[ CAS No. 868066-91-5 ] {[proInfo.proName]}

Name: 868066-91-5|5-Bromo-2-methylisoindolin-1-one|98%
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SKU: A215625
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Quality Control of [ 868066-91-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 868066-91-5 ]

Product Details of [ 868066-91-5 ]

CAS No. :	868066-91-5	MDL No. :	MFCD12755780
Formula :	C₉H₈BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WRFZBWHXIGUNLQ-UHFFFAOYSA-N
M.W :	226.07	Pubchem ID :	23158169
Synonyms :

Calculated chemistry of [ 868066-91-5 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	54.0
TPSA :	20.31 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.14
Log Po/w (XLOGP3) :	1.65
Log Po/w (WLOGP) :	1.5
Log Po/w (MLOGP) :	2.17
Log Po/w (SILICOS-IT) :	2.39
Consensus Log Po/w :	1.97

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.65
Solubility :	0.505 mg/ml ; 0.00223 mol/l
Class :	Soluble
Log S (Ali) :	-1.69
Solubility :	4.62 mg/ml ; 0.0204 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.42
Solubility :	0.0859 mg/ml ; 0.00038 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Safety of [ 868066-91-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 868066-91-5 ]

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

Upstream synthesis route of [ 868066-91-5 ]
Downstream synthetic route of [ 868066-91-5 ]

[ 868066-91-5 ] Synthesis Path-Upstream 1~10

1
[ 74-89-5 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	at 50℃; Sealed tube	[00530] Intermediate 51 b: 5-bromo-2-methyl-isoindolin-1 -one[00531] To a reaction tube containing methyl 4-bromo-2-(bromomethyl)benzoate (1 .2g, 3.gmmol) was added methylamine (2.OM in THF, lOmL, 2Ommol). The tube was sealed and the mixture was stirred and heated at 50 °C overnight. The mixture was then cooled to room temperature, filtered and the precipitate washed with THF. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography using an eluent of 0-100percent EtOAc in heptane to give 5-bromo-2- methyl-isoindolin-1-one (623mg, 2.7Smmol, 71percent yield) as a white solid.1H NMR (CDCI3, 400MHz) O/ppm: 7.73-7.68 (1H, m), 7.64-7.56 (2H, m), 4.36 (2H, 5), 3.19 (3H, 5). MS Method 3: RT: 3.18 mi m/z226.0/228.0 [M+H]
68%	With triethylamine In tetrahydrofuran at 100℃; for 12 h; Sealed tube	Synthesis of 5-bromo-2-methylisoindolin-1-one (2) A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (1, 1 g, 3.26 mmol), 2 M methylamine in tetrahydrofuran (1.95 mL, 3.9 mmol) and triethylamine (0.9 mL, 6.52 mmol) was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with water. The organic was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane to afford 5-bromo-2-methylisoindolin-1-one (2). Yield: 0.5 g, 68percent; MS (ESI) m/z 226, 228 [M+1]⁺.
0.112 g	at 90℃; for 24 h;	Step A: 5-bromo-2-methylisoindolin-l-one [0234] Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90°C) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). ^lU NMR (500 MHz, CDC1₃) δ ppm 3.19 (s, 3 H), 4.36 (s, 2 H), 7.57 - 7.62 (m, 2 H), 7.70 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]⁺ 226.3.

Reference： [1] Patent: WO2016/51193, 2016, A1, . Location in patent: Paragraph 00527; 00530; 00531
[2] Patent: US10112955, 2018, B2, . Location in patent: Page/Page column 29
[3] Patent: WO2013/148603, 2013, A1, . Location in patent: Paragraph 0233-0234
[4] Patent: EP3406612, 2018, A1, . Location in patent: Paragraph 0086; 0087

