[ CAS No. 1004294-80-7 ] {[proInfo.proName]}

Name: 1004294-80-7|6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one|95%
Brand: Ambeed
SKU: A181496
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Quality Control of [ 1004294-80-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1004294-80-7 ]

SDS Specification

Alternatived Products of [ 1004294-80-7 ]

Product Details of [ 1004294-80-7 ]

CAS No. :	1004294-80-7	MDL No. :	MFCD11849992
Formula :	C₁₄H₁₈BNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BUORFAFSDKNVNY-UHFFFAOYSA-N
M.W :	259.11	Pubchem ID :	46856415
Synonyms :

Calculated chemistry of [ 1004294-80-7 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	77.87
TPSA :	47.56 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.76
Log Po/w (WLOGP) :	0.7
Log Po/w (MLOGP) :	1.13
Log Po/w (SILICOS-IT) :	1.74
Consensus Log Po/w :	1.07

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.72
Solubility :	0.49 mg/ml ; 0.00189 mol/l
Class :	Soluble
Log S (Ali) :	-2.38
Solubility :	1.09 mg/ml ; 0.0042 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.49
Solubility :	0.00837 mg/ml ; 0.0000323 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.68

Safety of [ 1004294-80-7 ]

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

Application In Synthesis of [ 1004294-80-7 ]

* 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 [ 1004294-80-7 ]
Downstream synthetic route of [ 1004294-80-7 ]

[ 1004294-80-7 ] Synthesis Path-Upstream 1~5

1
[ 675109-26-9 ]
[ 73183-34-3 ]
[ 1004294-80-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium acetate In 1,4-dioxane at 70 - 120℃; for 18 h;	To a solution of 6-bromo-2,3-dihydro-isoindol-l-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl₂(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70°C for 2 hours under nitrogen then heated to 120⁰C for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO₄), filtered and concentrated in vacuo. The residue was sonicated in EtOAc, the suspension was filtered onto a sintered funnel and the collected grey solid was dried and used without further purification. 6-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l-one: (82 percent yield, 29 percent purity, main impurity being the boronic acid 43 percent) m/z (LC-MS, ESP): 519.5 [2M+H]⁺ R/T = 3.38 min

Reference： [1] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 117
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
[3] Patent: WO2017/107089, 2017, A1, . Location in patent: Page/Page column 37; 38
[4] Patent: WO2017/68412, 2017, A1, . Location in patent: Page/Page column 208; 209
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 11, p. 4978 - 4992

2
[ 478375-39-2 ]
[ 1004294-80-7 ]

Reference： [1] Patent: WO2015/189744, 2015, A1,

3
[ 103440-54-6 ]
[ 1004294-80-7 ]

Reference： [1] Patent: WO2015/189744, 2015, A1,

4
[ 54811-38-0 ]
[ 1004294-80-7 ]

Reference： [1] Patent: WO2015/189744, 2015, A1,

5
[ 73183-34-3 ]
[ 1004294-80-7 ]

Reference： [1] Patent: WO2015/189744, 2015, A1,

[ 1004294-80-7 ] Synthesis Path-Downstream 1~70

1
[ 675109-26-9 ]
[ 73183-34-3 ]
[ 1004294-80-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 70 - 120℃; for 18h;	To a solution of 6-bromo-2,3-dihydro-isoindol-l-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl2(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70C for 2 hours under nitrogen then heated to 1200C for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO4), filtered and concentrated in vacuo. The residue was sonicated in EtOAc, the suspension was filtered onto a sintered funnel and the collected grey solid was dried and used without further purification. 6-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l-one: (82 % yield, 29 % purity, main impurity being the boronic acid 43 %) m/z (LC-MS, ESP): 519.5 [2M+H]+ R/T = 3.38 min
70%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 12h;Inert atmosphere;	To a mixture of 6-bromoisoindolin-1-one (7.00 g, 3.30 mmol) and 1, 4-dioxane (125 mL), were added bis (pinacolato)diboron (17.00g, 6.60mmol), KOAc (8.50 g, 8.25 mmol) and Pd(dppf)Cl2 (2.50 g, 0.33 mmol). The reaction mixture was stirred at 90 oC for 12h under N2 atmosphere. After cooling to r. t. the reaction mixture was filtered. The solvent evaporated under reduced pressure then added ethyl acetate (80 mL). The precipitate was filtered to obtained black solid. Yield 70%, m.p. > 250oC. 1H NMR (300 MHz, CDCl3) delta (ppm): 8.36 (s, 1H, ArH), 8.00 (d, J = 7.60 Hz, 1H, ArH), 7.48 (d, J = 7.60 Hz, 1H, ArH), 7.03 (s, 1H, NH), 4.48 (s, 2H, CH2), 1.35 (s, 12H, CH3).
62%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃;	6-Bromoisoindolin-1-one (636 mg, 3.10 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (930 mg, 3.70 mmol), and Pd(dppf)Cl2 (125 mg, 0.150 mmol) were added to a dry flask and placed under N2. Potassium acetate (900 mg, 9.20 mmol) was weighed directly into the flask. The flask was then evacuated and back filled with N2. Anhydrous N,N-dimethylformamide (DMF) (18 mL) was added and the reaction was heated at 80 C. overnight. The reaction mixture was evaporated to dryness and the resulting material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (493 mg, 62%). ESI-MS m/z calc. 259.1, found 260.1 (M+1)+. Retention time 1.24 minutes.

