[ CAS No. 14963-96-3 ]

Name: 14963-96-3|4-Methoxyisobenzofuran-1,3-dione|97%
Brand: Ambeed
SKU: A370481
Price: 30.0 USD
Availability: InStock
Rating: 96 (32 reviews)

{[proInfo.proName]} ,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 14963-96-3

Structure of 14963-96-3 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Bulk Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 100K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 14963-96-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 14963-96-3 ]

SDS Specification

Alternatived Products of [ 14963-96-3 ]

Product Details of [ 14963-96-3 ]

CAS No. :	14963-96-3	MDL No. :	MFCD00034721
Formula :	C₉H₆O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KRKJKLCCCGDNCY-UHFFFAOYSA-N
M.W :	178.14	Pubchem ID :	291193
Synonyms :

Calculated chemistry of [ 14963-96-3 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.11
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	42.68
TPSA :	52.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.28
Log Po/w (XLOGP3) :	1.26
Log Po/w (WLOGP) :	1.01
Log Po/w (MLOGP) :	1.39
Log Po/w (SILICOS-IT) :	1.82
Consensus Log Po/w :	1.35

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.01
Solubility :	1.73 mg/ml ; 0.00969 mol/l
Class :	Soluble
Log S (Ali) :	-1.96
Solubility :	1.94 mg/ml ; 0.0109 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.59
Solubility :	0.456 mg/ml ; 0.00256 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 14963-96-3 ]

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 [ 14963-96-3 ]

* 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 [ 14963-96-3 ]
Downstream synthetic route of [ 14963-96-3 ]

[ 14963-96-3 ] Synthesis Path-Upstream 1~1

1
[ 14963-96-3 ]
[ 478-43-3 ]

Reference： [1] Patent: CN106966891, 2017, A,

[ 14963-96-3 ] Synthesis Path-Downstream 1~68

1
[ 908094-01-9 ]
[ 37418-88-5 ]
[ 14963-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	With diethyl ether

Reference： [1]Corbellini; Rossi [Gazzetta Chimica Italiana, 1931, vol. 61, p. 281,284] Amstutz; Fehnel; Neumoyer [Journal of the American Chemical Society, 1946, vol. 68, p. 349,352]
[2]Konno, Mitoshi; Nakae, Takahiko; Sakuyama, Shigeru; Odagaki, Yoshihiko; Nakai, Hisao; Hamanaka, Nobuyuki [Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 8, p. 1649 - 1674]

2
[ 14963-96-3 ]
[ 15721-20-7 ]
2-isobutyryl-6-methoxy-benzoic acid [ No CAS ]
2-isobutyryl-3-methoxy-benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diethyl ether

Reference： [1]Amstutz; Fehnel; Neumoyer [Journal of the American Chemical Society, 1946, vol. 68, p. 349,352]

3
[ 14963-96-3 ]
[ 4792-33-0 ]
[ 28281-58-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 53% 2: 37%	With sodium tetrahydroborate In tetrahydrofuran; acetic acid at 50℃; for 2h;
	With hydrogenchloride; acetic acid; zinc
	reduction;

	With sodium tetrahydroborate In tetrahydrofuran at -10 - 0℃; for 2h; Yield given. Yields of byproduct given;
	With tetrabutylammonium borohydride In tetrahydrofuran for 4h; Ambient temperature; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
	With sodium tetrahydroborate In tetrahydrofuran for 2h; Heating; Yield given. Yields of byproduct given;
	With L-Selectride In tetrahydrofuran at -78 - -30℃; for 2h; Yield given. Yields of byproduct given;
	With L-Selectride In tetrahydrofuran for 2h; Ambient temperature; Yield given. Yields of byproduct given;
	With lithium borohydride In tetrahydrofuran at -10 - 20℃; for 2h; other 3-substituted phthalic anhydrides; var. reducing agents and reaction conditions;
	With sodium tetrahydroborate Yield given; Yields of byproduct given;

