22246-66-8|5-Methoxyisoindolin-1-one| Ambeed

Structure of 22246-66-8

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Quality Control of [ 22246-66-8 ] Purity: 97% SDS Specification

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Product Details of [ 22246-66-8 ]

CAS No. :	22246-66-8
Formula :	C₉H₉NO₂
M.W :	163.17
SMILES Code :	O=C1NCC2=C1C=CC(OC)=C2
MDL No. :	MFCD08437636
InChI Key :	VVXUPZRABQQCKL-UHFFFAOYSA-N
Pubchem ID :	22064719

Safety of [ 22246-66-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 22246-66-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	47.89
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.67
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.74
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.41
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.84
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.82
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.1

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.62
Solubility	3.9 mg/ml ; 0.0239 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.12
Solubility	12.3 mg/ml ; 0.0752 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.01
Solubility	0.161 mg/ml ; 0.000984 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.77 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.28

Application In Synthesis of [ 22246-66-8 ]

* 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.

Downstream synthetic route of [ 22246-66-8 ]

[ 22246-66-8 ] Synthesis Path-Downstream 1~35

1
[ 368-39-8 ]
[ 22246-66-8 ]
[ 110568-76-8 ]

References: [1]Chemische Berichte,1988,vol. 121,p. 243 - 252.

2
[ 50727-04-3 ]
[ 22246-66-8 ]

References: [1]Chemische Berichte,1988,vol. 121,p. 243 - 252.

3
[ 22246-66-8 ]
[ 252061-66-8 ]

Yield	Reaction Conditions	Operation in experiment
79%		5-Hydroxy-2,3-dihydro-isoindol-1-oneTo a suspension of 5-Methoxy-2,3-dihydro-isoindol-1-one (5.65 g, 34.6 mmol) in dichloromethane (300 mL) was added boron tribromide (25.1 g, 100 mmol, 1.0 M solution in DCM) slowly over 20 min at 0 0C. The reaction was allowed to warm to room temperature after addition (3 h). The reaction was quenched with methanol (100 mL) at 0 0C and then allowed to stir for 3 h. The solution was concentrated and 500 mL of water was added and heated to 60 0C for 1 hour. The mixture was cooled and 5-Hydroxy-2,3-dihydro-isoindol-1-one was filtered off as a solid (4.10 g, 79%, CASNo. 252061-66-8). MS: ES: M+1: 150.0 (149.0)
72%		A mixture Of 5-METHOXY-2, 3-DIHYDRO-ISOINDOL-1-ONE (3.7 g, 23 mmol) and boron tri- bromide (1 M in [CH2C12,] 15.2 mL, 88 mmol) in [CH2CI2] (30 mL) [AT-78 C] was stirred for 16 h at RT. The mixture was then cooled [TO-78 C] and [MEOH] (25 mL) was added. After lh at-78 C the mixture was evaporated and the residue purified by chromatography [(SI02,] [CH2C12] : 2N NH3-MeOH 98: 2 to 90: 10) to afford the title product (2.5 g, 72%) as an off- white solid. MS m/e = 148.0 (M-H+).

References: [1]Patent: WO2008/20306,2008,A2 .Location in patent: Page/Page column 35-36.
[2]Patent: WO2004/14856,2004,A1 .Location in patent: Page 9; 14-15.
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 3975 - 3991.
[4]Journal of Medicinal Chemistry,1999,vol. 42,p. 4875 - 4889.
[5]Chemical and Pharmaceutical Bulletin,2011,vol. 59,p. 96 - 99.

4
[ 1007629-19-7 ]
[ 22246-66-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; water;pH 9.0;Product distribution / selectivity;	The 2-Aminomethyl-5-methoxy-benzoic acid methyl ester hydrochloride (160 g, 0.69 moles) was dissolved in 4 L of water and the pH was adjusted to 9 using 1 M aqueous NaOH.At pH = 9, a white solid precipitated out of the clear solution. The solid was filtered and washed with water (500 mL). The solid 6-Methoxy-2,3-dihydro-isoindol-1-one was dried under vacuum at 40 0C for 48 h. (90 g, 80% over 2 steps).

References: [1]Patent: WO2008/20306,2008,A2 .Location in patent: Page/Page column 26; 27.

5
[ 127510-95-6 ]
[ 22246-66-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogen;sponge nickel; In methanol; at 85℃; under 258.58099999999996 Torr;Product distribution / selectivity;	Alternatively, to a pressure vessel was charged Sponge Nickel (511 mmoles; 30.0 g), 2-Cyano-5-methoxy-benzoic acid methyl ester (523 mmoles; 100 g) and Methanol (2.4 L). The mixture was purged with nitrogen and hydrogen and then hydrogenated at 85 0C under 50 psi hydrogen until the reaction was complete. The mixture was filtered, washed with 1 :1 methanol-dichloromethane, and concentrated to afford 84.0 g of the crude product. The crude product was triturated with 800 mL of 1 :1 ethyl acetate-isooctane at 60 0C and cooled <n="29"/>to rt. The white precipitate was filtered on a Whatmann filter and washed with cold 1:1 EtOAc-isooctane to afford 6-Methoxy-2,3-dihydro-isoindol-1-one (71 g, 84% yield).