25%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere;	A mixture of 6-bromoisoindolin-1-one (2.0 g, 9.44 mmol), bis(pinacolato)diboron (2.41 g, 9.7 mmol), KOAc (1.86 g, 18.66 mmol) and Pd(dppf)2C12 (0.39 g, 0.49 mmol) in dioxane (50 mE) was stirred at 1000 C. overnight under a nitrogen atmosphere. The mixture was poured into water and extracted with EtOAc (100 mLx3). The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on silica gel (1/10 to 1/5 EtOAc in pet. ether) to give compound 13A (600 mg, 25% yield) as a white solid. ESI mlz 260.0 [M+1].
	With potassium acetate; at 80℃; for 10h;Inert atmosphere;	General procedure: To a solution of 6-bromo-2-methylisoindolin-1-one (5 g,22.1 mmol) in dmf (30 mL) was added bis(pinacolato)diboron (6.18 g,24.3 mmol) and potassium acetate (6.51 g,66.4 mmol). The reaction mixture was degassed and backfilled with N2 gas,and 1,1 ?-bis(diphenylphosphino)fenocene palladium(II)dichloride dichloromethane (0.903 g,1.106 mmol) was added.The reaction mixture was stined at 80 C for 10 hours. After diluting with EtOAc and water, The organic layer was concentrated and purified on silica column (100% EtOAc) to get the product as a mixture of the title compound as a boronic ester and boronic acid,which was not further purified.MS: 274 (m+1)?H NMR (500 MHz,CDCl3): oe 8.33 (s,1H),7.98 (d,7.5 Hz,1H),7.46 (d,7.5 Hz,1H),4.41 (s,2H),3.22 (s,3H),1.38 (s,12H). The following intermediates in table c were preparedaccording to scheme c using the procedure outlined in the synthesis intermediate cl using 1,1?-bis(di-tert-butylphosphino)fenocene palladium dichloride or 1,1 ?-bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex as the palladium catalyst with toluene or dmf as the reaction solvent. The starting material bromide was either commercially available,known in the literature,or prepared using the protocol in scheme B.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	Preparation 63: 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-isoindol-1 - one (1578) (1579) A stirred mixture of 6-bromo-2,3-dihydro-1 H-isoindol-1 -one (780 mg, 3.68 mmol), (1580) bis(pinacolato)diboron (1.089 g, 4.28 mmol) and potassium acetate (1.26 g, 12.87 mmol) anhydrous 1 ,4-dioxane (12 mL) was degassed with nitrogen for 5 minutes. 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (150 mg, 0.18 mmol) was then added and the reaction heated under nitrogen at 100C for 16 hours. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under vacuum to yield the title compound (1.1 g, 115 %) which was used crude without purification. MS: [M+H]+ = 260.

Reference： [1]Patent: WO2008/23161,2008,A1 .Location in patent: Page/Page column 117
[2]European Journal of Medicinal Chemistry,2019,vol. 164,p. 334 - 341
[3]Patent: US2009/143381,2009,A1 .Location in patent: Page/Page column 54-55
[4]Patent: US2018/291002,2018,A1 .Location in patent: Paragraph 0431
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 9542 - 9555
[6]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 37; 38
[7]Patent: WO2017/68412,2017,A1 .Location in patent: Page/Page column 208; 209
[8]Journal of Medicinal Chemistry,2018,vol. 61,p. 4978 - 4992

2
[ 1009303-44-9 ]
(1-oxoisoindolin-6-yl)boronic acid [ No CAS ]
[ 1004294-80-7 ]
C₂₅H₂₈N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 110℃; for 8.0h;	A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), the appropriate pinacolate boron ester or boronic acid (1.0 equiv) and <n="129"/>tetrakis(triphenylphosphine) palladium0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro- substrate) was stirred at 110 0C for 8 hours. Upon completion the reaction mixture was partitioned between water and CH2Cl2 and extracted with CH2Cl2. Combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 2 % MeOH in CH2Cl2 to give the desired product which was recrystallised from hexane/ CH2Cl2.