Reference： [1]Konno, Mitoshi; Nakae, Takahiko; Sakuyama, Shigeru; Odagaki, Yoshihiko; Nakai, Hisao; Hamanaka, Nobuyuki [Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 8, p. 1649 - 1674]
[2]Duncanson et al. [Journal of the Chemical Society, 1953, p. 1331] Blair et al. [Journal of the Chemical Society, 1955, p. 708,711]
[3]Boykin, David W.; Baumstark, Alfons L.; Kayser, Margaret M.; Soucy, Chantal M. [Canadian Journal of Chemistry, 1987, vol. 65, p. 1214 - 1217]
[4]Soucy; Favreau; Kayser [Journal of Organic Chemistry, 1987, vol. 52, # 1, p. 129 - 134]
[5]Braun, Manfred; Veith, Reiner; Moll, Gerard [Chemische Berichte, 1985, vol. 118, # 3, p. 1058 - 1070]
[6]Makhlouf, Mansour A.; Rickborn, Bruce [Journal of Organic Chemistry, 1981, vol. 46, # 23, p. 4810 - 4811]
[7]Soucy; Favreau; Kayser [Journal of Organic Chemistry, 1987, vol. 52, # 1, p. 129 - 134]
[8]Makhlouf, Mansour A.; Rickborn, Bruce [Journal of Organic Chemistry, 1981, vol. 46, # 23, p. 4810 - 4811]
[9]Soucy; Favreau; Kayser [Journal of Organic Chemistry, 1987, vol. 52, # 1, p. 129 - 134]
[10]Dang, Qun; Brown, Brian S.; Van Poelje, Paul D.; Colby, Timothy J.; Erion, Mark D. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1505 - 1510]

4
[ 14963-97-4 ]
[ 14963-96-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With acetic anhydride In tetrahydrofuran at 80℃; for 3h;	11 [0228] To a solution of 3-methoxyphthalic acid (3.0 g, 15.306 mmol) in THF (24 mL) at RT was added acetic anhydride (10 mL). The mixture was stirred at 80 oC for 3 hrs. The solvent was evaporated to give 4-methoxyisobenzofuran-1,3-dione (2.72 g, quant. yield) as a white solid. MS (ESI) m/z = 178.9 [M+H]+.
99%	With acetic anhydride In tetrahydrofuran for 4h; Heating / reflux;	56.56A Acetic anhydride (70 ml) was added to a mixture of 3-methoxyphthalic acid (51.0 g, 0.26 mol) in anhydrous tetrahydrofuran (250 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo and the resulting solid material was dried in a vacuum oven at 5O0C overnight to afford 3-methoxyphthalic anhydride (45.9 g, 99%) as a colourless solid. 1H NMR (DMSOd6) 7.97 (1 H, dd), 7.63 (1 H, d), 7.60 (1 H, d), 4.02 (3H, s). MS: [M+H]+ 179.
99%	With acetic anhydride In tetrahydrofuran for 4h; Heating / reflux;	56.A A suspension of dimethyl 3-methoxyphthalate (69.45 g, 0.31 mo.) [prepared as per J. Chem, Soc,Perkin Trans. 7, 1989, 391] in water (300 ml) was treated with potassium hydroxide (43.7 g, 0.78 mol) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol liberated during the course of the reaction was removed in vacuo, the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid and evaporated gently in vacuo to induce crystallization. The solid material was filtered off, washed with a little ice cooled water, sucked dry under reduced pressure and dried in a vacuum oven at 5O0C overnight to afford 3-methoxyphthalic acid (51.0 g, 84%) as a colourless solid. 1H NMR (DMSO-d6) 13.05 (2H, br s), 7.48 (2H, m), 7.33 (1H, m), 3.82 (3H, s). MS: [M+H]+ 197.Acetic anhydride (70 ml) was added to a mixture of 3-methoxyphthalic acid (51.0 g, 0.26 mol) in anhydrous tetrahydrofuran (250 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo and the resulting solid material was dried in a vacuum oven at 500C overnight to afford 3-methoxyphthalic anhydride (45.9 g, 99%) as a colourless solid. 1H NMR (DMSOd6) 7.97 (1 H, dd), 7.63 (1 H, d), 7.60 (1H, d), 4.02 (3H, s). MS: [M+H]+ 179.A mixture of 3-methoxyphthalic anhydride (24.0 g, 134.8 mmol) and formamide (120 ml) was stirred and held at 2100C for 5 hours and was then allowed to cool to room temperature overnight. Water (100 ml) was added and the solid material filtered off under reduced pressure. The crude product was washed sequentially with 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 3-methoxyphthalimide (8.95 g, 37%) as an off-white solid. 1H NMR (DMSOd6) 11.08 (1 H, br s), 7.78 (1H, dd), 7.45 (1H, d), 7.36 (1 H1 d), 3.93 (3H, s). MS: [M+Hf 178.A stirred solution of 3-methoxyphthalimide (8.95 g, 50.56 mmol) in anhydrous tetrahydrofuran (200 ml) at O0C was treated dropwise with a solution of borane in tetrahydrofuran (1M, 150 ml, 0.15 mol) and the resulting mixture was stirred and held at reflux for 16 hours. The mixture was cooled to O0C, methanol (60 ml) was added dropwise followed by 5M hydrochloric acid (60 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the mixture diluted with water (250 ml) and extracted with dichloromethane (3 x 250 ml). The aqueous layer was basified to pH 12 or above by the addition of 5M sodium hydroxide, extracted with dichloromethane (3 x 250 ml) and the combined extracts were evaporated to dryness in vacuo to afford 4-methoxyisoindoline (4.44 g, 59%) as a green oil which was used without further purification. 1H NMR (DMSO-d6) 7.18 (1H, t), 6.83 (1 H, d), 6.78 (1 H, d), 4.07 (2H1 s), 4.02 (2H, s), 3.78 (3H, s). MS: [M+H]+ 150.4-Methoxyisoindoline (4.4 g, 29.53 mmol) in 48% aqueous hydrobromic acid (50 ml) was stirred and held at reflux for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 4-hydroxyisoindoline hydrobromide (5.0 g, 78%) as a pale orange solid. 1H NMR (DMSO-d6) 9.95 (1 H, br s), 9.37 (2H, br s), 7.19 (1 H, t), 6.84 (1 H, d), 6.80 (1H, d), 4.48 (2H, t), 4.40 (2H, t). MS: [M+Hf 136.

