
[ 34598-49-7 ]
[ 1571828-22-2 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4125 - 4128
[2]Chemical Communications,2016,vol. 52,p. 11915 - 11918

21
[ 780705-64-8 ]
[ 73183-34-3 ]
[ 940284-98-0 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4287 - 4299
[2]Journal of Organic Chemistry,2020,vol. 85,p. 3596 - 3604

22
[ 57260-71-6 ]
[ 940284-98-0 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 4287 - 4299
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 665 - 687

23
[ 940284-98-0 ]
1-(5-Hydroxy-2-pyrimidinyl)-piperazine [ No CAS ]

Reference： [1]Patent: WO2014/160521,2014,A1

24
[ 940284-98-0 ]
2-(4-(6,7-dimethoxyquinazolin-4-yl)piperazin-1-yl)pyrimidin-5-ol [ No CAS ]

Reference： [1]Patent: WO2014/160521,2014,A1

25
[ 940284-98-0 ]
6,7-dimethoxy-4-(4-(5-((4-(trifluoromethyl)benzyl)oxy)pyrimidin-2-yl)piperazin-1-yl)quinazoline [ No CAS ]

Reference： [1]Patent: WO2014/160521,2014,A1

26
[ 24634-02-4 ]
[ 940284-98-0 ]
4-[5-(5-methoxy-1-oxo-1,2-dihydro-isoquinolin-3-yl)-pyrimidin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; ethanol; dichloromethane; water; at 120℃; for 2h;Inert atmosphere; Microwave irradiation;	3-Chloro-5-methoxy-2H-isoquinolin-1-one (100 mg, 0.48 mmol), 2-(4-Boc-piperazin-1- yl)pyrimidine-5-boronic acid pinacol ester (280 mg, 0.72 mmol), K2003 (132 mg, 0.96mmol) and Pd(dppf)C12 (1:1 complex with CH2CI2) (36 mg, 0.044 mmol) in DME/EtOH/H20 4:1:1 (2.5 mL) were added to a microwave vial and the reaction mixture purged with N2 for 10 mm. The reaction mixture was irradiated using a microwave reactor (300W, 120 00, 120 mm). The reaction mixture was concentrated in vacuo passed through a thiol cartridge (Silylcycle ig, 6 mL) eluting with CH2CI2, followed by MeOH. Theorganic fractions were concentrated in vacuo to afford 4-[5-(5-methoxy-1-oxo-1,2-dihydro- isoquinolin-3-yl)-pyrimidin-2-yl]-piperazine- 1 -carboxylic acid tert-butyl ester as a brown solid (210 mg, quant.) which was used in the next step without further purification.AnalpH2_MeOH_4min(1): Rt 3.28 mm; mlz 438 [M+1].

Reference： [1]Patent: WO2015/36759,2015,A1 .Location in patent: Page/Page column 163

27
[ 940284-98-0 ]
7-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-2-vinyl-2,3-dihydrobenzofuran-5 carboxamide [ No CAS ]
t-butyl 4-(5-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-2-vinyl-2,3-dihydrobenzofuran-7-yl)pyrimidin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; Sealed tube;	A reaction vial was charged with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine- 1 -carboxylate (16.09 mg, 0.041 mmol), 7-bromo-N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3 -yl)methyl)-2-methyl-2-vinyl-2,3 -dihydrobenzofuran-5-carboxamide (8.6 mg, 0.021 mmol) and dimethylformamide (0.5mL).A solution of sodium carbonate (87 tl, 0.087 mmol, 1 M) was added and thereaction degassed for ca. 15 minutes with a stream of nitrogen. Tetrakis(triphenyl phosphine)palladium(0) (2.38 1 mg, 2.06 1 jimol) was then added and degassing continued for a few minutes. The vial was sealed and heated to 100 C for ca. 120 minutes. The cooled reactions was diluted with DMF(1 .5 mL) and filtered. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-rim particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 1 0-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-tim particles; Mobile PhaseA: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 35-75% B over 25 minutes, then a 10-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.5mg (27%). ?H NMR (500MHz, DMSO-d6) oe 11.52 (br. s., 1H), 8.79 (s, 2H), 8.31-8.19 (m, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 6.11 (dd,J=17.4, 10.7 Hz, 1H), 5.88 (s, 1H),5.23 (d, J17.1 Hz, 1H), 5.10 (d, J10.4 Hz, 1H), 4.30 (d, J=4.9 Hz, 2H), 3.83 - 3.74 (m,4H), 3.42 (br. s., 4H), 3.29-3.21 (m, 1H), 3.19-3.11 (m, 1H), 2.17 (s, 3H), 2.12 (s, 3H),1.54 (s, 3H), 1.43 (s, 9H). MS(ES): mlz 601 [M+H].