References: [1]Tetrahedron Letters,2009,vol. 50,p. 1267 - 1269.
[2]Patent: WO2008/20306,2008,A2 .Location in patent: Page/Page column 26; 27-28.

6
C₁₃H₁₇NO₂ [ No CAS ]
[ 22246-66-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	With trifluoroacetic acid; for 2.5h;Reflux;	General procedure: The corresponding N-tert-butylisoindolin-1-one was dissolved in neat trifluoroacetic acid and refluxed until the starting material was consumed indicated by TLC. The trifluoroacetic acid was then removed under reduced pressure and the residue was purified by column chromatography (hexanes/AcOEt).

References: [1]Tetrahedron Letters,2007,vol. 48,p. 8285 - 8289.
[2]Tetrahedron,2011,vol. 67,p. 2693 - 2701.

7
[ 85-44-9 ]
NaCl [ No CAS ]
[ 22246-66-8 ]

References: [1]Chemische Berichte,1988,vol. 121,p. 243 - 252.

8
[ 28281-76-7 ]
[ 22246-66-8 ]

References: [1]Chemische Berichte,1988,vol. 121,p. 243 - 252.

9
[ 610-35-5 ]
[ 22246-66-8 ]

References: [1]Chemische Berichte,1988,vol. 121,p. 243 - 252.

10
[ 134-08-7 ]
[ 22246-66-8 ]

References: [1]Chemische Berichte,1988,vol. 121,p. 243 - 252.

11
[ 1885-13-8 ]
[ 22246-66-8 ]

References: [1]Chemische Berichte,1988,vol. 121,p. 243 - 252.

12
[ 22246-66-8 ]
[ 659737-57-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		A mixture [OF 6-METHOXY-2, 3-DIHYDRO-ISOINDOL-1-ONE] (167 mg, 1.0 mmol) and boron tri- bromide (1 M in [CH2C12,] 3.6 mL, 3.6 mmol) in [CH2CI2] (8 mL) [AT-78C] was stirred for 18 h at RT. The mixture was then cooled to-78C and [MEOH] (20 mL) was added. After 2 h at-78C the mixture was evaporated and the residue purified by chromatography [(SI02,] [CH2CL2] : 2N NH3-MeOH 9: 1) to afford the title product (147 mg, 100%) as a white solid. MS m/e = 148.0 (M-H+).
95%		6-Hydroxy-2,3-dihydro-isoindol-1-one<strong>[22246-66-8]6-Methoxy-2,3-dihydro-isoindol-1-one</strong> (90 g, 0.55 moles, 1 equiv) was suspended in 2.52 L of DCM and 661 mL of BBr3 ( 0.66 moles, 1.2 equiv, 1.0 M solution in DCM) was added over 2 h at 0 0C. After the addition was complete, the reaction mixture was allowed to warm to room temperature over 3 h then stirred overnight. The reaction mixture was quenched by the addition of 1 L of MeOH at 0 0C and then stirred at room temperature for 3 h.Solvent was evaporated under vacuum, and the crude material was triturated with minimum amount of MeOH (-400 mL). The solid was filtered and dried under vacuum at 50 0C for 24 h to give 46.3 g of 6-Hydroxy-2,3-dihydro-isoindol-1-one with >98 % purity (56%). The mother liquor was concentrated and triturated with minimum amount of MeOH to afford 32 g of additional 6-Hydroxy-2,3-dihydro-isoindol-1-one with >90 % purity (39%).
79%	With methanesulfonic acid; DL-methionine; at 85℃; for 24h;Product distribution / selectivity;	Alternatively, to a flask containing <strong>[22246-66-8]6-Methoxy-2,3-dihydro-isoindol-1-one</strong> (435 mmol, 71.0 g) and methionine (771 mmol, 115 g) was added methanesulfonic acid (9.15 mol, 600 mL, 880 g). The reaction was stirred at 85 0C for 24 h and then was cooled and 1 L of water was slowly added to the mixture which caused an exotherm. The mixture was cooled to 5 0C. A tan solid was recovered via filtration, washed with water containing 1% HCI, water, and then dried- in vacuum oven at 45 0C overnight to afford 6-Hydroxy-2,3-dihydro-isoindol-1-one (51.4 g, 79%). MS: ES: M+1: 164.0 (163.1 ) 1H NMR (400 MHz, DMSO-d6) delta ppm 3.76 (s, 3 H) 4.23 (S, 2 H) 7.07-7.12 (m, 2H) 7.41 (d, J=8.97 Hz, 1 H) 8.47 (s, 1 H)

