[ CAS No. 957198-30-0 ]

Name: 957198-30-0|4-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine|97%
Brand: Ambeed
SKU: A208155
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Quality Control of [ 957198-30-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 957198-30-0 ]

SDS Specification

Alternatived Products of [ 957198-30-0 ]

Product Details of [ 957198-30-0 ]

CAS No. :	957198-30-0	MDL No. :	MFCD07368246
Formula :	C₁₄H₂₂BN₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HNVAYPJNFUXYII-UHFFFAOYSA-N
M.W :	291.15	Pubchem ID :	16414213
Synonyms :

Calculated chemistry of [ 957198-30-0 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.71
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	84.23
TPSA :	56.71 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 :	No
Log Kp (skin permeation) :	-7.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.27
Log Po/w (WLOGP) :	0.23
Log Po/w (MLOGP) :	-0.01
Log Po/w (SILICOS-IT) :	0.72
Consensus Log Po/w :	0.44

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.52
Solubility :	0.87 mg/ml ; 0.00299 mol/l
Class :	Soluble
Log S (Ali) :	-2.06
Solubility :	2.54 mg/ml ; 0.00871 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.43
Solubility :	0.108 mg/ml ; 0.000371 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.16

Safety of [ 957198-30-0 ]

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

Application In Synthesis of [ 957198-30-0 ]

* 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 [ 957198-30-0 ]
Downstream synthetic route of [ 957198-30-0 ]

[ 957198-30-0 ] Synthesis Path-Upstream 1~1

1
[ 84539-22-0 ]
[ 73183-34-3 ]
[ 957198-30-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere	A mixture of 4- (5-bromopyrimidin-2-yl) morpholine (2.01 g, 8.23 mmol) , bis (pinacolato) diboron (3.8 g, 15 mmol) , potassium acetate (2.5 g, 25 mmol) and Pd (dppf) Cl₂(0.61 g, 0.83 mmol) in 1, 4-dioxane (30 mL) was stirred at 90 under N₂overnight. The reaction mixture was cooled to rt and diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 7/3 to give a white solid product (0.4 g, 88) .[1817]MS (ESI, pos. ion) m/z: 292.0 [M+1]⁺

Reference： [1] Patent: WO2016/615, 2016, A1, . Location in patent: Paragraph 00730

[ 957198-30-0 ] Synthesis Path-Downstream 1~60

1
[ 957198-30-0 ]
[ 583-53-9 ]
[ 1253936-67-2 ]

Yield	Reaction Conditions	Operation in experiment
39%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 100.0℃; for 0.5h;microwave irradiation;	2-(4-Morpholino)pyrimidine-5-boronic acid pinacol ester (300 mg, 1.03 mmol), 1,2- dibromobenzene (243 mg, 1.03 mmol), Bis(triphenylphosphine)palladium (II) chloride (72 mg, 0.10 mmol), aqueous Na2CO3 (2N, 2.58 mL, 5.15 mmol) and DMF (5 mL) are added to a 10 mL microwave tube. Reaction is carried out in a microwave oven at 100 0C for 30 min. The reaction mixture turns black. The mixture is poured into water and extracted with EtOAc. The organic layers are washed with water, brine, dried (Na2SO4) and concentrated. The crude product is purified using biotage eluting with 0-30% EtOAc/Hexane. The desired mono-coupled product elutes at 30% EtOAc. The di- coupled by-product elutes earlier. Removal of the solvent gives 4-[5-(2-bromo-phenyl)- pyrimidin-2-yl]-morpholine as a white solid (130 mg, 39%).

Reference： [1]Patent: WO2010/126811,2010,A1 .Location in patent: Page/Page column 139-140

2
[ 957198-30-0 ]
[ 1160756-09-1 ]
[ 1338377-41-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7334 - 7349

3
[ 957198-30-0 ]
[ 1453861-34-1 ]
[ 1453862-03-7 ]

Yield	Reaction Conditions	Operation in experiment
71.4%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110.0℃; for 0.166667h;Inert atmosphere; Microwave irradiation;	Example 107 Ethyl 2-(3-(4-((3-(2-morpholinopyrimidin-5-yl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 107) To a solution of ethyl 2-(3-(4-((3-bromobenzyl)oxy)phenyl)oxetan-3-yl)acetate (compound of Step 1 a of Example 39, 120 mg, 0.296 mM) and 4-(5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (103 mg, 0.355 mM) in 4 ml dioxane:water (4:1 ), potassium carbonate (82 mg, 0.592 mM) was added and the mixture was degassed with argon for 3 min. To the resulting solution palladium tetrakistriphenylphosphine (17.10 mg, 0.015 mM) was added and the mixture was heated at 1 10 QC for 10 min in microwave. After completion of the reaction, reaction mixture was extracted with ethyl acetate, dried, concentrated and purified by column chromatography to obtain the compound ethyl 2-(3-(4-((3-(2-morpholinopyrimidin-5- yl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (104 mg), as white solid. Yield: 71 .4 %; 1 HNMR (300 MHz, CDCI3) delta: 8.74 (s, 2H), 7.72 (s, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.50-7.40 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 5.14 (s, 2H), 4.75 (s, 4H), 3.90 (q, J = 7.2 Hz, 2H), 3.75 (d, J = 4.5 Hz, 4H), 3.67 (d, J = 4.5 Hz, 4H), 3.08 (s, 2H), 1.02 (t, J = 7.2 Hz, 3H); MS: (e/z) 490.4 (M+1 ).

Reference： [1]Patent: WO2013/128378,2013,A1 .Location in patent: Page/Page column 147; 148

4
[ 957198-30-0 ]
6-bromo-1-[2-(difluoromethoxy)benzyl]-2-(methoxymethyl)-1H-benzimidazole [ No CAS ]
1-[2-(difluoromethoxy)benzyl]-2-(methoxymethyl)-6-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 105.0℃; for 18h;Inert atmosphere;	Example 445 Method O 1-[2-(Difluoromethoxy)benzyl]-2-(methoxymethyl)-6-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-benzimidazole To Example 444 (50 mg, 0.12 mmol) were added <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (44 mg, 0.144 mmol), Pd(PPh3)4 (7.5 mg, 0.006 mmol), 2M aqueous Na2CO3 solution (0.5 mL) and 1,4-dioxane (2.5 mL). The reaction mixture was flushed with nitrogen and heated to 105 C. under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to ambient temperature, MP-TMT resin (Biotage, 0.76 mmol/g, 300 mg, 0.25 mmol) was added and the solution was agitated at room temperature overnight. Ethyl acetate (20 mL) was added and the mixture was passed through a silica pad cartridge, eluting with further ethyl acetate (25 mL) and finally a solution of 20% methanol in ethyl acetate (210 mL). The combined organic phases were concentrated in vacuo. The crude residue was purified by reverse phase preparative HPLC to give the title compound (17 mg, 30%) as a white solid. LCMS (pH 3) M+H 483, RT 1.92 minutes, UV purity 100%; LCMS (pH 10) M+H 483, RT 2.23 minutes, UV purity 100%.

Reference： [1]Patent: US2015/152065,2015,A1 .Location in patent: Paragraph 0746; 0747

5
[ 957198-30-0 ]
N-(3-((7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)oxy)phenyl)acrylamide [ No CAS ]
N-(3-((7-(2-morpholinopyrimidin-5-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)oxy)phenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90.0℃;Inert atmosphere;	To a mixture of N- (3- ( (7-bromo-5- ( (2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl) oxy) phenyl) acrylamide (0.41 g, 0.84 mmol) , 4- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl) morpholine (0.5 g, 2 mmol) , Pd (dppf) Cl2(0.1 g, 0.1 mmol) and potassium carbonate (0.20 g, 1.4 mmol) were added 1, 4-dioxane (20 mL) and water (5 mL) . The system was exchanged with N2and sitrred at 90 overnight. The reaction mixture was cooled to rt and diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM/MeOH (v/v) 9/1 to give a yellow solid product (0.24 g, 51) .[1820]MS (ESI, pos. ion) m/z: 574.8 [M+1]+.