Reference： [1]Patent: WO2015/77194,2015,A1 .Location in patent: Page/Page column 115; 116

28
[ 940284-98-0 ]
9-bromo-3,4-dimethyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)2,5-dihydrobenzo[b]oxepine-7-carboxamide [ No CAS ]
2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-7-(2-(piperazin-1-yl)pyrimidin-5-yl)-2-(prop-1-en-2-yl)-2,3-dihydrobenzofuran-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		A suspension of tetrakis(triphenylphosphine)palladium(0) (2.7 mg, 2.4 jimol) and tert-butyl 4-(5 -(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine- 1-carboxylate (0.0 18 g, 0.046 mmol) and 9-bromo-N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3 -yl)methyl)-3 ,4-dimethyl-2,5 -dihydrobenzo [b]oxepine-7-carboxamide (Example 86, 0.01 g, 0.023 mmol) in degassed DMF (1 mL) was treated with aq. potassium carbonate (0.046 mL, 0.070 mmol) and placed under nitrogen. This mixture was heated at 95C for lh. The reaction was cooled to 60C, quenched with glacialHOAc, and purified by prep. HPLC (Axia Luna 30 x 100 mm column, gradient elution with MeOH-water-TFA). Concentration of the appropriate fraction afforded a glass. This was stirred for 30 mm. with 4M HC1 in dioxane (1 mL) then concentrated and lyophilized from benzene to afford 2-methyl-N-((6-methyl-2-oxo-4-propyl- 1,2- dihydropyridin-3-yl)methyl)-7-(2-(piperazin- 1 -yl)pyrimidin-5-yl)-2-(prop- 1 -en-2-yl)-2,3-dihydrobenzofuran-5-carboxamide, 2 HC1 (0.01 g, 69 % yield) as a white powder. ?H NMR(400MHz, DMSO-d6) oe 11.52 (br.s, 1H), 9.09 (br. s, 2H), 8.83 (s, 2H), 8.23 (t, J4.6 Hz, 1H), 7.88 (d, J1.5 Hz, 1H), 7.68 (s, 1H), 5.90 (s, 1H), 5.00 (s, 1H), 4.85 (s, integration obscured by broad water signal), 4.31 (d, J4.6 Hz, 2H), 4.01 (t, J5.2 Hz, 4H), 3.30 (d,J=16.3 Hz, 1H), 3.21-3.11 (m, 5H), 2.51-2.45 (multiplicity, integrationobscured by solvent), 2.12 (s, 3H), 1.79 (s, 3H), 1.54-1.44 (m, 5H), 0.87 (t, J7.4 Hz,

Reference： [1]Patent: WO2015/77194,2015,A1 .Location in patent: Page/Page column 157; 158

29
[ 940284-98-0 ]
6-bromo-3-[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyrimidine [ No CAS ]
tert-butyl 4-[5-(3-[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyrimidin-6-yl)pyrimidin-2-yl]piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 125℃;Microwave irradiation;	INTERMEDIATE 4 fe/t-Butyl 4-r5-(3-{ r2-(difluoromethoxy)phenyllmethyl\|-2-methylimidazori,2-al- pyrimidin-6-yl)pyrimidin-2-yllpiperazine- 1 -carboxylate Prepared from Example 2 (80 mg, 0.22 mmol), iert-butyl 4-[5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-l-carboxylate (84 mg, 0.22 mmol), sodium carbonate (69 mg, 0.65 mmol) and Pd(dppf)Cl2 (17 mg, 0.022 mmol) in 1,4-dioxane (3 mL) and water (1 mL) according to General Method A. Purification of the crude product by preparative HPLC gave the title compound (110 mg, 91%). LCMS (ES+) 552 (M+H)+, RT 3.26 minutes. GENERAL METHOD A In a 10 mL microwave vial were taken Example 2 (80 mg, 0.22 mmol), the respective boronate acid or ester (1 equivalent) and sodium carbonate (69 mg, 0.65 mmol) in 1,4-dioxane (3 mL) and water (1 mL). The reaction mixture was degassed for 10 minutes and Pd(dppf)Ci2 (17 mg, 0.022 mmol) was added, followed by degassing again for an additional 10 minutes. The reaction mixture was heated at 125C for 1-2 h in a microwave reactor, then diluted with ethyl acetate (-20 mL) and filtered through celite. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The crude material was then purified by preparative HPLC to give the title compound.

