[ CAS No. 1180132-17-5 ] {[proInfo.proName]}

Name: 1180132-17-5|5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-amine|97%
Brand: Ambeed
SKU: A195845
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Quality Control of [ 1180132-17-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1180132-17-5 ]

SDS Specification

Alternatived Products of [ 1180132-17-5 ]

Product Details of [ 1180132-17-5 ]

CAS No. :	1180132-17-5	MDL No. :	MFCD14706690
Formula :	C₁₂H₂₀N₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MNJBMPQTXVZMFZ-UHFFFAOYSA-N
M.W :	220.31	Pubchem ID :	45489910
Synonyms :

Calculated chemistry of [ 1180132-17-5 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.58
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	73.96
TPSA :	45.39 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) :	-7.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.28
Log Po/w (XLOGP3) :	0.52
Log Po/w (WLOGP) :	-0.1
Log Po/w (MLOGP) :	0.69
Log Po/w (SILICOS-IT) :	0.93
Consensus Log Po/w :	0.86

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.61
Solubility :	5.37 mg/ml ; 0.0244 mol/l
Class :	Very soluble
Log S (Ali) :	-1.04
Solubility :	19.9 mg/ml ; 0.0904 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.65
Solubility :	0.491 mg/ml ; 0.00223 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.06

Safety of [ 1180132-17-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1180132-17-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1180132-17-5 ]
Downstream synthetic route of [ 1180132-17-5 ]

[ 1180132-17-5 ] Synthesis Path-Upstream 1~10

1
[ 121-44-8 ]
[ 156973-09-0 ]
[ 1180132-17-5 ]

Yield	Reaction Conditions	Operation in experiment
82.7%	With potassium carbonate In 1,2-dichloro-ethane at 30 - 35℃; for 8 h;	To a stirred 500 ml four-necked flask equipped with a thermometer and a condenser,100 g of 1,2-dichloroethane,12.5 g (0.1 mol) of 2-amino-5-aminomethylpyridine (IV),30.0 grams of potassium carbonate,A solution of 25.0 g (0.15 mol) of N, N-diethylethanamine and 20 g of 1,2-dichloroethane was added dropwise between 30 and 35 ° C over a period of about 2 hours.After 30 ~ 35 °C for 6 hours. Cooled to 20 ~ 25 °C, layered,The aqueous layer was extracted twice with 1,2-dichloroethane, 20 g each time,The organic phases were combined, 1,2-dichloroethane was distilled off,To the residue was added 75 g of methyl tert-butyl ether, 0.5 g of activated charcoal,80 ~ 82 ° C under stirring for 1 hour, filtered while hot,The filtrate is cooled to 0-5 ° C to crystallize, filtered, dried,18.2 g of 5- (4-ethylpiperazin-1-yl) methyl-2-aminopyridine was obtained as a white solid in a yield of 82.7percent and a liquid phase purity of 99.3percent.

Reference： [1] Patent: CN107337634, 2017, A, . Location in patent: Paragraph 0040; 0053; 0054; 0057; 0058; 0061; 0062

2
[ 1231930-25-8 ]
[ 1180132-17-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; lithium hexamethyldisilazane; CyJohnPhos In toluene at 80℃; Inert atmosphere	NaHB(OAc)₃ (2.60g, 12.23mmol) was added to a solution of 137 6-bromonicotinaldehyde (1.50g, 8.15mmol) and 92 1-ethylpiperazine (0.90g, 8.15mmol) in 103 DCM (15mL). The mixture was allowed to stir at RT overnight, after which it was filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1–10:1) to obtain 138 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (1.65g; yield, 71percent) as a yellow oil. Lithium bis(trimethylsilyl)amide (1N) (20mL, 20.0mmol) under N₂ was added to a solution of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (2.80g, 10.0mmol), Cy-John-Phos (700.0mg, 2.0mmol), and Pd₂(dba)₃ (915.0mg, 1.0mmol) in dry toluene (30mL). Then the mixture was heated to 80°C overnight, cooled to RT, filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1–10:1) to give INT-7 (1.52g; yield, 69percent) as a brown solid. ESI-MS: m/z 221.2 [M+H]⁺.
61%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; lithium hexamethyldisilazane; CyJohnPhos In toluene at 80℃; for 12 h; Inert atmosphere	A solution of 1 - ((6-bromopyridin-3-yl) methyl) -4-ethylpiperazine (2.84 g, 10 mmol) prepared in the first step was added to the reaction flask,2-dicyclohexylphosphinylbiphenyl (0.7 g, 2 mmol),Pd2 (dba) 3 (915 mg, 1 mmol) and anhydrous toluene (30 mL).The mixture was purged three times with nitrogen,LiHMDS (1 M in THF, 20 mL, 20 mmol) was added.The mixture was stirred at 80 ° C for 12 hours under a nitrogen atmosphere.Cool to room temperature, add water (50 mL), ethyl acetate (50 mL x 2).The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate,Suction filter. The residue was purified by column chromatography (DCM / MeOH / Et3N = 10: 1: 0.5percent)The resulting residue was purified to give the title compound (1.34 g, brown solid) in 61percent yield.
61%	With ([1,1’-biphenyl]-2-yl)dicyclohexylphosphine oxide; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; lithium hexamethyldisilazane In tetrahydrofuran; toluene at 80℃; for 12 h; Inert atmosphere	A solution of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (5.00g 17.70 mmol) prepared in the first step was added to the reaction flask, 2-dicyclohexylphosphinylbiphenyl (1.20 g, 3.54 mmol), Pd₂(dba)₃ (1.60 g, 1.78 mmol) and anhydrous toluene (50 mL). The mixture was purged three times with nitrogen, LiHMDS (1 M in THF, 35 mL, 35 mmol) was added. The mixture was stirred at 80 ° C for 12 hours under a nitrogen atmosphere. Cool to room temperature, add water (100 mL), extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, The residue was purified by column chromatography (DCM / MeOH / Et3N =10:1:0.5 percent) The resulting residue was purified to give compound 9a (2.37 g, 61.00percent) as yellow soild. 1H-NMR (DMSO-d₆, 400 MHz), δ: 7.75 (s, 1H), 7.24 (m, 1H), 6.39 (d, 1H), 5.78 (s, 2H), 3.23 (s, 2H), 2.24 (m, 8H), 0.93 (m, 3H). MS (ESI): mass calcd. for C₁₂H₁₈N₄O₂ 220, m/z found 221 [M+H]+.

36.4%	With copper(I) oxide; ammonium hydroxide In methanol at 70℃; for 16 h;	The above compound (6.98 g, 24.6 mmol, 1.0 eq.), cuprous oxide (97 mg, 1.23 mmol, 0.05 eq.) and methanol (10 ml) was dissolved in aqueous ammonia (30 ml), the reaction temperature was raised to 70 °C for 16 hours. Cooled and filtered, extracted with dichloromethane, concentrated under reduced pressure and purified by silica gel column chromatography give 5-((4-ethyl-piperidine-1-yl)methyl)pyridine-2-amine (2.0g, yield: 36.4percent).
670 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; lithium hexamethyldisilazane; CyJohnPhos In tetrahydrofuran at 65℃; for 0.333333 h; Inert atmosphere	A solution of 1- (6-bromo-pyridin-3-ylmethyl) -4-ethyl-piperazine (960 mg, 3.38 mmol) in anhydrous tetrahydrofuran (8 mL)Was added 2- (dicyclohexylphosphino) biphenyl (120 mg, 0.338 mmol)Tris (dibenzylideneacetone) dipalladium (154 mg, 0.169 mmol).Lithium hexamethyldisilazide (4.06 mL, 1 M, 4.06 mmol) was slowly added under nitrogen.The reaction flask was heated to 65 ° C,After 20 minutes the reaction flask was cooled to room temperature,50 mL of ethyl acetate was added,30mL water,Mixed after the liquid,The aqueous layer was again added with 30 mL of ethyl acetate,Liquid separation,Combined organic layer,Dried over anhydrous sodium sulfate and evaporated to dryness as a pale brown solid.The product of formula V-1 (670 mg) was purified by column chromatography,As a pale yellow solid.
1.52 g	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; lithium hexamethyldisilazane; CyJohnPhos In toluene at 80℃; Inert atmosphere	A reaction flask was charged with 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (2.84 g, 10 mmol) preparedin Step 1, 2-(dicyclohexylphosphino)biphenyl (700mg, 2mmol), Pd2(dba)3 (915 mg, 1 mmol) and toluene (30 mL), LHMDS(1 N) (20 ml, 20 mmol) was added under the protection of nitrogen gas. The mixture was heated to 80°C and allowedto react overnight, then cooled to room temperature, filtered, concentrated and separated by column chromatography(DCM/MeOH = 100:1-10:1) to give 1.52 g of the titled product (brown solid). MS (ESI): mass calcd. for C13H21N3 220.2, m/z found 221.2 [M+H]+.