99%	With acetic anhydride In tetrahydrofuran for 4h; Heating / reflux;	56.A Acetic anhydride (70 ml) was added to a mixture of 3-methoxyphthalic acid (51.0 g, 0.26 mol) in anhydrous tetrahydrofuran (250 ml) and the mixture was strirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo and the resulting solid material was dried in a vacuum oven at 5O0C overnight to afford 3-methoxyphthalic anhydride (45.9 g, 99%) as a colourless solid. 1H NMR (DMSO-d6) 7.97 (1 H, dd), 7.63 (1H1 d), 7.60 (1 H1 d), 4.02 (3H, s). MS: [M+H]+ 179.
99%	With acetic anhydride In tetrahydrofuran for 4h; Reflux;	56.A 56A. Acetic anhydride (70 ml) was added to a mixture of 3-methoxyphthalic acid (51.0 g, 0.26 mol) in anhydrous tetrahydrofuran (250 ml) and the mixture was stirred and held at reflux for 4 hours.Upon cooling to room temperature the solvent was removed in vacuo and the resulting solid material was dried in a vacuum oven at 50° C. overnight to afford 3-methoxyphthalic anhydride (45.9 g, 99%) as a colourless solid. 1H NMR (DMSO-d6) 7.97 (1H, dd), 7.63 (1H, d), 7.60 (1H, d), 4.02 (3H, s). MS: [M+H]+ 179.
97.8%	With acetic anhydride In tetrahydrofuran at 20 - 80℃; for 4h;	(S)-2-((2-(2,7-Dioxoazepan-3-yl)- 1 ,3-dioxoisoindolin-4-yl)oxy)-N-(6-(2-((1 -(4-(3-oxo-9- phenyl-2,3 -dihydro- [1 ,2,4ltriazolo[3 ,4-fl [1 ,6lnaphthyridin-8-yl)phenyl)cyclobutyl)amino)acetamido)hexyl)acetamide (Compound 73) [0582] To a solution of 3-methoxyphthalic acid (3.0 g, 15.3 mmol) in THF (30 mL) at rt was added acetic anhydride (10 mL) and the reaction was heated at 80°C for 4 hrs. The solvent was removed and the residue was dried under vacuum providing 4- methoxyisobenzofuran-1,3-dione (2.66 g, 97.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.98-7.94 (m, 1H), 7.63-7.59 (m, 2H), 4.01 (s, 3H).
95%	at 200℃;
94%	With acetic anhydride Reflux;	1.3 3) 3-methoxy-phthalic acid plus 2 times the weight of acetic anhydride, after heating and refluxing, cooling and crystallization,The 3-methoxy-phthalic anhydride is filtered,Yield 94%.
	at 170℃; Erhitzen unter vermindertem Druck;
	With acetic anhydride; acetyl chloride
	With acetic anhydride
	With acetic anhydride for 1h; Heating;
	With acetic anhydride Heating;
	With acetyl chloride for 6h; Yield given;
	Multi-step reaction with 2 steps 1: 65 percent / Amberlyst 15 beads / 48 h / Heating 2: thionyl chloride / 2 h / 20 °C
	With acetic anhydride In tetrahydrofuran for 4h; Reflux;	3.1.1. General Procedure for Synthesis of 4-Methoxy-2-benzofuran-1,3-dione (2) The 4-methoxy-2-benzofuran-1,3-dione was obtained from1, according to a previously published procedure [32], with slight modifications. Briefly, 2,3-dimethylphenyl methyl ether (3.4 g, 25 mmol) was dissolved in water (98 mL) and tert-butanol (42 mL). After potassium permanganate (25 g, 160 mmol) was added, the reaction mixture was refluxed for 12 h. The resulting suspension was filtered over Celite, concentrated to 50 mL, acidified with 37% hydrochloric acid, and left standing overnight at room temperature. The 3-methoxybenzene-1,2-dicarboxylic acid crystallized as a white solid (4.34 g) and was refluxed for 4 h in anhydrous tetrahydrofuran (24 mL) with the addition of acetic anhydride (7 mL). Upon cooling to room temperature, the reaction mixture was concentrated in vacuo and the white solid was dried at 50 °C for 48 h, to afford 4-methoxy-2-benzofuran-1,3-dione (3.82, 97%). HPLC:Rt= 0.931, MS calcd for [M + H]+: C9H6O4m/z: 178.14, found: 178.97;1H-NMR (300 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 7.59 (dd,J= 9.67, 7.91 Hz, 2 H) 7.90-7.97 (m, 1 H).

