[ CAS No. 1231930-42-9 ] {[proInfo.proName]}

Name: 1231930-42-9|6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole|97%
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SKU: A209941
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Quality Control of [ 1231930-42-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1231930-42-9 ]

SDS Specification

Alternatived Products of [ 1231930-42-9 ]

Product Details of [ 1231930-42-9 ]

CAS No. :	1231930-42-9	MDL No. :	MFCD25977328
Formula :	C₁₅H₁₃ClF₂N₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BDVDXNYOCBUMNP-UHFFFAOYSA-N
M.W :	322.74	Pubchem ID :	78358206
Synonyms :

Calculated chemistry of [ 1231930-42-9 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.27
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	81.53
TPSA :	43.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.99
Log Po/w (XLOGP3) :	3.65
Log Po/w (WLOGP) :	5.15
Log Po/w (MLOGP) :	3.03
Log Po/w (SILICOS-IT) :	4.38
Consensus Log Po/w :	3.84

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.51
Solubility :	0.0099 mg/ml ; 0.0000307 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.25
Solubility :	0.018 mg/ml ; 0.0000557 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.22
Solubility :	0.000194 mg/ml ; 0.000000603 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.62

Safety of [ 1231930-42-9 ]

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

Application In Synthesis of [ 1231930-42-9 ]

* 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 [ 1231930-42-9 ]
Downstream synthetic route of [ 1231930-42-9 ]

[ 1231930-42-9 ] Synthesis Path-Upstream 1~7

1
[ 1231930-37-2 ]
[ 2927-71-1 ]
[ 1231930-42-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In acetonitrile at 85℃; for 8 h; Inert atmosphere	To a suspension of 4-fluoro-l-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-benzo[d]imidazole (2-16, 318 nig, 1 mmol), 2,4-dichloro-5- fluoropyrimidine (2-17, 166 mg, 1 mmol), and Pd(PPrn)4 (115.6 mg, 0.1 mmol) in 6 mL of CH3CN was added 2 ml, of saturated Na₂C03 under an atmosphere of N₂. The mixture was heated to 85 °C and stirred for 8h. Then the reaction was cooled to room temperature, extracted with CHCh and isopropanol (V/V=4: 1) and the combined organic layers were washed with brine, dried over anhydrous Na2S€>4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10percent MeOH in DCM) to give 6-(2-cUoro-5-fluoropyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl IH-benzoj djirnidazole 2-18 as a gray solid (277 mg, 86percent). LCMS: m/z 323.1 [M+l].
66%	Stage #1: With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere Stage #2: at 80℃; for 5.5 h; Inert atmosphere	To a 250 mL 3-neck round bottom flask equipped with a N2 inlet, overhead stirrer, reflux condenser and temperature probe was charged 5-fluoro-2,4-dichloropyrimidine (2, 5.17 g,31.0 mmol, 1.4 equiv), Na2CO3 (5.86 g, 55.3 mmol, 2.5 equiv), water (9 mL), and DME (45 mL). The solution was degassed by sparging N2 subsurface for 30 min. After subsurface sparging, PdCl2(PPh3)2 (46.6 mg, 66 lmol, 0.03 equiv) was added in one portion. The resulting solution was heated to 80 C. In a separate 100 mL round bottom flask was charged boronic ester 3 (7.04 g, 22.1 mmol,1.0 equiv) and DME (40 mL). The resulting solution was added to the heated solution by syringe pump over the course of 1.5 h. After all of boronic ester 3 was added, the reaction solution was stirred at 80 C for an additional 4 h, at which time the reaction was complete as judged by HPLC analysis. The reaction mixture was then cooled to ambient temperature and diluted with ice cold water (300 mL) and stirred for 25 min. The resulting slurry was collected by filtration and the resulting wetcake was slurried in IPA (105 mL) and heated to 80 C for 3.5 h. The heated slurry was then allowed to cool to ambient temperature over 16 h and the solid was collected by filtration and washed with IPA (35 mL). The wetcake was dried in a vacuum oven at 45 C for 18 h to obtain the desired biaryl compound 6 in 66percent yield. Compound 6: IR (film)mmax = 3413, 2972, 2940, 2892, 1567, 1507, 1401, 1388, 1348, 1210 cm1; 1HNMR (500 MHz, CDCl3): d = 8.50 (d, J = 3.4 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.77(d, J = 11.7 Hz, 1H), 4.74 (septet, J = 7.0 Hz, 1H), 2.69 (s, 3H), 1.69 (d, J = 7.0 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3): d = 155.3, 154.8, 154.2, 153.9, 153.2,148.4, 136.6, 134.7, 125.5, 108.8, 108.2, 48.7, 21.5, 15.2 ppm; HR-MS [ESI]:Calcd for C15H14N4ClF2 [M+H+]: 323.0870, found 323.0864.
14.4 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water at 80 - 84℃; for 1 h; Inert atmosphere	Bubble nitrogen into a mixture of 2,4-dichloro-5-fluoro-pyrimidine (12.7 g), bis(triphenylphosphine)palladium(II) chloride (4.9 g), sodium carbonate 2 M in water (103.7 mL) and 1 ,2-dimethoxyethane (120 mL). Heat in a pre-heated oil bath at 80 °C and add drop wise a solution of 4-fluoro-l-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-benzoimidazole (22 g) in 1,2-dimethoxy ethane (200 mL). Stir the mixture at 84 °C for 1 hour. Cool to room temperature, add ethyl acetate (800 mL) and wash twice with brine (100 mL). Dry over magnesium sulfate and remove the solvent under vacuum. Triturate with acetonitrile to afford 14.4 g of the title compound. (0098) MS (ES⁺): m/z= 323 (M+H)⁺.

13.18 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water at 85℃; for 1 h; Inert atmosphere	The compound of formula XXII-1 (9.95 g, 59.60 mmol) was dissolved in ethylene glycol dimethyl ether (210 mL) and 2MAqueous solution of sodium carbonate (140 mL), compound of formula XVII-1 (17.5 g, 54.18 mmol),Bis (triphenylphosphine) palladium chloride (1.0 g).Nitrogen exchange reaction bottle of air, open the oil bath heating, stirring at 85C 1h. The reaction flask was cooled to roomThe reaction solution was poured into 300mL of water, a large number of solid precipitation, vacuum filtration after the full stirring, the filter cake was dried gray-white solidBody 13.18g
5 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water at 80 - 84℃; for 1 h; Inert atmosphere	Under N2 atmosphere, 2,4-dichloro-5-fluoro-pyrimidine (6.3 g), commercially available, was dissolved in 1,2-dimethoxyethane (60 mL). Bis(triphenylphosphine)palladium(II) chloride (2.5 g) and 2M aqueous sodium carbonate solution (50 mL) were then added. Mixed solution was dropped at 80 °C4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl) -1H-benzimidazole(10 g) 1,2-dimethoxyethane (50 mL) solution. The reaction was stirred at 84 °C for 1 hour and the reaction was monitored by TLC. Cooled to room temperature, the resulting mixture was extracted with EtOAc (40 mL X 3) and the combined organic phases were washed with saturated brine (40 mL X 3). After drying over anhydrous sodium sulfate, the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target Compound (5g).
2.6 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 4 h;	2.3 g of 2,4-dichloro-5-fluoropyrimidine was dissolved in 20 ml of ethylene glycol dimethyl ether and added with an aqueous solution of sodium carbonate (4 g) and 0.9 g of Pd(PPh3)2Cl2, and heated to 80 ° C with stirring.Add 3.9g to the solution.4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-boronic acid pinacol ester in ethylene glycol dimethyl ether solution, maintained at 80 ° C for 4 h,The heating was stopped, and 50 ml of ethyl acetate was added thereto, and the mixture was stirred to room temperature. The reaction mixture was washed with brine and dried over anhydrous magnesium sulfate.Concentrated to give an oily material which was purified6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole 2.6 g as a pale yellow solid.