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[2] Patent: CN106608879, 2017, A, . Location in patent: Paragraph 0142-0143; 0147-0148
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 974 - 978
[4] Patent: CN105622638, 2016, A, . Location in patent: Paragraph 0221
[5] Patent: US2010/160340, 2010, A1, . Location in patent: Page/Page column 9
[6] Patent: WO2015/130540, 2015, A1, . Location in patent: Page/Page column 21
[7] Patent: CN106467517, 2017, A, . Location in patent: Paragraph 0113; 0114; 0115; 0016; 0117; 0118
[8] Patent: CN107266421, 2017, A, . Location in patent: Paragraph 0167; 0168 0169; 0170
[9] Patent: EP3385262, 2018, A1, . Location in patent: Paragraph 0101; 0102; 0103

3
[ 5308-25-8 ]
[ 70258-18-3 ]
[ 1180132-17-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	at 60 - 70℃; for 2 h; Green chemistry	2-Chloro-5-chloromethylpyridine (162 g, 1.0 mol), tap water 300 mL, and N-ethylpiperazine (171 g, 1.5 mol) were added to a 1 L reaction flask.Raise to 60-70 ° C, stir for 2 h, cool to room temperature,Potassium carbonate (138 g, 1.0 mol) was added and stirred for 10 minutes, the aqueous phase was separated, and dried to give 225 g of product, yield 94percent.

Reference： [1] Patent: CN108440401, 2018, A, . Location in patent: Paragraph 0014; 0032-0040; 0047; 0048

4
[ 5308-25-8 ]
[ 1180132-17-5 ]

Reference： [1] Patent: WO2015/130540, 2015, A1,
[2] Patent: CN106316935, 2017, A,
[3] Patent: CN106608879, 2017, A,
[4] Patent: CN106467517, 2017, A,
[5] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[6] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 974 - 978
[7] Patent: EP3385262, 2018, A1,

5
[ 149806-06-4 ]
[ 1180132-17-5 ]

Reference： [1] Patent: WO2015/130540, 2015, A1,
[2] Patent: CN106608879, 2017, A,
[3] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 974 - 978
[5] Patent: EP3385262, 2018, A1,

6
[ 1231930-25-8 ]
[ 1180132-17-5 ]

Reference： [1] Organic Process Research and Development, 2017, vol. 21, # 9, p. 1447 - 1451

7
[ 5308-25-8 ]
[ 149806-06-4 ]
[ 1180132-17-5 ]

Reference： [1] Patent: CN105622638, 2016, A,
[2] Patent: CN107266421, 2017, A,

8
[ 33225-73-9 ]
[ 1180132-17-5 ]

Reference： [1] Patent: CN106316935, 2017, A,

9
[ 1180132-17-5 ]
[ 1231930-42-9 ]
[ 1231929-97-7 ]

Yield	Reaction Conditions	Operation in experiment
57.3%	With potassium carbonate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; bis(dibenzylideneacetone)-palladium⁽⁰⁾ In tert-Amyl alcohol at 100℃; for 19 h;	In analogy to Example 33 of WO 2010/075074, nitrogen was bubbled for 5 min through a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2- methyl- lH-benz-imidazole (5 g; 15.5 mmol), 5-(4-ethyl-piperazin- l-ylmethyl)- pyridin-2-ylamine (3.48 g; 15.8 mmol), K2CO3 (4.71 g; 34.1 mmol) and Xantphos (179 mg; 0.3 mmol) in t-amylalcohol (25 mL). Tris(dibenzylidene- acetone)dipalladium(O) ( 142 mg; 0.2 mmol) was added and the slurry heated to 100°C. The slurry was stirred for 19 h when HPLC indicated complete conversion of pyrimidyl benzimidazol. The mixture was allowed to cool to room temperature and diluted with dichloromethane. The slurry was filtered over a Whatman glass fiber filter and the obtained filtrate extracted with aqueous HC1 (4N; 2 x 25 mL). The collected aqueous extracts were stirred with charcoal (250 mg), filtered (Whatman) and basified with aqueous NaOH (17percent ; 30 mL). The resulting mixture was extracted with DCM (2 x 20), dried over Na2S04, filtered, stirred over Quadrasil (800 mg), filtered and concentrated under reduced pressure. The remaining crude yellow solid was slurried in acetone, filtered, washed with acetone and dried under reduced pressure to isolate a fine yellowish powder. Yield: 4.5 g (57.3percent) Chemical purity: 99.4percent (peak area at λ=320 nm).
22.11 g	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In 1,4-dioxane at 110℃; for 2 h; Inert atmosphere	Bubble nitrogen into a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro- l-isopropyl-2-methyl-lH-benzoimidazole (15.9 g), 5-(4-ethyl-piperazin-l-ylmethyl)- pyridin-2-ylamine (10.85 g), cesium carbonate (32.10 g), tris(dibenzylideneacetone) dipalladium (1.82 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.35 g) in 1,4- dioxane (197.06 mL). Heat the mixture in a pre-heated oil bath at 110 °C for 2 hours. Cool to room temperature, dilute with dichloromethane and filter over a CELITE® pad. Remove the solvent under vacuum and purify by silica gel column chromatography, eluting with dichloromethane/ methanol (2 ) and then dichloromethane/ methanol-NH₃ 2 M 2 percent to afford 22.11 g of the title compound. MS (ES⁺): m/z= 507 (M+H)⁺.

Reference： [1] Patent: WO2017/108781, 2017, A1, . Location in patent: Page/Page column 13; 14
[2] Patent: US2010/160340, 2010, A1, . Location in patent: Page/Page column 14
[3] Patent: WO2015/130540, 2015, A1, . Location in patent: Page/Page column 23

10
[ 1180132-17-5 ]
[ 1231929-97-7 ]

Reference： [1] Patent: US2017/305884, 2017, A1,

[ 1180132-17-5 ] Synthesis Path-Downstream 1~58

1
[ 1180132-17-5 ]
[ 1231930-42-9 ]
[ 1231929-97-7 ]