Reference： [1]Patent: WO2008/23161,2008,A1 .Location in patent: Page/Page column 127-128; 178

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;Inert atmosphere; Heating;	General procedure: To a solution of 6-bromo-2-methylisoindolin-l-one (5 g, 22.1 mmol) in DMF (30 mL) was added bis(pinacolato)diboron (6.18 g, 24.3 mmol) and potassium acetate (6.51 g, 66.4 mmol). The reaction mixture was degassed and backfilled with N2 gas, and l, l'-bis(diphenyl-phosphino)ferrocene palladium(II)dichloride dichloromethane (0.903 g, 1.106 mmol) was added. The reaction mixture was stirred at 80 C for 10 hours. After diluting with EtOAc and water, the organic layer was concentrated and purified on silica column (100% EtOAc) to get the product as a mixture of the title compound as a boronic ester and boronic acid, which was not further purified. MS: 274 (M+1). 1H MR (500 MHz, CDC13): delta 8.33 (s, 1 H), 7.98 (d, 7.5 Hz, 1 H), 7.46 (d, 7.5 Hz, 1 H), 4.41 (s, 2 H), 3.22 (s, 3 H), 1.38 (s, 12 H). The procedure can utilize l, l'-bis(di-tert-butylphosphino)ferrocene palladium di chloride or l,l'-bis(diphenylphosphino) ferrocene palladium(II)dichloride dichloromethane complex as the palladium catalyst with toluene or DMF as the reaction solvent. The starting material bromide was either commercially available, known in the literature, or prepared using the protocol in scheme L.

4
[ 1004294-80-7 ]
[ 52157-62-7 ]
C₁₅H₁₃NO₃S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9542 - 9555

5
[ 1004294-80-7 ]
[ 1313399-36-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9542 - 9555

6
[ 1004294-80-7 ]
[ 1313397-77-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9542 - 9555

7
[ 1004294-80-7 ]
[ 1620056-27-0 ]
[ 1620056-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In 1,4-dioxane; methanol; water; at 160℃; for 0.333333h;Microwave irradiation;	In a microwave tube was charged with 29B (50 mg, 0.1 mmol), 6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)isoindolin- l-one ( 39 mg, 0.15 mmol), LiCl ( 13 mg, 0.3 mmol), Na2C03 ( 25 mg, 0.3mmol) and 3 mg of Pd(PPh3)2Cl2. To the mixture was added 0.7 mL of 1,4- dioxane, 0.2 mL of methanol and 0.2 mL of H20. The mixture was heated up to 160 C for 20 min in a Microwave Synthesizer. After cooled down, it was partitioned between ethyl acetate and water. The organic layer was separated and concentrated. The residue was purified on silica gel chromatography eluting with ethyl acetate and hexanes to afford the title compound. MS (m/z) 533.78 [M+H]+.

Reference： [1]Patent: WO2014/110297,2014,A1 .Location in patent: Paragraph 0250

8
[ 1004294-80-7 ]
(S)-N-(1-(3-bromo-5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]
(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)N-(2-(3,5-difluorophenyl)-1-(5-(3-hydroxy-3-methylbut-1-ynyl)-3-(3-oxoisoindolin-5-yl)pyridin-2-yl)ethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; lithium chloride; In 1,2-dimethoxyethane; water; at 150℃; for 0.333333h;	[0409] To (S)-N- (1 -(3-bromo-5- (3-hydroxy-3-methylbut- 1 -ynyl)pyridin-2-yl)-2- (3,5- difluorophenyl)ethyl)-2-(3- (difluoromethyl)-4,4,7 ,7-tetrafluoro-4,5 ,6,7-tetrahydro- 1 H-indazol- 1- yl)acetamide (16 mg, 0.02 mmol) in DME (0.7 mL) was added 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-1-one (7 mg, 0.03 mmol), Pd(PPh3)2Cl2 (2 mg), LiC1 (1 mg), and aq 2M K2C03 (30 jiL). The reaction was heated in a microwave reactor to 150 C for 20 mm. The reaction was purified by RP HPLC to provide the desired product. ?H NMR (400 MHz, Methanol-d4) oe 8.69 (d, 1H), 7.62 - 7.49 (m, 2H), 7.43 (s, 1H), 7.28 (s, 1H), 6.98 - 6.58 (m, 4H), 6.26 (d, 2H), 5.34 (d, 2H), 5.18 (s, 1H), 5.05 (s, 2H), 4.48 (s, 2H), 3.02 (t, J= 7.5 Hz, 3H), 2.49 (s, 7H), 1.56 (s, 5H). MS (m/z) 732.1[M+H]?.