78%		To a suspension of (74) (7.07 g, 43.4 mmol) in CH2Cl2 (600 ml) was added BBr3(IM in CH2Cl2, 86.7 ml). The reaction mixture was stirred at room temperature for 4 hr. The solvent and boron residue was removed in vacuo and the remaining solid was dissolved in CH2Cl2, the solution was neutralized with 1 N NaOH (PH = 6.5). Desired compound was precipitated out and filtered. The organic solution was separated and washed with sat. NaCl, dried over Na2SO4 to give the title compound (combined weight 5.1 g, 78 %). MS (ES) m/z 150.1.
	With boron tribromide; In dichloromethane; at -78 - 20℃;Heating / reflux;	Scheme 9Intermediate 23:Example Compound 13 (150 mg, 0.92 mmol) was dissolved in DCM (20 mL) and cooled to -78 C. To this mixture, BBr3 (1 M, 1.2 mL) was added dropwise. <n="76"/>After 1 hour, the mixture was warmed to room temperature and stirred for another 2 hours. Then, another portion of BBr3 (1 M, 1.2 ml_) was added and the resulting mixture was heated to reflux and stirred overnight. After cooling to room temperature, EtOAc (100 ml_) was added and the organics washed with water, brine and dried over Na2SO4. After concentration, the residue was used in the next step without further purification. HPLC-MS tR = 0.58 min (UV254 nm); mass calculated for formula C8H7NO2 149.0, observed LCMS m/z 150.1 (M+H).

References: [1]Patent: WO2004/14856,2004,A1 .Location in patent: Page 10; 23.
[2]Patent: WO2008/20306,2008,A2 .Location in patent: Page/Page column 26; 28.
[3]Tetrahedron Letters,2009,vol. 50,p. 1267 - 1269.
[4]Patent: WO2008/20306,2008,A2 .Location in patent: Page/Page column 26; 28.
[5]Patent: WO2006/138549,2006,A1 .Location in patent: Page/Page column 73.
[6]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 222 - 227.
[7]Patent: WO2009/14637,2009,A2 .Location in patent: Page/Page column 74-75.

13
[ 286434-74-0 ]
[ 22246-66-8 ]

Yield	Reaction Conditions	Operation in experiment
43%	With ammonium cerium(IV) nitrate; water; In acetonitrile; at 20℃; for 1h;	A mixture [OF 6-METHOXY-2- (4-METHOXY-BENZYL)-2, 3-DIHYDRO-ISOINDOL-1-ONE] (300 mg, 1.1 mmol) and ammonium ceric nitrate (2.2 g, 4.0 mmol) in acetonitrile: water (12 mL, 2: 1) was stirred at RT for 1 h. Then the mixture was poured into water and extracted with ethyl acetate. The combined extracts were then washed with sodium hydrogen carbonate and water. The organic layer was then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography [(SI02,] dichloromethane: [MEOH] 20: 1) to afford the title product (75 mg, 43%) as a light yellow solid. MS m/e = 164.2 (M). Alternatively, a mixture [OF 6-METHOXY-2- (4-METHOXY-BENZYL)-2, 3-DIHYDRO-ISOINDOL-1-ONE] (98.5 mg, 0.35 mmol) in dichlormethane (10 mL) containing TFA (1.6 mL, 20.8 mmol) and TfOH (0.6 mL, 7.0 mmol) was heated overnight at [40 C.] Then the mixture was poured into sodium hydrogen carbonate and water and the product extracted with di- chloromethane. The combined organic layers were then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography [(SI02,] dichloro- methane: [MEOH] 20: 1) to afford the title product (24 mg, 42%) as a light yellow solid. MS m/e = 164.2 (M). i) 6-Hydroxy-2, [3-DIHYDRO-ISOINDOL-1-ONE] A mixture [OF 6-METHOXY-2, 3-DIHYDRO-ISOINDOL-1-ONE] (167 mg, 1.0 mmol) and boron tri- bromide (1 M in [CH2C12,] 3.6 mL, 3.6 mmol) in [CH2CI2] (8 mL) [AT-78C] was stirred for 18 h at RT. The mixture was then cooled to-78C and [MEOH] (20 mL) was added. After 2 h at-78C the mixture was evaporated and the residue purified by chromatography [(SI02,] [CH2CL2] : 2N NH3-MeOH 9: 1) to afford the title product (147 mg, 100%) as a white solid. MS m/e = 148.0 (M-H+).
42%	With trifluorormethanesulfonic acid; trifluoroacetic acid; In dichloromethane; at 40℃;	A mixture [OF 6-METHOXY-2- (4-METHOXY-BENZYL)-2, 3-DIHYDRO-ISOINDOL-1-ONE] (300 mg, 1.1 mmol) and ammonium ceric nitrate (2.2 g, 4.0 mmol) in acetonitrile: water (12 mL, 2: 1) was stirred at RT for 1 h. Then the mixture was poured into water and extracted with ethyl acetate. The combined extracts were then washed with sodium hydrogen carbonate and water. The organic layer was then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography [(SI02,] dichloromethane: [MEOH] 20: 1) to afford the title product (75 mg, 43%) as a light yellow solid. MS m/e = 164.2 (M). Alternatively, a mixture [OF 6-METHOXY-2- (4-METHOXY-BENZYL)-2, 3-DIHYDRO-ISOINDOL-1-ONE] (98.5 mg, 0.35 mmol) in dichlormethane (10 mL) containing TFA (1.6 mL, 20.8 mmol) and TfOH (0.6 mL, 7.0 mmol) was heated overnight at [40 C.] Then the mixture was poured into sodium hydrogen carbonate and water and the product extracted with di- chloromethane. The combined organic layers were then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography [(SI02,] dichloro- methane: [MEOH] 20: 1) to afford the title product (24 mg, 42%) as a light yellow solid. MS m/e = 164.2 (M). i) 6-Hydroxy-2, [3-DIHYDRO-ISOINDOL-1-ONE] A mixture [OF 6-METHOXY-2, 3-DIHYDRO-ISOINDOL-1-ONE] (167 mg, 1.0 mmol) and boron tri- bromide (1 M in [CH2C12,] 3.6 mL, 3.6 mmol) in [CH2CI2] (8 mL) [AT-78C] was stirred for 18 h at RT. The mixture was then cooled to-78C and [MEOH] (20 mL) was added. After 2 h at-78C the mixture was evaporated and the residue purified by chromatography [(SI02,] [CH2CL2] : 2N NH3-MeOH 9: 1) to afford the title product (147 mg, 100%) as a white solid. MS m/e = 148.0 (M-H+).

