[ CAS No. 1313399-38-0 ] {[proInfo.proName]}

Name: 1313399-38-0|2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one|97%
Brand: Ambeed
SKU: A122995
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Quality Control of [ 1313399-38-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1313399-38-0 ]

SDS Specification

Alternatived Products of [ 1313399-38-0 ]

Product Details of [ 1313399-38-0 ]

CAS No. :	1313399-38-0	MDL No. :	MFCD12755781
Formula :	C₁₅H₂₀BNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VBWYOZWWAKZWKG-UHFFFAOYSA-N
M.W :	273.14	Pubchem ID :	46856416
Synonyms :

Calculated chemistry of [ 1313399-38-0 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.53
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	82.78
TPSA :	38.77 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.94
Log Po/w (WLOGP) :	1.04
Log Po/w (MLOGP) :	1.39
Log Po/w (SILICOS-IT) :	1.67
Consensus Log Po/w :	1.21

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.91
Solubility :	0.335 mg/ml ; 0.00123 mol/l
Class :	Soluble
Log S (Ali) :	-2.38
Solubility :	1.14 mg/ml ; 0.00418 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.16
Solubility :	0.0189 mg/ml ; 0.0000693 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.8

Safety of [ 1313399-38-0 ]

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

Application In Synthesis of [ 1313399-38-0 ]

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

Upstream synthesis route of [ 1313399-38-0 ]
Downstream synthetic route of [ 1313399-38-0 ]

[ 1313399-38-0 ] Synthesis Path-Upstream 1~6

1
[ 1254319-51-1 ]
[ 73183-34-3 ]
[ 1313399-38-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium acetate In dimethyl sulfoxide at 90℃; for 5 h; Inert atmosphere	6-Bromo-2-raethylisoindolin-l-one (723 mg, 3.41 mmol), bis(pinacolato)diboron (1.04 g, 4.09 mmol), potassium acetate (1.00 g, 10.2 mmol) and PdCl2(dppf) catalyst (139 mg, 0.17 mmol) were weighed into a flask which was sealed under N₂. DMSO (15 mL) was added, and the entire mixture stirred at 90°C for 5 h. Upon cooling, the reaction mixture was diluted with water (250 mL) and extracted with CH₂C1₂ (5x50 mL). The combined CH₂C1₂ fractions were in turn washed with water (2x100 mL), brine (100 mL), dried (Na₂S04), filtered and the solvent removed under reduced pressure to yield the crude product. Purification was carried out by flash column chromatography on silica gel (20percent THF/CH₂C1₂ as eluant) to give the title compound as a crystalline beige solid (262 mg, 28percent). NMR [400 MHz, (CD₃)₂SO] δ 7.91 (br s, 1 H), 7.85 (dd, J = 7.6, 1.0 Hz, 1 H), 7.59 (dd, J = 7.5, 0.6 Hz, 1 H), 4.49 (s, 2 H), 3.07 (s, 3 H), 1.32 (s, 12 H). LRMS (APCI⁺) calcd for Ci₅H₂iBN0₃ 274 (MH⁺), found 274.

Reference： [1] Patent: WO2011/75784, 2011, A1, . Location in patent: Page/Page column 113-114
[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

2
[ 675109-26-9 ]
[ 1313399-38-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555

3
[ 478375-39-2 ]
[ 1313399-38-0 ]

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

4
[ 103440-54-6 ]
[ 1313399-38-0 ]

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

5
[ 54811-38-0 ]
[ 1313399-38-0 ]

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

6
[ 73183-34-3 ]
[ 1313399-38-0 ]