Reference： [1]Patent: WO2016/615,2016,A1 .Location in patent: Paragraph 00731

6
[ 957198-30-0 ]
N-(3-((7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)oxy)phenyl)acrylamide [ No CAS ]
N-(3-((7-(2-morpholinopyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)oxy)phenyl)acrylamide [ No CAS ]

Reference： [1]Patent: WO2016/615,2016,A1

7
[ 84539-22-0 ]
[ 73183-34-3 ]
[ 957198-30-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90.0℃;Inert atmosphere;	A mixture of 4- (5-bromopyrimidin-2-yl) morpholine (2.01 g, 8.23 mmol) , bis (pinacolato) diboron (3.8 g, 15 mmol) , potassium acetate (2.5 g, 25 mmol) and Pd (dppf) Cl2(0.61 g, 0.83 mmol) in 1, 4-dioxane (30 mL) was stirred at 90 under N2overnight. The reaction mixture was cooled to rt and diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 7/3 to give a white solid product (0.4 g, 88) .[1817]MS (ESI, pos. ion) m/z: 292.0 [M+1]+

Reference： [1]Patent: WO2016/615,2016,A1 .Location in patent: Paragraph 00730

8
[ 957198-30-0 ]
7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1-isopropylimidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]
N-[(4-ethoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1-isopropyl-7-[2-(morpholin-4-yl)pyrimidin-5-yl]imidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 110.0℃; for 1h;Inert atmosphere; Microwave irradiation;	100 mg (0.25mmol) 7-chloro-N- [(4-ethoxy-6-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl] -1- isopropylimidazo[1,5-a]pyridine-5-carboxamide (intermediate 201A), 79,5 mg (0.27 mmol) <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> and 29 mg (25 pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.25 ml (0.5 mmol) aqueous sodium carbonate solution (2N), 0.8 ml ethanol und 1.5 ml 1 ,2-dimethoxyethane was added and the resulting mixture heated for 1 h to 110 C in a Biotage Initiator microwave oven. The reaction mixture was concentrated in vacuo and the residue re10 dissolved in DM50, filtered and purified by HPLC (preparative HPLC conditions 1) to yield 37.5mg (28%) of the target compound.?H NMR (400 MHz, DMSO-d6) oe [ppm] = 1.23 (t, 3 H), 1.29 (d, 6 H), 2.17 (s, 3 H), 3.43 (sept, 1 H), 3.67-3.75 (m, 8 H), 4.09 (q, 2 H), 4.34 (d, 2 H), 6.08 (s, 1 H), 7.46 (s, 1 H), 8.04 (s, 1 H), 8.61(t, 1 H), 8.86 (s, 1 H), 8.88 (s, 2 H), 11.44 (s, 1 H).LCMS (conditions 2.1): R 0,9 mm; MS (ESI): [M + H] = 532.

Reference： [1]Patent: WO2016/102493,2016,A1 .Location in patent: Page/Page column 158; 159

9
[ 957198-30-0 ]
3-{3-[4-({N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalanyl}amino)phenyl]-1H-1,2,4-triazol-5-yl}-2,2,3,3-tetrafluoropropanoic acid [ No CAS ]

Reference： [1]Patent: US2016/244437,2016,A1

10
[ 957198-30-0 ]
3-(3-{4-[(N-[trans-4-(aminomethyl)cyclohexyl]carbonyl}-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalanyl)amino]phenyl}-1H-1,2,4-triazol-5-yl)-2,2,3,3-tetrafluoropropanoic acid hydrochloride [ No CAS ]

Reference： [1]Patent: US2016/244437,2016,A1

11
[ 957198-30-0 ]
3-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine [ No CAS ]
N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)-pyrimidin-5-yl]-L-phenylalanine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 1.5h;Microwave irradiation;	Example 144A N-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalanine 3-Bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanine (368 mg, 0.76 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> were dissolved in dimethyl sulphoxide (6 ml), and tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.076 mmol), sodium carbonate (242 mg, 2.3 mmol) and water (1.15 ml, 63.6 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 90 min and then purified chromatographically by HPLC (Method 8). This gave 61 mg (14% of theory) of the title compound. 1H NMR (300 MHz, DMSO-d6): delta=ppm 0.66-0.86 (m, 2H), 1.03-1.27 (m, 3H), 1.35 (s, 9H), 1.44-1.69 (m, 5H), 1.87-2.02 (m, 1H), 2.65-2.76 (m, 2H), 2.94 (dd, 1H), 3.09 (dd, 1H), 3.60-3.76 (m, 8H), 3.87-3.98 (m, 1H), 6.65-6.81 (m, 1H), 6.94 (d, 1H), 7.03 (d, 1H), 7.23 (t, 1H), 7.27-7.41 (m, 2H), 8.62 (s, 2H). LC-MS (Method 4): Rt=1.12 min; MS (ESIpos): m/z=568.3 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1219; 1220; 1221

12
[ 957198-30-0 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 2.5h;Microwave irradiation;	Example 110A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide 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>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (111 mg, 0.38 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 150 min and reacted further as crude product. LC-MS (Method 4): Rt=1.15 min; MS (ESIpos): m/z=711.4 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1114; 1115; 1116

13
[ 957198-30-0 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 2h;Microwave irradiation;	Example 128A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.23 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (99 mg, 0.34 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (26 mg, 23 mumol), sodium carbonate (72 mg, 0.68 mmol) and water (0.34 ml, 19 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 43 mg (25% of theory) of the title compound. LC-MS (Method 4): Rt=1.26 min; MS (ESIpos): m/z=744.5 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1169; 1170; 1171

14
[ 957198-30-0 ]
3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl]-L-phenylalaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 1.5h;Microwave irradiation;	Example 124A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl]-L-phenylalaninamide (150 mg, 0.23 mmol) and <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (107 mg, 0.35 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 gmol), sodium carbonate (74 mg, 0.70 mmol) and water (0.35 ml, 19.5 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 9). This gave 15 mg (9% of theory) of the title compound. LC-MS (Method 4): Rt=1.19 min; MS (ESIpos): m/z=726.4 [M+H]+.

Reference： [1]Patent: US2016/244437,2016,A1 .Location in patent: Paragraph 1157; 1158; 1159

15
[ 957198-30-0 ]
methyl 3-{5-[4-({4-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanyl}amino)phenyl]triazol-3-yl}-2,2,3,3-tetrafluoropropanoate [ No CAS ]
3-{5-[4-({N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalanyl}amino)phenyl]-1H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluoropropanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In N,N-dimethyl-formamide; at 120.0℃; for 0.5h;	Example 86A 3-{5-[4-({N-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-L-phenylalanyl}amino)phenyl]-1H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluoropropanoic acid 125 mg (0.16 mmol) of methyl 3-{5-[4-({4-bromo-N-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-L-phenylalanyl}amino)phenyl]triazol-3-yl}-2,2,3,3-tetrafluoropropanoate and 93 mg (0.32 mmol) of <strong>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> were dissolved in 1.3 ml of dimethylformamide, 0.16 ml (0.32 mmol) of 2 M sodium carbonate solution was added and the mixture was degassed. After addition of 12 mg (0.02 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, the reaction mixture was stirred at 120 C. for 30 min. The reaction solution was filtered through a Millipore syringe filter and purified via preparative HPLC (mobile phase: acetonitrile/water with 0.1% trifluoroacetic acid (gradient)). This gave 72 mg (51% of theory) of the title compound. LC-MS (Method 1): Rt=0.95 min; MS (ESIpos): m/z=854.5 [M+H]+.

Reference： [1]Patent: US2016/280699,2016,A1 .Location in patent: Paragraph 0691; 0692; 0693

16
[ 64-18-6 ]
[ 957198-30-0 ]
4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide formate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%		Example 26A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide formate 4-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>[957198-30-0]4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]morpholine</strong> (107 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 9). This gave 28 mg (18% of theory) of the title compound. LC-MS (Method 4): Rt=1.19 min; MS (ESIpos): m/z=711 [M+H-HCOOH]+.