2
[ 552330-86-6 ]
[ 74-88-4 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere	General procedure: Bromoisoindolin-1-one (2.0 g, 9.43 mmol) was dissolved with warming in DMF (150 mL),then cooled to 0°C. NaH (415 mg, 10.4 mmol) was added and the mixture stirred under N2 at 0°C for 0.5 h. Methyl iodide (0.65 mL, 10.4 mmol) was added dropwise and the reaction allowed to warm to room temperature and stir for another I h. A small quantity of water was added to quench the reaction then the DMF removed under reduced pressure to give an oily yellow residue which was dissolved in EtOAc (150 mL). This solution waswashed with water (3x100 mL), brine (100 mL) and dried (Na2SO4)., Removal of the solvent under reduced pressure gave a solid which was purified by filtration through a plug of silica gel (10percent acetone/CH2C12 as eluant). The title compound was isolated as a very pale yellow crystalline solid (1.64 g, 80percent). ‘ H NMR [400 MHz, (CD3)2S0] ö 7.85 (dd, J= 1.5, 0.6 Hz, 1 H), 7.66 (dd, J= 8.0, 1.7 Hz, 1 H), 7.59 (d, J— 8.0 Hz, I H), 4.46 (s,2 H), 3.05 (s, 3 H). LRMS (APCI) calcd for C9H8BrNO 226, 228 (MH), found 226, 228.
61.9%	Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0℃; for 2 h;	5-Bromo-2-methylisoindolin-1-one To a solution of 5-bromoisoindolin-1-one (2500 mg, 11.79 mmol) in DMF (20 mL) under nitrogen, at 0 °C, was added NaH (566 mg, 14.15 mmol) and the mixture was stirred for 30 min. After which, Mel (0.885 mL, 14.15 mmol) was added dropwise and the mixture was stirred at 0 °C for 2 h. The reaction was quenched with sat. aqueous NH₄CI, and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine, dried and concentrated to afford 5-bromo-2-methylisoindolin-1-one (2500 mg, 7.30 mmol, 61.9 percent yield). LC-MS: m/z 226 (M+H)⁺1.02 min (ret. time).

Reference： [1] Patent: WO2014/28968, 2014, A1, . Location in patent: Page/Page column 64
[2] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 572

3
[ 888030-79-3 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
57.3%	Stage #1: at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 4 h;	A 150 mL sealed tube was charged with 4-bromo-2- (hydroxymethyl) -N-tnethylbenzamide (3.34 g, 13.7 mmol) and 1,3- dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 0⁰C and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) was added slowly. The tube was capped and the reaction mixture was stirred at room temperature for 30 minutes. This was recooled to 0⁰C and N,N,N,N- tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) was added in one portion; this mixture was stirred at room temperature for 4 hours. The tube was placed in a 150°C oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL) , then washed with IM aqueous HCl . The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL) , dried with MgSO₄, filtered, then concentrated to give a yellow oil . This was purified by column chromatography, eluting with 1 - 4percent MeOH/DCM to give 5-bromo-2-methylisoindolin-l-one (1.774 g, 57.3percent yield) as a yellow solid.

Reference： [1] Patent: WO2008/8539, 2008, A2, . Location in patent: Page/Page column 102

4
[ 888030-79-3 ]
[ 868066-91-5 ]

Reference： [1] Synlett, 2006, # 5, p. 801 - 803

5
[ 124-40-3 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Reference： [1] Patent: WO2010/128324, 2010, A1, . Location in patent: Page/Page column 119

6
[ 99548-55-7 ]
[ 868066-91-5 ]

Reference： [1] Patent: WO2014/28968, 2014, A1,
[2] Patent: WO2015/92713, 2015, A1,
[3] Patent: WO2016/51193, 2016, A1,

7
[ 888030-82-8 ]
[ 868066-91-5 ]

Reference： [1] Synlett, 2006, # 5, p. 801 - 803

8
[ 64169-34-2 ]
[ 868066-91-5 ]

Reference： [1] Synlett, 2006, # 5, p. 801 - 803

9
[ 78471-43-9 ]
[ 868066-91-5 ]

Reference： [1] Patent: WO2014/28968, 2014, A1,
[2] Patent: WO2015/92713, 2015, A1,

10
[ 68837-59-2 ]
[ 868066-91-5 ]

Reference： [1] Patent: WO2014/28968, 2014, A1,
[2] Patent: WO2015/92713, 2015, A1,