Reference： [1]Patent: WO2015/86499,2015,A1 .Location in patent: Page/Page column 84; 85-86

30
[ 940284-98-0 ]
5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole [ No CAS ]
[ 76-05-1 ]
4′-((dimethylamino)methyl)-2-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-sulfonamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The residue was dissolved in TFA (500 mu) and anisole (7.23 mg, 0.067 mmol) and heated to 45C for 18 hr. The reaction mixture was purified by reverse phase HPLC column (acetonitrile/water/0.05% TFA system) and eluted with 0% to 20% MeCN in water. The solution was concentrated to afford 4'-((dimethylamino)methyl)-2-(lH-tetrazol-5-yl)-[l,l'- biphenyl]-3-sulfonamide,TFA salt. LC-MS: calculated for C16H18N6O2S 358.4; observed m/e: 359.3 (M+H)+; NMR delta (ppm) (MeOH): 8.24 (d, 1H), 7.88 (t, 1H), 7.78 (d, 1H), 7.40 (d, 2H), 7.22 (d, 2H), 4.26 (s, 2H), 2.80 (s, 6H).

Reference： [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 240

31
[ 940284-98-0 ]
5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole [ No CAS ]
[ 824-94-2 ]
3-(2-(piperazin-1-yl)pyrimidin-5-yl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
3-(2-(piperazin-1-yl)pyrimidin-5-yl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A microwave reaction vial was charged with tert-butyl 4-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine-l-carboxylate (259 mg, 0.663 mmol) and a mixture of 3-bromo-2-(l-(4-methoxybenzyl)(lH-tetrazol-5-yl))benzenesulfonamide and 3- bromo-2-(2-(4-methoxybenzyl)(lH-tetrazol-5-yl))benzenesulfonamide (225 mg, 0.530 mmol). EtOH (5303 mu) and potassium phospate tribasic (1 M aq. solution, 1591 mu, 1.591 mmol) were added and the reaction mixture was sparged with 2 for 10 min. 1, l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (34.6 mg, 0.053 mmol) was added and the reaction vessel was sealed and heated to 100C for 1 hr in a microwave. The crude reaction mixture was diluted with water and EtOAc. The organic was washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by reverse phase HPLC on a C18 column eluted with 5% to 90% MeCN in water with 0.05% TFA. The solution was concentrated to provide a mixture of 3-(2-(piperazin-l-yl)pyrimidin-5-yl)-2-(l-(and 2-)2-(4-methoxybenzyl)- 2H-tetrazol-5-yl)benzenesulfonamide. LC-MS: calculated for C28H33 9O5S 607.2; observed m/e: 608.6 (M+H)+;