Yield	Reaction Conditions	Operation in experiment
57.3%	With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In tert-Amyl alcohol; at 100℃; for 19h;	In analogy to Example 33 of WO 2010/075074, nitrogen was bubbled for 5 min through a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-l-isopropyl-2- methyl- lH-benz-imidazole (5 g; 15.5 mmol), 5-(4-ethyl-piperazin- l-ylmethyl)- pyridin-2-ylamine (3.48 g; 15.8 mmol), K2CO3 (4.71 g; 34.1 mmol) and Xantphos (179 mg; 0.3 mmol) in t-amylalcohol (25 mL). Tris(dibenzylidene- acetone)dipalladium(O) ( 142 mg; 0.2 mmol) was added and the slurry heated to 100C. The slurry was stirred for 19 h when HPLC indicated complete conversion of pyrimidyl benzimidazol. The mixture was allowed to cool to room temperature and diluted with dichloromethane. The slurry was filtered over a Whatman glass fiber filter and the obtained filtrate extracted with aqueous HC1 (4N; 2 x 25 mL). The collected aqueous extracts were stirred with charcoal (250 mg), filtered (Whatman) and basified with aqueous NaOH (17% ; 30 mL). The resulting mixture was extracted with DCM (2 x 20), dried over Na2S04, filtered, stirred over Quadrasil (800 mg), filtered and concentrated under reduced pressure. The remaining crude yellow solid was slurried in acetone, filtered, washed with acetone and dried under reduced pressure to isolate a fine yellowish powder. Yield: 4.5 g (57.3%) Chemical purity: 99.4% (peak area at lambda=320 nm).
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere;Product distribution / selectivity;	Example 1[5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine Bubble nitrogen into a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole (15.9 g), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (10.85 g), cesium carbonate (32.10 g), tris(dibenzylideneacetone) dipalladium (1.82 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.35 g) in 1,4-dioxane (197.06 mL). Heat the mixture in a pre-heated oil bath at 110 C. for 2 h. Cool to RT, dilute with DCM and filter over a celite pad. Remove the solvent under vacuum and purify by silica gel column chromatography, eluting with DCM/methanol (2%) and then DCM/methanol-NH3 2 M 2% to afford 22.11 g of the title compound. MS (ES+): m/z=507 (M+H)+.
22.11 g	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere;	Bubble nitrogen into a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro- l-isopropyl-2-methyl-lH-benzoimidazole (15.9 g), 5-(4-ethyl-piperazin-l-ylmethyl)- pyridin-2-ylamine (10.85 g), cesium carbonate (32.10 g), tris(dibenzylideneacetone) dipalladium (1.82 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.35 g) in 1,4- dioxane (197.06 mL). Heat the mixture in a pre-heated oil bath at 110 C for 2 hours. Cool to room temperature, dilute with dichloromethane and filter over a CELITE pad. Remove the solvent under vacuum and purify by silica gel column chromatography, eluting with dichloromethane/ methanol (2 ) and then dichloromethane/ methanol-NH3 2 M 2 % to afford 22.11 g of the title compound. MS (ES+): m/z= 507 (M+H)+.

Reference： [1]Patent: WO2017/108781,2017,A1 .Location in patent: Page/Page column 13; 14
[2]Patent: US2010/160340,2010,A1 .Location in patent: Page/Page column 14
[3]Patent: WO2015/130540,2015,A1 .Location in patent: Page/Page column 23

2
[ 1231930-25-8 ]
[ 1180132-17-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper(I) oxide; ammonia; In dimethyl sulfoxide; at 65 - 75℃;Sealed tube;	A 100 mL sealed tube charged with compound 7 (2 g, 7 mmol), CU20 (20 mg) andDMSO (20 mL), was then bubbled in NHJ for 10 minutes. The mixture was stirred at 65-75 Covernight. After completion and cooling down tort, the mixture was adjusted to PH= 12- 14with 2 N NaOH and extracted with DCM (30 mL x 3). The combined organic layers werewashed with brine (30 mL x 3).dried over sodium sulfate, concentrated and the residue waswashed with PE to give the product ( 1.1 g, 71%). 1 H NMR (3 00 MHz, D MSO-d6) 8 7. 7 5 ( s, 1H), 7.26 (d, J = 7.2 Hz, 1 H), 6.39 (d, J = 7.5 Hz, 1 H), 3.23 (s, 2 H), 2.54-2.50 (m, 2 H), 2.31-2.26 (m, 8 H), 0.96 (t, J = 7.2 Hz, 3 H). LCMS: (M+Ht: 221.0.
69%	With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; CyJohnPhos; In toluene; at 80℃;Inert atmosphere;	NaHB(OAc)3 (2.60g, 12.23mmol) was added to a solution of 137 6-bromonicotinaldehyde (1.50g, 8.15mmol) and 92 1-ethylpiperazine (0.90g, 8.15mmol) in 103 DCM (15mL). The mixture was allowed to stir at RT overnight, after which it was filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1-10:1) to obtain 138 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (1.65g; yield, 71%) as a yellow oil. Lithium bis(trimethylsilyl)amide (1N) (20mL, 20.0mmol) under N2 was added to a solution of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (2.80g, 10.0mmol), Cy-John-Phos (700.0mg, 2.0mmol), and Pd2(dba)3 (915.0mg, 1.0mmol) in dry toluene (30mL). Then the mixture was heated to 80C overnight, cooled to RT, filtered and concentrated under a vacuum, and purified by silica gel column chromatography (DCM/MeOH=100:1-10:1) to give INT-7 (1.52g; yield, 69%) as a brown solid. ESI-MS: m/z 221.2 [M+H]+.
61%	With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; CyJohnPhos; In toluene; at 80℃; for 12h;Inert atmosphere;	A solution of 1 - ((6-bromopyridin-3-yl) methyl) -4-ethylpiperazine (2.84 g, 10 mmol) prepared in the first step was added to the reaction flask,2-dicyclohexylphosphinylbiphenyl (0.7 g, 2 mmol),Pd2 (dba) 3 (915 mg, 1 mmol) and anhydrous toluene (30 mL).The mixture was purged three times with nitrogen,LiHMDS (1 M in THF, 20 mL, 20 mmol) was added.The mixture was stirred at 80 C for 12 hours under a nitrogen atmosphere.Cool to room temperature, add water (50 mL), ethyl acetate (50 mL x 2).The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate,Suction filter. The residue was purified by column chromatography (DCM / MeOH / Et3N = 10: 1: 0.5%)The resulting residue was purified to give the title compound (1.34 g, brown solid) in 61% yield.