Reference： [1]Patent: WO2014/134566,2014,A2 .Location in patent: Paragraph 0409

9
[ 1004294-80-7 ]
(S)-N-(1-(3,5-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]
(S)-N-(1-(3,5-bis(3-oxoisoindolin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; lithium chloride; In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide; at 150℃; for 0.333333h;Microwave irradiation;	[0424] To (S)-N- (1 -(3 ,5-dibromopyridin-2-yl)-2- (3 ,5-difluorophenyl)ethyl)-2- (3- (difluoromethyl)-4,4,7 ,7-tetrafluoro-4,5 ,6,7 -tetrahydro- 1 H-indazol- 1 -yl)acetamide (50 mg, 0.074 mmol) in DME (0.8 mL) and DMF (0.2 mL) was added 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoindolin-1-one (48 mg, 0.19 mmol), Pd(PPh3)2C12 (5 mg), LiC1 (2 mg), and aq 2M K2C03 (110 jiL). The reaction was heated in a microwave reactor to 150 C for 20 mm. The reaction was purified by RP HPLC to provide the desired product. ?H NMR (400 MHz,Methanol-d4) oe 9.02 (d, 1H), 8.11 (d, 1H), 7.97 (dd, 1.7 Hz, 1H), 7.89 (d, 1H), 7.72 (d, 1H), 7.67- 7.48 (m, 3H), 7.42 (d, 1H), 6.70 - 6.61 (m, 2H), 6.37 - 6.30 (m, 2H), 5.44 (t, 1H), 5.07 (s, 2H),4.51 (d, 4H), 3.18 -3.01 (m, 3H), 2.50 (dd, 4H). MS (m/z) 798.1[M+Hf?.

Reference： [1]Patent: WO2014/134566,2014,A2 .Location in patent: Paragraph 0424

10
[ 1004294-80-7 ]
(S)-N-(1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]
(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)N-(2-(3,5-difluorophenyl)-1-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/134566,2014,A2

11
[ 1004294-80-7 ]
(S)-N-(1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]
(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(methylthio)-5-(3-oxoisoindolin-5-yl)pyrimidin-4-yl)ethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 155℃; for 0.416667h;Microwave irradiation;	[0454] In a microwave tube were charged with compound 21F (300 mg, 0.47 mmol), 6- (4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindolin- 1-one (181 mg, 0.7 mmol) and PdC12[P(Cy)3]2 (17 mg, 0.023 mmol). To the mixture was added 10 mL of 1,4-dioxane and 1.4 mL of sodium bicarbonate aqueous solition (1M). The mixture was heated to 155 C for 25 mm in a microwave synthesizer. After cooled to room temperature, it was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over Mg504, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound 21G. MS (m/z) 697.32 [M+H]j.
	With trans-bis(tricyclohexylphosphine)palladium(II) dichloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 155℃; for 0.416667h;Microwave irradiation;	[0268] Syndesis of (S)-2-(3-( fluoromemy^mdazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(2-(memylmio)-5-(3-oxoisoindolm^yl)pyrimidin-4-yl)ethyl)acetamidc (7G): A microwave tube was charged withcompound 7F ( 300 mg, 0.47 mmol), 6-(4,4,5,5-tetrameuiyl-l,3,2-dioxaborolan-2- yl)isoindolin-1-one ( 181 mg, 0.7 mmol) and PdCl2[P(cy)3]2 (17 mg, 0.023 mmol). To it was added 10 mL of 1,4-dioxane and 1.4 mL of sodium bicarbonate aqueous solution (1M). The reaction mixture was heated to 155 C for 25 min in a microwave synthesizer. After cooled to room temperature, it was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgS04, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound 7G. MS (m/z) 697.32 [M+H]+.