Reference： [1] Patent: WO2017/185031, 2017, A1, . Location in patent: Page/Page column 96
[2] Tetrahedron Letters, 2015, vol. 56, # 7, p. 949 - 951
[3] Patent: US2010/160340, 2010, A1, . Location in patent: Page/Page column 11
[4] Patent: WO2015/130540, 2015, A1, . Location in patent: Page/Page column 22-23
[5] Patent: CN107266421, 2017, A, . Location in patent: Paragraph 0043; 0052; 0053
[6] Patent: CN104892580, 2018, B, . Location in patent: Paragraph 0064; 0065; 0066in
[7] Patent: CN107827875, 2018, A, . Location in patent: Paragraph 0051; 0052; 0054

2
[ 1231930-33-8 ]
[ 1231930-42-9 ]

Reference： [1] Patent: WO2015/130540, 2015, A1,
[2] Patent: CN107266421, 2017, A,
[3] Patent: CN107827875, 2018, A,

3
[ 1118-69-0 ]
[ 1231930-42-9 ]

Reference： [1] Patent: WO2015/130540, 2015, A1,
[2] Patent: CN107266421, 2017, A,

4
[ 67567-26-4 ]
[ 1231930-42-9 ]

Reference： [1] Patent: WO2015/130540, 2015, A1,
[2] Patent: CN107827875, 2018, A,

5
[ 1231930-29-2 ]
[ 1231930-42-9 ]

Reference： [1] Patent: WO2015/130540, 2015, A1,

6
[ 42717-36-2 ]
[ 1231930-42-9 ]

Reference： [1] Patent: CN107827875, 2018, A,

7
[ 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

[ 1231930-42-9 ] Synthesis Path-Downstream 1~88

1
[ 1231930-37-2 ]
[ 2927-71-1 ]
[ 1231930-42-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In acetonitrile; at 85℃; for 8.0h;Inert atmosphere;	To a suspension of 4-fluoro-l-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-benzo[d]imidazole (2-16, 318 nig, 1 mmol), 2,4-dichloro-5- fluoropyrimidine (2-17, 166 mg, 1 mmol), and Pd(PPrn)4 (115.6 mg, 0.1 mmol) in 6 mL of CH3CN was added 2 ml, of saturated Na2C03 under an atmosphere of N2. The mixture was heated to 85 C and stirred for 8h. Then the reaction was cooled to room temperature, extracted with CHCh and isopropanol (V/V=4: 1) and the combined organic layers were washed with brine, dried over anhydrous Na2S?>4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give 6-(2-cUoro-5-fluoropyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl IH-benzoj djirnidazole 2-18 as a gray solid (277 mg, 86%). LCMS: m/z 323.1 [M+l].
75.63%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In Isopropyl acetate; at 30 - 85℃;Inert atmosphere;	Argon/Nitrogen was bubbled into a mixture of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H- benzoimidazole (20 g, 0.0737 mol), bis(pinacolato)diborane (22.5 g, 0.0886 mol), triphenylphosphine (0.193 g, 0.00073 mol), and potassium acetate (21.72 g, 0.2213 moles) in isopropyl acetate (60 mL). Bis(triphenylphosphine)palladium(II) dichloride (2.07 g, 0.00294 mol) was added to the reaction mixture which was then heated to 85-90 C for 2-4 hours. The completion of the reaction was monitored by TLC/HPLC. The reaction mass was cooled to 30-35 C. 2,4- Dichloro-5-fluoro pyrimidine (13.54 g, 0.0811 mol), potassium carbonate solution, and isopropylacetate 60 mL were charged to the reaction mass at 30-35 C and bubbled with organ/nitrogen for 30 minutes. The reaction mixture was heated to 80-85 C and maintained for 3-4 hours. The completion of the reaction was monitored by TLC/HPLC. The reaction mass was cooled to 30-3 5C and stirred for 3-4 hours, filtered, and the solid product was washed with isopropyl acetate. The wet material was then dissolved in methylene dichloride and treated with N-acetyl-L30 cysteine at 40-45 C for 2 hours. The pH of the reaction mass was adjusted to 11.0-12.0 with a sodium hydroxide solution, stirred for 30 minutes at 30-35 C, and the layers were separated. The organic layer was washed with water and distilled under vacuum at 40-45 C. Isopropyl acetate was charged to the residue and the temperature was raised to 60-65 C for 30 minutes. The reaction mass was cooled to 30-35 C, stirred for 1-2 hours, then filtered. The solid product waswashed with isopropyl acetate and dried at 50-55 C to yield 18 g (75.63 %) of 6-(2-chloro-5- fluoro-pyrimidin-4-yl)-4-fluoro- 1 -isopropyl-2-methyl- 1 H-benzoimidazole with a purity of 99.40%.
66%		To a 250 mL 3-neck round bottom flask equipped with a N2 inlet, overhead stirrer, reflux condenser and temperature probe was charged 5-fluoro-2,4-dichloropyrimidine (2, 5.17 g,31.0 mmol, 1.4 equiv), Na2CO3 (5.86 g, 55.3 mmol, 2.5 equiv), water (9 mL), and DME (45 mL). The solution was degassed by sparging N2 subsurface for 30 min. After subsurface sparging, PdCl2(PPh3)2 (46.6 mg, 66 lmol, 0.03 equiv) was added in one portion. The resulting solution was heated to 80 C. In a separate 100 mL round bottom flask was charged boronic ester 3 (7.04 g, 22.1 mmol,1.0 equiv) and DME (40 mL). The resulting solution was added to the heated solution by syringe pump over the course of 1.5 h. After all of boronic ester 3 was added, the reaction solution was stirred at 80 C for an additional 4 h, at which time the reaction was complete as judged by HPLC analysis. The reaction mixture was then cooled to ambient temperature and diluted with ice cold water (300 mL) and stirred for 25 min. The resulting slurry was collected by filtration and the resulting wetcake was slurried in IPA (105 mL) and heated to 80 C for 3.5 h. The heated slurry was then allowed to cool to ambient temperature over 16 h and the solid was collected by filtration and washed with IPA (35 mL). The wetcake was dried in a vacuum oven at 45 C for 18 h to obtain the desired biaryl compound 6 in 66% yield. Compound 6: IR (film)mmax = 3413, 2972, 2940, 2892, 1567, 1507, 1401, 1388, 1348, 1210 cm1; 1HNMR (500 MHz, CDCl3): d = 8.50 (d, J = 3.4 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.77(d, J = 11.7 Hz, 1H), 4.74 (septet, J = 7.0 Hz, 1H), 2.69 (s, 3H), 1.69 (d, J = 7.0 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3): d = 155.3, 154.8, 154.2, 153.9, 153.2,148.4, 136.6, 134.7, 125.5, 108.8, 108.2, 48.7, 21.5, 15.2 ppm; HR-MS [ESI]:Calcd for C15H14N4ClF2 [M+H+]: 323.0870, found 323.0864.