61%	With ([1,1?-biphenyl]-2-yl)dicyclohexylphosphine oxide; tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; In tetrahydrofuran; toluene; at 80℃; for 12h;Inert atmosphere;	A solution of 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (5.00g 17.70 mmol) prepared in the first step was added to the reaction flask, 2-dicyclohexylphosphinylbiphenyl (1.20 g, 3.54 mmol), Pd2(dba)3 (1.60 g, 1.78 mmol) and anhydrous toluene (50 mL). The mixture was purged three times with nitrogen, LiHMDS (1 M in THF, 35 mL, 35 mmol) was added. The mixture was stirred at 80 C for 12 hours under a nitrogen atmosphere. Cool to room temperature, add water (100 mL), extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, The residue was purified by column chromatography (DCM / MeOH / Et3N =10:1:0.5 percent) The resulting residue was purified to give compound 9a (2.37 g, 61.00%) as yellow soild. 1H-NMR (DMSO-d6, 400 MHz), delta: 7.75 (s, 1H), 7.24 (m, 1H), 6.39 (d, 1H), 5.78 (s, 2H), 3.23 (s, 2H), 2.24 (m, 8H), 0.93 (m, 3H). MS (ESI): mass calcd. for C12H18N4O2 220, m/z found 221 [M+H]+.
36.4%	With copper(I) oxide; ammonium hydroxide; In methanol; at 70℃; for 16h;	The above compound (6.98 g, 24.6 mmol, 1.0 eq.), cuprous oxide (97 mg, 1.23 mmol, 0.05 eq.) and methanol (10 ml) was dissolved in aqueous ammonia (30 ml), the reaction temperature was raised to 70 C for 16 hours. Cooled and filtered, extracted with dichloromethane, concentrated under reduced pressure and purified by silica gel column chromatography give 5-((4-ethyl-piperidine-1-yl)methyl)pyridine-2-amine (2.0g, yield: 36.4%).
	With lithium hexamethyldisilazane;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; at 50 - 65℃;Product distribution / selectivity;	Preparation 205-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamineAdd lithium 1,1,1,3,3,3-hexamethyl-disilazane (1055 mL) slowly to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (250 g), dicyclohexylphosphino)biphenyl (18.50 g), tris(dibenzylideneacetone)dipalladium (24.17 g) and THF (250 mL) at 50 C. Heat the mixture at 65 C. overnight. Cool to 37 C. and add water (500 mL). Remove half of the solvent under vacuum and add DCM (2.5 L). Filter over a celite pad and remove part of the solvent. Add methanol (300 mL) and methyl tert-butyl ether (MtBE, 600 mL) to the mixture and cool in an ice bath. Then, add hydrochloric acid 2 M in ethyl ether (800 mL) and a 32% aqueous solution of hydrochloric acid (100 mL). Remove the organic layer, and add an aqueous solution of sodium hydroxide 2 M (2500 mL). Extract the aqueous phase three times with DCM and remove the solvent under vacuum. Solve in 90 mL of toluene at 50 C. until complete dissolution and then add 80 mL of MtBE. Stir overnight at RT. Add additional MtBE (100 mL) for complete precipitation. Filter the solid and dry to afford 108.24 g of the title compound. MS (ES+): m/z=221 (M+H)+.
	With ammonia; In methanol; at 40 - 75℃;	Add liquid ammonia (50.0 kg) to a degassed mixture of l-(6-bromo-pyridin-3- ylmethyl)-4-ethyl-piperazine (14.2 kg), cuprous oxide (200 g), and MeOH (57 kg) at T < 40C. Heat the mixture at 65-75 C overnight. Cool to 20-30 C and filter over a CELITE pad. Concentrate the filtrate and add dichloromethane (113 kg) and adjust the pH to 12-14 with sodium hydroxide 2N (23 kg) separate the phases and wash the organic phase with dichloromethane (58 X 2 kg) and combine the organic layers. Filter the mixture through CELITE and concentrate. Dissolve the residue in toluene (9.7 kg) and crystallize by the addition of methyl tert-butyl ether (8.3 kg) to give 6.0 kg of the title compound. Obtain further purification through a toluene recrystallization. MS (ES+): m/z= 221 (M+H)+.
670 mg	With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; CyJohnPhos; In tetrahydrofuran; at 65℃; for 0.333333h;Inert atmosphere;	A solution of 1- (6-bromo-pyridin-3-ylmethyl) -4-ethyl-piperazine (960 mg, 3.38 mmol) in anhydrous tetrahydrofuran (8 mL)Was added 2- (dicyclohexylphosphino) biphenyl (120 mg, 0.338 mmol)Tris (dibenzylideneacetone) dipalladium (154 mg, 0.169 mmol).Lithium hexamethyldisilazide (4.06 mL, 1 M, 4.06 mmol) was slowly added under nitrogen.The reaction flask was heated to 65 C,After 20 minutes the reaction flask was cooled to room temperature,50 mL of ethyl acetate was added,30mL water,Mixed after the liquid,The aqueous layer was again added with 30 mL of ethyl acetate,Liquid separation,Combined organic layer,Dried over anhydrous sodium sulfate and evaporated to dryness as a pale brown solid.The product of formula V-1 (670 mg) was purified by column chromatography,As a pale yellow solid.
	With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; CyJohnPhos; In tetrahydrofuran; at 65℃; for 0.333333h;Inert atmosphere;	1- (6-Bromo-pyridin-3-ylmethyl) -4-ethyl- piperazine (960 mg, 3.38 mmol) was dissolved in dry tetrahydrofuran (8 mL)Join2- (dicyclohexylphosphino) biphenyl(120 mg, 0.338 mmol), tris (dibenzylideneacetone) dipalladium (154 mg,0.169 mmol). Lithium hexamethyldisilazide (4.06 mL, 1 M, 4.06 mmol) was slowly added under nitrogen. reactionThe bottle oil bath was heated to 65C, 20min after the reaction flask was cooled to room temperature, 50mL ethyl acetate, 30mL water, after mixingThe liquid and the aqueous layer were added again with 30 mL of ethyl acetate. The layers were separated and the combined organic layers were dried over anhydrous sodium sulfate and swirled to give a light brown solidbody. Purification by column chromatography gave a pale yellow solid
1.52 g	With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; CyJohnPhos; In toluene; at 80℃;Inert atmosphere;	A reaction flask was charged with 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (2.84 g, 10 mmol) preparedin Step 1, 2-(dicyclohexylphosphino)biphenyl (700mg, 2mmol), Pd2(dba)3 (915 mg, 1 mmol) and toluene (30 mL), LHMDS(1 N) (20 ml, 20 mmol) was added under the protection of nitrogen gas. The mixture was heated to 80C and allowedto react overnight, then cooled to room temperature, filtered, concentrated and separated by column chromatography(DCM/MeOH = 100:1-10:1) to give 1.52 g of the titled product (brown solid). MS (ESI): mass calcd. for C13H21N3 220.2, m/z found 221.2 [M+H]+.

Reference： [1]Patent: WO2019/35008,2019,A1 .Location in patent: Paragraph 616; 623; 624
[2]European Journal of Medicinal Chemistry,2018,vol. 144,p. 1 - 28
[3]Patent: CN106608879,2017,A .Location in patent: Paragraph 0142-0143; 0147-0148
[4]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978
[5]Patent: CN105622638,2016,A .Location in patent: Paragraph 0221
[6]Patent: US2010/160340,2010,A1 .Location in patent: Page/Page column 9
[7]Patent: WO2015/130540,2015,A1 .Location in patent: Page/Page column 21
[8]Patent: CN106467517,2017,A .Location in patent: Paragraph 0113; 0114; 0115; 0016; 0117; 0118
[9]Patent: CN107266421,2017,A .Location in patent: Paragraph 0167; 0168 0169; 0170
[10]Patent: EP3385262,2018,A1 .Location in patent: Paragraph 0101; 0102; 0103

3
[ 5308-25-8 ]
[ 1180132-17-5 ]

Reference： [1]Patent: WO2015/130540,2015,A1
[2]Patent: CN106316935,2017,A
[3]Patent: CN106608879,2017,A
[4]Patent: CN106467517,2017,A
[5]European Journal of Medicinal Chemistry,2018,vol. 144,p. 1 - 28
[6]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978
[7]Patent: EP3385262,2018,A1
[8]Patent: WO2019/35008,2019,A1
[9]Patent: CN109761959,2019,A
[10]Patent: CN110156754,2019,A
[11]Organic Process Research and Development,2019,vol. 23,p. 2549 - 2555

4
[ 149806-06-4 ]
[ 1180132-17-5 ]

Reference： [1]Patent: WO2015/130540,2015,A1
[2]Patent: CN106608879,2017,A
[3]European Journal of Medicinal Chemistry,2018,vol. 144,p. 1 - 28
[4]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978
[5]Patent: EP3385262,2018,A1
[6]Patent: WO2019/35008,2019,A1

5
[ 1180132-17-5 ]
5-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-3-(propan-2-yl)-2H-indazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.475 g	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 4h;Inert atmosphere;	A mixture of 5-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-3-(propan-2-yl)-2H- indazole (E) (700 mg 2.3 mmol, 1.3 equiv.), 5-((4-ethylpiperazin-l-yl)methylpyridin-2- amine (G) (389 mg, 1.8 mmol, 1.0 equiv.), CS2CO3 (2.3 g, 7.2 mmol, 4.0 equiv.), Pd2(dba)3 (0.164 g, 0.18 mmol, 0.1 equiv.) and Xantphos (0.104 g, 0,18 mmol, 0.1 equiv.) in 10 mL of 1,4-dioxane was degassed with N2, then heated while stirring at 110C for 4h. The mixture was cooled to room temperature, then filtered through a Dicalite filtering medium, and the filter pad was washed thoroughly with CH2C12. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using a CH2Cl2-2% NH3/MeOH gradient to afford 0.475 g of N-(5-((4-ethylpiperazin- yl)methyl)pyridin-2-yl-5-fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2- amine (1). MS m z MH+ 489; 1H NMR (300 MHz, CDC13, ppm): delta 0.97 (t, 3H, J = 7.1 Hz), 1.51 (d, 2H, J= 7.0 Hz), 2.27-2.51 (overlapping m, 10 H), 3.33 (s, 3H), 3.54-3.68 (m, 1H), 4.15 (s, 3H), 7.64-8.71 (overlapping m, 7H), 10.00 (s, 1H).