Reference： [1]Patent: WO2014/134566,2014,A2 .Location in patent: Paragraph 0454
[2]Patent: WO2016/33243,2016,A1 .Location in patent: Paragraph 0268

12
[ 1004294-80-7 ]
(S)-5,5’-(6-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridine-2,5-diyl)bis(2-fluorobenzamide) [ No CAS ]
(S)-N-(1-(3,6-bis(3-oxoisoindolin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In 1,4-dioxane; methanol; water; at 170℃; for 0.25h;Microwave irradiation;	[0417] The title compound (6) was prepared according to the method presented for the synthesis of compound 5G of Example 5 utilizing <strong>[1004294-80-7]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)isoindolin-1-one</strong> and 5F. 1H NMR (400 MHz, CD3OD) oe 8.84 (d, J= 8.1 Hz, 1H), 8.72 (s, 1H), 8.49 (d, J= 7.9 Hz, 1H), 7.98 (d, J= 8.1 Hz, 2H), 7.72 (dd, J= 23.8, 8.0 Hz, 2H), 7.60 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 6.97 - 6.57 (m, 2H), 6.33 (m, 2H), 5.49 (m, 2H), 5.10 (s, 2H), 4.57 (s, 2H), 4.49 (s, 2H), 3.24-2.95 (m, 2H), 2.47 (m, 4H).MS (m/z)781 .02[M+H].

Reference： [1]Patent: WO2014/134566,2014,A2 .Location in patent: Paragraph 0416; 0417

13
[ 1004294-80-7 ]
3-bromo-5-chloro-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
5-chloro-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-3-(3-oxoisoindolin-5-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In ethanol; at 100℃; for 1.0h;Inert atmosphere; Microwave irradiation;	A reaction vial was charged with 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoindolin-l-one (73.2 mg, 0.283 mmol) and 3-bromo-5-chloro-2-(2-(4-methoxybenzyl)-2H- tetrazol-5-yl)benzenesulfonamide (144 mg, 0.314 mmol). EtOH (3139 mu) and potassium phosphate tribasic (942 mu, 0.942 mmol) were added and the reaction mixture was sparged with N2 for 10 min. l, l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (20.46 mg, 0.031 mmol) was added and the reaction was heated to 100C for 1 hr in a microwave. The crude reaction mixture was diltued with EtOAc and water. The aqueous phase was extracted with EtOAc (x2) and the combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by reverse phase HPLC on a CI 8 column eluted with 5% to 90% MeCN in water with 0.05% TFA. The solution was concentrated to provide 5 -chloro-2-(2-(4-methoxybenzyl)-2H-tetrazol-5 -yl)-3 -(3 -oxoisoindolin-5 - yl)benzenesulfonamide. LC-MS: calculated for C23H19C1N604S 510.09; observed m/e (M+H)+: 511.3.
	With potassium phosphate; bis(tri-t-butylphosphine)palladium(0); In ethanol; at 100℃; for 1.0h;Inert atmosphere; Microwave irradiation;	Step C: 5-Chloro-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-3-(3-oxoisoindolin-5-yl)benzenesulfonamide (0823) A reaction vial was charged with <strong>[1004294-80-7]6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one</strong> (73.2 mg, 0.283 mmol) and 3-bromo-5-chloro-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (144 mg, 0.314 mmol). EtOH (3139 mul) and potassium phosphate tribasic (942 mul, 0.942 mmol) were added and the reaction mixture was sparged with N2 for 10 min. 1,1?-bis(di-tert-butylphosphino)ferrocene palladium dichloride (20.46 mg, 0.031 mmol) was added and the reaction was heated to 100 C. for 1 hr in a microwave. The crude reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (×2) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase HPLC on a C18 column eluted with 5% to 90% MeCN in water with 0.05% TFA. The solution was concentrated to provide 5-chloro-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-3-(3-oxoisoindolin-5-yl)benzenesulfonamide. LC-MS: calculated for C23H19ClN6O4S 510.09; observed m/e (M+H)+: 511.3.

Reference： [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 228
[2]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0823

14
methyl 2-(aminomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]
[ 1004294-80-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	In methanol; for 3.0h;Reflux;	Preparation 32 6-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-isoindol-1-one A solution of methyl 2-(aminomethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (Preparation 33, 45 g, 0.15 mmol) in MeOH (0.5 L) was stirred at reflux for 3 hours. The reaction was cooled, concentrated in vacuo and the residue washed with water (2 chi 50ml_) and methanol (2 chi 100ml_) to afford the title compound (35 g, 90%). 1 H NMR (400 MHz, DMSO-d6): delta ppm 1 .31 (s, 12H), 4.40 (s, 2H), 7.60 (d, 1 H), 7.88 (d, 1 H), 7.93 (s, 1 H), 8.59 (br s, 1 H).