Reference： [1]Patent: US2016/280699,2016,A1 .Location in patent: Paragraph 0510; 0511; 0512

17
[ 957198-30-0 ]
4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
N-alpha-[trans-4-(aminomethyl)cyclohexyl]carbonyl}-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2016/280699,2016,A1

18
[ 957198-30-0 ]
tert-butyl 8-bromo-3,4-dihydroimidazo [1,2-a: 5 ,4-b’]dipyridine-1(2H)-carboxylate [ No CAS ]
tert-butyl 8-(2-morpholinopyrimidin-5-yl)-3,4-dihydroimidazo[1,2-a:5,4-b’]dipyridine-1 (2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90.0℃; for 16h;Inert atmosphere; Sealed tube;	A mixture of tert-butyl 8-bromo-7-methyl-3,4-dihydroimidazo [1,2-a: 5,4-b?j dipyridine- 1 (2H)-carboxylate (200 mg, 0.546 mmol), (6-methoxypyridin-3 -yl)boronic(84 mg, 0.546 mmol), 2 M solution of aqueous potassium carbonate (426 pi, 0.852mmol), and dioxane (4 mL) was purged with bubbled nitrogen for 10 mm. PdC12(dppf)- CH2C12 adduct (44.6 mg, 0.055 mmol) was added, the vial was purged with nitrogen, sealed with a Teflon cap and heated at 90 C for 16 h. The reaction mixture was cooledroom temperature and added to a saturated solution of aqueous sodium bicarbonate.mixture was extracted with ethyl acetate. The combined organic layers were washedbrine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (100% ethyl acetate) to afford tert-butyl 8-(6-methoxypyridin-3-yl)-7-methyl-3 ,4-dihydroimidazo[ 1,2-a: 5 ,4-b?j dipyridine-1(2H)-carboxylate (189 mg, 0.455 mmol, 83% yield). Following the metal-mediated coupling procedure and purification method used in the preparation of Intermediate 1 B, tert-butyl 8-bromo-3,4-dihydroimidazo[ 1,2-a: 5,4-b?j dipyridine-1(2H)-carboxylate (Intermediate 5A, 120 mg, 0.341 mmol) was reacted with 4-(5 -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (109 mg,0.375 mmol) to afford tert-butyl 8-(2-morpholinopyrimidin-5 -yl)-3 ,4-dihydroimidazo[1,2-a:5,4-b?jdipyridine-1(2H)-carboxylate (120 mg, 0.275 mmol, 81% yield). LC/MS (M+H) 437.3; ?H NMR (500MHz, chloroform-d) oe 8.56 (s, 2H), 8.01 (s, 1H), 7.57 (d, J9.3 Hz, 1H), 7.25 (dd, J9.3, 1.7 Hz, 1H), 3.84 (dt, J33.3, 4.5 Hz, 1OH), 2.97 (t, J=6.6 Hz, 2H), 2.12 (dq,J=6.5, 5.8 Hz, 2H), 1.50 (br. s., 9H).

Reference： [1]Patent: WO2016/149439,2016,A1 .Location in patent: Page/Page column 39; 52

19
[ 957198-30-0 ]
rac-(1R,9bR)-8-bromo-1-(2-(difluoromethoxy)phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one [ No CAS ]
rac-(1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85.0℃; for 0.75h;Inert atmosphere;	General procedure: Step 7: r c-(l ?,9b ?)-l-(2-(Difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2^-dihydro- lH-pyrrolo[2,l-a]isoiiidoI-5(9bH)-oise A flask under nitrogen was charged with 8-bromo-l-(2-(difluorometlioxy)phenyl)-2,3-diliydro-lH- pyrrolo[2,l -a]isoindol-5(9bH)-one (0.090 g, 0.228 mmol) as an approximately 1 :1 mixture of diastereomers, 1 ,4-dioxane (4 mL) and water (1 mL), 4-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)mo:^oline (0.073 g, 0.251 mmol), cesium carbonate (0.149 g, 0.457 mmol) and PdCl2(PPh3)2 (0.01 1 g, 0.016 mmol). The mixture was heated to about 85 C for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. The material was purified by preparative reverse phase chromatography (Table C, Method 1). The shorter Rt compound fraction was lyophilized to give the title compound (0.0206 g, 19%); LC/MS (Table A, Method a) R. = 2.20 min; MS m/z: 479 (M+H)+

Reference： [1]Patent: WO2016/168638,2016,A1 .Location in patent: Page/Page column 81; 85

20
[ 957198-30-0 ]
8-bromo-1-(2-(difluoromethoxy)phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one [ No CAS ]
rac-(1R,9bR)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one [ No CAS ]
rac-(1R,9bS)-1-(2-(difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%; 22%	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85.0℃; for 0.75h;Inert atmosphere;	Step 7: r c-(l ?,9b ?)-l-(2-(Difluoromethoxy)phenyl)-8-(2-morpholinopyrimidin-5-yl)-2^-dihydro- lH-pyrrolo[2,l-a]isoiiidoI-5(9bH)-oise A flask under nitrogen was charged with 8-bromo-l-(2-(difluorometlioxy)phenyl)-2,3-diliydro-lH- pyrrolo[2,l -a]isoindol-5(9bH)-one (0.090 g, 0.228 mmol) as an approximately 1 :1 mixture of diastereomers, 1 ,4-dioxane (4 mL) and water (1 mL), 4-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)mo:^oline (0.073 g, 0.251 mmol), cesium carbonate (0.149 g, 0.457 mmol) and PdCl2(PPh3)2 (0.01 1 g, 0.016 mmol). The mixture was heated to about 85 C for about 45 min. The mixture was cooled to rt then concentrated under reduced pressure. The material was purified by preparative reverse phase chromatography (Table C, Method 1). The shorter Rt compound fraction was lyophilized to give the title compound (0.0206 g, 19%); LC/MS (Table A, Method a) R. = 2.20 min; MS m/z: 479 (M+H)+

Reference： [1]Patent: WO2016/168638,2016,A1 .Location in patent: Page/Page column 81

21
[ 957198-30-0 ]
rac-(1R,10bR)-9-bromo-1-(2-(difluoromethoxy)phenyl)-3,4-dihydro-1H-[1,4]oxazino[3,4-a]isoindol-6(10bH)-one [ No CAS ]
rac-(1R,10bR)-1-(2-(difluoromethoxy)phenyl)-9-(2-morpholinopyrimidin-5-yl)-3,4-dihydro-1H-[1,4]oxazino[3,4-a]isoindol-6(10bH)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 80.0℃; for 2.5h;	Step 4: rac-(l/^10bli)-l-(2-(Difluoromethoxy)phenyl)-9^^ 1 H~ [ 1 ,4] ox azi n o [3,4-a] isomdol-6( 10bH)~oae A flask under nitrogen was charged with with rac-(li?J 0bi?)-9-bromo-l-(2-(difluoromethoxy)phenyi)- 3,4-dihydro-lH-[l,4]oxazino[3,4-]isoindol-6(10bH)-one (0.200 g, 0.488 mmol), 4-(5-(4,4,5,5- tetramethyi-l,3,2-dioxaboroian-2-yl)pyrimidin-2-yl)moi"pholine (0.170 g, 0.585 mmol), 1,4-dioxane (8 mL), water (2 mL), cesium carbonate (0.238 g, 0.731 mmol) and dCi?i i'Pi i - (0.0342 g, 0.049 mmol). The mixture was warmed to about 80 C for about 2.5 h then cooled to rt, diluted with EtOAc (70 mL) and washed with water (2 x 10 mL). The organic layer was dried over MgS04 then filtered and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (5- 80% EtOAc/heptane). The appropriate fractions were collected and concentrated under reduced pressure to give the title compound (0.150 g, 59%); LC/MS (Table A, Method a) R, = 2.13 min; MS m/z: 495 (M?H) FontWeight="Bold" FontSize="10"

Reference： [1]Patent: WO2016/168638,2016,A1 .Location in patent: Page/Page column 83

22
[ 957198-30-0 ]
6-bromo-3-(2-(difluoromethoxy)phenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one [ No CAS ]
3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90.0℃; for 0.5h;Inert atmosphere;	Example 1 : 3-(2-(Difluoromethoxy)phenyl)-6-(2-morphoIinop rimidin-5-yl)-2,3- dihydropyrizoIo[i,2-a]indaz I-9(Ui)-osie 6-Bromo~3-(2-(difluoromethoxy)phenyj)-2,3~dihydiOpyrazolo[l ,2-a]indazol-9(l H)-one (0.400 g, 1.012 mmol) (Preparation 1), 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimLdin-2-yl)mophiholine (0.442 g, 1.52 mmol) and cesium carbonate (0.989 g, 3.04 mmol) were added to a flask with 1,4-dioxane (3 mL) and water (0.75 mL). The flask was purged and flushed with N2. Pd(Ph3P)4 (0.082 g, 0.071 mmol) was then added and mixture was purged again and then heated to 90 C under N2 for about 30 min. The mixture was cooled to rt and aqueous sodium bicarbonate solution (5 ml.) and EtOAc (10 ml,) were added. The acqueous layer was extracted with EtOAc (3 x 5 mL), then the organics were dried over MgS04 and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel (0 - 100% EtOAc/DCM then 0 - 10% MeOH/DCM). The fractions were concentrated then purified further via flash chromatography on silica gel (100% EtOAc) to give the title compound (0.335 g, 69%). LC/MS (Table A, Method a) R, - 2.07 min; MS m/z 480 (M+H) TNF IC50 = A