Reference： [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 238

32
[ 940284-98-0 ]
5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole [ No CAS ]
3-(2-(piperazin-1-yl)pyrimidin-5-yl)-2-(2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The mixture of 3-(2-(piperazin-l-yl)pyrimidin-5-yl)-2-(l-(and 2-)2-(4- methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide was dissolved in TFA (2 mL) and anisole (200 mu) and heated to 45C overnight. Purification by reverse phase HPLC with Phenomenex Polar RP column eluted with 0% to 80% MeCN in water. The solution was lyopholized to provide the title compound. LC-MS: calculated for C15H17 9O2S 387.4; observed m/e: 387.4 (M+H)+; 'H NMR delta (ppm) (DMSO): 8.75 (br s, 1H), 8.05-8.03 (m, 1H), 7.98 (s, 2H), 7.81 (br s, 1H), 7.70-7.69 (m, 1H), 3.90 (t, 2H), 3.17 (t, 2H).
		Step C: 5-(2-(Benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole (0291) To a solution of 5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole in a mixture of chloroform and water (6 mL and 8 mL, respectively) were added potassium carbonate (1.544 g, 11.17 mmol), tetrabutylammonium chloride (0.311 g, 1.12 mmol) followed by a solution of 1-(chloromethyl)-4-methoxybenzene (1.14 mL, 8.38 mmol) in 2 mL of CHCl3 at 15 C. The resulting mixture was slowly warm to rt, and heated at 50 C. for 3 hr. The reaction mixture was cooled to rt, and transferred to a sep. funnel. The organic layer was separated, dried over MgSO4, filtered and purified using 5 to 80% ethyl acetate in hexanes to provide a mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole. Step D: 3-Bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide (0292) To a solution of the mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole in DCM (40 mL) was added water (0.251 mL, 13.9 mmol) followed by acetic acid (0.796 ml, 13.91 mmol). The resulting mixture was cooled to 0 C., then a solution of sulfuryl chloride (1.131 mL, 13.91 mmol) in DCM (2 mL) was slowly added. The reaction mixture was slowly warmed to rt, and stirred for 4 hr, and then evaporated to dryness. To this residue was added THF (5 mL) and then a mixture of aqueous ammonium hydroxide and THF (20 mL each) at 0 C. The reaction mixture was slowly warmed to rt and stirred for 1.5 hr. The resulting solution was diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and purified by column chromatography on silica gel eluted with 10 to 90% ethyl acetate in hexanes to provide mixture of 3-bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide. Step A: 3-(2-(Piperazin-1-yl)pyrimidin-5-yl)-2-(1-(and 2-)2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (0841) A microwave reaction vial was charged with <strong>[940284-98-0]tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate</strong> (259 mg, 0.663 mmol) and a mixture of 3-bromo-2-(1-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide (225 mg, 0.530 mmol). EtOH (5303 mul) and potassium phosphate tribasic (1 M aq. solution, 1591 muL, 1.591 mmol) were added and the reaction mixture was sparged with N2 for 10 min. 1,1?-bis(di-tert-butylphosphino)ferrocene palladium dichloride (34.6 mg, 0.053 mmol) was added and the reaction vessel was sealed and heated to 100 C. for 1 hr in a microwave. The crude reaction mixture was diluted with water and EtOAc. The organic was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC on a C18 column eluted with 5% to 90% MeCN in water with 0.05% TFA. The solution was concentrated to provide a mixture of 3-(2-(piperazin-1-yl)pyrimidin-5-yl)-2-(1-(and 2-)2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide. LC-MS: calculated for C28H33N9O5S 607.2; observed m/e: 608.6 (M+H)+; Step B: 3-(2-(Piperazin-1-yl)pyrimidin-5-yl)-2-(2H-tetrazol-5-yl)benzenesulfonamide (0842) The mixture of 3-(2-(piperazin-1-yl)pyrimidin-5-yl)-2-(1-(and 2-)2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide was dissolved in TFA (2 mL) and anisole (200 muL) and heated to 45 C. overnight. Purification by reverse phase HPLC with Phenomenex Polar RP column eluted with 0% to 80% MeCN in water. The solution was lyopholized to provide the title compound. LC-MS: calculated for C15H12N9O2S 387.4; observed m/e: 387.4 (M+H)+; 1HNMR delta (ppm) (DMSO): 8.75 (br s, 1H), 8.05-8.03 (m, 1H), 7.98 (s, 2H), 7.81 (br s, 1H), 7.70-7.69 (m, 1H), 3.90 (t, 2H), 3.17 (t, 2H).

Reference： [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 238
[2]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0291; 0292; 0841; 0842

33
[ 940284-98-0 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
tert-butyl 4-(5-{3-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]phenyl}pyrimidin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 2h;Microwave irradiation;	Example 104A tert-Butyl 4-(5-{3-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]phenyl}pyrimidin-2-yl)piperazine-1-carboxylate 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[940284-98-0]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate</strong> (140 mg, 0.36 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 120 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 70 mg (36% of theory) of the title compound. LC-MS (Method 4): Rt=1.39 min; MS (ESIpos): m/z=810.5 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1096; 1097; 1098

34
[ 940284-98-0 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide [ No CAS ]
tert-butyl 4-[5-(3-{(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[(3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]propyl}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 1.5h;Microwave irradiation;	Example 155A tert-Butyl 4-[5-(3-{(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[(3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]propyl}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide and <strong>[940284-98-0]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate</strong> are dissolved in dimethyl sulphoxide, and tetrakis(triphenylphosphine)palladium(0), sodium carbonate and water are added. The reaction mixture is stirred at 110 C. in a microwave (Biotage Initiator) for 90 min, cooled, filtered and purified chromatographically by HPLC. This gives the title compound.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1248; 1249