Reference： [1]Patent: WO2015/189744,2015,A1 .Location in patent: Page/Page column 70

15
methyl 2-(bromomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]
[ 1004294-80-7 ]

Reference： [1]Patent: WO2015/189744,2015,A1

16
[ 478375-39-2 ]
[ 1004294-80-7 ]

Reference： [1]Patent: WO2015/189744,2015,A1

17
[ 103440-54-6 ]
[ 1004294-80-7 ]

Reference： [1]Patent: WO2015/189744,2015,A1

18
[ 54811-38-0 ]
[ 1004294-80-7 ]

Reference： [1]Patent: WO2015/189744,2015,A1

19
[ 73183-34-3 ]
[ 1004294-80-7 ]

Reference： [1]Patent: WO2015/189744,2015,A1

20
[ 889939-26-8 ]
[ 1004294-80-7 ]
6-(4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate; In 1,4-dioxane; water; at 105℃; for 2.0h;Inert atmosphere;	To an appropriate sized microwave vial, 4-bromo-2-iodo-1- (phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridine (200 mg, 0.43 mmol), 6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)isoindolin-1-one (123 mg, 0.47 mmol), sodium bicarbonate (127 mg, 1.23 mmol), 1 ,4-dioxane (3 ml.) and water (1.5 ml.) were added. The mixture was degassed with nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(ll)dichloride (48mg, 0.043 mmol) was added and the solution heated at 105 C for 2h. After cooling to room temperature, the mixture was poured into water, and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue 6-(4-bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2,3-b]pyridin-2- yl)isoindolin-1-one was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C2i H14BrN303S: 469.3; found: 469.9.

Reference： [1]Patent: WO2015/187684,2015,A1 .Location in patent: Page/Page column 136

21
[ 1004294-80-7 ]
(S)-tert-butyl (1-(3-bromo-6-(pyimidin-5-ylethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate [ No CAS ]
(S)-tert-butyl (2-(3,5-difluorophenyl)-1-(3-(3-oxoisoindolin-5-yl)-6-(pyrimidin-5-ylethynyl)pyridin-2-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trans-bis(triphenylphosphine)palladium dichloride; sodium carbonate; lithium chloride; In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide; at 150℃; for 0.333333h;Microwave irradiation;	[0243] Synthesis of (S)-tert-butyl (2-(3,5-difluorophenyl)-1-(3-(3-oxoisoindolin-5-yl)-6- (pyrimidin-5-ylethynyl)pyridin-2-yl)ethyl)carbamate (1H): To a mixture of (S)-tert-butyl (1- (3-bromo-6-(pyrirmidin-5-ylethynyl)pyridin-2-yl)-2-(3 (26 mg, 0.05 mmol), 6-(4A5,5-tetramethyl-1 ,2-dioxaborolan-2-yl)isomdolin-1-one (20 mg, 0.075 mmol), LiCl (6 mg), and Na2C03(8.4 mg, 0.1 mmol) was added DME/DMF7H20 (4/1/1, 2 mL) and Pd(PPb^Ck (5 mg). The reaction was heated in a microwave reactor to 150 C for 20 min then purified by RP HPLC to provide the desired product. MS (m/z) 567.89 [M+H]+.

Reference： [1]Patent: WO2016/33243,2016,A1 .Location in patent: Paragraph 0243

22
[ 1004294-80-7 ]
(S)-N-(1-(3-bromo-5-(cyclopropylethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]
(S)-N-(1-(5-(cyclopropylethynyl)-3-(3-oxoisoindolin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trans-bis(triphenylphosphine)palladium dichloride; potassium carbonate; lithium chloride; In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide; at 150℃; for 0.333333h;Microwave irradiation;	General procedure: [0243] Synthesis of (S)-tert-butyl (2-(3,5-difluorophenyl)-1-(3-(3-oxoisoindolin-5-yl)-6- (pyrimidin-5-ylethynyl)pyridin-2-yl)ethyl)carbamate (1H): To a mixture of (S)-tert-butyl (1- (3-bromo-6-(pyrirmidin-5-ylethynyl)pyridin-2-yl)-2-(3 (26 mg, 0.05 mmol), 6-(4A5,5-tetramethyl-1 ,2-dioxaborolan-2-yl)isomdolin-1-one (20 mg, 0.075 mmol), LiCl (6 mg), and Na2C03(8.4 mg, 0.1 mmol) was added DME/DMF7H20 (4/1/1, 2 mL) and Pd(PPb^Ck (5 mg). The reaction was heated in a microwave reactor to 150 C for 20 min then purified by RP HPLC to provide the desired product. MS (m/z) 567.89 [M+H]+.