[ 868066-91-5 ] Synthesis Path-Downstream 1~49

1
[ 888030-79-3 ]
(5-bromo-3<i>H</i>-isobenzofuran-1-ylidene)-methyl-amine [ No CAS ]
[ 868066-91-5 ]

Reference： [1]Synlett,2006,p. 801 - 803

3
[ 888030-79-3 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
57.3%		A 150 mL sealed tube was charged with 4-bromo-2- (hydroxymethyl) -N-tnethylbenzamide (3.34 g, 13.7 mmol) and 1,3- dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 00C and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) was added slowly. The tube was capped and the reaction mixture was stirred at room temperature for 30 minutes. This was recooled to 00C and N,N,N,N- tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) was added in one portion; this mixture was stirred at room temperature for 4 hours. The tube was placed in a 150°C oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL) , then washed with IM aqueous HCl . The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL) , dried with MgSO4, filtered, then concentrated to give a yellow oil . This was purified by column chromatography, eluting with 1 - 4percent MeOH/DCM to give 5-bromo-2-methylisoindolin-l-one (1.774 g, 57.3percent yield) as a yellow solid.

Reference： [1]Patent: WO2008/8539,2008,A2 .Location in patent: Page/Page column 102

4
[ 868066-91-5 ]
[ 73183-34-3 ]
[ 1002309-19-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 85℃;Inert atmosphere;	[00532] Intermediate Sic: 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yI)isoindolin-1-one[00533] A round bottomed flask containing bis(pinacolato)diboron (354mg, 1 .3gmmol) and KOAc (326mg, 3.32mmol) in 1 ,4-dioxane (6.5mL) was evacuated/backfilled with nitrogen. Pd(dppt)C12.CH2CI2 (54mg, 0.O7mmol) was added and the flask was evacuated/backfilled with nitrogen again. The reaction mixture was then stirred and heated at 85 C overnight. After this timethe mixture was cooled to room temperature, filtered through a plug of celite and the solid was washed with EtOAc. The filtrate was concentrated and the residue purified by column chromatography using an eluent of 0-100% EtOAc in heptane to give 2-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (324mg,1.lgmmol, 89% yield) as a brown solid.1H NMR (CDCI3, 400MHz) O/ppm: 7.92 (1H, dd, J= 7.6Hz, 0.4Hz), 7.90-7.89 (1H, m), 7.85 (1H, dd, J 7.6Hz, 0.4Hz), 4.39 (2H, 5), 3.23 (3H, 5), 1.38 (12H, 5).MS Method 3: RT: 3.61 mi m/z 274.1 [M+H]
	With potassium acetate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 22h;	In a sealable tube was combined Pd2dba3 (0.0270 g, 0.0295 mmol), 2- (dicyclohexylphosphino) -2' , 4', 6'- tri-i-propyl-1, 1' -biphenyl (0.0563 g, 0.118 mmol) , 4 , 4, 5, 5- tetramethyl-2- (4,4, 5 , 5-tetramethyl-l, 3 , 2-dioxaborolan-2-yl) - 1, 3, 2-dioxaborolane (0.450 g, 1.77 mmol), 5-bromo-2- <n="113"/>methylisoindolin-1-one (see Tsuritani, T., et al Synlett 2006, 5 801-803} (0.267 g, 1.18 mmol) , potassium acetate (0.232 g, 2.36 mmol) and 2 mL dioxane . The mixture was blanketed with N2, sealed and heated at 80 C for 22 h. The mixture was allowed to cool to rt then diluted with EtOAc, and the organic layer washed with water, sat. NaHCO3, then dried over Na2SO4, filtered and evaporated. The residue was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The title compound was collected as a tan solid.
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere of nitrogen;	To a solution of 5-bromo-2-methylisoindolin-l-one (Example 31, step (i), 60.4 g) in dioxane (2 L) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (67.8 g), potassium acetate (65.4 g) and Pd(dppf)Cl2 (6 g) under an atmosphere of nitrogen. The mixture was heated to 1000C and stirred for 4 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica eluting with petroleum ether / ethyl acetate (6:1 to 2: 1) to afford the sub-titled compound (72 g).1H NMR (400 MHz, CDCl3): delta 7.89-7.88 (m, 2H), 7.83-7.81 (m, IH), 4.35 (s, 2H), 3.19 (s, 3H), 10.34 (s, 12H).