35
[ 940284-98-0 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-L-phenylalaninamide [ No CAS ]
tert-butyl 4-[5-(3-{(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]propyl}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 1.5h;Microwave irradiation;	Example 103A tert-Butyl 4-[5-(3-{(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]propyl}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[940284-98-0]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate</strong> (143 mg, 0.37 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 90 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 70 mg (36% of theory) of the title compound. LC-MS (Method 4): Rt=1.29 min; MS (ESIpos): m/z=798.5 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1093; 1094; 1095

36
[ 940284-98-0 ]
methyl 6-bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl)indoline-4-carboxylate [ No CAS ]
methyl 6-[2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrimidin-5-yl]-3-methyl-1-tetrahydropyran-4-yl-indoline-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;	A mixture of 24c (200 mg, 0.56 mmol), <strong>[940284-98-0]tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate</strong> (265 mg, 0.68 mmol, 1.2 eq) and K2CO3 (230 mg, 1.68 mmol, 3 eq) in dioxane:water (4:1, 8 mL) was degassed with N2 for 15 min. To this solution was added PdCl2(dppf)?CH2Cl2 (23 mg, 0.028 mmol, 0.05 eq) and the mixture was again degassed with N2 for 10 min. The reaction mixture was allowed to stir at 90 C for 16 h. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave a crude residue which was purified by SiO2 chromatography using methanol-CH2Cl2 to afford 230 mg (76%) of methyl 6-[2-(4-tert-butoxycarbonylpiperazin-1-yl)pyrimidin-5-yl]-3-methyl-1-tetrahydropyran-4-yl-indoline-4-carboxylate as brownish liquid (42).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 217 - 222

37
[ 940284-98-0 ]
N-(4-azidophenyl)-4-(5-(1-oxo-indan-5-yl)pyrimidin-2-yl)piperazin-1-carbothioamide [ No CAS ]

Reference： [1]Chemical Communications,2016,vol. 52,p. 11915 - 11918

38
[ 940284-98-0 ]
5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole [ No CAS ]
[ 824-94-2 ]
C₂₈H₃₃N₉O₅S [ No CAS ]
C₂₈H₃₃N₉O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step C: 5-(2-(Benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole (0291) To a solution of 5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole in a mixture of chloroform and water (6 mL and 8 mL, respectively) were added potassium carbonate (1.544 g, 11.17 mmol), tetrabutylammonium chloride (0.311 g, 1.12 mmol) followed by a solution of 1-(chloromethyl)-4-methoxybenzene (1.14 mL, 8.38 mmol) in 2 mL of CHCl3 at 15 C. The resulting mixture was slowly warm to rt, and heated at 50 C. for 3 hr. The reaction mixture was cooled to rt, and transferred to a sep. funnel. The organic layer was separated, dried over MgSO4, filtered and purified using 5 to 80% ethyl acetate in hexanes to provide a mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole. Step D: 3-Bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide (0292) To a solution of the mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole in DCM (40 mL) was added water (0.251 mL, 13.9 mmol) followed by acetic acid (0.796 ml, 13.91 mmol). The resulting mixture was cooled to 0 C., then a solution of sulfuryl chloride (1.131 mL, 13.91 mmol) in DCM (2 mL) was slowly added. The reaction mixture was slowly warmed to rt, and stirred for 4 hr, and then evaporated to dryness. To this residue was added THF (5 mL) and then a mixture of aqueous ammonium hydroxide and THF (20 mL each) at 0 C. The reaction mixture was slowly warmed to rt and stirred for 1.5 hr. The resulting solution was diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and purified by column chromatography on silica gel eluted with 10 to 90% ethyl acetate in hexanes to provide mixture of 3-bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide. Step A: 3-(2-(Piperazin-1-yl)pyrimidin-5-yl)-2-(1-(and 2-)2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (0841) A microwave reaction vial was charged with <strong>[940284-98-0]tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate</strong> (259 mg, 0.663 mmol) and a mixture of 3-bromo-2-(1-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide (225 mg, 0.530 mmol). EtOH (5303 mul) and potassium phosphate tribasic (1 M aq. solution, 1591 muL, 1.591 mmol) were added and the reaction mixture was sparged with N2 for 10 min. 1,1?-bis(di-tert-butylphosphino)ferrocene palladium dichloride (34.6 mg, 0.053 mmol) was added and the reaction vessel was sealed and heated to 100 C. for 1 hr in a microwave. The crude reaction mixture was diluted with water and EtOAc. The organic was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC on a C18 column eluted with 5% to 90% MeCN in water with 0.05% TFA. The solution was concentrated to provide a mixture of 3-(2-(piperazin-1-yl)pyrimidin-5-yl)-2-(1-(and 2-)2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide. LC-MS: calculated for C28H33N9O5S 607.2; observed m/e: 608.6 (M+H)+;