	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 80 - 84℃;Inert atmosphere;Product distribution / selectivity;	Preparation 436-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazoleBubble nitrogen into a mixture of 2,4-dichloro-5-fluoro-pyrimidine (12.7 g), bis(triphenylphosphine)palladium(II) chloride (4.9 g), sodium carbonate 2 M in water (103.7 mL) and 1,2-dimethoxyethane (120 mL). Heat in a pre-heated oil bath at 80 C. and add drop wise a solution of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazole (22 g) in 1,2-dimethoxyethane (200 mL). Stir the mixture at 84 C. for 1 h. Cool to RT, add EA (800 mL) and wash twice with brine (100 mL). Dry over magnesium sulfate and remove the solvent under vacuum. Triturate with acetonitrile to afford 14.4 g of the title compound. MS (ES+): m/z=323 (M+H)+.
14.4 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 80 - 84℃; for 1.0h;Inert atmosphere;	Bubble nitrogen into a mixture of 2,4-dichloro-5-fluoro-pyrimidine (12.7 g), bis(triphenylphosphine)palladium(II) chloride (4.9 g), sodium carbonate 2 M in water (103.7 mL) and 1 ,2-dimethoxyethane (120 mL). Heat in a pre-heated oil bath at 80 C and add drop wise a solution of 4-fluoro-l-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-benzoimidazole (22 g) in 1,2-dimethoxy ethane (200 mL). Stir the mixture at 84 C for 1 hour. Cool to room temperature, add ethyl acetate (800 mL) and wash twice with brine (100 mL). Dry over magnesium sulfate and remove the solvent under vacuum. Triturate with acetonitrile to afford 14.4 g of the title compound. (0098) MS (ES+): m/z= 323 (M+H)+.
13.18 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 1.0h;Inert atmosphere;	The compound of formula XXII-1 (9.95 g, 59.60 mmol) was dissolved in ethylene glycol dimethyl ether (210 mL) and 2MAqueous solution of sodium carbonate (140 mL), compound of formula XVII-1 (17.5 g, 54.18 mmol),Bis (triphenylphosphine) palladium chloride (1.0 g).Nitrogen exchange reaction bottle of air, open the oil bath heating, stirring at 85C 1h. The reaction flask was cooled to roomThe reaction solution was poured into 300mL of water, a large number of solid precipitation, vacuum filtration after the full stirring, the filter cake was dried gray-white solidBody 13.18g
5 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 80 - 84℃; for 1.0h;Inert atmosphere;	Under N2 atmosphere, 2,4-dichloro-5-fluoro-pyrimidine (6.3 g), commercially available, was dissolved in 1,2-dimethoxyethane (60 mL). Bis(triphenylphosphine)palladium(II) chloride (2.5 g) and 2M aqueous sodium carbonate solution (50 mL) were then added. Mixed solution was dropped at 80 C4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl) -1H-benzimidazole(10 g) 1,2-dimethoxyethane (50 mL) solution. The reaction was stirred at 84 C for 1 hour and the reaction was monitored by TLC. Cooled to room temperature, the resulting mixture was extracted with EtOAc (40 mL X 3) and the combined organic phases were washed with saturated brine (40 mL X 3). After drying over anhydrous sodium sulfate, the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target Compound (5g).
2.6 g	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 4.0h;	2.3 g of 2,4-dichloro-5-fluoropyrimidine was dissolved in 20 ml of ethylene glycol dimethyl ether and added with an aqueous solution of sodium carbonate (4 g) and 0.9 g of Pd(PPh3)2Cl2, and heated to 80 C with stirring.Add 3.9g to the solution.4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-boronic acid pinacol ester in ethylene glycol dimethyl ether solution, maintained at 80 C for 4 h,The heating was stopped, and 50 ml of ethyl acetate was added thereto, and the mixture was stirred to room temperature. The reaction mixture was washed with brine and dried over anhydrous magnesium sulfate.Concentrated to give an oily material which was purified6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole 2.6 g as a pale yellow solid.
135 mg	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; at 85℃; for 2.0h;Inert atmosphere;	2,4-Dichloro-5-fluoropyrimidine (110 mg, 0.65880 mmol) (represented by formula 1-b), 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazole (180 mg, 0.5657 mmol), (bis(triphenylphosphine))palladium dichloride (30 mg) were added to 2M sodium carbonate solution (1 mL) and ethylene glycol dimethyl ether (3 mL), and the mixture was stirred under nitrogen atmosphere at 85 C. for 2 hours. After cooling to room temperature, the reaction solution was diluted with 10 mL ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and recrystallized from acetonitrile, filtered to give compound 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-benzimidazole represented by formula 1-c (135 mg, 0.4183 mmol). LC-MS: m/z: (M+H)+=323.2.

Reference： [1]Patent: WO2017/185031,2017,A1 .Location in patent: Page/Page column 96
[2]Patent: WO2019/102492,2019,A1 .Location in patent: Page/Page column 40; 41
[3]Tetrahedron Letters,2015,vol. 56,p. 949 - 951
[4]Patent: US2010/160340,2010,A1 .Location in patent: Page/Page column 11
[5]Patent: WO2015/130540,2015,A1 .Location in patent: Page/Page column 22-23
[6]Patent: CN107266421,2017,A .Location in patent: Paragraph 0043; 0052; 0053
[7]Patent: CN104892580,2018,B .Location in patent: Paragraph 0064; 0065; 0066in
[8]Patent: CN107827875,2018,A .Location in patent: Paragraph 0051; 0052; 0054
[9]Patent: US2019/10153,2019,A1 .Location in patent: Paragraph 0205; 0207

2
[ 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

3
[ 1231930-42-9 ]
[ 69879-22-7 ]
C₂₁H₁₈F₂N₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; palladium dichloride; In tert-Amyl alcohol; at 100℃; for 18.0h;Inert atmosphere;	To a 250 mL 3-neck round bottom flask equipped with a N2 inlet, overhead stirrer and temperature probe was charged aminoaldehyde 4 (6.13 g, 50.2 mmol, 1.25 equiv), biaryl compound 6 (12.96 g, 40.2 mmol, 1.0 equiv), PdCl2 (214 mg, 1.21 mmol, 0.03 equiv), K2CO3 (5.6 g, 40.2 mmol, 1.0 equiv), and 2-methyl-2-butanol (130 mL). The resulting slurry was heated to 100 C for 18 h at which point the reaction was deemed complete by HPLC analysis. The slurry was then cooled to ambient temperatures and the solid was collected by filtration. The wetcake was washed with water (30 mL) followed by acetone (30 mL) and then dried in a vacuum oven at 45 C for 16 h to afford aldehyde 7 (16.3 g, 40.1 mmol, 99% yield) as an off-white solid. Compound 7: IR (film) mmax = 3229, 3173, 3041,1973, 1681, 1576, 1421, 1370, 1292, 1222, 1117 cm1; 1H NMR (600 MHz, TFAd):d = 9.94 (s, 1H), 8.90 (s, 1H), 8.68 (s, 1H), 8.65 (d, J = 9.2 Hz, 1H), 8.42 (s, 1H),8.07 (d, J = 10.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 5.00 (m, 1H), 2.92 (s, 3H), 1.74(d, J = 6.7 Hz, 6H) ppm; 13C NMR (150 MHz, TFA-d): d = 192.6, 155.8, 155.7,155.3, 155.0, 154.3, 151.9, 149.0, 145.5, 144.2, 135.4, 133.2, 128.9, 124.4, 119.4,115.8, 114.1, 55.4, 21.9, 13.7 ppm; HR-MS [ESI]: Calcd for C21H18F2N6OH+[M+H+]: 409.1583, found 409.1579.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 949 - 951