References: [1]Patent: WO2004/14856,2004,A1 .Location in patent: Page 10; 23.
[2]Patent: WO2004/14856,2004,A1 .Location in patent: Page 23.

14
[ 788081-99-2 ]
[ 22246-66-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With ammonia; In methanol; at 125℃; for 2h;	A solution of methyl 2-(bromomethyl)-5-methoxybenzoate ((75), 5.0 g, 19.3 mmol) in MeOH was placed in pressure flask and to it ammonia/methanol (2M, 30 ml) was added. Resulting mixture was stirred at 125 0C for 2 hr. The solvent and excess NH3 was removed in vacuo and the residue was triturated with Hexane/EtOAc (1:2 ratio). The compound was filtrated under vacuum and air-dried for 2 hr to give the title compound ( 2.51 g, 65 % ) as a pale yellow solid. The filtrated was concentrated and purified on silica gel (Hexane/EtOAc/MeOH 3:1:0.5 ratio) to yield another 270 mg of desired compound. Combined yield was 86 %. MS (ES) m/z 164.1.
67%	With ammonia; In methanol; at 60℃;	Intermediate 13 :Compound 12 (32.0 g, 124.0 mmol) was dissolved in 7 M ammonia in MeOH (150 ml_) and stirred in a sealed pressure flask at 60 C overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was suspended in ethyl acetate and stirred for 30 minutes. The solids were filtered and dissolved in methylene chloride. The methylene chloride was washed with water, dried over sodium sulfate, and concentrated to provide the desired product 13 (13.5 g, 67%). Mass calculated for formula C9H9 NO2, 163.17, observed LCMS m/z 164.2 (M+H), NMR (H1); 4.20(2H,CH2) 3.73(3H, -OCH3),3.88,6.86-7.5(m,3H,Aromatic), 8.0(NH)
67%	With ammonia; In methanol; at 60℃;Sealed flask;	Part C: Compound 3 (32.0 g, 124.0 mmol) was dissolved in 7 M ammonia in MeOH (150 mL) and stirred in a sealed pressure flask at 60 0C overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was suspended in ethyl acetate and stirred for 30 minutes. The solids were filtered and dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over sodium sulfate, and concentrated to provide the desired product 4 (13.5 g, 67%).