Reference： [1]Patent: WO2016/168638,2016,A1 .Location in patent: Page/Page column 64

23
[ 957198-30-0 ]
6-bromo-3-(2-methoxyphenyl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one [ No CAS ]
3-(2-methoxyphenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; for 0.2h;Reflux;	Example 12: 3-(2-Methoxyphenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[l,2- oliiK A mixture of 2-(4-iotaetaomicron 1iotaomicron1etaomicron)rho)tau iotaeta{eta6-5-BetathetaGammaomicroneta? acid pinacol ester (0.063 g, 0.217 mmol), 6-bromo- 3-(2-mefhoxyphenyl)-2,3-dihydropyrazolo[l ,2-a]inda5:ol-9(lH)-one (0.052 g, 0.145 mmol) (Preparation 17), Pd(Ph3P)4 (0.017 g, 0.014 mmol), and cesium carbonate (0.141 g, 0.434 mmol) in 1,4-dioxa.ne ( 1.2 mLVwater (0.3 mL) was heated at reflux for about 12 min. After cooling, the reaction mixture was partitioned between EtOAc (5 mL) and water (5 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 2 mL). The combined organics were washed with saturated aqueous NaCl (5 mL), dried over Na2S0 , filtered, and concentrated under reduced pressure. The material was purified via flash chromatography on silica gel (0-50% of 1 :9 MeOH:EtOAc/DCM) to give the title compound (0.056 g, 87 %).; LC/MS (Table A, Method a) R, - 2.03 min; MS m/z: 444 (M+H)+.

Reference： [1]Patent: WO2016/168638,2016,A1 .Location in patent: Page/Page column 75; 76

24
[ 957198-30-0 ]
6-bromo-2-methyl-1H-indazol-3(2H)-one [ No CAS ]
2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-indazol-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 90.0℃; for 2h;Inert atmosphere;	Preparation 2 : 2-MethyI-6-(2-morpholinopyrimidin-5- l)-lH-indazol-3(2H)- i'dl PPh ; ') FontWeight="Bold" FontSize="10" (0.6 g, 0.5 mmol) was added to a suspension of 6-bromo-2-methyl-lH-indazol-3(2H)-one (1.67 g, 7.35 mmol) (Preparation 1), 4-(5-(4,4,5,5 elTamethyl-l ,3,2-dioxaborolan-2-yl)pyrimidin-2- yl)morpholine (2.57 g, 8.83 mmol) and CsiC03(5.99 g, 18.4 mmol) in 1 ,4-dioxane (20 mL) and water (5.0 mL) under N2. The mixture purged with N2 and then heated to about 90 C for about 2 h. The reaction mixture was allowed to cool to rt. DCM (30 mL) with a few drops of MeOH and water (20 mL) were added. The solid was collected by filtration then dried to give the title product (1.88 g, 82%); LC/MS (Table A, Method e) R, = 1.41 min; MS m/z; 312 (M+H)+

Reference： [1]Patent: WO2016/168633,2016,A1 .Location in patent: Page/Page column 67

25
[ 957198-30-0 ]
6-bromo-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-indazol-3(2H)-one [ No CAS ]
1-(2-(difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-indazol-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100.0℃; for 2h;Inert atmosphere;	Example 5: l-(2-(Difluoromethoxy)bcnzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-lH-i 3(2H)-one 1,4-Dioxane (2 mL) and water (0.5 mL) were added to 6-bromo- l ~(2-(difluoromethoxy)benzyl)~2-methyl~ lH-indazol-3(2H)-one (0.060 g, 0.16 rnmol) (Preparation 4, step 1), 4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (0.059 g, 0.20 rnmol) and Cs2C03 (0.128 g, 0.391 rnmol). The mixture was placed under N2. Pd(PPh3)4 (0.013 g, 1 1 muiotaetaomicron) was added. The mixture was purged with N2 and then heated to about 100 C. After about 2 h, the reaction mixture was allowed to coo to rt. Water (5 mL) was added and then the mixture was extracted with 5% MeOH/DCM (2 x 1 0 mL). The combined organics were dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10-100% EtOAc/DCM) to give the title product (60 mg, 82%); LC/MS (Table A, Method a) R, = 2.07 min; MS m/z: 468 ( M i l s ' t/i X iC50 = A).

Reference： [1]Patent: WO2016/168633,2016,A1 .Location in patent: Page/Page column 134

26
[ 957198-30-0 ]
6-bromo-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-pyrazolo[4,3-b]pyridin-3(2H)-one [ No CAS ]
1-(2-(difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85.0℃; for 0.75h;Inert atmosphere;	Step 4: l-(2-(Dflsoromettooxy)foeizy)-2-mettoy-6^ b]pyridiii-3(2H)-one A mixture of 6-bromo-l-(2-(difluoromethoxy)benzyr)-2-methyl-lH-pyrazolo[4,3-b]pyridin-3 (0.025 g, 0.065 rnmol, 4-(5~(4,4,5,5 etramethyl~l,3,2~dioxaborolan^ (0.023 g, 0.078 mmol), cesium carbonate (0.045 g, 0.14 mol) and PdCl2(PPh3)2 (0.004 g, 0.006 mmol) in 1,4-dioxane (1 mL) and water (0,25 mL) was degassed with N2 then heated to about 85 C for about 45 min. The reaction mixture was cooled, filtered through a 0.45 muMu filter then purified by preparative reverse phase ITPLC (Table A, Method c). Lyophilization of the appropriate fractions yielded the title compound (0.012 g, 40%); LC/MS (Table A, Method a) R, = 1.88 min; MS m/z: 469 (M+H)+(TNF 1C50 = C).

Reference： [1]Patent: WO2016/168633,2016,A1 .Location in patent: Page/Page column 157

27
[ 957198-30-0 ]
6-chloro-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-pyrazolo[3,4-b]pyridin-3(2H)-one [ No CAS ]
1-(2-(difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 100.0℃; for 0.5h;Inert atmosphere;	Step 4: l-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-lH-pyrazolo[3,4- b]pyridin-3(2H)-one A mixture of 6-chloro- 1 -(2-(difluoromethoxy)benzyl)-2-methyl- lH-pyrazolo[3,4-b]pyridin-3(2H)-one (0.075 g, 0.22 mmol), 4-(5-(4,4,5,5 etramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)moipholine (0.081 g, 0.28 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in 1 ,4-dioxane (2 ml.) and water (0.5 mL) under N2 was treated with PdCT2(PPh3)2 (0.011 g, 0.015 mmol). The mixture was purged with 2 and then heated to about 100 C for about 30 min. The reaction mixture was cooled, filtered through a 0.45 muMu filter then purified by preparative reverse phase HPLC (Table A, Method d). Lvophilization of the appropriate fractions yielded the title compound (0.086 g, 83%); LC/MS (Table A, Method a) R, = 2.15 min; MS m/z: 469 (M?H)+ (TNF IC50 = B).

Reference： [1]Patent: WO2016/168633,2016,A1 .Location in patent: Page/Page column 158-159

28
[ 957198-30-0 ]
6-chloro-1-(2-(difluoromethoxy)benzyl)-2-methyl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one [ No CAS ]
1-(2-(difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 100.0℃; for 1h;Inert atmosphere;	Step 4: l-(2-(Difluoromethoxy)benzyl)-2-methyl-6-(2-morpholinopyrimidin-5-yl)-lH-pyrazolo[4,3- c]pyridin-3(2H)-one A mixture of 6-chloro-l -(2-(difluoromethoxy)benzyl)-2-memyl-lH^yrazolo[4,3-c]pyridin-3(2/i)-one (0.270 g, 0.795 mmol), 4-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholine (0.301 g, 1.03 mmol), cesium carbonate (0.647 g, 1.99 mmol), 1 ,4-dioxane (6.0 mL) and water (1.5 ml,) was degassed with N2. PdCl2(PPh3)2 (0.056 g, 0.079 mmol) was added to the mixture. The reaction was degassed under N2 and heated at about 100 C for about 1 h then allowed to cool to rt. The reaction mixture was partitioned between EtOAc (30 mL) and sat. aq. NaCl (30 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The material was purified via flash chromatography on silica gel (0-3% MeOH/DCM) to yield the title compound (0.280 g, 71%); LC/MS (Table A, Method e) R, = 1.88 min; MS m/z: 469 (M+H)+. (TNF IC50 = C).