4
[ 1118-69-0 ]
[ 1231930-42-9 ]

Reference： [1]Patent: WO2015/130540,2015,A1
[2]Patent: CN107266421,2017,A
[3]Patent: WO2019/102492,2019,A1
[4]Patent: US2019/152954,2019,A1

5
[ 1231930-29-2 ]
[ 1231930-42-9 ]

Reference： [1]Patent: WO2015/130540,2015,A1

6
[ 1231930-33-8 ]
[ 1231930-42-9 ]

Reference： [1]Patent: WO2015/130540,2015,A1
[2]Patent: CN107266421,2017,A
[3]Patent: CN107827875,2018,A
[4]Patent: US2019/10153,2019,A1

7
[ 67567-26-4 ]
[ 1231930-42-9 ]

Reference： [1]Patent: WO2015/130540,2015,A1
[2]Patent: CN107827875,2018,A
[3]Patent: WO2019/102492,2019,A1

8
[ 1231930-42-9 ]
3-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propan-1-ol [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1

9
[ 1231930-42-9 ]
6-ethyl-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1

10
[ 1231930-42-9 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl) pyrimidin-2-yl)-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1
[2]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

11
[ 1231930-42-9 ]
1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl) pyrimidin-2-yl) amino)-7, 8-dihydro-1, 6-naphthyridin-6(5H)-yl)-2-hydroxyethan-1-one [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1

12
[ 1231930-42-9 ]
6-(3-((tert-butyldimethylsilyl)oxy)propyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1

13
[ 1231930-42-9 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1

14
[ 1231930-42-9 ]
2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethanol [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1

15
[ 1231930-42-9 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl) pyrimidin-2-yl) - 6-(2-methoxyethyl)-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine [ No CAS ]

Reference： [1]Patent: WO2016/15604,2016,A1

16
[ 1231930-42-9 ]
[ 116480-62-7 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.15%	With tris-(dibenzylideneacetone)dipalladium(0); dimethylbisdiphenylphosphinoxanthene; caesium carbonate; In 1,4-dioxane; at 110℃; for 4.0h;Inert atmosphere;	[00275] A mixture of6-(2-chloro-5 -fluoropyrimidin-4-yl)-4-fluoro- 1-i sopropyl-2-methyl- 1H-benzo[d]imidazole (100 mg, 0.31 mmol, prepared by the preparative method of example 43 of WO 2010075074), 3 -(1-methyl-i ,2,3 ,6-tetrahydropyridin-4-yl)- 1H-indol-5-amine (72 mg, 0.31 mmol), cesium carbonate (0.20 g, 0.62 mmol), dimethylbisdiphenylphosphinoxanthene (18 mg, 0.025 mmol) and tris(dibenzylideneacetone)dipalladium (14 mg, 0.016 mmol) in 1,4-dioxane (15 mL) under N2 was stirred at 110 C for 4 h. The reaction mixture was cooled to rt and diluted with DCM (40 mL) and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCM/MeOH (V/V) = 10/1 to give a yellow solid product (15 mg, 9.15 %). MS-ESI: (ESI, pos.ion) m/z: 514.5[M+1] and?HNMR (400 IVIFlz, CDC13) 8.87 (d, J 9.0 Hz, 1H), 8.61 (d, J 3.4 Hz, 1H), 8.38 (d, J3.8 Hz, 1H), 8.26 (s, 1H), 8.22 (d, J 1.8 Hz, 1H), 8.16 (s, 1H), 7.85 (dd, J= 25.7, 11.7 Hz, 2H),7.60 (d, J= 7.3 Hz, 1H), 6.32 (s, 1H), 4.77-4.65 (m, 1H), 3.11 (s, 2H), 2.74 (s, 2H), 2.73 (s, 2H),2.69 (s, 3H), 2.43 (s, 3H), 1.75 (d, J 6.9 Hz, 6H).

Reference： [1]Patent: WO2016/15604,2016,A1 .Location in patent: Paragraph 00275

17
[ 1149333-40-3 ]
[ 1231930-42-9 ]
tert-butyl 2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.0%	With tris-(dibenzylideneacetone)dipalladium(0); dimethylbisdiphenylphosphinoxanthene; caesium carbonate; In 1,4-dioxane; at 110℃; for 3.0h;Inert atmosphere;	[00276] A mixture of6-(2-chloro-5 -fluoropyrimidin-4-yl)-4-fluoro- 1-i sopropyl-2-methyl- 1H-benzo[d]imidazole (322 mg, 1.0 mmol, prepared by the preparative method of example 43 of WO 2010075074), tert-butyl 2-amino-7,8-dihydro-1,6-naphthyridine-6(51])-carboxylate (250 mg, 1.0 mmol, intermedia 34 of WO 2009056556), cesium carbonate (652 mg, 2.0 mmol),dimethylbisdiphenylphosphinoxanthene (58 mg, 0.1 mmol) andtris(dibenzylideneacetone)dipalladium (92 mg, 0.1 mmol) in 1,4-dioxane (25 mL) under N2 was stirred at 110 C for 3 h.The reaction mixture was cooled to rt and diluted with DCM (30 mL) and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with DCIVJIMeOH (V/V) = 10/1 to give a light yellow solid product (246 mg, 46.0 %).MS-ESI: (ESI, pos.ion) m/z: 536.4 [M+1].
110 mg	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 12.0h;Inert atmosphere;	6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-benzimidazole (110 mg, 0.3409 mmol) (represented by formula 1-c), tert-butyl 2-amino-7,8-dihydro-1,6-naphthyridine-6-carboxylate (85 mg, 0.3410 mmol), cesium carbonate (222 mg, 1.1507 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.02938 mmol), tris(dibenzylideneacetone)dipalladium (13 mg) were added to 1,4-dioxane (3 mL), and the mixture was stirred under nitrogen atmosphere at 110 C. for 12 hours. After cooling to room temperature, the reaction solution was diluted with 10 mL ethyl acetate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol 0-10%) to give tert-butyl 2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate represented by formula 1-d (110 mg, 0.2054 mmol). LC-MS: m/z: (M+H)+=536.2.
	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 16.0h;Inert atmosphere;	General procedure: To a solution of compounds 1a-1l (1 eq.) in dioxane were added tert-butyl 2-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.1 eq.), Cs2CO3 (2.0 eq.), Pd2 (dba)3 (0.07 eq.), and Xantphos (0.06 eq.). Then, the mixture was stirred at 110C for 16h under an atmosphere of nitrogen. LC-MS analysis indicated that the reaction was complete. The reaction mixture was concentrated and the residue was then treated with 4moL/L HCl in dioxane (4mL) at room temperature for 3h. Upon completion, the solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford the desired compounds 2a-2l.