Reference： [1]Patent: WO2016/14904,2016,A1 .Location in patent: Page/Page column 21; 24

6
[ 5308-25-8 ]
[ 149806-06-4 ]
[ 1180132-17-5 ]

Reference： [1]Patent: CN105622638,2016,A
[2]Patent: CN107266421,2017,A

7
[ 33225-73-9 ]
[ 1180132-17-5 ]

Reference： [1]Patent: CN106316935,2017,A

8
(6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)methanone [ No CAS ]
[ 1180132-17-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With lithium aluminium tetrahydride; In tetrahydrofuran; at -10 - 20℃; for 2h;	Compound 11 (2.3 g 10 mmol) was dissolved in 50 mL of tetrahydrofuran, and lithium aluminum hydride (0.46 g, 12 mmol) was slowly added at -10 C. After the addition, the mixture was stirred at room temperature for 2 hours at -10 C. Add 10% aqueous sodium hydroxide solution (5 mL), dilute with 50 mL water, extract three times with dichloromethane (30 mL×3), combine with organic phase, saturated sodium bicarbonate solution (30 mL), saturated brine (30 mL) , dried over anhydrous sodium sulfate, and rotary evaporation of the solvent gave a yellow solid, recrystallized from ethyl acetate to give a white solid 12 (2.0 g, 91%).
87.2%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3h;Inert atmosphere;	100 ml of the reactor was added tetrahydrofuran (50 ml)Under nitrogen protection, the temperature of the reaction system was reduced to 0 C,Lithium aluminum hydride (3.1 g, 85.2 mmol) was added to tetrahydrofuran,Followed by the addition of a compound of formula IV (5.0 g, 21.3 mmol)0 C reaction after 3 hours to stop the reaction,0 slowly dropping 1N sodium hydroxide, stirring, no gas release. Dichloromethane was extracted three times (50 ml each).The isolated organic phase was washed with saturated sodium chloride solution,Dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by column chromatography (200 to 300 mesh silica gel,Dichloromethane: methanol = 200: 1,150: 1,100: 1 gradient elution, collecting a single product spotted eluate, concentrated),4.1 g of solid was obtained, yield: 87.2%, HPLC purity 97.2% (area normalization method).

Reference： [1]Patent: CN110156754,2019,A .Location in patent: Paragraph 0020-0021;
[2]Patent: CN106316935,2017,A .Location in patent: Paragraph 0085; 0086; 0087; 0088; 0089

9
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)-pyridin-2-yl)-5-fluoro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 12h;	Add to the reaction flask7- (2-Chloro-5-fluoropyrimidin-4-yl) -5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo [d] pyrrole[1,2-a] imidazole (100 mg, 0.3 mmol, prepared as in Example 1)5 - ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (66 mg, 0.3 mmol)Cesium carbonate (195 mg, 0.6 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol)XantPhos (35 mg, 0.06 mmol) and anhydrous 1,4-dioxane (5 mL).The mixture was heated and stirred at 120 C for 12 hours.Cooled to room temperature, water (10 mL) and ethyl acetate (20 mL x 3) were added to the solution.The organic phase was combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by column chromatography (DCM / MeOH = 10: 1)To give the title compound (50 mg, white solid) in 32% yield.
25%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 110℃; for 2h;Inert atmosphere;	Nitrogen was bubbled into a solution of compound 14 (140 mg, 0.42 mmol, 1 eq), compound 8 (97 mg, 0.44 mmol, 1.05 eq), Pd2(dba)3 (37 mg, 0.04 mmol, 0.1 eq), Xantphos (49 mg, 0.084 mmol, 0.2 eq) and CS2CO3 (189 mg, 0.84 mmol, 2 eq) in dioxane (28 mL) for 5 minutes. The mixture was stirred at 110 C for 2 h. After completion, the mixture was cooled down to rt, the mixture was diluted with DCM (50 mL) and filtered through Celite, washed with DCM (20 mL), dried over sodium sulfate, concentrated and purified by pre-HPLC to give the desired product (54 mg, 25%). NMR (300 MHz, CDC ) delta 8.47- 8.39 (m, 3 H), 8.28 (s, 1 H), 8.10 (s, 1 H), 7.83 (d, J = 11.7 Hz, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 3.53 (s, 2 H), 3.19- .15 (m, 2 H), 2.64- 2.50 (m, 12 H), 1.74 (s, 6 H), 1.14 (t, J = 7.5 Hz, 3 H). LCMS: (M+H)
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0204-0206
[2]Patent: WO2019/35008,2019,A1 .Location in patent: Paragraph 616; 633; 634
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

10
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-2-methyl-2,3-dihydro-1H-benzo[d]pyrrole[1,2-a]imidazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(5-fluoro-2-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the microwave reaction flask7- (2-Chloro-5-fluoropyrimidin-4-yl)-5-fluoro-2-methyl-2,3-dihydro-1H-benzo [d]Pyrrole [1,2-a] imidazole (96 mg, 0.3 mmol, prepared as in Example 5)5 - ((4-ethylpiperazineYl) methyl) pyridin-2-amine (66 mg, 0.3 mmol)Cesium (195 mg, 0.6 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol), XantPhos (35 mg, 0.06 mmol) and anhydrous 1,4-dioxane (2 mL)The mixture was microwave reacted at 150 C for 1 hour. Cooled to room temperature,Water (10 mL) was added and extracted with ethyl acetate (20 mL x 3).The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate,Filtered, concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20: 1)The resulting residue was purified to give the title compound amine (30 mg, yellow solid)Yield 20%.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0509-0511
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

11
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-2-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [ No CAS ]
4-(2-ethyl-5-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-((4-ethylpiperazine-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the reaction flask7- (2-chloro-5-fluoropyrimidin-4-yl) -5-fluoro-2-methyl-2,3-dihydro-1H-benzo [d]Pyrrolo [1,2-a] imidazole (100 mg, 0.3 mmol, prepared as in Example 6)5 - ((4-ethylpiperazineYl) methyl) pyridin-2-amine(66 mg, 0.3 mmol), cesium carbonate (195 mg, 0.6 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol)XantPhos (35 mg, 0.06 mmol) and 1,4-dioxane (2 mL).The mixture was microwave reacted at 150 C for 1 hour. Cooled to room temperature, water (10 mL) was added,Ethyl acetate (20 mL x 3). Combine organic phase,Saturated sodium chloride solution (10 mL),Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by column chromatography (DCM / MeOH = 20: 1)To give the title compound (30 mg, yellow solid) in 20% yield.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0523-0525
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

12
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrole[1,2-a]imidazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(5-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.8%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the reaction flask7- (2-Chloro-5-fluoropyrimidin-4-yl)Fluoro-1-methyl-2,3-dihydro-1H-benzo [d]Pyrrole [1,2-a] imidazole (96 mg, 0.3 mmol, prepared as in Example 2)5 - ((4-ethylpiperazin-1-yl)Methyl) pyridin-2-amine (66 mg, 0.3 mmol)Cesium carbonate (195 mg, 0.6 mmol), Pd2 (dba) 3 (27 mg, 0.03 mmol)XantPhos (35 mg, 0.06 mmol) and 1,4-dioxane (2 mL).The mixture was microwave reacted at 150 C for 1 hour.Cooled to room temperature, extracted with water (10 mL), and extracted with ethyl acetate (20 mL x 3).The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate,Filtered, concentrated under reduced pressure. The residue was purified by thin layer chromatography (DCM / MeOH = 10: 1)The resulting residue was purified to give the title compound (45 mg, white solid)Yield 29.8%.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0603-0605
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