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

[ 1313399-38-0 ] Synthesis Path-Downstream 1~33

1
[ 1254319-51-1 ]
[ 73183-34-3 ]
[ 1313399-38-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃; for 5h;Inert atmosphere;	6-Bromo-2-raethylisoindolin-l-one (723 mg, 3.41 mmol), bis(pinacolato)diboron (1.04 g, 4.09 mmol), potassium acetate (1.00 g, 10.2 mmol) and PdCl2(dppf) catalyst (139 mg, 0.17 mmol) were weighed into a flask which was sealed under N2. DMSO (15 mL) was added, and the entire mixture stirred at 90C for 5 h. Upon cooling, the reaction mixture was diluted with water (250 mL) and extracted with CH2C12 (5x50 mL). The combined CH2C12 fractions were in turn washed with water (2x100 mL), brine (100 mL), dried (Na2S04), filtered and the solvent removed under reduced pressure to yield the crude product. Purification was carried out by flash column chromatography on silica gel (20% THF/CH2C12 as eluant) to give the title compound as a crystalline beige solid (262 mg, 28%). NMR [400 MHz, (CD3)2SO] delta 7.91 (br s, 1 H), 7.85 (dd, J = 7.6, 1.0 Hz, 1 H), 7.59 (dd, J = 7.5, 0.6 Hz, 1 H), 4.49 (s, 2 H), 3.07 (s, 3 H), 1.32 (s, 12 H). LRMS (APCI+) calcd for Ci5H2iBN03 274 (MH+), found 274.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;	To a solution of <strong>[1254319-51-1]6-bromo-2-methylisoindolin-1-one</strong> (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.

Reference： [1]Patent: WO2011/75784,2011,A1 .Location in patent: Page/Page column 113-114
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 9542 - 9555
[3]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 37; 38

2
[ 1313399-38-0 ]
[ 1313399-40-4 ]

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

3
[ 1313399-38-0 ]
[ 1313397-78-2 ]

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

4
[ 52157-62-7 ]
[ 1313399-38-0 ]
C₁₆H₁₅NO₃S [ No CAS ]

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

5
[ 675109-26-9 ]
[ 1313399-38-0 ]

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

6
methyl 2-(bromomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]
[ 1313399-38-0 ]

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

7
methyl 2-[(methylamino)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]
[ 1313399-38-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	In acetonitrile; for 2.0h;Reflux;	Preparation 34 2-Methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 /-/-isoindol-1- one A solution of methyl 2-[(methylamino)methyl]-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzoate (Preparation 35, 40 g, 0.14 mol) in acetonitrile (0.5 L) was heated to reflux for 2 hours. The reaction was cooled and concentrated in vacuo. The residue was diluted with EtOAc (500 mL), washed with brine (2 x 100 mL) and concentrated in vacuo to afford the title compound as a grey solid (35 g, 99%). 1 H NMR (400 MHz, CDCI3): delta ppm 1 .35 (s, 12H), 3.20 (s, 3H), 4.38 (s, 2H), 7.42 (d, 1 H), 7.90 (d, 1 H), 8.30 (s, 1 H). MS m/z 274 [M+H]+

Reference： [1]Patent: WO2015/189744,2015,A1 .Location in patent: Page/Page column 71

8
[ 478375-39-2 ]
[ 1313399-38-0 ]

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

9
[ 103440-54-6 ]
[ 1313399-38-0 ]

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

10
[ 54811-38-0 ]
[ 1313399-38-0 ]

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

11
[ 73183-34-3 ]
[ 1313399-38-0 ]

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

Yield	Reaction Conditions	Operation in experiment
	With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 1-(2-([2,2'-bipyridin]-5-yl)phenyl)-3-cyclohexylthiourea; In para-xylene; at 25.0℃; for 24.0h;	General procedure: Meta- selective l3orylation of an Aromatic Compoundwith an Iridium Catalyst. In a dried test tube, to a p-xylene (1.5 mE) solution of N,N-dihexylbenzamide (72.4 mg, 0.250 mmol, 1.00 equiv), [Ir(OMe) (cod)]2 (1.2 mg, 1.9 jtmol, 0.75 mol %), 1 -(2-([2,2?-bipyridin]-S-yl) phenyl)-3-cyclohexylurea (1.2 mg, 3.8 tmol, 1.5 mol %) andbis (pinacolato)diboron (47.6 mg, 0.188 mmol, 0.750 equiv) were added and stirred at 25 C. for 24 hours. The solvent was removed under reduced pressure, and then the products were isolated and prepared by recycling preparative HPLC.63% yield [meta/para=7.5]; colorless oil; 11B NMR (130 MHz, CDCl3) delta 31.9; IR (neat, nu/cm -1) 2930, 1627, 1410, 1355, 1140, 1027, 965, 851, 754, 683; HRMS (ESI+) Calcd for C25H44BNNaO4 ([M+Na]+) 468.3256, Found 468.3246. N,N-Dihexyl-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide: 1H NMR (400 MHz, CDCl3) delta 0.80 (t, J=7.4 Hz, 3H), 0.91 (t, J=6.7 Hz, 3H), 1.06-1.08 (m, 4H), 1.16-1.50 (m, 22H), 1.62-1.64 (m, 2H), 3.01-3.04 (m, 2H), 3.48-3.49 (m, 2H), 3.82 (s, 3H), 6.87 (d, J=8.3 Hz, 1H), 7.63 (s, 1H), 7.76 (d, J=8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) delta 14.1, 14.2, 22.5, 22.8, 24.7, 26,3, 26.7, 27.6, 28.4, 31.4, 31.8, 44.4, 48.5, 55.4, 83.7, 110.1, 126.6, 134.4, 137.0, 157.8, 169.2. N,N-Dihexyl-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide: 1H NMR (400 MHz, CDCl3) delta 0.80 (t, J=7.4 Hz, 3H), 0.91 (t, J=6.7 Hz, 3H), 1.06-1.08 (m, 4H), 1.18-1.50 (m, 20H), 1.62-1.64 (m, 4H), 3.01-3.04 (m, 2H), 3.48-3.49 (m, 2H), 3.85 (s, 3H), 7.17 (d, J=7.2 Hz, 1H), 7.29 (s, 1H), 7.41 (d, J=7.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) delta 14.1, 14.2, 22.5, 22.8, 25.0, 26,3, 26.8, 27.5, 28.4, 31.4, 31.8, 44.3, 48.3, 55.6, 84.1, 116.4, 127.1, 127.4, 130.0, 154.6, 169.2.