Reference： [1]Patent: WO2016/15604,2016,A1 .Location in patent: Paragraph 00276
[2]Patent: US2019/10153,2019,A1 .Location in patent: Paragraph 0205; 0208
[3]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 1.0h;Inert atmosphere;	General procedure: A mixture of 2,4-dichloro-5-fluoropyrimidine (9.95 g, 59.60 mmol) in ethylene glycol dimethyl ether (210 mL)A 2M aqueous solution of sodium carbonate (140 mL) was added successively,4-fluoro-1-isopropyl-2- [D3] methyl-6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2 Yl) -1H- [5,7-D2] benzimidazole (17.5 g, 54.18 mmol)Bis (triphenylphosphine) palladium chloride (1.0 g).Nitrogen replacement reaction flask in the air,Open the oil bath heating,The reaction was stirred at 85 C for 1 h.The reaction flask was cooled to room temperature,The reaction solution was poured into 300 mL of water,A large number of solid precipitation,Fully stirred after decompression pumping,The cake was dried to give the compound of formula IV-1 (13.18 g)As an off-white solid.

19
[ 1231930-42-9 ]
(6-aminopyridin-3-yl)(4-ethylpiperazin-1-yl)methanone [ No CAS ]
C₂₇H₃₀F₂N₈O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
395 mg	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 3.0h;Inert atmosphere; Reflux;	The compound of formula IV-2 (428 mg, 1.33 mmol)The compound of formula XIII-1 (314 mg, 1.33 mmol)Cesium carbonate (532 mg, 2.66 mmol) was successively added to dioxane (15 mL)Nitrogen replacement reaction flask in the air,Was added tris (dibenzylideneacetone) dipalladium (30 mg)9,9-dimethyl-4,5-dibenzophenylphosphine anthracene (50 mg).Under nitrogen, the reaction mixture was heated to reflux.After 3 hours the reaction solution was cooled to room temperature,30 mL of ethyl acetate was added,Vacuum removal of inorganic salts and metals such as insoluble.The filtrate was added to 20 mL of water,Dispensing,The aqueous layer was added with 20 mL of ethyl acetate,Dispensing,Combined organic layer,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent to give an off-white solid.The product of formula XIV-1 (395 mg) was purified by column chromatography,As a white solid.

Reference： [1]Patent: CN106467517,2017,A .Location in patent: Paragraph 0315; 0316; 0317; 0318; 0319; 0320

20
[ 1231930-42-9 ]
5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(5-(piperazin-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine trifluoroacetic acid [ No CAS ]

Reference： [1]Patent: WO2017/185031,2017,A1

21
[ 1231930-42-9 ]
tert-butyl (4-(4-((6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazin-1-yl)butyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/185031,2017,A1

22
[ 1231930-42-9 ]
N-(5-((4-(4-aminobutyl)piperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine trifluoroacetic acid [ No CAS ]

Reference： [1]Patent: WO2017/185031,2017,A1

23
[ 1231930-42-9 ]
2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(4-(4-((6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazin-1-yl)butyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2017/185031,2017,A1

24
[ 1231930-42-9 ]
[ 1178566-52-3 ]
[ 1231930-48-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-butyl alcohol; at 110℃; for 8.0h;Inert atmosphere;	To a suspension of 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-l-isopropyl-2- methyl-lH-benzo[d]imidazole (2-18, 258 mg, 0.8 mmol), tert-butyl 4~((6~aminopyridin-3- yl)methyl)piperazine-l-carboxylate (2-19, 350.6 mg, 1.2 mmol) and Cs2COs (782 mg, 2.4 mmol) in 5 mL of -BuOH were added Pd2(dba)3 (73.3 mg, 0.08 mmol) and Xantphos (23 mg, 0.04 mmol) under an atmosphere of N2. The mixture was heated to i l0C and stirred for 8h. The mixture was then cooled to room temperature, extracted with CHCta and isopropanoi (V7V=4: 1), and the combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give fe/ -butyl 4-((6-(5- fluoro-4-(4-fluoro-l-isopropyl-2-memyl-lH-benzo\|"d]inudazol-6-yl)pyrimidin-2- ylamino)pyridin-3-yl)methyl)piperazine-l-carboxyiate 2-20 as a white solid (403 mg, 87%). LCMS: m/z 579,3 [M+ 1 ] .

Reference： [1]Patent: WO2017/185031,2017,A1 .Location in patent: Page/Page column 96; 97

25
N-(4-bromo-2,6-difluorophenyl)-N'-isopropylethanimidamide [ No CAS ]
[ 1231930-42-9 ]

Reference： [1]Patent: CN107266421,2017,A
[2]Patent: WO2019/102492,2019,A1

26
[ 652138-83-5 ]
[ 1231930-42-9 ]
C₂₆H₂₈F₂N₈O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
850 mg	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 20℃; for 3.0h;Inert atmosphere; Reflux;	Compound of Formula XV-1 (645 mg, 2 mmol), compound of Formula XXIV-1 (440 mg, 2 mmol), cesium carbonate (652 mg,2 mmol) were sequentially added to dioxane (15 mL), the atmosphere of the reaction flask was purged with nitrogen, and tris (dibenzylidene-propylKetone) dipalladium (30 mg), 9,9-dimethyl-4,5-bisdiphenylphosphine oxide (40 mg). Heat to the reaction mixture under nitrogen atmosphereReflux. After 3h the reaction was cooled to room temperature, 50mL of ethyl acetate was added and vacuum filtered. The filtrate was added 40mL of water, liquid separation,The aqueous layer was added 50mL ethyl acetate, liquid separation, combined organic layer, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent was light brownColor solid. Crude was added, 20mL ethyl acetate, stirred at room temperature for 30min, vacuum filtered. The white solid was repeated 850 mg twice.

Reference： [1]Patent: CN107266421,2017,A .Location in patent: Paragraph 0043; 0057; 0058

27
[ 1231930-42-9 ]
5-(4-pentadeuteroethylpiperazin-1-ylmethyl)pyridin-2-ylamine [ No CAS ]
N-(5-((4-(ethyl-d₅)piperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(benzoylthio)-9,9-dimethylxanthene; caesium carbonate; In 1,4-dioxane; at 110℃; for 2.0h;Inert atmosphere;	Under N2 atmosphere, in <strong>[1231930-42-9]6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole</strong> (1.5 g), 5- (4-pentafluoroethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (1.1 g) in 1,4-dioxane (20 mL), Cesium carbonate (3.0 g), tris(dibenzylideneacetone)dipalladium (0.2 g), and 4,5-bis(benzoylthio)-9,9-dimethylformine are added in portions. Base weight (0.2g). The mixture was heated at 110 C. for 2 hours and the reaction was monitored by TLC. Cool to room temperature and stir The solution was poured into ice water (50 mL). This system was extracted with dichloromethane (30 mL X 3). The organic phases are combined and washed with brine(20 mL X 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.8 g of a brown, viscous crude product. The crude product was chromatographed on silica gel Purification gave the title compound as an off white solid.