13
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-1-ethyl-5-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [ No CAS ]
4-(1-ethyl-5-fluoro-2,3-dihydro-1H-benzo[d]pyrrole[1,2-a]imidazol-7-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the microwave reaction flask7- (2-chloro-5-fluoropyrimidin-4-yl)Fluoro-1-ethyl-2,3-dihydro-1H-benzo [d]Pyrrole [1,2-a] imidazole (100 mg, 0.3 mmol, prepared in Example 3)5 - ((4-ethylpiperazin-1-yl)Methyl) pyridin-2-amine(66 mg, 0.3 mmol), Cs2CO3 (195 mg, 0.6 mmol)Pd2 (dba) 3 (55 mg, 0.06 mmol), Xantphos (35 mg, 0.06 mmol)And anhydrous 1,4-dioxane (2 mL). The mixture was microwave reacted at 150 C for 1 hour.Cooled to room temperature, extracted with water (10 mL), and extracted with ethyl acetate (20 mL x 3).The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2)Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by thin layer chromatography (DCM / MeOH = 10: 1)To give the title compound (31 mg, yellow solid) in 20% yield.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0662-0665
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

14
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-2,2-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(5-fluoro-2,2-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 0.75h;Microwave irradiation;	Add to the reaction flask7- (2-Chloro-5-fluoropyrimidin-4-yl)Fluoro-2,2-dimethyl- dihydro-lH-benzo [d]Pyrrolo [1,2-a]Imidazole (100 mg, 0.3 mmol, prepared as in Example 4)5 - ((4-ethylpiperazin-1-yl)Methyl) pyridin-2-amine (66 mg, 0.3 mmol)Cesium carbonate (195 mg, 0.6 mmol), Pd2 (dba) 3 (27 mg, 0.03 mmol), XantPhos (35 mg, 0.06 mmol) and 1,4-dioxane (2 mL).The mixture was microwave reacted at 150 C for 45 minutes.Cooled to room temperature, water (10 mL) and ethyl acetate (20 mL x 3) were added to the solution.The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate,Filtered, concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10: 1)The resulting residue was purified to give the title compound (20 mg, yellow solid) in 14% yield.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0565-0567
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

15
[ 1180132-17-5 ]
7-(2-chloro-pyrimidin-4-yl)-5-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrole[1,2-a]imidazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-4-(5-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrole[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the microwave reaction flask7- (2-Chloro-pyrimidin-4-yl)Fluoro-1-methyl-2,3-dihydro-1H-benzo [d]Pyrrole [1,2-a] imidazole (100 mg, 0.33 mmol,Prepared in a similar manner to Example 9)5 - ((4-ethylpiperazin-1-yl)Methyl) pyridin-2-amine (73 mg, 0.33 mmol), Cs2CO3 (195 mg, 0.66 mmol)Pd2 (dba) 3 (55 mg, 0.06 mmol), Xantphos(35 mg, 0.06 mmol) and anhydrous 1,4-dioxane (2 mL).The mixture was microwave reacted at 150 C for 1 hour. Cooled to room temperature,Water (10 mL) and ethyl acetate (20 mL x 3) were added to the solution.The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2)Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by column chromatography (DCM / MeOH = 10: 1)To give the title compound (62 mg, yellow solid) in 39% yield.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0682-0684
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

16
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(5-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.4%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid. 1H-NMR (DMSO-d6, 400 MHz), delta: 9.97 (s, 1H), 8.68 (d, 1H), 8.17 (d, 2H), 8.06 (s, 1H), 7.70 (m, 2H), 4.22 (m, 2H), 3.43 (s, 2H), 3.01 (m, 2H), 2.69 (m, 2H), 2.33 (m, 10H), 0.96 (m, 3H). MS (ESI): mass calcd. for C26H28F2N8 490, m/z found 491 [M+H] +.
9.3%	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the microwave reaction flask7- [2-Chloro-5-fluoropyrimidin-4-yl) -5-fluoro-2,3-dihydro-1H-benzo [d] pyrrole [1,2-a] imidazole (100 mg, 0.33 mmol, Example 11 Preparation),5 - ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine(7 mg, 0.33 mmol, prepared in second step), sodium tert-butoxide (64 mg, 0.66 mmol), Pd2 (dba) 3 (30 mg, 0.033 mmol)XantPhos (38 mg, 0.066 mmol) and anhydrous 1,4-dioxane (5 mL).The mixture was microwave reacted at 150 C for 1 hour.Cooled to room temperature, extracted with water (10 mL), and ethyl acetate (40 mL x 3).The organic phases were combined, washed with saturated sodium chloride solution (40 mL x 2), dried over anhydrous sodium sulfate,Filtered, concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10: 1)The resulting residue was purified to give the title compound (15 mg, yellow solid)Yield 9.3%.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978
[2]Patent: CN106608879,2017,A .Location in patent: Paragraph 0142-0143; 0150-0151

17
[ 1180132-17-5 ]
8-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluoro-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(6-fluoro-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.5%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the microwave reaction flask(2-chloro-5-fluoropyrimidin-4-yl) -6-fluoro-1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyridine 0.32 mmol, prepared in Example 7),5 - ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine(68 mg, 0.32 mmol), Cs2CO3 (195 mg, 0.6 mmol)Pd2 (dba) 3 (55 mg, 0.06 mmol), Xantphos (35 mg, 0.06 mmol)And anhydrous 1,4-dioxane (2 mL). The mixture was microwave reacted at 150 C for 1 hour.Cooled to room temperature, water (10 mL) and ethyl acetate (20 mL x 3) were added to the solution.The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate,Filtered, concentrated under reduced pressure. The residue was purified by thin layer chromatography (DCM / MeOH = 10: 1)The resulting residue was purified to give the title compound (33 mg, pale yellow solid)Yield 20.5%.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0169-0171
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

18
[ 1180132-17-5 ]
2-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepane [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepin-2-yl)pyrimidin-2-aminee [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	A solution of 2- (2-chloro-5-fluoropyrimidin-4-yl) -4-fluoro-7,8,9,10-tetrahydro-6H-benzo [4,5] imidazole[1,2-a] azepane (100 mg, 0.3 mmol, prepared as in Example 8)5 - ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine(66 mg, 0.3 mmol), Cs2CO3 (195 mg, 0.6 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol), Xantphos (35 mg,0.06 mmol) and anhydrous 1,4-dioxane (2 mL). The mixture was microwave reacted at 150 C for 1 hour. Cooled to room temperature,Water (10 mL) and ethyl acetate (20 mL x 3) were added to the solution. The organic phase was combined and washed with saturated sodium chloride solution(20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (DCM / MeOH = 20: 1)To give the title compound (20 mg, yellow solid) in 13% yield.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0189-0192
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

19
[ 1180132-17-5 ]
7-(2-chloropyrimidin-4-yl)-5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation;	Add to the reaction flask7- (2-Chloro-5-fluoropyrimidin-4-yl) -5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo [d] pyrrolo[1,2-a] imidazole (100 mg, 0.32 mmol, prepared as in Example 9), 5-((4-ethylpiperazin-1-yl)Methyl) pyridin-2-amine (70 mg, 0.32 mmol), cesium carbonate (208 mg, 0.64 mmol)Pd2 (dba) 3 (55 mg, 0.06 mmol), XantPhos (35 mg, 0.06 mmol)And anhydrous 1,4-dioxane (2 mL). The mixture was microwave reacted at 150 C for 1 hour.Cooled to room temperature, extracted with water (10 mL), and extracted with ethyl acetate (20 mL x 3).The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2)Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by column chromatography (DCM / MeOH = 20: 1)To give the title compound (16 mg, pale yellow solid) in 10% yield.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0239-0241
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