67%	With ammonia; In methanol; at 60℃;	Part C: Compound 302 (32.0 g, 124.0 mmol) was dissolved in 7 M ammonia in MeOH (150 ml) and stirred in a sealed pressure flask at 60 0C overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was suspended in ethyl acetate and stirred for 30 minutes. The solids were filtered and dissolved in methylene chloride. The methylene chloride was washed with water, dried over sodium sulfate, and concentrated to provide the desired product 303 (13.5 g, 67%).
67%	With ammonia; In methanol; at 60℃;Sealed tube;	Compound 3 (32.0 g, 124.0 mmol) was dissolved in 7 M ammonia in MeOH (150 mL) and stirred in a sealedpressure flask at 60 C overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure.The residue was suspended in ethyl acetate and stirred for 30 minutes. The solids were filtered and dissolved in methylenechloride. The organic layer was washed with water, dried over sodium sulfate, and concentrated to provide the desiredproduct 4 (13.5 g, 67%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 222 - 227.
[2]Patent: WO2006/138549,2006,A1 .Location in patent: Page/Page column 73.
[3]Patent: WO2009/14637,2009,A2 .Location in patent: Page/Page column 70-71.
[4]Patent: WO2010/54279,2010,A1 .Location in patent: Page/Page column 100-101.
[5]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7283 - 7287.
[6]Patent: WO2007/84451,2007,A1 .Location in patent: Page/Page column 135.
[7]Patent: EP2346857,2019,B1 .Location in patent: Paragraph 0158; 0161.

15
[ 100367-77-9 ]
[ 22246-66-8 ]
[ 1023298-62-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 105℃; for 12h;	Example 39; Preparation of Intermediate Compound 39A; To a pressure tube charged with 2-bromo-4-carboethoxythiazole (2.5 g, 10.6 mmol) and a stir bar was added 6-methoxyisoindolin-1 -one (2.1 g, 12.7 mmol), K3PO4 (4.9 g, 23.3 mmol), Pd2(dba)3 (0.58 g, 0.64 mmol), Xant-Phos (0.62g, 1.1 mmol). Dioxane (20 mL) was added and N2 was bubbled thru the solution for 10 EPO <DP n="152"/>min before the vessel was capped. The mixture stirred at 105 C for 12h and was cooled to rt. The mixture was filtered thru a pad of Celite and was washed with CH2CI2/Me0H (20:1 ; 2 x 10 mL). The resulting filtrate was concentrated under reduced pressure and place under high vacuum. The crude product was purified using flash chromatography using a gradient from CH2Cb to 97:3 CH2CI2/acetone to provide 3.1 g (91% yield) of compound 39A as a brown solid. LC-MS [M+H] = 400.2; 98% purity.

References: [1]Patent: WO2008/54749,2008,A1 .Location in patent: Page/Page column 149-150.

16
[ 1107625-43-3 ]
[ 22246-66-8 ]
[ 1107625-57-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃; for 16h;	Scheme 18A mixture of 4-{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-pyridin-4-yl}- piperazine-1 -carboxylic acid tert-butyl ester (xxx, 100mg, 0.22mmol), the 6- methoxy-2,3-dihydro-isoindol-1-one, 1.2 equivalent,Tris(dibenzylideneacetone)dipalladium(0) (20mg, 0.02mmol), Xantphos (26mg, 0.04mmol), Potassium Phosphate (139mg, 0.66mmol) in 5ml of Dioxane was heated to 85C for 16 hours. Resulting suspension was passed through a filter to remove insoluble solid. Organic layer was concentrated in vacuo. The crude compound was purified by Prep-LC to yield compound 76. HPLC-MS tR = 3.84 min (UV254 nm); Mass calculated for formula C29H32 N6O5, 544.17, observed LCMS m/z 545.20.

References: [1]Patent: WO2009/14637,2009,A2 .Location in patent: Page/Page column 93.

17
[ 1107626-41-4 ]
[ 22246-66-8 ]
[ 1107626-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃;	Compound 289: <n="140"/>To a 25 ml round bottom flask charged with compound 249 (84 mg, 0.2 mmol), lactam (49 mg, 0.3 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), Xant-phos (23 mg, 0.04 mmol) and K3PO4 (106 mg, 0.5 mmol) was added dioxane (5 ml_). The mixture was thoroughly degassed by alternately connected the flask to vacuum and Argon. This resulting mixture was then heated at 80 C overnight, diluted by EtOAc (40 ml) and washed with brine. After concentration, the residue was purified with Prep-LC to give the product 289. HPLC-MS tR = 1.45 min (UV254 nm); mass calculated for formula C28H31N7O5 545.2, observed LCMS m/z 546.3 (M+H).

References: [1]Patent: WO2009/14637,2009,A2 .Location in patent: Page/Page column 138-139.

18
[ 1107627-12-2 ]
[ 22246-66-8 ]
[ 1107627-13-3 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 434: Scheme 33A solution of compound <strong>[22246-66-8]6-methoxy-2,3-dihydro-isoindol-1-one</strong> (2 equivalents) in DMSO (1 mL) was treated with NaH (60% dispersion in oil, 2 equivalents) for 15 minutes at room temperature. Compound 433 (1 equivalent) was then added to this solution at room temperature and this solution was stirred at room <n="183"/>temperature for 16 hour. LCMS analysis indicated that the reaction was complete. The reaction mixture was quenched with sat. Ammonium chloride (0.5 ml_) and acetonitrile (0.5 ml_). Purification by Prep-LC afforded compound 434. HPLC-MS tR = 3.56 min (UV254 nm); mass calculated for formula C28H3IN7O5 545.24, observed LCMS m/z 546.2 (M+H).