Reference： [1]Patent: CN104892580,2018,B .Location in patent: Paragraph 0048; 0049; 0050; 0051; 0052

28
[ 1231930-42-9 ]
5-(4-pentadeuteroethylpiperazin-1-ylmethyl)pyridin-2-ylamine [ No CAS ]
[5-(4-pentadeuteroethylpiperazin-1-ylmethyl)pyridin-2-yl][5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl]amine methanesulfonic acid [ No CAS ]

Reference： [1]Patent: CN104892580,2018,B

29
[ 1231930-42-9 ]
[ 1421372-03-3 ]
5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.5 g	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 140℃; for 3.0h;Inert atmosphere;	Under a nitrogen atmosphere, 0.5 g of 2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline,0.42 g of <strong>[1231930-42-9]6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole</strong>, 0.43 g of Pd2 (dba) 3, 0.39g of BINAP and 1g of Cs2CO3 are dissolved in 1,4-dioxane,The mixture was heated at 140 C for 3 h, cooled and filtered to remove the insoluble material, and the filter cake was washed with dichloromethane.The filtrate was evaporated to dryness under reduced pressure and then separated using silica gel column chromatography.5-Fly-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(2-methoxy-4-(4) -methylpiperazin-1-yl)-5-nitrophenyl)pyrimidine-2-amine 0.5 g as a reddish brown solid.

Reference： [1]Patent: CN107827875,2018,A .Location in patent: Paragraph 0060; 0061; 0062; 0065; 0066

30
[ 1231930-42-9 ]
N'-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)-1,3-phenylenediamine [ No CAS ]

Reference： [1]Patent: CN107827875,2018,A

31
[ 1231930-42-9 ]
N'-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-4-(4-tert-butoxycarbonylpiperazin-1-yl)-1,3-phenylenediamine [ No CAS ]

Reference： [1]Patent: CN107827875,2018,A

32
[ 1231930-42-9 ]
N-5-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-tert-butoxycarbonylpiperazin-1-yl)phenylacrylamide [ No CAS ]

Reference： [1]Patent: CN107827875,2018,A

33
[ 1231930-42-9 ]
N₁-(2-dimethylaminoethyl)-N₄-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5-methoxy-N₁-methyl-1,2,4-benzenetriamine [ No CAS ]

Reference： [1]Patent: CN107827875,2018,A

34
[ 1231930-42-9 ]
N-5-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenylacrylamide [ No CAS ]

Reference： [1]Patent: CN107827875,2018,A

35
[ 1231930-42-9 ]
N-5-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(piperazin-1-yl)phenylacrylamide [ No CAS ]

Reference： [1]Patent: CN107827875,2018,A

36
[ 1231930-42-9 ]
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide [ No CAS ]

Reference： [1]Patent: CN107827875,2018,A

37
[ 1231930-42-9 ]
2-methoxy-4-(4-tert-butoxycarbonylpiperazin-1-yl)-5-nitroaniline [ No CAS ]
5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]midazol-6-yl)-N-(2-methoxy-4-(4-tert-butoxycarbonylpiperazin-1-yl)-5-nitrophenyl)-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
240 mg	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 140℃; for 3.0h;Inert atmosphere;	110 mg of 2-methoxy-4-(4-tert-butoxycarbonylpiperazin-1-yl)-5-nitroaniline under nitrogen,103 mg of <strong>[1231930-42-9]6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole</strong>, 88 mg of Pd2 (dba)3 ,80 mg of BINAP and 203 mg of Cs2CO3 were dissolved in 20 ml of 1,4-dioxane, and the mixture was heated at 140 C for 3 h.The insoluble matter in the reaction liquid was cooled and filtered, and the filter cake was washed with dichloromethane, and the filtrate was evaporated to dryness under reduced pressure.5-Fly-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(2-methoxy-4-(4) - tert-Butoxycarbonylpiperazin-1-yl)-5-nitrophenyl)pyrimidin-2-amine 240 mg as a tan solid.

Reference： [1]Patent: CN107827875,2018,A .Location in patent: Paragraph 0071; 0072; 0073; 0076; 0077

38
[ 1231930-42-9 ]
N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-2-nitrobenzene-1,4-diamine [ No CAS ]
N¹-(2-dimethylaminoethyl)-N⁴-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5-methoxy-N¹-methyl-2-nitro-1,4-phenylendiamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80 mg	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 140℃; for 3.0h;Inert atmosphere;	Under nitrogen, 118 mg of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-2-nitro-1,4-phenylenediamine,140 mg of <strong>[1231930-42-9]6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole</strong>,282 mg of Cs2CO3, 120 mg of Pd2(dba)3 and 108 mg of BINAP were dissolved in 20 ml of 1,4-dioxane, and the mixture was heated at 140 C for 3 h.The insoluble matter in the reaction liquid was cooled and filtered, and the filter cake was washed with dichloromethane, and the filtrate was evaporated to dryness under reduced pressure.Obtaining N1-(2-dimethylaminoethyl)-N4-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl) Pyrimidine-2-yl)-5-methoxy-N1-methyl-2-nitro-1,4-phenylenediamine 80 mg as a reddish brown solid.

Reference： [1]Patent: CN107827875,2018,A .Location in patent: Paragraph 0084; 0085; 0086; 0089; 0090

39
(E)-N′-(4-bromo-2,6-difluorophenyl)-N-isopropylacetimidamide [ No CAS ]
[ 1231930-42-9 ]

Reference： [1]Patent: CN107827875,2018,A
[2]Patent: US2019/152954,2019,A1

40
[ 42717-36-2 ]
[ 1231930-42-9 ]

Reference： [1]Patent: CN107827875,2018,A

41
[ 1231930-42-9 ]
[ 1174428-75-1 ]
3-{p-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-1,3-diaza-3H-inden-5-yl)-2- pyrimidinylamino]phenyl}-5-morpholino-4-oxa-1-thia-7-indenone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 110℃; for 6.0h;Inert atmosphere;	In a 8 mL vial, commercially available 6-(2-chloro-5-fluoro-4-pyrimidinyl)-4-fluoro-l-isopropyl-2-methyl- 1,3-diaza-lH-indene (73 mg, 0.225 mmol), 3-(p-aminophenyl)-5-mo holino-4-oxa-l-thia-7- indenone (49 mg, 0.15 mmol), Cs2C03 (98 mg, 0.30 mmol), BINAP (9 mg, 0.015 mmol) and Pd(OAc)2 (2.0 mg, 0.0075 mmol) were degassed under N2 for 10 minutes. Degassed 1,4-dioxane (3 mL) was added and the resulting mixture was stirred at 110 C for 6 hours. LCMS indicated complete consumption of starting material and formation of product. The reaction was cooled and directly purified by chromatography on silica-gel, eluting with a CH2Cl2/MeOH gradient. The product, Compound 5, was obtained as a beige solid, after trituration with EtOAc. Yield = 14 mg (0.023 mmol, 14 %). (0574) LC/MS - HPLC (254 nm) - Rt 2.60 min. MS (ESI) m/z 615.4 [M + H]+. Purity = 97.3 % by UV (254 nm).