20
[ 1180132-17-5 ]
7-(2-chloro-5-fluoropyrimidin-4-yl)-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrole[1,2-a]imidazole [ No CAS ]
4-(1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	Add to the microwave reaction flask, 7- (2-Chloro-5-fluoropyrimidin-4-yl) -1,1-dimethyl-2,3-dihydro-1H-benzo [d] pyrrole[1,2-a] imidazole (200 mg, 0.63 mmol, prepared according to the procedure of Example 10)5 - ((4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (139 mg, 0.63 mmol)Cesium carbonate (410 mg, 1.26 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol)BINAP (37 mg, 0.06 mmol) and anhydrous 1,4-dioxane (5 mL).The mixture was microwave reacted at 120 C for 1 hour.Cooled to room temperature, extracted with water (10 mL), and extracted with ethyl acetate (20 mL x 3).The organic phase was combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by column chromatography (DCM / MeOH = 10: 1)To give the title compound (134 mg, pale yellow solid) in 43% yield.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation;	General procedure: To a solution of 5a (0.10 g, 0.33 mmol) and 9a (0.07 g, 0.33 mmol) in 1,4-dioxane (2 mL), were added Cs2CO3 (0.21 g, 0.65 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and XantPhos (0.03 g, 0.06 mmol). The mixture was heated to 120 C for 60 min with microwave, then cooled to room temperature, diluted with water (10 mL), and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20:1) to give compound 10a (0.02 g, 12.40%) as a yellow solid.

Reference： [1]Patent: CN106608879,2017,A .Location in patent: Paragraph 0254-0256
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 974 - 978

21
[ 1180132-17-5 ]
6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-(D<SUB>3</SUB>)methyl-(5,7-D<SUB>2</SUB>)-benzimidazole [ No CAS ]
[5-(4-ethylpiperazin-1-ylmethyl)-pyridin-2-yl][5-fluoro-4-(7-fluoro-3-isopropyl-2-(D₃)methyl-(5,7-D₂)benzimidazol-5-yl)pyrimidin-2-yl]amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.8%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 2h;Inert atmosphere; Reflux;	A solution of 6- (2-chloro-5-fluoropyrimidin-4-yl) -4-fluoro-1-isopropyl-2- [D3] methyl-1H- [5,7-D2] benzimidazole (788 mg , 2.41 mmol),5- (4-ethylpiperazin-1-ylmethyl) -pyridin-2-ylamine (530 mg, 2.41 mmol)Cesium carbonate (1.57 g, 4.82 mmol) was successively added to dioxane (20 mL)Nitrogen replacement reaction flask in the air,Rapid addition of tris (dibenzylideneacetone) dipalladium (50 mg)9,9-dimethyl-4,5-dibenzophenylphosphine anthracene (80 mg).Under nitrogen, the reaction mixture was heated to reflux.After 2 hours the reaction solution was cooled to room temperature,30 mL of ethyl acetate was added,Vacuum filtration.The filtrate was added to 20 mL of water,Liquid separation,Water layer into 20mL ethyl acetate,Liquid separation,Combined organic layer,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solventLight brown solid.Crude add 9mL petroleum ether,3 mL of ethyl acetate,Stirred at room temperature for 30 minutes,Vacuum filtration,858 mg of the compound of formula I-1,As an off-white solid (yield 69.8%).

Reference： [1]Patent: CN106467517,2017,A .Location in patent: Paragraph 0119; 0120; 0121; 0122; 0123; 0124

22
[ 1231930-25-8 ]
[ 1180132-17-5 ]
C₁₂H₁₉N₃O [ No CAS ]

Reference： [1]Organic Process Research and Development,2017,vol. 21,p. 1447 - 1451

23
[ 1180132-17-5 ]
1-isopropyl-5-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indole [ No CAS ]
N-(5-(4-ethylpiperazin-1-methyl)pyridin-2-yl)-5-fluoro-4-(1-isopropyl-1H-indol-5-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.9%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 8h;Inert atmosphere;	1 - isopropyl -5 - (2 - chloro -5 - fluoro pyrimidine -4 - yl) - 1H - indole (150 mg, 0 . 52 mmol), 5 - [(4 - ethyl piperazine -1 - yl) methyl] pyridine -2 - amine (114 mg, 0 . 52 mmol), Pd2 (Dba)3 (50 mg, 0 . 052 mmol), Xantphos (45 mg, 0 . 05278 mmol) and cesium carbonate (254 mg, 0 . 78 mmol) added to the 1, 4 - dioxane (815 ml) in, N2 Under the protection of the 100 C reaction 8 h. Concentrating the solvent to dry, the residue plus H2 O (30 ml)/dichloromethane (DCM, 50 ml) stirring extraction, the organic layer drying, filtering, and concentrated to obtain yellow solid, over silica gel column (eluant dichloromethane/methanol: 1/30 - 1/20) shall be yellow solid N - (5 - (4 - ethyl piperazine -1 - methyl) - pyridine -2 - yl) -5 - fluoro -4 - (1 - isopropyl - 1H - indole -5 - yl) pyrimidine -2 - amine (I - 1,125 mg, yield 50.9%),

Reference： [1]Patent: CN107286134,2017,A .Location in patent: Paragraph 0056; 0057; 0061

24
[ 1180132-17-5 ]
C₁₆H₁₅ClFN₃ [ No CAS ]
C₂₈H₃₄FN₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos;Inert atmosphere; Microwave irradiation; Sealed tube; Heating;	General procedure: To a microwave vial equipped with magnetic stir bar, intermediate 2 (0.155 mmol) and 4 (0.186 mmol) were dissolved in 1 mL of dioxane, then K2CO3 powder (0.31 mmol), Pd2(dba)3 (0.015 mmol) and X-phos (0.029 mmol) were added and the mixture was bubbled with Ar for 15mins. Then the reaction vessel was sealed and irradiated with Biotage Initiator + for 0.5-2 hours at a temperature of 120 C. The resulting reaction mixture was cooled to room temperature and diluted with dichloromethane and water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and then concentrated to dryness. The residue was loaded on a column and flashed on silica gel to afford the desired compound (5a-5k) as product.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5332 - 5336

25
[ 1180132-17-5 ]
C₁₅H₁₄ClFN₄ [ No CAS ]
C₂₇H₃₃FN₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos;Inert atmosphere; Microwave irradiation; Sealed tube; Heating;	General procedure: To a microwave vial equipped with magnetic stir bar, intermediate 2 (0.155 mmol) and 4 (0.186 mmol) were dissolved in 1 mL of dioxane, then K2CO3 powder (0.31 mmol), Pd2(dba)3 (0.015 mmol) and X-phos (0.029 mmol) were added and the mixture was bubbled with Ar for 15mins. Then the reaction vessel was sealed and irradiated with Biotage Initiator + for 0.5-2 hours at a temperature of 120 C. The resulting reaction mixture was cooled to room temperature and diluted with dichloromethane and water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and then concentrated to dryness. The residue was loaded on a column and flashed on silica gel to afford the desired compound (5a-5k) as product. 5a LC-MS: 489.2 (M+1); 1H-NMR: (400 MHz, CDCl3) delta 8.86(s, 1H), 8.27(s, 1H), 8.19(s, 1H), 8.11(s, 1H), 7.71(s, 2H), 7.60(d, J=10.8Hz, 1H), 4.73-4.80(m, 1H), 3.65(s, 2H), 3.48-3.51 (m, 2H), 3.05-3.10(m, 4H), 2.84-2.96(m, 4H), 2.70(s, 3H), 1.72(d, J=7.2Hz, 6H), 1.47-1.51(t, J=7.0Hz, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5332 - 5336

26
[ 1180132-17-5 ]
[ 1231929-97-7 ]