Reference： [1]Patent: WO2016/168633,2016,A1 .Location in patent: Page/Page column 160-161

29
[ 957198-30-0 ]
7-bromo-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine [ No CAS ]
7-(2-morpholinopyrimidin-5-yl)-4-phenyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; at 100.0℃; for 4h;Sealed tube;	In a 4 mL vial equipped with a magnetic stirrer was added 7-bromo-4-phenyl-3,4-dihydro-lH- benzo[4,5]imidazo[2, l-c][l,4]oxazine (0.100 g, 0.304 mmol, Preparation 26), 4-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)mophiholine (0.133 g, 0.456 mmol), and Pd(dppf)Cl2 FontWeight="Bold" FontSize="10" DCM (0.024 g, 0.030 mmol). 4 mL of dry, degassed 1,4-dioxane was added to the vial followed by the addition of 1M Cs2C03 (0.600 mL, 0.6 mmol). The vial was sealed and heated at about 100 C for about 4 h. The mixture was filtered through Celite, and evaporated to dryness, and purified by flash-column chromatography on silica gel (1-10% MeOH/DCM) to obtain the title compound (0.071 g, 64%); LC/MS (Table 1, Method e) P = 1.36 min; MS m/z: 414 (M+H)+ . (TNF IC50=A).

Reference： [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 257

30
[ 957198-30-0 ]
[ 1279027-03-0 ]
[ 1279028-30-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 90.0℃; for 24h;Inert atmosphere;	General procedure: To a mixture of tert-butyl {2-[(3-bromobenzyl)(methyl)amino]-2-oxoethyl}carbamate (2; 226 mg, 0.63 mmol) in DME (2.3 mL)/water (1.1 mL) were added 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine (3a; 193 mg, 0.66 mmol), Na2CO3 (201 mg, 1.90 mmol), and Pd(PPh3)4 (22 mg, 0.019 mmol)under a nitrogen atmosphere. The mixture was stirred at 90 C for 24 h. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with waterand extracted with CHCl3. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH = 98:2), and washed with iPr2O to give the product (230 mg, 83%) as a colorless solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4110 - 4122

31
[ 957198-30-0 ]
[ 1279027-03-0 ]
N-methyl-N-{3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}glycinamide (2R,3R)-tartrate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4110 - 4122

32
[ 957198-30-0 ]
α-cumyl bromodifluoromethanesulfenate [ No CAS ]
4-(5-((bromodifluoromethyl)thio)pyrimidin-2-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With [(1,2-bis(diphenylphosphino)ethane)CuCl]; sodium t-butanolate; In toluene; at 50.0℃; for 2h;Glovebox; Sealed tube;	In the glove box, the DPPECuCl (25 mg, 10 muM %) and NaOt Bu (15 mg, 30 muM %) is added to the in tube sealing, and then adding <strong>[957198-30-0]4-(5-(boronic acid pinacol ester)pyrimidine-2-yl)morpholine</strong> (0.5 mmol, 1.0 equiv, 146 mg) and compound I-1 (0.6 mmol, 1.2 equiv, 178 mg), 2 ml toluene, 50 C stirring 2 h. After the reaction, steaming and under reduced pressure, the residue passes through the rapid silica gel column chromatography, to obtain white solid 143 mg, yield 88%. After hydrogen spectrum identifying the purity of greater than 95%.

Reference： [1]Patent: CN107011219,2017,A .Location in patent: Paragraph 0152-0154
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 2413 - 2417
Angew. Chem.,2019,vol. 131,p. 2435 - 2439,5

33
[ 957198-30-0 ]
[ 15852-73-0 ]
[ 1400754-84-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80.0℃; for 2.5h;Inert atmosphere;	General procedure: To a solution of 4-(5-bromopyrimidin-2-yl)morpholine (17;4.10 g, 16.8 mmol) and ethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (6.34 g, 21.8 mmol) in DME(82 mL)/H2O (41 mL) were added Na2CO3 (5.34 g, 50.4 mmol),and Pd(PPh3)4 (1.94 g, 1.68 mmol) under an argon atmosphere.The mixture was stirred at 80 C for 2.5 h. After being cooled toroom temperature, the mixture was diluted with H2O and EtOAc.The mixture was filtered, and the filtrate was separated. Theorganic layer was washed with H2O and brine, dried over Na2SO4,and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (hexane/EtOAc = 17:3 to 3:2) and columnchromatography on amino functionalized silica gel (hexane/EtOAc = 9:1 to 7:3) to give the product (5.29 g, 96%) as a colorlesssolid. 1H NMR (DMSO-d6): d 1.19 (3H, t, J = 7.1 Hz), 3.64-3.79 (8H,m), 3.72 (2H, s), 4.10 (2H, q, J = 7.1 Hz), 7.25 (1H, d, J = 7.6 Hz),7.35-7.45 (1H, m), 7.50-7.58 (2H, m), 8.70 (2H, s); MS (ESI) m/z[M+H]+ 328.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 6024 - 6038

34
[ 957198-30-0 ]
[ 15852-73-0 ]
3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate (2R,3R)-tartrate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 6024 - 6038

35
[ 957198-30-0 ]
N-(5-bromo-4-fluoro-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]
N-[4-fluoro-2-(4-methylpiperazin-1-yl)-5-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 120.0℃; for 1h;Microwave irradiation; Inert atmosphere;	In a 5 niL microwave vial N-(5-bromo-4-fluoro-2-(4-methylpiperazin- l-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (29.67 mg, 0.062 mmol), <strong>[957198-30-0]2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester</strong> (54.3 mg, 0.187 mmol), sodium carbonate, anhydrous (65.9 mg, 0.622 mmol), XPhos (5.93 mg, 0.012 mmol) and XPhos Pd G2 (9.78 mg, 0.012 mmol) were dissolved in water (1166 mu) and 1,4-dioxane (1943 mu) to give a white suspension. The suspension was stirred for 5 min, degassed, purged with N2, and micro waved for 60 min at 120 C. The solvent was evaporated and 15 ml of CH2CI2 were added. The suspension was sonicated and extracted from water. The solvent was evaporated in vacuo yielding the crude product that was purified by flash column chromatography on silica gel (0- 100%, 89% CH2CI2, 10% MeOH, 1% NH4Ac/CH2Cl2) to afford the desired compound in 61% yield. 11H NMR (500 MHz, MeOD) delta 8.55 (s, 2H), 7.97 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 12.0 Hz, 1H), 6.92 (s, 1H), 3.86 - 3.82 (m, 4H), 3.78 - 3.74 (m, 4H), 3.01 (s, 4H), 2.66 (s, 4H), 2.37 (s, 3H); LCMS [M+H]+ 562.7.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00202; 00204

36
[ 957198-30-0 ]
(2S,6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2,6-trimethylpiperazine [ No CAS ]
4-(5-(2-fluoro-5-nitro-4-((3S,5R,)-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidin-2-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; at 110.0℃; for 2h;Microwave irradiation;	To a 20 mL microwave vial charged with (2S,6R)-4-(4-bromo-5-fluoro-2- nitrophenyl)-l,2,6-trimethylpiperazine (1.04 g, 3 mmol), 2-(4^omicron etaomicron1etaomicron^etaetaeta^eta6-5- boronic acid pinacol ester (1.22 g, 4.2 mmol), and Pd(dppf)Cl2 (220 mg, 0.3 mmol, 10 mol%) was added dioxane (10 mL), followed by 1 M aq K3PO4 (5.0 mL, 5 mmol). The resulting mixture was irradiated in microwave at 110 oC for 2 h, diluted with H20 (10 mL) and extracted with EtOAc (30 mL x 2). The combined extracts were concentrated and purified by Biotage SNAP KP-Sil and 100 g column (EtO Ac/hex 0-100% then MeOH/DCM 0-15%) to give the crude nitro. LCMS [M+H]+ = 431.3.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00210

37
[ 957198-30-0 ]
1-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine [ No CAS ]
1-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; at 95.0℃;Inert atmosphere; Sealed tube;	A 30 mL vial was charged with a mixture of l-(4-bromo-5-fiuoro-2- nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (0.092 g, 0.277 mmol), 2-(4- Mo holino)pyrimidine-5-boronic acid pinacol ester (0.113 g, 0.388 mmol), XPhos Pd G2 (4.36 mg, 5.54 muetaiotaomicron) and XPhos (2.64 mg, 5.54 muetaiotaomicron). The vial was sealed with a cap/septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (4 ml) and 2M Aq sodium carbonate (0.692 ml, 1.385 mmol) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated in an aluminum block overnight at 95 C. LCMS [BJW-5015-0054-01; more polar method] indicated clean conversion to the desired product. The reaction mixture was loaded onto celite and purified by flash [0.5-10% MeOH/DCM + 1% NH4OH] to afford l-(5-fluoro-4-(2- mophiholinopyrilnidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyltauolidin-3-amine (0.271 mmol, 98 % yield) as a yellow film that was >95% pure by LCMS. LCMS [M+H]+: 417.3.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00228