Reference： [1]Patent: WO2018/140730,2018,A1 .Location in patent: Paragraph 0226

42
[ 1231930-42-9 ]
6-(2-(dimethylamino)ethyl)-2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ No CAS ]

Reference： [1]Patent: US2019/10153,2019,A1

43
[ 869198-95-8 ]
[ 1231930-42-9 ]
tert-butyl 2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45 mg	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 18.0h;Inert atmosphere;	6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (100 mg, 0.31 mmol) (represented by formula 1-c), <strong>[869198-95-8]tert-butyl 2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylate</strong> (100 mg, 0.4 mmol) (represented by formula I-13-a), tris(dibenzylideneacetone)dipalladium (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 0.05 mmol) and cesium carbonate (326 mg, 1 mmol) were dissolved in 1,4-dioxane (6 mL) and the mixture was stirred under argon atmosphere at 100 C. for 18 hours. Then the reaction solution was concentrated and purified by column chromatography (dichloromethane/methanol: 0% to 10%) to give tert-butyl 2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (45 mg) as pale yellow solid. LC-MS: m/z: (M+H)+=537.2.

Reference： [1]Patent: US2019/10153,2019,A1 .Location in patent: Paragraph 0252; 0253

44
[ 1231930-42-9 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-hydrobenzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine hydrochloride [ No CAS ]

Reference： [1]Patent: US2019/10153,2019,A1

45
[ 1231930-42-9 ]
2-dimethylamino-1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)acetamide [ No CAS ]

Reference： [1]Patent: US2019/10153,2019,A1

46
[ 1231930-42-9 ]
5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl) pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
280 mg	With ammonia; In 1,4-dioxane; water; at 100℃; for 16.0h;Sealed tube;	6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-benzimidazole (500 mg, 1.55 mmol) (represented by formula 1-c), aqueous ammonia (5 mL, 35%) and 1,4-dioxane (5 mL) were added to a sealed tube and the mixture was stirred at 100 C. for 16 hours, then concentrated and diluted with dichloromethane (30 mL). After 30 minutes under ultrasound, the mixture was filtered, and the residue was rinsed with dichloromethane and dried to give 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine represented by formula I-15-a (280 mg, 0.92 mmol) as a pale yellow solid. LC-MS m/z: (M+H)+=304.2.

Reference： [1]Patent: US2019/10153,2019,A1 .Location in patent: Paragraph 0257; 0258

47
[ 1231930-33-8 ]
[ 2927-71-1 ]
[ 1231930-42-9 ]

Yield	Reaction Conditions	Operation in experiment
76%		Compound 3 (27.11 g, 100 mmol) and tetrahydrofuran (136 mL) were added to a three-neck flask. After stirring and dissolving, the ice salt bath is cooled to 0 to 5 C. Vacuum switching nitrogen 3 times, 2.0 M isopropylmagnesium chloride tetrahydrofuran solution (110 mmol, 55.0 mL) was added dropwise. The internal temperature is maintained at 0 to 5 C for 0.5 to 1 hour. 2,4-Dichloro-5-fluoropyrimidine (18.37 g, 110 mmol) Dissolved in tetrahydrofuran (136 mL) under nitrogen. The catalyst iron triacetylacetonate (1.78 g, 5 mmol) was added. After stirring uniformly, the prepared Grignard reagent solution is added dropwise to the reaction bottle containing pyrimidine. After the completion of the dropwise addition, the temperature was raised to 55 to 60 C for 4 to 6 hours. After the reaction is completed, the reaction is quenched by adding a saturated aqueous solution of ammonium chloride. The mixture was extracted three times with ethyl acetate (216 mL). The combined organic phases were washed twice (216 mL), Dry with sodium sulfate, filter, Most of the ethyl acetate was removed by concentration and petroleum ether (125 mL) was added. Precipitating solid beating, Filtered and dried, Compound 5 was obtained (24.53 g, 76%).
60%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In diethylene glycol dimethyl ether; at 80℃; for 4.0h;Inert atmosphere;	Under a nitrogen atmosphere, 60 2,4-dichloro-5-fluoropyrimidine (517 mg, 3.1 mmol), 61 sodium carbonate (583 mg, 5.5 mmol) was dissolved in a mixed solution of 1 mL 48 water and 5 mL 62 ethylene glycol dimethyl ether, 63 PdCl2(PPh3)2 (4.7 mg, 66 mumol) was added, heated to 80 C., and then a solution of 64 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-1H-benzo[d]imidazole (700 mg, 2.2 mmol) in ethylene glycol dimethyl ether (40 mL) was added, stirred at this temperature for 4 hours, and then 30 mL water was added, stirring was continued for 25 minutes, filtered and dired the filter cake at 80 C. and then washed with isopropyl alcohol, the product 65 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole 425 mg was obtained after drying, yield: 60%. LC-MS(APCI): m/z=322.7 (M+1).

Reference： [1]Patent: CN109761959,2019,A .Location in patent: Paragraph 0053-0055
[2]Patent: US2019/152954,2019,A1 .Location in patent: Paragraph 0315-0316

48
[ 1231930-42-9 ]
5-(N-acrylamido)-4-((N,1-(2-(N,N-dimethylamino)ethyl)-N,1-methyl)amino)-2-methoxyaniline [ No CAS ]
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 100℃; for 3.0h;Inert atmosphere;	Under nitrogen protection, 389 Pd2(dba)3 (60 mg) and Xantphos (80 mg) were added into 65 <strong>[1231930-42-9]6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole</strong> (281 mg, 0.87 mmol), 31 N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (170 mg, 0.58 mmol) and 56 potassium carbonate (200 mg, 1.46 mmol) in 515 2-methyl-2-butanol (10 mL), and the reaction mixture was reacted under nitrogen protection at 100 C. for 3 hrs. After cooling to room temperature, it was filtered on Celite, concentrated under reduced pressure, and the filtrate was separated on column chromatography (eluant:dichloromethane/methanol (v/v)=10:1), to afford 130 mg of a yellow solid, yield was 38.8%. LC-MS(APCI): m/z=579.3 (M+1)+, purity is 92.77% (HPLC), 1H NMR (400 MHz, DMSO): delta 9.85 (s, 1H), 8.71 (s, 1H), 8.58 (d, J=3.9 Hz, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.74 (d, J=11.8 Hz, 1H), 6.99 (s, 1H), 6.25 (d, J=17.0 Hz, 1H), 5.79-5.65 (m, 1H), 4.87-4.75 (m, 1H), 3.85 (s, 3H), 3.25-3.04 (m, 2H), 2.70-2.58 (m, J=4.0 Hz, 8H), 2.50 (s, 6H), 1.56 (d, J=6.9 Hz, 6H).