Reference： [1]Patent: US2017/305884,2017,A1

27
[ 420-04-2 ]
[ 1180132-17-5 ]
N-[5-(4-ethylpiperazine-1-yl-methyl)pyridine-2-yl]guanidine nitrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.2%	With nitric acid; In ethanol; water; at 0 - 80℃;Inert atmosphere;	Add 5-(4-ethyl-piperazine-1 -yl methyl)-2-amin- opyridine (VIII) (2.2 g, 10 mmol) and anhydrous ethyl alcohol 25 mL into the reaction flask, low the temperature to 0 C., and add 65% nitric acid 0.45 mL and 50% cyanamide aqueous solution (1 mL, 12 mmol) in sequence, and then, raise the temperature slowly to 80 C., and conduct stirring reaction for 8-12 hours. Lower the temperature to 0 C., and again add 65% nitric acid 0.45 mL and 50% cyanamide aqueous solution (1 mL, 12 mmol), and then raise the temperature slowly to 80 C., and conduct stirring operations again for 6-8 hours, and detect completion of the reaction with TLC sampling. Lower the temperature to room temperature, and there will be precipitation. Make filtration, and recrystallize the filter cake with ethyl acetate and n-hexane (2:1, V/V) mixed solvent, and make vacuum drying to obtain luminous yellow solid N-[5-(4-ethyl-pip- erazine-1 -yl methyl) pyridine-2-yl]guanidine nitrate (IX) 2.8 g, the yield rate is 86.2%; mass spectrum (El): mlz 326 (M+H).

Reference： [1]Patent: US2017/305884,2017,A1 .Location in patent: Paragraph 0056

Yield	Reaction Conditions	Operation in experiment
	With copper(I) oxide; ammonium hydroxide; In methanol; at 70℃;Inert atmosphere; Sealed tube;	General procedure: Nitrogen was bubbled into a mixture of tert-butyl 4-((6-bromopyridin-3 -yl)methyl)piperazine- 1 -carboxylate (1 a) (3.56 g, 10 mmol), Cu20 (0.50 g,0.3 mmol) in NH3.H20 (20 mL) and MeOH (20 mL), and the mixture was heated at 70C in sealed tube for overnight. The reaction mixture was cooled to r.t., and filtered. The filtrate was concentrated, diluted with NaOH aqueous solution (2 N, 50 mL), and extracted with DCM (2100 mL). The extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give crude product as yellow oil, recrystallized by MTBE to give tert-butyl 4-((6-aminopyridin-3 -yl)methyl)piperazine- 1 -carboxylate (ib).
	With copper(I) oxide; ammonia; In methanol; at -78 - 70℃; for 12h;Sealed tube;	General procedure: 78 C, in ammonia, add methanol (20mL) to a 100mL sealed tube, then 1-((5-bromopyridin-2-yl)methyl)-4-methylpiperazine (1.000 g) was added in sequence. with cuprous oxide (0.532 g) was added to the solution volume to 30 mL. The outer bath was taken out, naturally warmed to room temperature, and then heated to 70 C for 12 hours. The filtrate was collected by filtration and then concentrated. Purified by column chromatography (DCM / MeOH = 15 / 1) 0.730 g of 6-((4-methylpiperazin-1-yl)methyl)pyridin-3-amine was obtained.

29
[ 1180132-17-5 ]
5-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-2,3,3-trimethyl-3H-indole [ No CAS ]
N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoro-2,3,3-trimethyl-3H-indol-5-yl)pyrimidine-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;	Pd2(dba)3 (86.4mg, 0.09mmol) and Xant-phos (109.2mg, 0.19mmol) were added under N2 to a solution of 154 1E (290.0mg, 0.94mmol), INT-7 (228.6mg, 1.04mmol), and 152 potassium phosphate (400.5mg, 1.88mmol) in 111 1,4-dioxane (10mL). Then the mixture was reacted in the microwave at 150C for 1h. The mixture was cooled to RT, filtered, diluted with water (10mL), and extracted with DCM (10mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na2SO4, concentrated under a vacuum, and purified by preparative thin-layer chromatography to obtain 157 compound 1 (140.3mg; yield, 30%) as a yellow solid. Purity: 99.6%; retention time: 3.10min. MP: 152.9-153.4C. High-resolution mass spectrometry (HRMS)-ESI: [M+H]+ observed 492.2677, calculated 492.2687.1H NMR (400MHz, CDCl3) delta 8.72 (s, 1H), 8.49 (d, 1H, J=3.2Hz), 8.38 (d, 1H, J=8.4Hz), 8.31 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.73 (d, 1H, J=8.4Hz), 3.52 (s, 2H), 2.54-2.41 (m, 10H), 2.38 (s, 3H), 1.40 (s, 6H), 1.10 (t, 3H, J=7.2Hz). 13C NMR (100MHz, CDCl3) delta 191.29, 155.37 (d, JC-F=3.0Hz), 154.76 (d, JC-F=252.0Hz), 152.17, 152.00, 150.94 (d, JC-F=9.0Hz), 149.63 (d, JC-F=89.0Hz), 149.37 (d, JC-F=3.0Hz), 147.39 (d, JC-F=26.0Hz), 142.82 (d, JC-F=11.0Hz), 139.05, 132.05 (d, JC-F=6.0Hz), 127.27, 117.97 (dd, JC-F=3.0Hz), 116.32 (dd, JC-F=7.0Hz), 111.39, 59.84, 54.85, 52.91 (2C), 52.74 (2C), 52.28, 23.03 (2C), 15.84, 11.95.
140.3 mg	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;Microwave irradiation; Inert atmosphere;	A reaction flask was charged with 5-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro -2,3,3-trimethyl-3H-indole (290.0mg, 0.94 mmol) prepared in step 5, 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amino (228.6 mg, 1.04 mmol) preparedin Step 2, potassium phosphate (400.5 mg, 1.88 mmol), 10 ml of dioxane, Pd2(dba)3 (86.4 mg, 0.09 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (109.2 mg, 0.19 mmol). Microwave reaction was carried out at 150C underthe protection of nitrogen gas for 1 h. The reaction product was cooled to room temperature, filtered, added with 10mlof water, extracted three times with dichloromethane (10 ml for each time). The organic phases were combined, washedonce with 30 ml of saturated salt solution, dried with anhydrous sodium sulfate, filtered, subjected to rotary evaporationto remove solvent, and separated by silica gel column chromatography (dichloromethane: methanol = 30:1) to give thetitled compound (140.3 mg, y ellow solid). 1H-NMR(400MHz,CDCl3) delta8.72(s,1H), 8.49(d,1H,J=3.2Hz), 8.38(d,1H,J=8.4Hz), 8.31(s,1H), 7.92(s,1H),7.89(s,1H), 7.73(d,1H,J=8.4Hz), 3.52(s,2H), 2.54-2.41(m,10H), 2.38(s,3H), 1.40(s,6H), 1.10(t,3H,J=7.2Hz). MS(ESI):m/z 492.2[M+H]+.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 144,p. 1 - 28
[2]Patent: EP3385262,2018,A1 .Location in patent: Paragraph 0113; 0114; 0115

30
[ 1180132-17-5 ]
5-(2-chloro-5-fluoropyrimidin-4-yl)-3-ethyl-7-fluoro-2,3-dimethyl-3H-indole [ No CAS ]
4-(3-ethyl-7-fluoro-2,3-dimethyl-3H-indol-5-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 1h;	General procedure: Pd2(dba)3 (86.4mg, 0.09mmol) and Xant-phos (109.2mg, 0.19mmol) were added under N2 to a solution of 154 1E (290.0mg, 0.94mmol), INT-7 (228.6mg, 1.04mmol), and 152 potassium phosphate (400.5mg, 1.88mmol) in 111 1,4-dioxane (10mL). Then the mixture was reacted in the microwave at 150C for 1h. The mixture was cooled to RT, filtered, diluted with water (10mL), and extracted with DCM (10mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na2SO4, concentrated under a vacuum, and purified by preparative thin-layer chromatography to obtain 157 compound 1 (140.3mg; yield, 30%) as a yellow solid.