Reference： [1]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0291; 0292; 0841

39
[ 940284-98-0 ]
N⁴-benzyl-N⁴-(3'-chloro-[1,1'-biphenyl]-2-yl)pyrimidine-2,4-diamine [ No CAS ]
tert-butyl 4-(5-(2'-((2-aminopyrimidin-4-yl)(benzyl)amino)-[1,1'-biphenyl]-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3511 - 3517

40
[ 940284-98-0 ]
5-bromo-4-fluoro-2-(morpholin-4-yl)aniline [ No CAS ]
N-[4-fluoro-2-morpholin-4-yl-5-(2-piperazin-1-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/147700,2017,A1

41
[ 940284-98-0 ]
5-bromo-4-fluoro-2-(morpholin-4-yl)aniline [ No CAS ]
tert-butyl 4-(5-(5-amino-2-fluoro-4-morpholinophenyl)pyrimidin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;	To a 5 mL microwave vial charged with 5-bromo-4-fluoro-2-(morpholin-4-yl)aniline (190 mg, 0.691 mmol), 2-(4-boc-piperazino)pyrimidine-5- boronic acid pinacol ester (323 mg, 0.829 mmol), bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (48.9 mg, 0.069 mmol) and potassium phosphate tribasic (0.440 g, 2.072 mmol) was added 1,4-dioxane (12 mL) / water (1.3 mL) (9 : 1 mixture) to give a white suspension. The suspension was stirred for 5 min, degassed, purged with N2, and microwaved for 60 min at 110 C. The solvent was evaporated and 15 mL of CH2CI2 were added. The suspension was sonicated and extracted from water (15 mL). The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0-100%, 89% CH2C12, 10% MeOH, 1% NH4Ac/CH2Cl2). The compound was freeze dried for 2 days to afford the title reagent. 11H NMR (500 MHz, MeOD) delta 8.49 (d, J = 1.0 Hz, 2H), 6.87 (d, J = 12.1 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 3.85 (dd, J = 10.0, 7.1 Hz, 8H), 3.52 (s, 4H), 2.94 - 2.90 (m, 4H), 1.49 (s, 9H); LCMS [M+l]+ = 459.40.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00633

42
[ 940284-98-0 ]
(R)-3-bromo-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine [ No CAS ]
tert-butyl (R)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;	General procedure: Step 1. A reaction solution of 3-bromo-5-((2,4-dichlorobenzyl)oxy)pyridine (12a) (200.00?mg, 0.60?mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (13n) (195.00?mg, 0.63?mmol) in 1,4-dioxane (20.00?mL) was purged with nitrogen. Then PdCl2 (PPh3)2 (10.53?mg, 0.015?mmol) and 1.0?M of Na2CO3 (121.89?mg, 1.15?mmol) aqueous solution were added. The resulting mixture was purged with nitrogen and stirred at 90?C for 2?h. The reaction mixture was filtered through a Celite pad and washed well with MeOH. The residue was partitioned between DCM and saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting crude mixture was purified by a silica gel column, eluting with EA:Hexane (1:1) to collect the intermediate product tert-butyl 5-((2,4-dichlorobenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1' (2'H)-carboxylate (201.00?mg, 77%);