	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl acetamide; at 100℃;Inert atmosphere;	Step B: 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoindolin-l-one [0236] 5-Bromo-2-methylisoindolin-l-one (0.112 g, 0.495 mmol), bis(pinacolato)diboron (0.189 g, 0.743 mmol), potassium acetate (0.146 g, 1.486 mmol), and PdCl2(dppf)CH2Cl2 adduct (0.020 g, 0.025 mmol) were suspended in DMA (1.0 mL). The mixture was degassed with N2 and heated in a sand bath at 100C overnight. The reaction mixture was subsequently cooled, diluted with EtOAc (10 mL), and passed through a syringe filter. The filtrate was diluted with water (10 mL) and the layers were separated. The aqueous layer was washed with EtOAc (2 x 5 mL). The organic layers were combined and concentrated in vacuo to give the title compound as a brown residue, which was used without further purification.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;	In a vial was combined <strong>[868066-91-5]5-bromo-2-methylisoindolin-1-one</strong> (226 mg, 1.00 mmol) [Ark Pharm cat AK-37748], 4,4,5,5,4?,4?,5?,5?-octamethyl-[2,2?]bi[[1,3,2]dioxaborolanyl] (0.533 g, 2.10 mmol), potassium acetate (294 mg, 3.00 mmol), 1,4-dioxane (5.0 mL), and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (36.6 mg, 0.050 mmol). The vial was de-gassed by bubbling nitrogen through the solvent for 5 minutes then heated to 90 C. overnight. The mixture was allowed to cool to room temperature and was then filtered using a syringe filter. The filtrate was then concentrated under reduced pressure and used without further purification. LC-MS calculated for C15H21BNO3(M+H)+: m/z=274.2. found 274.1.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 5h;	5-Bromo-2-methylisoindolin-1-one synthesized in step 1 (Formula 5-2, 2.1 g, 9.20 mmol), potassium acetate (2.26 g, 23 mmol, 2.5 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.225 g, 0.28 mmol, 0.03 eq) and B 2 Pin 2 (2.34 g, 9.20 mmol, 1 eq) were dissolved in 1,4-dioxane (20 ml). The temperature was raised to 100 ° C and the reaction mixture was stirred for 5 hours.After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, then dried over anhydrous MgSO 4,The solvent was removed under reduced pressure.Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain the target compound (Formula 5-3).

Reference： [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00527; 00532; 00533
[2]Patent: WO2008/8539,2008,A2 .Location in patent: Page/Page column 111-112
[3]Patent: WO2010/128324,2010,A1 .Location in patent: Page/Page column 119
[4]Patent: WO2013/148603,2013,A1 .Location in patent: Paragraph 0235-0236
[5]Patent: US2016/9712,2016,A1 .Location in patent: Paragraph 0783
[6]Patent: KR2019/109007,2019,A .Location in patent: Paragraph 0219; 0223-0225

5
[ 888030-82-8 ]
[ 868066-91-5 ]

Reference： [1]Synlett,2006,p. 801 - 803

6
[ 64169-34-2 ]
[ 868066-91-5 ]

Reference： [1]Synlett,2006,p. 801 - 803

7
[ 124-40-3 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; for 18h;Heating; Reflux;	A solution of methyl 4-bromo-2-(bromomethyl)benzoate (410 mmol) in MeNH2ZMeOH (1500 niL) was heated to reflux and stirred for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica eluting with petroleum ether / ethyl acetate (6:1 to 3:1) to afford the sub-titled compound (48.5 g).1H NMR (400 MHz, CDCl3): delta 7.63-7.61 (m, IH), 7.53-7.54 (m, 2H), 4.29 (s, 2H), 3.12 (s, 3H).