38
[ 957198-30-0 ]
cis-4-(4-bromo-5-methoxy-2-nitrophenyl)-1,2,6-trimethylpiperazine [ No CAS ]
4-(5-(2-methoxy-5-nitro-4-(cis-3,4,5-trimethylpiperazin-1-yl)phenyl)pyrimidin-2-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 90.0℃; for 18h;Inert atmosphere;	A reaction vial was charged with a mixture of cis-4-(4-bromo-5- methoxy-2-nitrophenyl)-l,2,6-trimethylpiperazine (0.11 g, 0.31 mmol), 2-(4- mo holino)pyrimidine-5-boronic acid pinacol ester (0.098 g, 0.34 mmol), XPhos Pd G2 (5 mg, 6 muetaiotaomicron) and XPhos (3 mg, 6 muetaiotaomicron). The vial was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (3 mL) and 2 M aqueous sodium carbonate (0.5 mL) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated to 90 C in an aluminum block for 18 h. After cooling to room temperature the reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] to afford 4-(5-(2-methoxy-5-nitro-4-(cis-3,4,5-trimethylpiperazin-1- yl)phenyl)pyrimidin-2-yl)moipholine (0.14 g, 100 %). LCMS [M+H]+: 443.3.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00295

39
[ 957198-30-0 ]
N-(5-bromo-4-(trifluoromethyl)-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]
N-[5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[rac-(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-4-(trifluoromethyl)phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 110.0℃; for 1h;Microwave irradiation; Inert atmosphere;	N-(5 -bromo-4-(trifluoromethyl)-2-((3S , 5R)-3 ,4, 5 -trimethylpiperazin- 1 - yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxarnide (50 mg, 0.09 mmol), <strong>[957198-30-0]2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester</strong> (37 mg, .126 mmol), XPhos Pd G2 (14 mg, 0.018 mmol), Xphos (9 mg, 0.018 mmol) and sodium carbonate, anhydrous (95 mg, 0.9 mmol) were taken in a microwave vial. 1,4-Dioxane (4 ml) and water (1 ml) were added and stirred for 5 min. The white suspension was purged with argon and the reaction mixture was heated in the microwave for 60 min at 110 C. The mixture was concentrated onto celite and purified on preparative column, eluting with water/acetonitrile gradient to isolate the title compound as a white solid (10.5 mg, 17 %). 1H NMR (500MHz, METHANOL-d4) delta = 8.30 (s, 2H), 8.05 (s, 1H), 7.99 (br. s., 1H), 7.62 (s, 1H), 7.01 - 6.84 (m, 1H), 3.87 - 3.82 (m, 4H), 3.79 - 3.75 (m, 4H), 3.15 (d, J=11.7 Hz, 2H), 3.02 (br. s., 2H), 2.90 - 2.81 (m, 2H), 2.66 - 2.64 (m, 3H), 1.29 (d, J=6.2 Hz, 6H); LCMS [M+H]+ 640.7.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00305

40
[ 957198-30-0 ]
N-(5-bromo-4-methyl-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]
N-[4-methyl-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[rac-(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; at 110.0℃; for 2h;Microwave irradiation;	General procedure: To a 5 niL microwave vial charged with N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-l -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6- dihydropyridine-3-carboxamide (50.5 mg, 0.1 mmol), 4-(mo holino)phenylboronic acid (41.4 mg, 0.2 mmol), and Pd(dppf)Cl2 (14.6 mg, 0.02 mmol, 20 mol%) was added dioxane (3 mL), followed by 1 M aq K3PO4 (0.5 mL, 0.5 mmol). The resulting mixture was irradiated in microwave at 110 C for 2 h. LCMS showed completion of the reaction. The crude reaction mixture was loaded onto celite, dried and purified using Biotage SNAP KP-Sil 25g (gradient: EtOAc/hex 0-100% then MeOH/DCM 0-30%). Fractions showing impure product were concentrated, loaded onto celite, and repurified by Biotage SNAP C18 30g (gradient: CH3CN (0.1% TFA)/H20 5-30%). Fractions showing product were combined, passed through porapak 6cc, concentrated and dried to give the title compound as an off white solid (24.6 mg, 40% yield). ^-NMR (500 MHz, MeOD-d4) delta 7.96 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.07 - 7.00 (m, 3H), 6.92 (s, 1H), 3.91 - 3.81 (m, 4H), 3.25 - 3.17 (m, 4H), 3.05 (d, J=l l. l Hz, 2H), 2.67 - 2.52 (m, 4H), 2.39 (s, 3H), 1.18 (d, J=6.0 Hz, 6H); LC-MS [M+ H]+ 588.36. The title compound (white solid, 26.4 mg, 45%) was prepared according to a procedure similar to the last step of Example 29 using N-(5-bromo-4- methyl-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6- dihydropyridine-3-carboxamide (50 mg, 0.1 mmol) and 2-(4^omicron etaomicron1etaomicron^Gammapi^eta6-5- boronic acid pinacol ester (58 mg, 0.2 mmol). 1H NMR (500MHz, METHANOL-d4) delta = 8.37 (s, 2H), 7.96 (s, 1H), 7.74 (s, 1H), 7.16 (s, 1H), 6.91 (s, 1H), 3.86 - 3.76 (m, 8H), 3.01 (d, J=11.4 Hz, 2H), 2.71 - 2.62 (m, 2H), 2.61 - 2.53 (m, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.18 (d, J=1.0 Hz, 6H); LCMS [M + H]+ 586.3.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00246; 00309

41
[ 957198-30-0 ]
4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine [ No CAS ]
4-(5-(4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-nitrophenyl)pyrimidin-2-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
> 95%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 90.0℃; for 3h;Inert atmosphere; Sealed tube;	A 100 mL round bottomed flask was charged with a mixture of (S)-4-(4- bromo-5-fluoro-2-nitrophenyl)-l,2-dimethylpiperazine (1.60 g, 4.8 mmol), 2-(4- mo holino)pyrimidine-5-boronic acid pinacol ester (1.50 g, 5.2 mmol), XPhos Pd G2 (0.075 g, 0.10 mmol) and XPhos (0.045 g, 0.10 mmol). The flask was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-dioxane (40 mL) and 2 M aqueous sodium carbonate (12 mL) were added via syringe and the flask was evacuated and backfilled an additional time. The reaction was heated to 90 C for 3 h in an oil bath. After cooling to room temperature the reaction was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with additional DCM. The combined organic extracts were dried over magnesium sulfate and after removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [0.5-10% MeOH/DCM + 1% NH4OH] afforded (S)-4-(5-(4-(3,4-dimethylpiperazin-1-yl)-2-fluoro-5-nitrophenyl)pyrirnidin-2- yl)morpholine (2.0 g, >95%). LCMS [M+H]+: 417.2.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00334

42
[ 957198-30-0 ]
(S)-4-(4-bromo-5-chloro-2-nitrophenyl)-1,2-dimethylpiperazine [ No CAS ]
(S)-4-(5-(2-chloro-4-(3,4-dimethylpiperazin-1-yl)-5-nitrophenyl)pyrimidin-2-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100.0℃; for 3h;Inert atmosphere; Sealed tube;	A vial was charged with (S)-4-(4-bromo-5-chloro-2-nitrophenyl)-l,2- dimethylpiperazine (0.40 g, 1.1 mmol), 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (0.37 g, 1.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol). The vial was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (7 mL) and 2 M aqueous sodium carbonate (3 mL) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated to 100 C for 3 h. After cooling to room temperature the reaction mixture was concentrated onto celite and flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded (S)-4-(5-(2-chloro-4-(3,4-dimethylpiperazin-1-yl)-5- nitrophenyl)pyrimidin-2-yl)morpholine (0.28 g, 56 %). LCMS [M+H]+: 433.2.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00340