13
[ 1313399-38-0 ]
6-chloro-5-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)picolinonitrile [ No CAS ]
5-{1-[(1-methylcyclopentyl)methyl]-1H-pyrazol-4-yl}-6-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)pyridine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; water; at 60.0℃; for 5.0h;Inert atmosphere;	To 2-methyl-6-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindolin- 1-one(intermediate Cl, 545 mg, 2.0 mmol), 6-chloro-5-( 1 -((1 -methylcyclopentyl)methyl)- 1H-pyrazol-4-yl)picolinonitrile (intermediate Gl,500 mg, 1.66 mmol), potassium carbonate (1 M in water, 4.99 mL, 4.99 mmol) and THF (8.3 mL) was added to a vial under an atmosphere Of N2(g). 1,lBis(di tert-butylphosphino)fenocene palladium dichloride (87 mg, 0.133 mmol) was added and the system was a purged and flushed with N2 (g) and it was stined at 60 C for 5 hr. After cooling to RT, thereaction was diluted with water and was extracted with EtOAc. The organic was dried withanhydrous sodium sulfate and was concentrated under reduced pressure. The crude material waspurified by silica gel column (0-60% 3:1 EtOAc:EtOH/hexanes) to yield the title compound. MS:412 (M+1)?H NMR (500 MHz, CDCl3): oe 7.87-7.89 (m, 2H), 7.67 (d, J = 8.02 Hz, 1H), 7.59 (dd, J= 7.77, 1.67 Hz, 1H), 7.45 (d, J = 7.78 Hz, 1H), 7.31 (s, 1H), 6.89 (s, 1H), 4.39 (s, 3H), 3.83 (s, 2H),3.19 (s, 3H), 1.52-1.61 (m, 4H), 1.36-1.41 (m, 2H), 1.19-1.24 (m, 2H), 0.80 (s, 3H).

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 2411 - 2425
[2]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 65

14
[ 1313399-38-0 ]
3-{1-[(1-methylcyclopentyl)methyl]-1H-pyrazol-4-yl}-2-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-5,6-dihydro-7H-cyclopenta-[b]pyridin-7-one [ No CAS ]

Reference： [1]Patent: WO2017/107089,2017,A1

15
[ 1313399-38-0 ]
6-(5,6-difluoro-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-methylisoindolin-1-one [ No CAS ]

Reference： [1]Patent: WO2017/107089,2017,A1

16
[ 1313399-38-0 ]
6-(7-hydroxy-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-methylisoindolin-1-one [ No CAS ]

Reference： [1]Patent: WO2017/107089,2017,A1

17
[ 1313399-38-0 ]
[ 406676-37-7 ]
6-(3-chloro-5,6-difluoropyridin-2-yl)-2-methylisoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 50.0℃; for 4.0h;	3-Chloro-5,6-difluoro-2-iodopyridine (100 mg, 0.363 mmol), 2-methyl-6-(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindolin- 1-one (intermediate Cl, 99 mg, 0.363mmol), PdC12(dppf) (26.6 mg, 0.036 mmol) and potassium carbonate (1 M in water, 1.45 mL, 1.45mmol) were added into a vial with dioxane (5 mL). The system was degassed three times before itwas heated to 50 C for 4 h. The reaction mixture was cooled to RT and diluted with water andEtOAc. The organic was separated, dried over anhydrous sodium sulfate, and was concentrated to dryness. The resultant residue was purified by silica gel chromatography (0-40% EtOAc/hexanes) to afford the title compound. MS: 295 (M+1).