Reference： [1]Patent: WO2010/128324,2010,A1 .Location in patent: Page/Page column 119

8
[ 74-89-5 ]
[ 78471-43-9 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	In tetrahydrofuran; at 50℃;Sealed tube;	[00530] Intermediate 51 b: 5-bromo-2-methyl-isoindolin-1 -one[00531] To a reaction tube containing methyl 4-bromo-2-(bromomethyl)benzoate (1 .2g, 3.gmmol) was added methylamine (2.OM in THF, lOmL, 2Ommol). The tube was sealed and the mixture was stirred and heated at 50 C overnight. The mixture was then cooled to room temperature, filtered and the precipitate washed with THF. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography using an eluent of 0-100% EtOAc in heptane to give 5-bromo-2- methyl-isoindolin-1-one (623mg, 2.7Smmol, 71% yield) as a white solid.1H NMR (CDCI3, 400MHz) O/ppm: 7.73-7.68 (1H, m), 7.64-7.56 (2H, m), 4.36 (2H, 5), 3.19 (3H, 5). MS Method 3: RT: 3.18 mi m/z226.0/228.0 [M+H]
68%	With triethylamine; In tetrahydrofuran; at 100℃; for 12h;Sealed tube;	Synthesis of 5-bromo-2-methylisoindolin-1-one (2) A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (1, 1 g, 3.26 mmol), 2 M methylamine in tetrahydrofuran (1.95 mL, 3.9 mmol) and triethylamine (0.9 mL, 6.52 mmol) was heated at 100 C. for 12 h in a sealed tube. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and washed with water. The organic was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane to afford 5-bromo-2-methylisoindolin-1-one (2). Yield: 0.5 g, 68%; MS (ESI) m/z 226, 228 [M+1]+.
0.112 g	In methanol; at 90℃; for 24h;	Step A: 5-bromo-2-methylisoindolin-l-one [0234] Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90C) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). lU NMR (500 MHz, CDC13) delta ppm 3.19 (s, 3 H), 4.36 (s, 2 H), 7.57 - 7.62 (m, 2 H), 7.70 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]+ 226.3.

	In methanol; ethanol;Reflux;	To a solution of compound 1a (15 g, 50 mmol) in methanol (150 ml) was added methylamine (25 ml, 33% inethanol), and the reaction was refluxed overnight. After the organic solvent was drained off, the mixture was separatedby silica gel column chromatography (PE/EA= 3:1) to provide a yellow oily compound 1b.HNMR(CDCl3),7.5-7.7(m,3H),4.3(s,2H),3.1(s,3H).MS(ESI)m/z:225.9(M+H)+.
	for 18h;Reflux;	Methyl 4-bromo-2- (bromomethyl) benzoate (Formula 5-1, 2.5 g, 8.12 mmol) was dissolved in 2M methanamine (122 ml, 244 mmol, 30 eq) and then stirred at reflux for 18 hours. After completion of the reaction, Extracted with dichloromethane. The organic layer was washed with H 2 O, dried over anhydrous MgSO 4, and the solvent was removed under reduced pressure.Thereafter, the reaction mixture was separated and purified by MPLC (hexane / ethyl acetate; 70:30) to obtain a target compound (Formula 5-2).

Reference： [1]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00527; 00530; 00531
[2]Patent: US10112955,2018,B2 .Location in patent: Page/Page column 29
[3]Patent: WO2013/148603,2013,A1 .Location in patent: Paragraph 0233-0234
[4]Patent: EP3406612,2018,A1 .Location in patent: Paragraph 0086; 0087
[5]Patent: KR2019/109007,2019,A .Location in patent: Paragraph 0219-0222

9
[ 868066-91-5 ]
[ 1567836-36-5 ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

10
[ 868066-91-5 ]
[ 1567836-37-6 ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

11
[ 868066-91-5 ]
[ 1567836-38-7 ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

12
[ 868066-91-5 ]
[ 1567837-79-9 ]