43
[ 957198-30-0 ]
8-(4-bromo-5-fluoro-2-nitrophenyl)octahydropyrazino[2,1-c][1,4]oxazine [ No CAS ]
8-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)octahydropyrazino[2,1-c][4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; at 90.0℃; for 2h;Inert atmosphere;	A 30mL vial was charged with a mixture of 8-(4-bromo-5-fluoro-2- nitrophenyl)octahydropyrazino[2,l-c][l,4]oxazine (112 mg, 0.311 mmol), 2-(4- mo holino)pyrimidine-5-boronic acid pinacol ester (127 mg, 0.435 mmol), XPhos Pd G2 (4.89 mg, 6.22 muetaiotaomicron) and XPhos (2.96 mg, 6.22 muetaiotaomicron). Then sodium carbonate solution (2molar) (0.777 ml, 1.555 mmol) was added via syringe and the vial was flushed with argon. The reaction was stirred at 90 C for 2 hours then the reaction mixture was partitionned into water and DCM and the product was extracted by DCM (3x20mL). The organic phase was dried over MgSC>4 and after filtration and solvents removal, the crude material was dry loaded and purified by flash chromatography [0- 10% MeOH/DCM] to afford the desired 8-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)- 2-nitrophenyl)octahydropyrazino[2,l-c] [l,4]oxazine (143.6 mg, 0.291 mmol, 94 % yield) as a brown oil. LCMS [M+H]+ 444.9.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00392

44
[ 957198-30-0 ]
trans-1-(4-bromo-5-fluoro-2-nitrophenyl)-4-fluoro-N,N-dimethylpyrrolidin-3-amine [ No CAS ]
trans-4-fluoro-1-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 90.0℃; for 18h;Inert atmosphere; Sealed tube;	A 30 mL vial was charged with a mixture of trans--( -bromo-5- fluoro-2-nitrophenyl)-4-fluoro-N,N-dimethylpyrrolidin-3-amine (0.13 g, 0.36 mmol), <strong>[957198-30-0]2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester</strong> (0.12 g, 0.39 mmol), XPhos Pd G2 (6 mg, 7 muetaiotaomicron) and XPhos (4 mg, 7 muetaiotaomicron). The vial was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (3 mL) and aqueous sodium carbonate (2 M, 0.6 mL) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated to 90 C in an aluminum block for 18 h. After cooling to room temperature the reaction mixture was concentrated onto celite and purification by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded the product (0.16 g, 95 %). LCMS [M+H]+: 435.4.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00629

45
[ 957198-30-0 ]
(R)-1-(4-bromo-5-fluoro-2-nitrophenyl)-N-ethyl-N-methylpyrrolidin-3-amine [ No CAS ]
(R)-N-ethyl-1-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-N-methylpyrrolidin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 90.0℃;Inert atmosphere; Sealed tube;	A reaction vial was charged with a mixture of (R)-l-(4-bromo-5-fluoro-2- nitrophenyl)-N-ethyl-N-methylpyrrolidin-3-amine (0.11 g, 0.32 mmol), 2-(4- mophiholino)pyrimidine-5-boronic acid pinacol ester (0.10 g, 0.35 mmol), XPhos Pd G2 (5.0 mg, 6.4 muetaiotaomicron) and XPhos (3.0 mg, 6.4 muetaiotaomicron). The vial was sealed with a septum, evacuated and backfilled with nitrogen. 1,4-Dioxane (3 mL) and 2 M aqueous sodium carbonate (0.6 mL) were added via syringe and the vial was evacuated and backfilled an additional time. The reaction was heated to 90 C in an aluminum block overnight. After cooling to room temperature the reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] to afford (R)- N-ethyl- 1 -(5 -fluoro-4-(2-mo holinopyrimidin-5 -yl)-2-nitrophenyl)-N-methylpyrrolidin- 3-amine (0.11 g, 78 %). LCMS [M+H]+: 431.4.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00675

46
[ 957198-30-0 ]
(R)-N-(5-bromo-4-fluoro-2-(3-(methyl(2,2,2-trifluoroethyl)amino)pyrrolidin-1-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide [ No CAS ]
N-[4-fluoro-5-(2-morpholin-4-ylpyrimidin-5-yl)-2-[rac-(3R)-3-[methyl(2,2,2-trifluoroethyl)amino]pyrrolidin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); sodium carbonate; XPhos; In 1,4-dioxane; water; at 90.0℃; for 18h;Sealed tube; Inert atmosphere;	A vial was charged with 2-(4-mo holino)pyrimidine-5-boronic acid pinacol ester (0.044 g, 0.15 mmol), (R)-N-(5-bromo-4-fluoro-2-(3-(methyl(2,2,2- trifluoroethyl)amino)pyrrolidin-l-yl)phenyl)-4-(trifluoromethyl)-6-(2- (trimethylsilyl)ethoxy)nicotinamide (0.050 g, 0.076 mmol), XPhos Pd G2 (0.0012 g, 1.5 muetaiotaomicron) and XPhos (0.0007 g, 1.5 muetaiotaomicron). The vial was sealed and evacuated and backfilled with nitrogen. 1,4-Dioxane (1.3 mL) and aqueous sodium carbonate, (0.15 mL, 0.27 mmol) were added via syringe and the vial evacuated and backfilled an additional time. The reaction was heated to 90 C for 18 h. After cooling to room temperature the reaction mixture was concentrated onto celite and purified by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] to afford the silyl protected amide. The intermediate product was dissolved in DCM (2 mL) and treated with TFA (0.30 mL). After stirring for 1 h the volatiles were removed in vacuo and the product was isolated with a catch and release protocol using a PoraPak RXN CX ion exchange column to afford the title compound (R)-N-(4-fluoro-2-(3-(methyl(2,2,2- trifluoroethyl)amino)pyltauolidin-l-yl)-5-(2-mo holinopyrimidin-5-yl)phenyl)-6- oxo- 4-(trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (0.020 g, 41 %). l NMR (500MHz, DMSO-d6) delta = 12.57 (br s, 1H), 9.79 (s, 1H), 8.50 (s, 2H), 7.96 (br s, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.79 (s, 1H), 6.68 (d, J=13.8 Hz, 1H), 3.73 (br d, J=4.9 Hz, 4H), 3.68 (br d, J=4.8 Hz, 4H), 3.29 - 3.08 (m, 4H), 2.38 (s, 3H), 2.11 (br dd, J=5.5, 10.8 Hz, 1H), 1.79 - 1.67 (m, 1H); LCMS [M+H]+: 644.3.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00896

47
[ 957198-30-0 ]
trans-1-(4-bromo-5-fluoro-2-nitrophenyl)-4-methoxy-N-(2-methoxyethyl)-N-methylpyrrolidin-3-amine [ No CAS ]
trans-1-(5-fluoro-4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-4-methoxy-N-(2-methoxyethyl)-N-methylpyrrolidin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 110.0℃; for 0.666667h;Inert atmosphere; Microwave irradiation;	A microwave vial was charged with 2-(4-morpholino)pyrimidine-5- boronic acid pinacol ester (0.037 g, 0.13 mmol), potassium phosphate (0.053 g, 0.25 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.006 g, 8.4 muetaiotaomicron). The vial was sealed with a septum and then evacuated and backfilled with nitrogen. A solution of trans-l-(4-bromo-5-fluoro-2-nitrophenyl)-4- methoxy-N-(2-methoxyethyl)-N-methylpyrrolidin-3-amine (0.034 g, 0.084 mmol) in 1,4-dioxane (4.4 mL) was added via syringe followed by water (0.5 mL). The reaction was irradiated to a temperature of 110 C for 40 min. The reaction mixture was partitioned between water and DCM. The layers were separated and the aqueous layer was extracted with an additional portion of DCM. The combined organic extracts were dried over magnesium sulfate. After removal of the inorganics by filtration the filtrate was concentrated to dryness and the residue was purified by flash chromatography [0.5-7.5% MeOH/DCM + 0.5% NH4OH] to afford trans- 1 -(5-fluoro- 4-(2-morpholinopyrimidin-5-yl)-2-nitrophenyl)-4-methoxy-N-(2-methoxyethyl)-N- methylpyrrolidin-3 -amine (0.043 g, 100 %). LCMS [M+H]+: 491.5.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00956