Reference： [1]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 102; 103

18
[ 1313399-38-0 ]
2-chloro-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate [ No CAS ]
2-(2-methyl-3-oxoisoindolin-5-yl)-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; bis(tri-t-butylphosphine)palladium(0); In tetrahydrofuran; water; at 40.0℃; for 2.0h;Inert atmosphere;	To a vial was added 2-chloro-3 -(1 -((1 -methylcyclopentyl)methyl)- 1 H-pyrazol-4-yl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (intermediate G18, 40 mg, 0.107 mmol), THF (3 mL), water (0.3 mL), 2-methyl-6-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindolin- 1-one(intermediate C1,35.1 mg, 0.128 mmol), K3P04 (68.1 mg, 0.321 mmol) and 1,1?-bis(di-tert- butylphosphino)fenocene palladium dichloride (6.97 mg, 10.70 jimol). The reaction mixture was placed under N2(g) and was stined for 2 h at 40 C. The reaction mixture was filtered and was concentrated in vacuo before purification by purified by prep-TLC (100% EtOAc) to give the title compound. MS: 485 (M+1).

Reference： [1]Patent: WO2017/107089,2017,A1 .Location in patent: Page/Page column 100

19
[ 1254319-51-1 ]
[ 73183-34-3 ]
[ 1313399-38-0 ]
(2-methyl-3-oxoisoindolin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;	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).

Reference： [1]Patent: WO2019/5587,2019,A1 .Location in patent: Page/Page column 72-73

20
[ 1313399-38-0 ]
5-(2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-2-((1-methylcyclopentyl)methyl)oxazole [ No CAS ]
2-methyl-6-(3-(2-((1-methylcyclopentyl)methyl)oxazol-5-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In tetrahydrofuran; water; at 70.0℃; for 1.0h;	To a stirred solution of 5- (2-chloro-6, 7-dihydro-5H-cyclopenta [b] pyridin-3-yl) -2- ( (1-methylcyclopentyl) methyl) oxazole (30 mg, 0.095 mmol) in THF/H2O (3/1 mL) was added 2-methyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-1-one (25.9 mg, 0.095 mmol) , K3PO4(20.10 mg, 0.095 mmol) and Pd (dtbpf) Cl2(61.7 mg, 0.095 mmol) , the reaction mixture was stirred at 70 for 1h. LCMS indicated the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated in vacuum, the residue was further purified by prep. HPLC (basic condition) to give the title compound. MS: 428.2 (M+1) .1HNMR (METHANOL-d4, 400 MHz) : delta7.90 (s, 1H) , 7.71 (s, 1H) , 7.55-7.66 (m, 2H) , 6.63 (s, 1H) , 4.55 (s, 2H) , 3.20 (s, 3H) , 3.00-3.11 (m, 4H) , 2.60 (s, 2H) , 2.22 (t, J7.4 Hz, 2H) , 1.55 (d, J4.7 Hz, 4H) , 1.28-1.41 (m, 2H) , 1.09-1.21 (m, 2H) , 0.77 (s, 3H) .

Reference： [1]Patent: WO2019/238,2019,A1 .Location in patent: Page/Page column 54-55