Reference： [1]Patent: US2019/152954,2019,A1 .Location in patent: Paragraph 0523; 0524

49
[ 122833-04-9 ]
[ 1231930-42-9 ]
5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.9%	With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 100℃; for 3.0h;Inert atmosphere;	Under nitrogen protection, tert-pentanol (5 mL) was added into the mixture of <strong>[1231930-42-9]6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole</strong> (compound 8, 200 mg, 0.62 mmol) and 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (compound 6, 165 mg, 0.75 mmol), potassium carbonate (214 mg, 1.55 mmol), Pd2(dba)3 (37 mg) and Xant-Phos (46 mg), and the reaction was stirred and reacted under nitrogen protection at 100 C. for 3 hours. After cooling to room temperature, it was filtered on Celite, the filter cake was washed with dichloromethane, the filtrate was concentrated under reduced pressure, and the filtrate was separated on column chromatography (eluant:dichloromethane /methanol (v/v)=13:1), to afford 47 mg of a yellow solid. Yield was 14.9%. LC-MS(APCI): m/z=508.3 (M+1); 1H NMR (500 MHz, DMSO-d6) (delta/ppm) 8.49 (d, J=3.7 Hz, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.59 (d, J=12.2 Hz, 1H), 6.65 (d, J=1.1 Hz, 1H), 6.48 (dd, J=8.6, 1.8 Hz, 1H), 4.79 (M, 1H), 3.79 (s, 3H), 3.16 (M, 4H), 2.61 (s, 3H), 2.56 (M, 4H), 2.29 (s, 3H), 1.56 (d, J=6.8 Hz, 6H).

Reference： [1]Patent: US2019/152954,2019,A1 .Location in patent: Paragraph 0678; 0679

50
[ 1231930-42-9 ]
tert-butyl(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl) (methyl)carbamate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

51
[ 1231930-42-9 ]
diethyl(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl)ethyl) (methyl)phosphoramidate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

52
[ 1231930-42-9 ]
1-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl)-1-methylguanidine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

53
[ 1231930-42-9 ]
(E)-N-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl)ethyl)-N'-hydroxy-N-methylacetimidamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

54
[ 1231930-42-9 ]
N-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)-N-methyl-1H-imidazole-1-carbothioamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

55
[ 1231930-42-9 ]
N-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl)ethyl)-N,P,P-trimethylphosphinic amide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

56
[ 1231930-42-9 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-6-(2-(methyl(2-(trimethylsilyl)ethyl)amino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

57
[ 1231930-42-9 ]
N₁-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5h)-yl)ethyl)-N₁-methylethane-1,2-diamine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

58
[ 1231930-42-9 ]
1-(2-((2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl) (methyl)amino)ethyl)guanidine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

59
[ 1231930-42-9 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

60
[ 1231930-42-9 ]
tert-butyl (2-((2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)(methyl)amino)ethyl)carbamate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

61
[ 1231930-42-9 ]
N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-6-(2-(methyl(prop-2-yn-1-yl)amino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

62
[ 1231930-42-9 ]
6-(2-(dimethylamino)ethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

63
[ 1231930-42-9 ]
1-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)-1-methylthiourea [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 352 - 364

64
[ 1231930-42-9 ]
C₂₄H₂₆F₂N₈*ClH [ No CAS ]

Reference： [1]Patent: US2019/202806,2019,A1

65
[ 1231930-42-9 ]
C₄₀H₃₅F₃N₁₀O₂ [ No CAS ]

Reference： [1]Patent: US2019/202806,2019,A1

66
[ 571188-59-5 ]
[ 1231930-42-9 ]
C₂₉H₃₄F₂N₈O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 103℃; for 24.0h;Inert atmosphere;	To the solution of compound 1 (20.0 g, 62.0 mmol, 1 eq) and 2 (17.3 g, 62.0 mmol, 1 eq) in dioxane (500 mL) were added BINAP (4.8 g, 7.8 mmol, 0.125 eq), tBuOK (8.7 g, 77.5 mmol, 1.25 eq) and Pd2(dba)3 (3.4 g, 3.7 mmol, 0.06 eq). The reaction mixture was stirred under N2 at 103 C. for 24 h, followed by hot filtration. The filtrate was concentrated in vacuo and the residue was poured into water. The resulting mixture was filtrated. The filter cake was rinsed with water (150 mL×2) and EtOAc (150 mL×2) successively, and then dried to afford the product 3 (22.5 g, 64%). 1H NMR (400 MHz, DMSO) delta 9.81 (s, 1H), 8.64 (d, J=3.9 Hz, 1H), 8.26 (s, 1H), 8.06 (dd, J=12.5, 6.0 Hz, 2H), 7.67 (d, J=12.3 Hz, 1H), 7.44 (dd, J=9.1, 3.0 Hz, 1H), 4.85 (m, 1H), 3.49-3.47 (m, 4H), 3.09-3.07 (m, 4H), 2.64 (s, 3H), 1.62 (d, J=6.9 Hz, 6H), 1.43 (s, 9H).

Reference： [1]Patent: US2019/202806,2019,A1 .Location in patent: Paragraph 0210; 0211; 0212

67
[ 75-75-2 ]
[ 1180132-17-5 ]
[ 1231930-42-9 ]
[5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl][5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)pyrimidin-2-yl]-amine methanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.65 g		Compound 9 (24.23 g, 110 mmol) and toluene (160 mL) were added to a three-neck flask. Stir well and cool to -5 to 0 C. Add hexamethylsilylamine lithium tetrahydrofuran solution (1.0 M, 120 mL, 120 mmol), After stirring at low temperature for 30 to 45 minutes, compound 5 (32.27 g, 100 mmol) was added dropwise. After the addition is completed, the temperature is raised to room temperature at 25 to 30 C for 10 to 16 hours. At the end of the reaction, saturated ammonium chloride (323 mL) was added. Extracted 3 times with ethyl acetate (160 mL). The organic phase was washed twice with saturated brine (160 mL). Dry over anhydrous sodium sulfate, After concentration, it was recrystallized from methylene chloride ethyl acetate mixture to afford compound 10 (43.57 g, 86%).Compound 10 (50.66 g, 100 mmol) was added to a three-necked flask. Add absolute ethanol (251 mL), After stirring and stirring, methanesulfonic acid (14.42 g, 150 mmol) was added. After the addition is completed, the temperature is raised to 50 to 55 C for 4 to 5 hours. The reaction was slowly cooled to 0 to 5 C for 1 hour. filter, The solid was washed with ethanol (50 mL). dry, The product Abemaciclib methanesulfonate 11 (56.65 g, 94%) was obtained.

Reference： [1]Patent: CN109761959,2019,A .Location in patent: Paragraph 0069-0071; 0073-0075

68
N-(4-bromo-2,6-difluorophenyl)acetamide [ No CAS ]
[ 1231930-42-9 ]

Reference： [1]Patent: CN109761959,2019,A

69
C₁₁H₁₄BrFN₂O [ No CAS ]
[ 1231930-42-9 ]

Reference： [1]Patent: CN109761959,2019,A

70
[ 1231930-42-9 ]
N-(4-aminophenyl)-N'-(3-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]
N-(4-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)phenyl)-N'-(3-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4 dimethylcyclohexane; at 100℃; for 12.0h;Inert atmosphere; Sealed tube;	General procedure: To a suspension of 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro- 1-isopropyl-2-methyl-1H-benzo[d]imidazole (7)(645.48 mg, 2 mmol) in 20 mL 1,4-dioxane were added compound 3A-K, 4D,4F,4H,4J,4K(2 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), BINAP (62 mg, 0.1 mmol) and Cs2CO3 (978 mg, 3 mmol) and the flask was purged with Ar. Then the flask was sealed and the mixture was heated for 12 h at 100 C. The reaction was cooled to rt, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5A-K,6D,6F,6H,6J,6K.