Reference： [1]Patent: WO2014/28968,2014,A1

13
[ 868066-91-5 ]
2,4-difluoro-N-(5-(5-(2-methyl-1-oxoisoindolin-5-yl)thiophen-2-yl)pyridin-3-yl)benzenesulfonamide, sodium salt [ No CAS ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

14
[ 868066-91-5 ]
[ 1567836-81-0 ]

Reference： [1]Patent: WO2014/28968,2014,A1

15
[ 868066-91-5 ]
[ 1567836-94-5 ]

Reference： [1]Patent: WO2014/28968,2014,A1

16
[ 868066-91-5 ]
[ 1567837-01-7 ]

Reference： [1]Patent: WO2014/28968,2014,A1

17
[ 868066-91-5 ]
[ 6165-68-0 ]
[ 1567836-35-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;	General procedure: Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solution of 2 M Na2CO3 (3 mL) and Pd(dppf)C12 (94 mg, 0.12 mmol) were added and the entire mixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30 mmol) was added and reflux continued under N2 overnight. Upon cooling, themixture was diluted with water (100 mL) and extracted with CH2C12 (6x50 mL). The combined organic fractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give a crude solid which was purified by flash column chromatography on silica gel (EtOAc as eluant). The title compound was isolated as a light-brown solid (510 mg, 97percent). ?H NMR [400 MHz, (CD3)2S0] 8 7.87 (s, 1 H), 7.77 (dd, J? 7.9, 1.6 Hz,1 H), 7.67 (dd, J 7.9, 0.3 Hz, 1 H), 7.61-7.66 (m, 2 H), 7.18 (dd, J 5.0, 1.4 Hz, 1 H),4.49 (s, 2 H), 3.08 (s, 3 H). LRMS (APCI) calcd for C13H,2NOS 230 (MH), found 230.
97%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;	5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97percent). 1H NMR[400 MHz, (CD3)2SO] delta 7.87 (s, 1 H), 7.77 (dd, J = 7.9, 1.6 Hz, 1 H), 7.67 (dd, J = 7.9, 0.3Hz, 1 H), 7.61-7.66 (m, 2 H), 7.18 (dd, J = 5.0, 1.4 Hz, 1 H), 4.49 (s, 2 H), 3.08 (s, 3 H).LRMS (APCI+) calcd for C13H12NOS 230 (MH+), found 230.

Reference： [1]Patent: WO2014/28968,2014,A1 .Location in patent: Page/Page column 64; 65
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1050 - 1054

18
[ 552330-86-6 ]
[ 74-88-4 ]
[ 868066-91-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		General procedure: Bromoisoindolin-1-one (2.0 g, 9.43 mmol) was dissolved with warming in DMF (150 mL),then cooled to 0°C. NaH (415 mg, 10.4 mmol) was added and the mixture stirred under N2 at 0°C for 0.5 h. Methyl iodide (0.65 mL, 10.4 mmol) was added dropwise and the reaction allowed to warm to room temperature and stir for another I h. A small quantity of water was added to quench the reaction then the DMF removed under reduced pressure to give an oily yellow residue which was dissolved in EtOAc (150 mL). This solution waswashed with water (3x100 mL), brine (100 mL) and dried (Na2SO4)., Removal of the solvent under reduced pressure gave a solid which was purified by filtration through a plug of silica gel (10percent acetone/CH2C12 as eluant). The title compound was isolated as a very pale yellow crystalline solid (1.64 g, 80percent). ? H NMR [400 MHz, (CD3)2S0] oe 7.85 (dd, J= 1.5, 0.6 Hz, 1 H), 7.66 (dd, J= 8.0, 1.7 Hz, 1 H), 7.59 (d, J? 8.0 Hz, I H), 4.46 (s,2 H), 3.05 (s, 3 H). LRMS (APCI) calcd for C9H8BrNO 226, 228 (MH), found 226, 228.
61.9%		5-Bromo-2-methylisoindolin-1-oneTo a solution of 5-bromoisoindolin-1-one (2500 mg, 11.79 mmol) in DMF (20 mL) under nitrogen, at 0 °C, was added NaH (566 mg, 14.15 mmol) and the mixture was stirred for 30 min. After which, Mel (0.885 mL, 14.15 mmol) was added dropwise and the mixture was stirred at 0 °C for 2 h. The reaction was quenched with sat. aqueous NH4CI, and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine, dried and concentrated to afford 5-bromo-2-methylisoindolin-1-one (2500 mg, 7.30 mmol, 61.9 percent yield). LC-MS: m/z 226 (M+H)+1.02 min (ret. time).