21
[ 1313399-38-0 ]
6-chloro-5-(1-((1-methylcyclopropyl)methyl)-1H-pyrazol-4-yl)picolinonitrile [ No CAS ]
5-{1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}-6-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)pyridine-2-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90.0℃; for 5.0h;Inert atmosphere;	2-methyl-6-(4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindolin- 1-one (60.1 mg, 0.220 mmol),6-chloro-5 -(1 -((1 -methylcyclopropyl)methyl)- 1 H-pyrazol-4-yl)picolinonitrile (50 mg, 0.183 mmol),1,1?-bis(di-tert-butylphosphino)ferrocene palladium dichloride (11.95 mg, 0.018 mmol) and potassium carbonate (76 mg, 0.5 50 mmol) were added to a reaction vial with dioxane (5 ml) and Water (1 ml) and it was degassed three times. The reaction was then heated to 90 C for 5 hr. After cooling and workup the crude material was separated on Flash LC (A: Hexane, B:30% EtOH inEtOAc, gradient: 0%B to 30%B, 40 mm.) to give the title compound. MS: 384(M+1). ?H NMR (CDCL3, 500 MHz): 7.93 (m, 2 H), 7.70 (d, 1 H), 7.60 (m, 1 H), 7.51 (d, 1 H), 7.30 (s, 1 H), 7.05 (s, 1 H), 4.42 (s, 2 H), 3.81 (s, 2 H), 3.20 (s, 3 H), 0.90 (s,3 H), 0.51 (m, 2 H), 0.35 (m, 2 H).

Reference： [1]Patent: WO2019/5588,2019,A1 .Location in patent: Page/Page column 105

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[ 1313399-38-0 ]
6-chloro-5-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)picolinonitrile [ No CAS ]
6-(2-methyl-3-oxoisoindolin-5-yl)-5-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)picolinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-tri-i-propyl-1,1?-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; In tetrahydrofuran; at 70.0℃;Inert atmosphere;	A microwave vial containing chloro(2-dicyclohexylphosphino-2?,4?,6?-tri-i-propyl- 1,1 ?-biphenyl) [2-(2-aminoethyl)phenyl] palladium(ii) methyl-t-butyl ether adduct (11.39 mg, 0.014 mmol), 2-methyl-6-(4,4, 5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)isoindolin- 1-one (83 mg, 0.303 mmol), and 6-chloro-5 -(1 -((1 -(trifluoromethyl)cyclopropyl)methyl)- 1 H-pyrazol-4-yl)picolinonitrile (90 mg, 0.275 mmol) was sealed and purged with nitrogen and THF (1837 tl) was added. purging continued for 30 mm after K3P04 (551 .il, 0.551 mmol) was added. The reaction mixture was stirred overnight at 70 C. LC-MS indicated product formation. The product was purified by column chromatography (0-->100% Ethyl Acetate in Hexane over 15 CV then 0->100% Ethanol/EthylAcetate 1/3 in EthylAcetate over 5 CV) to give the title compound. MS: 438 (M+1). ?H NMR ( CDCL3, 500 MHz):7.93 (m, 2 H), 7.71 (d, 1 H), 7.62 (m, 1 H), 7.51 (d, 1 H), 7.30 (s, 1 H), 7.11 (s, 1 H), 4.49 (s, 2 H),4.25 (s, 2 H), 3.25 (s, 3 H), 1.1 (m, 2 H), 0.90 (m, 2 H).

Reference： [1]Patent: WO2019/5588,2019,A1 .Location in patent: Page/Page column 107

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3-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one [ No CAS ]
[ 73183-34-3 ]
[ 1313399-38-0 ]
(2-methyl-3-oxoisoindolin-5-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80.0℃; for 10.0h;Inert atmosphere;	To a solution of 6-bromo-2-methylisoindolin-i-one (5 g, 22.i mmol) in DMF (30 mL) was added bi s(pinacolato)diboron (6. i 8 g, 24.3 mmol) and potassium acetate (6.5 i g, 66.4 mmol). The reactionmixture was degassed and backfilled with N2 gas, and i,i?-bis(diphenyl-phosphino)ferrocene palladium(II)dichloride dichloromethane (0.903 g, i. i06 mmol) was added. The reaction mixture was stirred at 80 C for iO hours. After diluting with EtOAc and water, the organic layer was concentrated and purified on silica column (iOO% 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+i). ?HNIVIR (500 MHz, CDC13): oe 8.33 (s, i H), 7.98 (d, 7.5 Hz, i H), 7.46 (d, 7.5 Hz, i H), 4.4i (s, 2 H),3.22(s,3 H), i.38(s, i2H).

Reference： [1]Patent: WO2019/5588,2019,A1 .Location in patent: Page/Page column 42

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[ 1313399-38-0 ]
2-chloro-6-fluoro-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)pyridine [ No CAS ]
6-(6-fluoro-3-{1-[(1-methylcyclopentyl)methyl]-1H-pyrazol-4-yl}pyridin-2-yl)-2-methyl-2,3-dihydro-1H-isoindol-1-one [ No CAS ]