Reference： [1]Patent: WO2016/33243,2016,A1 .Location in patent: Paragraph 0243; 0251

23
[ 1004294-80-7 ]
(S)-N-(1-(5-bromo-2-(methylthio)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide [ No CAS ]
C₃₆H₂₄F₈N₈O₂ [ No CAS ]

Reference： [1]Patent: WO2016/33243,2016,A1

24
[ 1004294-80-7 ]
2-chloro-6-(fluoromethyl)-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)pyridine [ No CAS ]
3-(6-(fluoromethyl)-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 25 - 50℃; for 3.0h;Schlenk technique; Inert atmosphere;	To a degassed solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7- dihydro-5H-pynolo [3 ,4-b]pyridin-5-one (intermediate Cl, 150 mg, 0.192 mmol), 2-chloro-6- (fluoromethyl)-3 -(1 -((1 -methylcyclopentyl)methyl)- 1 H-pyrazol-4-yl)pyridine (intermediate Gl 5, 59.2 mg, 0.192 mmol) and potassium phosphate (82 mg, 0.3 84 mmol) in dioxane (2 mL) and water (0.2 mL) was added 1,1?-bis(di-tert-butylphosphino)ferrocene palladium dichloride (12.5 mg, 0.0 19mmol) at 25 C in a Schlenk tube under N2(g). The resulting mixture was stined at 50 C for 3 h and the mixture was diluted with EtOAc (20 mL) and water (10 mL) before being filtered through celite pad. The filtrate was separated and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-TLC(1:1 petroleum ether/EtOAc) to the title compound. MS: 406 (M+1).

Reference： [1]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 97

25
[ 1004294-80-7 ]
6-(5-chloro-2-[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Reference： [1]Patent: WO2017/68412,2017,A1

26
[ 1004294-80-7 ]
6-(5-chloro-2-[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Reference： [1]Patent: WO2017/68412,2017,A1

27
[ 1004294-80-7 ]
6-(5-chloro-2-[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Reference： [1]Patent: WO2017/68412,2017,A1

28
[ 1004294-80-7 ]
6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Reference： [1]Patent: WO2017/68412,2017,A1

29
[ 1004294-80-7 ]
6-{5-methyl-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one formate salt [ No CAS ]

Reference： [1]Patent: WO2017/68412,2017,A1

30
[ 1004294-80-7 ]
[ 5750-76-5 ]
6-(2,5-dichloropyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1 ?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; sodium carbonate; In 1,4-dioxane; water; at 50℃; for 1.0h;Inert atmosphere;	Preparation 64: 6-(2,5-dichloropyrimidin-4-yl)-2,3-dihydro-1 H-isoindol-1-one (1582) (1583) A mixture of 2,4,5-trichloropyrimidine (5.25 g, 28.6 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2,3-dihydro-1 H-isoindol-1-one (5.25 g, 20.3 mmol) and S-Phos Pd G3 (79 mg, 0.10 mmol) in 1 ,4-dioxane (250 mL) was treated with 1 M aqueous sodium carbonate (60.8 mL, 60.8 mmol), degassed with nitrogen for 10 min and stirred at 50 C for 1 h. The mixture was allowed to cool to RT and stirred for 18 h. The mixture was partitioned between ethyl acetate (250 mL) and water (250 mL) and the resulting suspension was filtered. The solid was suspended in ethyl acetate and the mixture was stirred for 3 days. The precipitate was filtered, washed with ethyl acetate and dried to the title compound (7.1 1 g, 125%) as a brown solid. LC- MS: [M+H]+ = 280.