Reference： [1]Patent: WO2014/28968,2014,A1 .Location in patent: Page/Page column 64
[2]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 572

19
[ 78471-43-9 ]
[ 868066-91-5 ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Patent: WO2015/92713,2015,A1

20
[ 68837-59-2 ]
[ 868066-91-5 ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Patent: WO2015/92713,2015,A1

21
[ 99548-55-7 ]
[ 868066-91-5 ]

Reference： [1]Patent: WO2014/28968,2014,A1
[2]Patent: WO2015/92713,2015,A1
[3]Patent: WO2016/51193,2016,A1

22
[ 868066-91-5 ]
[ 1161499-39-3 ]
[ 1579996-77-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2357 - 2367

23
[ 868066-91-5 ]
[ 1579996-83-0 ]
C₂₃H₂₇N₃O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2357 - 2367

24
[ 868066-91-5 ]
[ 1254319-24-8 ]
[ 1254319-52-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2357 - 2367

25
[ 868066-91-5 ]
tert-butyl (2S)-2-[[4-[(3-cyano-1H-indol-5-yl)oxy]phenyl]carbamoyl]pyrrolidine-1-carboxylate [ No CAS ]
C₃₄H₃₃N₅O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3611 - 3625

26
[ 868066-91-5 ]
tert-butyl (2S)-2-[[4-[(3-cyano-1H-indol-5-yl)oxy]phenyl]carbamoyl]pyrrolidine-1-carboxylate [ No CAS ]
(2S)-N-[4-[3-cyano-1-(2-methyl-1-oxoisoindolin-5-yl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3611 - 3625

27
[ 868066-91-5 ]
C₃₁H₃₄N₂O₆S [ No CAS ]

Reference： [1]Patent: WO2015/92713,2015,A1

28
[ 868066-91-5 ]
3-(2-methyl-1-oxoisoindolin-5-yl)-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/92713,2015,A1

29
[ 868066-91-5 ]
[ 140-88-5 ]
(E)-ethyl 3-(2-methyl-1-oxoisoindolin-5-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.6%	With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine; In acetonitrile; at 80℃; for 3h;	(E)-Ethyl 3-(2-methyl-1-oxoisoindolin-5-yl)acrylateA mixture of tri-o-tolylphosphine (0.242 g, 0.796 mmol), ethyl acrylate (1.594 g, 15.92 mmol), <strong>[868066-91-5]5-bromo-2-methylisoindolin-1-one</strong> (1.8 g, 7.96 mmol), Pd(OAc)2(0.089 g, 0.398 mmol), and TEA (2.220 mL, 15.92 mmol) in CH3CN (25.0 mL) was stirred at 80 °C for 3 h. The reaction was filtered and concentrated and the residue was purified by flash column chromatography eluting with petroleum ether/EtOAc (1/5), to afford (E)-ethyl 3-(2- methyl-1-oxoisoindolin-5-yl)acrylate (1.02 g, 3.95 mmol, 49.6 percent yield). LC-MS: m/z 247 (M+H)+1.50 min (ret. time).

Reference： [1]Patent: WO2015/92713,2015,A1 .Location in patent: Page/Page column 572

30
[ 868066-91-5 ]
2-(2-methyl-1-oxo-isoindolin-5-yl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2016/51193,2016,A1

31
[ 868066-91-5 ]
[ 100939-90-0 ]
5-(4-(3-chlorobenzoyl)piperazin-1-yl)-2-methylisoindolin-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 5507 - 5520

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[ 868066-91-5 ]
[ 13331-23-2 ]
5-(furan-2-yl)-2-methylisoindolin-1-one [ No CAS ]