References: [1]Patent: WO2009/14637,2009,A2 .Location in patent: Page/Page column 181-182.

19
[ 4965-36-0 ]
[ 22246-66-8 ]
[ 1135435-13-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	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 100℃;	EXAMPLE 51; [0241] This example illustrates a preparation of 6-methoxy-2-(quinolin-7-yl)isoindolin-l- one in an embodiment of the invention.; Pd2(dba)3, Xantphos Cs2CO3, dioxane; [0242] A mixture of 6-methoxyisoindolin-l-one (0.057g, 0.349 mmol), 7-bromoquinoline (0.087 g, 0.419 mmol), tris(dibenzylideneacetone)dipalladium (0.016 g, 0.0174 mmol), Xantphos (0.030 g, 0.0524 mmol), cesium carbonate (0.171 g, 0.524 mmol), and dioxane (4 mL) was heated under nitrogen in a sealed tube at 100 0C overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (5 mL) and filtered. The filtrate was concentrated, and the residue was purified by chromatography (silica, 0-70% ethyl acetate in dichloromethane) to afford 6-methoxy-2-(quinolin-7-yl)isoindolin-l-one (0.086 g, 85%) as an off-white solid: mp 220-223 0C; 1H NMR (500 MHz, CDCl3) delta 8.90 (dd, J= 3.7, 1.7 Hz, IH), 8.78 (dd, J= 9.0, 2.2 Hz, IH), 8.15 (dd, J= 8.2, 1.2 Hz, IH), 8.03 (d, J= 2.2 Hz, IH), 7.88 (d, J= 9.0 Hz, IH), 7.44 (m, 2H), 7.36 (dd, J= 8.2, 4.3 Hz, IH), 7.20 (d, J= 8.3, 2.5 Hz, IH), 4.96 (s, 2H), 3.91 (s, 3H); ESI MS m/z 291 [M + H]+.

References: [1]Patent: WO2009/42907,2009,A1 .Location in patent: Page/Page column 96.

20
[ 1150102-37-6 ]
[ 22246-66-8 ]
[ 1150101-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 16h;	To a solution of compound 1A (80 mg, 0.17 mmol) in dioxane {3 mL) was added <strong>[22246-66-8]6-methoxy-2,3-dihydro-isoindol-1-one</strong> (42 mg, 0.26 mmol), potassium phosphate (109 mg, 0.513 mmol), tris(dibenzylideneacetone)dipalladium(0) (15.7 mg, 0.02 mmol) and xantphos (19.8 mg, 0.03 mmol). The resulting reaction was heated to 85 C and allowed to stir at this temperature for 16 hours. The resulting suspension was passed through a filter to remove insoluble solid and the filtrate was concentrated in vacuo. The residue obtained was purified using Prep-HPLC (Varian Persue XRS 10 micron, 21.2X250 column with water-acetonitrile, 0.1% trifluoroacetic acid, 0-95% as eluent and a run time of 40 minutes) to provide compound 3A with MH+ m/z of 551.30 having retention time of 3.47 min

References: [1]Patent: WO2009/58728,2009,A1 .Location in patent: Page/Page column 60.

21
[ 1007455-19-7 ]
[ 22246-66-8 ]

References: [1]Tetrahedron Letters,2009,vol. 50,p. 1267 - 1269.

22
[ 18997-19-8 ]
[ 22246-66-8 ]
[ 944718-09-6 ]

Yield	Reaction Conditions	Operation in experiment
67%		Part D: Compound 4 (2.2 g, 13.4 mmol) was dissolved in THF (250 mL) and DMPU (40 ml_). Sodium t-butoxide (1.55 g, 16.13 mmol) was added and stirred for 5 hours. Chloromethylpivalate (3.0 mL, 20.1 mmol) was added dropwise and stirred overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2, 25% ethyl acetate/hexanes) afforded the desired product 5 (2.5 g, 67%).
67%		Compound 4 (2.2 g, 13.4 mmol) was dissolved in THF (250 mL) and DMPU (40 mL). Sodium t-butoxide (1.55g, 16.13 mmol) was added and stirred for 5 hours. Chloromethylpivalate (3.0 mL, 20.1 mmol) was added dropwise andstirred overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. Thecombined ethyl acetate layers were washed with water, brine, dried over sodium sulfate and concentrated. Purificationby column chromatography (SiO2, 25% ethyl acetate/hexanes) afforded the desired product 5 (2.5 g, 67%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7283 - 7287.
[2]Patent: WO2010/54279,2010,A1 .Location in patent: Page/Page column 101.
[3]Patent: EP2346857,2019,B1 .Location in patent: Paragraph 0158; 0162.