48
[ 957198-30-0 ]
N-(5-bromo-4-fluoro-2-((3R,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy)nicotinamide [ No CAS ]
N-(4-fluoro-5-(2-morpholinopyrimidin-5-yl)-2-((3R,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		A reaction vial was charged with 2-(4^omicron etaomicron1etaomicron^Gammaiotatau^eta6-5^thetaGammaomicroneta acid pinacol ester (0.017 g, 0.057 mmol), XPhos Pd G2 (0.00075 g, 0.96 muiotaetaomicron) and XPhos (0.00046 g, 0.96 muetaiotaomicron). The vial was sealed with a septum and evacuated and backfilled with nitrogen. A solution of N-(5-bromo-4-fluoro-2-((3R,5R)-3,4,5- trimethylpiperazin- 1 -yl)phenyl)-4-(trifluoromethyl)-6-(2-(trimethylsilyl)ethoxy Nicotinamide (0.029 g, 0.048 mmol) in 1,4-dioxane (0.8 mL) was added via syringe, followed by aqueous sodium carbonate (0.084 mL, 2 M) and the vial was evacuated and backfilled an additional time. The reaction was heated to 80 C for 18 h. The reaction mixture was partitioned between DCM and water and the layers were separated. The aqueous layer was extracted with an additional portion of DCM and the combined organics were dried over magnesium sulfate. After removal of the inorganics by filtration the filtrate was concentrated to dryness and the residue was purified by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] to afford the silyl protected intermediate which was dissolved in DCM (2 mL) and treated with TFA (0.2 mL) at room temperature. After stirring for 1 h the volatiles were removed in vacuo and the title compound was isolated using a catch and release protocol with a PoraPak Rxn CX ion exchange column to afford the title compound N-(4-fluoro-5-(2- mo holinopyrimidin-5-yl)-2-((3R,5R)-3,4,5-trimethylpiperazin-l-yl)phenyl)-6-oxo-4- (trifluoromethyl)-l,6-dihydropyridine-3-carboxamide (0.014 g, 51%). 1H NMR (500MHz, DMSO-d6) delta = 9.30 (s, 1H), 8.53 (s, 2H), 8.03 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.07 (d, J=12.3 Hz, 1H), 6.80 (s, 1H), 3.79 - 3.72 (m, 4H), 3.70 - 3.65 (m, 4H), 2.90 (br d, J=9.3 Hz, 2H), 2.84 - 2.77 (m, 2H), 2.64 (br dd, J=6.2, 10.8 Hz, 2H), 2.20 (s, 3H), 0.97 (d, J=6.4 Hz, 6H); LCMS [M+H]+: 590.6.

Reference： [1]Patent: WO2017/147700,2017,A1 .Location in patent: Paragraph 00688

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100.0℃; for 4.5h;	General procedure: A mixture of 0.5 g (2.48 mmol) 5-bromo-N,N-dimethyl-pyrimidin-2-amine, 0.8 g (3.24 mmol) bis(pinacolato)diborone, 0.6 g (6.38 mmol) KOAc, 0.2 g (0.25 mmol) (0358) Pd(dppf)CI2 * DCM and dioxane is heated to 100C for 4.5 h. After cooling to RT, the reaction mixture is filtered through a pad of Celite and evorated, water is added and the mixture is extracted with EtOAc. The organic phases are pooled, dried and evaporated The crude product is purified by FC. (0359) Yield: 0.6 g (96%), ESI-MS: m/z = 250 (M+H)+, Rt(HPLC): 0.22 min (HPLC-A)

50
[ 957198-30-0 ]
(R)-3-bromo-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine [ No CAS ]
(R)-4-(5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)pyrimidin-2-yl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; at 90.0℃; for 2h;Inert atmosphere;	General procedure: A reaction solution of 3-bromo-5-((2,4-dichlorobenzyl)oxy)pyridine (12a) (150.00mg, 0.45mmol) and 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)piperidine (13c) (138.27mg, 0.45mmol) in 1,4-dioxane (15.00mL) was purged with nitrogen. Then PdCl2(PPh3)2 (15.44mg, 0.022mmol) and 1.0M of Na2CO3 (143.08mg, 1.35mmol) aqueous solution were added. The resulting mixture was purged with nitrogen and stirred at 90C for 2h. 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 and the resulting crude mixture was purified by a silica gel column, eluting with EA:Hexane (1:1) to collect the title product (15) as a yellow solid (116.00mg, 59%)

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

51
[ 957198-30-0 ]
[ 1253936-69-4 ]

Reference： [1]Patent: WO2010/126811,2010,A1

52
[ 957198-30-0 ]
[ 1253936-68-3 ]

Reference： [1]Patent: WO2010/126811,2010,A1

53
[ 957198-30-0 ]
[ 1253936-96-7 ]

Reference： [1]Patent: WO2010/126811,2010,A1

54
[ 957198-30-0 ]
[ 1253936-70-7 ]

Reference： [1]Patent: WO2010/126811,2010,A1

55
[ 957198-30-0 ]
[ 80-48-8 ]
4-(5-methylpyrimidin-2-yl)morpholine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 17197 - 17202

56
[ 512-56-1 ]
[ 957198-30-0 ]
4-(5-methylpyrimidin-2-yl)morpholine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 17197 - 17202

57
[ 32176-12-8 ]
[ 957198-30-0 ]
4-(5-(methyl-d3)pyrimidin-2-yl)morpholine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 17197 - 17202

58
[ 957198-30-0 ]
[ 74-88-4 ]
4-(5-methylpyrimidin-2-yl)morpholine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 17197 - 17202

59
[ 957198-30-0 ]
3-bromo-2,4-difluoro-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline [ No CAS ]
2,4-difluoro-3-(2-morpholinopyrimidin-5-yl)-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; at 110.0℃; for 3h;Inert atmosphere; Microwave irradiation;	To a 20 mL microwave vial charged with 3-bromo-2,4-difluoro-6-((3S,5R)-3,4,5- trimethylpiperazin-1-yl)aniline (334 mg, 1 mmol), 2-(4-morpholino)pyrimidine-5- boronic acid pinacol ester (437 mg, 1.5 mmol) and Pd(dppf)C12 (59 mg, 0.08 mmol, 8 mol%) was added dioxane (8 mL), followed by 1 M aq K3P04 (2 mL, 2 mmol). The resulting mixture was purged with N2 and irritated in microwave at 110 C for 3 h. After separation of the organic layer, the aqueous layer was extracted with EtOAc (5 mL x 2). The combined organic layers were concentrated to give a dark greenish brown solid which was triturated with MeOH (10 mL), filtered and rinsed well with MeOH (5 mL) and dried under vacuum to give 2,4-difluoro-3-(2-morpholinopyrimidin-5-yl)-6- ((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline as a brown solid (374 mg, 86% based on 96.23% purity). LCMS [M + Hj 419.5. To a solution of 4-fluoro-2- (trifluoromethyl)benzoyl chloride (0.045 mL, 0.3 mmol) in DCM (3 mL) at RT was added Et3N (0.084 mL, 0.6 mmol). After addition, the resulting mixture was stirred at RT for 5 mm, then a solution of 2,4-difluoro-3-(2-morpholinopyrimidin-5-yl)-6- ((3S,5R)-3,4,5-trimethylpiperazin-1-yl)aniline (42 mg, 0.1 mmol) in DCM (2 mL) was added. The resulting mixture was stirred at RT for 2 h. After quenching with sat. NaHCO3 (15 mL) and stirring for 10 mm at RT, the mixture was extracted with DCM (20 mL x 2). The combined extracts were combined, concentrated and purified by flash chromatography (gradient: EtOAc/hex 0-100% then MeOH/DCM 0-10%) and prepHPLC to give the title compound as a beige solid (formic acid salt, 22.1 mg, 34%).

Reference： [1]Patent: WO2019/46944,2019,A1 .Location in patent: Paragraph 00156; 00157

60
[ 957198-30-0 ]
7-bromo-N-(pyrazin-2-yl)quinolin-4-amine [ No CAS ]
7-(2-morpholinopyrimidin-5-yl)-N-(pyrazin-2-yl)quinolin-4-amine [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2020,vol. 11,p. 249 - 257

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P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 957198-30-0 ]

Quality Control of [ 957198-30-0 ]

Related Doc. of [ 957198-30-0 ]

Product Details of [ 957198-30-0 ]

Calculated chemistry of [ 957198-30-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 957198-30-0 ]

Application In Synthesis of [ 957198-30-0 ]

[ 957198-30-0 ] Synthesis Path-Upstream 1~1

[ 957198-30-0 ] Synthesis Path-Downstream 1~60

Related Functional Groups of [ 957198-30-0 ]

Organoboron

Related Parent Nucleus of [ 957198-30-0 ]

Morpholines

Pyrimidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 957198-30-0 ]

Related Parent Nucleus of
[ 957198-30-0 ]