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 405 - 422

43
[ 940284-98-0 ]
3-bromo-5-((2,4-dichlorobenzyl)oxy)pyridine [ No CAS ]
tert-butyl 4-(5-(5-((2,4-dichlorobenzyl)oxy)pyridin-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;	General procedure: Step 1. A reaction solution of 3-bromo-5-((2,4-dichlorobenzyl)oxy)pyridine (12a) (200.00?mg, 0.60?mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (13n) (195.00?mg, 0.63?mmol) in 1,4-dioxane (20.00?mL) was purged with nitrogen. Then PdCl2 (PPh3)2 (10.53?mg, 0.015?mmol) and 1.0?M of Na2CO3 (121.89?mg, 1.15?mmol) aqueous solution were added. The resulting mixture was purged with nitrogen and stirred at 90?C for 2?h. The reaction mixture was filtered through a Celite pad and washed well with MeOH. The residue was partitioned between DCM and saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting crude mixture was purified by a silica gel column, eluting with EA:Hexane (1:1) to collect the intermediate product tert-butyl 5-((2,4-dichlorobenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1' (2'H)-carboxylate (201.00?mg, 77%);

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 405 - 422

44
[ 940284-98-0 ]
1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazin-1-yl)pent-4-yn-1-one [ No CAS ]

Reference： [1]Patent: WO2018/204416,2018,A1

45
[ 940284-98-0 ]
1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperazin-1-yl)-5-(trimethylsilyl)pent-4-yn-1-one [ No CAS ]

Reference： [1]Patent: WO2018/204416,2018,A1

46
[ 940284-98-0 ]
2-(piperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 2h;	[00461] To a solution of tert-butyl 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)piperazine-l-carboxylate (2 g, 5.12 mmol, 1 equiv) in dioxane (8.73 mL) was added HCI (4M in dioxane) (12.8 mL, 51.2 mmol, 10 equiv). The reaction stirred for 2 h at room temperature and concentrated to a solid. The crude material was suspended in DCM and concentrated under reduced pressure twice and then dried under reduced pressure for 18 h to yield the product as a yellow solid (1.7 g, 100% yield). LCMS (ESI) m/z: [M + H] calcd for Ci4H23BN402: 291.19; found 291.1.

Reference： [1]Patent: WO2018/204416,2018,A1 .Location in patent: Paragraph 00461

47
[ 940284-98-0 ]
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(3-(trimethylsilyl)prop-2-yn-1-yl)piperazin-1-yl)pyrimidine [ No CAS ]

Reference： [1]Patent: WO2018/204416,2018,A1

48
[ 940284-98-0 ]
7-bromo-N-(pyrazin-2-yl)quinolin-4-amine [ No CAS ]
tert-butyl 4-(5-(4-(pyrazin-2-ylamino)quinolin-7-yl)pyrimidin-2-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 665 - 687

49
[ 940284-98-0 ]
7-(2-(piperazin-1-yl)pyrimidin-5-yl)-N-(pyrazin-2-yl)quinolin-4-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 665 - 687

50
[ 940284-98-0 ]
(S)-N-(3-bromo-6-(3,4-dimethylpiperazin-1-yl)-2,4-difluorophenyl)-4-fluoro-2-(trifluoromethyl)benzamide [ No CAS ]
(S)-N-(6-(3,4-dimethylpiperazin-1-yl)-2,4-difluoro-3-(2-(piperazin-1-yl)pyrimidin-5-yl)phenyl)-4-fluoro-2-(trifluoromethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.8 mg		To a 5 mL microwave vial charged with N-(3-bromo-2-fluoro-6- ((3 S,5R)-3 ,4,5-trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1,6- dihydropyridine-3-carboxamide (52.2 mg, 0.1 mmol), 2-(cyclopropylmethoxy)-5- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine (55 mg, 0.2 mmol), and Pd(dppf)C12 (15 mg, 0.02 mmol, 20 mol%) was added dioxane (3 mL), followed by 1 M aq. K3P04 (0.5 mL, 0.5 mmol). The resulting mixture was irradiated in a microwave apparatus at 110 C for 2 h, diluted with H20 (10 mL) and extracted with EtOAc (20 mL x 2). The combined extracts were concentrated and purified by Biotage (SNAP KPSil 25 g column, gradient: EtOAc/hex 0-100% then MeOH/DCM 0-15%) to give the title compound the title compound as a brown solid (48.7 mg, 7 8%). LCMS [M + Hj+592.3.

Reference： [1]Patent: WO2019/46944,2019,A1 .Location in patent: Paragraph 00148; 00359

51
[ 940284-98-0 ]
4-(5-(6-carbamoylpyridin-2-yl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]