23
[ 83636-46-8 ]
[ 22246-66-8 ]
[ 950739-11-4 ]

References: [1]Synthetic Communications,2011,vol. 41,p. 67 - 72.

24
[ 1268389-55-4 ]
[ 22246-66-8 ]
[ 1268389-56-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 16h;	A mixture of tert-butyl 4-(3-(5-bromofuran-2~carboxamido)pyridin-4- yl)piperazine-1-carboxylate (1.3, 100 mg, 0.20 mmol), the 6-methoxy-2,3- dihydro-isoindol-1-one,(1.4, 1.2 equivalent), Tris{dibenzylideneacetone) dipalladium(O) (20mg, 0.02mmol), Xantphos (26mg, 0.04mmol), Potassium acetate (139mg, 0.66mmol) in 5mi of Dioxane was heated to 850C for 16 hours. Resulting suspension was diluted with ethyl acetate and passed through a celite filter to remove insoluble solid. Organic layer was concentrated in vacuo. The crude compound was purified by Prep-LC to yield compound, tert-buty. 4- (3-(5-(6-methoxy-1"thetaxoisoindolin-2-yl)furan-2-carboxamido)pyridin-4- yl)piperazine-1 -carboxylate (1.5). HPLC-MS tR = 3.84 min (UV254 nm); Mass calculated for formula C28H3IN5O6, 533.23; observed LCMS m/z 534.20(M+H).

References: [1]Patent: WO2011/25706,2011,A2 .Location in patent: Page/Page column 140.

25
C₁₆H₂₃NO₃S₂ [ No CAS ]
[ 22246-66-8 ]

References: [1]Tetrahedron,2011,vol. 67,p. 2693 - 2701.

26
[ 22675-83-8 ]
[ 22246-66-8 ]

References: [1]Tetrahedron,2011,vol. 67,p. 2693 - 2701.

27
N'-(4-methoxybenzyl)-N,N-dimethylurea [ No CAS ]
[ 22246-66-8 ]

References: [1]Beilstein Journal of Organic Chemistry,2011,vol. 7,p. 1219 - 1227.
[2]Journal of the American Chemical Society,2020,vol. 142,p. 3636 - 3644.

28
[ 35598-05-1 ]
[ 22246-66-8 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 3975 - 3991.

29
[ 1404362-95-3 ]
[ 22246-66-8 ]
[ 1404362-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere;	N-(3-bromo-4-memylphenyl)-3-(2-cyanopropmethyl)benzamide (52 mg, 0.104 mmol) was mixed with 6-methoxyisoindolin-l-one (25.12 mg, 0.154 mmol), pd2(dba)3 (9.52 mg, 0.01 mmol), Xantphos (12.03 mg, 0.021 mmol) and K3P04 (66.14 mg, 0.312 mmol) under argon and then dioxane (2 mL) was introduced. The mixture was heated at 100C for 12 h. It was cooled to room temperature and the ethyl acetate (5 mL), followed by water (5 mL), was added. Two layers were separated and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic layer was washed with brine (15 ml), dried (Na2S04), filtered and evaporated under reduced pressure to provide crude 3-(2-cyanopropan-2-yl)-iV-(3-(6-methoxy-l-oxoisoindolin-2-yl)-4- memylphenyl)-N-((2-(trimethylsilyl)ethoxy)methyl)benzamide which was purified by column chromatography (Si02, 0-20% ethyl acetate-hexane).

References: [1]Patent: WO2012/148792,2012,A1 .Location in patent: Page/Page column 39-40.

30
[ 1023299-32-2 ]
[ 22246-66-8 ]
[ 1026670-06-3 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	General procedure: A mixture of tert-butyl 4-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (47 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 2.5 mumol), Xantphos (5.8 mg, 10 mumol) or X-Phos (4.8 mg, 10 mumol), cesium carbonate (98 mg, 0.30 mmol) and amine (0.15 mmol) in dioxane (0.5 mL) was stirred under an atmosphere of argon at 100 C for 15 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo, and to the residue was added TFA (0.5 mL, neat). The reaction mixture was stirred at room temperature for 15 minutes. TFA was removed in vacuo, and the residue was purified by reverse phase HPLC to afford the final compound.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594.

31
[ 1023298-53-4 ]
[ 22246-66-8 ]
[ 1026668-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	A mixture of tert-butyl 4-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (47 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 2.5 mumol), Xantphos (5.8 mg, 10 mumol) or X-Phos (4.8 mg, 10 mumol), cesium carbonate (98 mg, 0.30 mmol) and amine (0.15 mmol) in dioxane (0.5 mL) was stirred under an atmosphere of argon at 100 C for 15 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo, and to the residue was added TFA (0.5 mL, neat). The reaction mixture was stirred at room temperature for 15 minutes. TFA was removed in vacuo, and the residue was purified by reverse phase HPLC to afford the final compound.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594.