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4978 - 4992
[2]Patent: WO2017/68412,2017,A1 .Location in patent: Page/Page column 209

31
[ 1004294-80-7 ]
(4-chloropyrimidin-2-yl)-(2-methyl-2H-pyrazol-3-yl)amine [ No CAS ]
6-{2-[(1-methyl-1H-pyrazol-5-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46 mg	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 24.0h;Inert atmosphere;	Example 124: 6-{2-[(1-methyl-1 H-pyrazol-5-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1 H- isoindol-1-one (2604) (2605) A stirred mixture of 4-chloro-N-(1-methyl-1 H-pyrazol-5-yl)pyrimidin-2-amine (Preparation 113) (250 mg, 1.19 mmol, 70 % pure), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1 H-isoindol-1-one (Preparation 63) (773 mg, 2.39 mmol), K2C03 (330 mg, 2.39 mmol) and 1 ,4- dioxane : water (3 : 1 , 4 ml_) was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (68 mg, 0.06 mmol) was then added and the reaction heated under nitrogen at 90C for a total of 24 hours. After cooling to room temperature the mixture was diluted with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to yield 6-{2-[(1- methyl-1 H-pyrazol-5-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1 H-isoindol-1-one (46 mg, 12%). 1H NMR (400 MHz, Me-d3-OD): 8.54 (1 H, d), 8.51 (1 H, d), 8.40 (1 H, dd), 7.73 (1 H, dd), 7.48-7.45 (2H, m), 6.39 (1 H, d), 4.56 (2H, s), 3.80 (3H, s). MS: [M+H]+ = 307.

Reference： [1]Patent: WO2017/68412,2017,A1 .Location in patent: Page/Page column 398

32
[ 1780-31-0 ]
[ 1004294-80-7 ]
6-(2-chloro-5-methylpyrimidin-4-yl)-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16.0h;Inert atmosphere;	A stirred mixture of 2,4-dichloro-5-methylpyrimidine (157 mg, 0.96 mmol), 6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-isoind0l-1-one (Preparation 63) (250 mg, 0.96 mmol), K2C03 (266 mg, 1.93 mmol) and 1 ,4-dioxane : water (3 : 1 , 3 mL) was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (55 mg, 0.05 mmol) was then added and the mixture heated at 80 C under nitrogen for a total of 16 hours. The reaction was allowed to cool to room temperature and then diluted with water. The mixture was extracted with EtOAc (x3) and the combined organic layers were filtered and evaporated under vacuum to yield 6-(2-chloro-5- methylpyrimidin-4-yl)-2,3-dihydro-1 H-isoindol-1-one as a colourless solid. MS: [M+H]+ = 260/262.

Reference： [1]Patent: WO2017/68412,2017,A1 .Location in patent: Page/Page column 401; 402

33
[ 1004294-80-7 ]
[ 1514-82-5 ]
6-(3,3,3-trifluoroprop-1-en-2-yl)isoindolin-1-one [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 15073 - 15077
Angew. Chem.,2017,vol. 129,p. 15269 - 15273,5

34
[ 1004294-80-7 ]
6-(1,1-difluoro-6-methoxyhex-1-en-2-yl)isoindolin-1-one [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 15073 - 15077
Angew. Chem.,2017,vol. 129,p. 15269 - 15273,5

35
[ 1004294-80-7 ]
6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4978 - 4992

36
[ 1004294-80-7 ]
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(1-methyl-1H-imidazol-2-yl)isoindolin-1-one [ No CAS ]

Reference： [1]Patent: US2018/291002,2018,A1

37
[ 1004294-80-7 ]
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(6-cyclopropylpyridazin-3-yl)isoindolin-1-one [ No CAS ]

Reference： [1]Patent: US2018/291002,2018,A1

38
[ 1004294-80-7 ]
C₁₅H₁₃N₃O [ No CAS ]

Reference： [1]Patent: US2018/291002,2018,A1

39
[ 1004294-80-7 ]
[ 16681-59-7 ]
C₁₂H₁₁N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; ethanol; water; at 100℃;Inert atmosphere;	A mixture of 13A (321 mg, 1.98 mmol), <strong>[16681-59-7]2-bromo-1-methyl-1H-imidazole</strong> (626 mg, 2.41 mmol), K2C03 (1.10 g, 7.92 mmol) and Pd(PPh3)4 (114 mg, 0.098 mmol) in dioxane (20 mE), ethanol (10 mE) and water (10 mE) was stirred at 1000 C. overnight under a nitrogen atmosphere. The mixture was poured into water and extracted with EtOAc (100 mLx3). The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on silica gel (1%-2% MeOH in DCM) to give compound 138 (200 mg, 47% yield) as a yellow solid. ESI mlz 214.0 [M+1].

Reference： [1]Patent: US2018/291002,2018,A1 .Location in patent: Paragraph 0431; 0433

40
[ 17973-86-3 ]
[ 1004294-80-7 ]
C₁₂H₈BrN₃O [ No CAS ]