32
[ 1023298-74-9 ]
[ 22246-66-8 ]
[ 1023298-83-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	General procedure: A mixture of tert-butyl 4-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (47 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 2.5 mumol), Xantphos (5.8 mg, 10 mumol) or X-Phos (4.8 mg, 10 mumol), cesium carbonate (98 mg, 0.30 mmol) and amine (0.15 mmol) in dioxane (0.5 mL) was stirred under an atmosphere of argon at 100 C for 15 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo, and to the residue was added TFA (0.5 mL, neat). The reaction mixture was stirred at room temperature for 15 minutes. TFA was removed in vacuo, and the residue was purified by reverse phase HPLC to afford the final compound.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594.

33
[ 1023299-28-6 ]
[ 22246-66-8 ]
[ 1026670-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	General procedure: A mixture of tert-butyl 4-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (47 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 2.5 mumol), Xantphos (5.8 mg, 10 mumol) or X-Phos (4.8 mg, 10 mumol), cesium carbonate (98 mg, 0.30 mmol) and amine (0.15 mmol) in dioxane (0.5 mL) was stirred under an atmosphere of argon at 100 C for 15 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo, and to the residue was added TFA (0.5 mL, neat). The reaction mixture was stirred at room temperature for 15 minutes. TFA was removed in vacuo, and the residue was purified by reverse phase HPLC to afford the final compound.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594.

34
[ 1023299-30-0 ]
[ 22246-66-8 ]
[ 1026670-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	General procedure: A mixture of tert-butyl 4-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (47 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 2.5 mumol), Xantphos (5.8 mg, 10 mumol) or X-Phos (4.8 mg, 10 mumol), cesium carbonate (98 mg, 0.30 mmol) and amine (0.15 mmol) in dioxane (0.5 mL) was stirred under an atmosphere of argon at 100 C for 15 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo, and to the residue was added TFA (0.5 mL, neat). The reaction mixture was stirred at room temperature for 15 minutes. TFA was removed in vacuo, and the residue was purified by reverse phase HPLC to afford the final compound.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594.

35
[ 1023299-35-5 ]
[ 22246-66-8 ]
[ 1026670-08-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;	General procedure: A mixture of tert-butyl 4-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (47 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg, 2.5 mumol), Xantphos (5.8 mg, 10 mumol) or X-Phos (4.8 mg, 10 mumol), cesium carbonate (98 mg, 0.30 mmol) and amine (0.15 mmol) in dioxane (0.5 mL) was stirred under an atmosphere of argon at 100 C for 15 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo, and to the residue was added TFA (0.5 mL, neat). The reaction mixture was stirred at room temperature for 15 minutes. TFA was removed in vacuo, and the residue was purified by reverse phase HPLC to afford the final compound.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594.

Historical Records

Technical Information

• Acyl Group Substitution • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Bucherer-Bergs Reaction • Chan-Lam Coupling Reaction • Clemmensen Reduction • Complex Metal Hydride Reductions • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Fischer Indole Synthesis • Grignard Reaction • Henry Nitroaldol Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Lawesson's Reagent • Leuckart-Wallach Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Nomenclature of Ethers • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Amines • Preparation of Ethers • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Amines • Reactions of Ethers • Reformatsky Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Stobbe Condensation • Tebbe Olefination • Ugi Reaction • Wittig Reaction • Wolff-Kishner Reduction

Related Functional Groups of
[ 22246-66-8 ]

Ethers

A212875 [132680-54-7]

6-Methoxyisoindolin-1-one

Similarity: 1.00

A287724 [50727-04-3]

5-Methoxyisoindoline-1,3-dione

Similarity: 0.98

A201453 [59084-72-9]

5,6-Dimethoxyisoindolin-1-one

Similarity: 0.96

A324446 [3400-22-4]

4-Methoxy-N-methylbenzamide

Similarity: 0.95

A167996 [366453-22-7]

4-Methoxyisoindolin-1-one

Similarity: 0.93

Amides

A212875 [132680-54-7]

6-Methoxyisoindolin-1-one

Similarity: 1.00

A287724 [50727-04-3]

5-Methoxyisoindoline-1,3-dione

Similarity: 0.98

A201453 [59084-72-9]

5,6-Dimethoxyisoindolin-1-one

Similarity: 0.96

A324446 [3400-22-4]

4-Methoxy-N-methylbenzamide

Similarity: 0.95

A167996 [366453-22-7]

4-Methoxyisoindolin-1-one

Similarity: 0.93

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P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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CAS No.: 22246-66-8

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