Reference： [1]Current Patent Assignee: BIOTHERYX INC - WO2019/40274, 2019, A1 Location in patent: Paragraph 0228
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44029, 2008, A1 Location in patent: Page/Page column 245
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44041, 2008, A1 Location in patent: Page/Page column 267-268
[4]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2008/44045, 2008, A1 Location in patent: Page/Page column 319-320
[5]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2010/152184, 2010, A1 Location in patent: Page/Page column 103
[6]Current Patent Assignee: BIOTHERYX INC - WO2017/201069, 2017, A1 Location in patent: Paragraph 0582
[7]Gupta, Dahmendra N.; Hodge, Philip; Hurley, Peter N. [Journal of the Chemical Society. Perkin transactions I, 1989, p. 391 - 394]
[8]Current Patent Assignee: SANWEI INDUSTRIAL TECH RESEARCH INSTITUTE OF CHANG - CN107698442, 2018, A Location in patent: Paragraph 0019; 0022; 0024
[9]Blair et al. [Journal of the Chemical Society, 1955, p. 708,711] Girardet [Helvetica Chimica Acta, 1931, vol. 14, p. 4511]
[10]Asahina; Asano [Chemische Berichte, 1930, vol. 63, p. 2059,2062][Yakugaku Zasshi, 1930, vol. 50, p. 1103,1107, 1108]
[11]Leffler; Graybill [Journal of Physical Chemistry, 1959, vol. 63, p. 1457,1460]
[12]Soucy; Favreau; Kayser [Journal of Organic Chemistry, 1987, vol. 52, # 1, p. 129 - 134]
[13]Makhlouf, Mansour A.; Rickborn, Bruce [Journal of Organic Chemistry, 1981, vol. 46, # 23, p. 4810 - 4811]
[14]De Silva; Reed; Billedeau; Wang; Norris; Snieckus [Tetrahedron, 1992, vol. 48, # 23, p. 4863 - 4878]
[15]Gupta, Dahmendra N.; Hodge, Philip; Hurley, Peter N. [Journal of the Chemical Society. Perkin transactions I, 1989, p. 391 - 394]
[16]Czopek, Anna; Partyka, Anna; Bucki, Adam; Pawłowski, Maciej; Kołaczkowski, Marcin; Siwek, Agata; Głuch-Lutwin, Monika; Koczurkiewicz, Paulina; Pękala, Elżbieta; Jaromin, Anna; Tyliszczak, Bożena; Wesołowska, Anna; Zagórska, Agnieszka [Molecules, 2020, vol. 25, # 17]

5
[ 186581-53-3 ]
[ 14963-96-3 ]
[ 13321-74-9 ]
[ 68409-21-2 ]
[ 68409-20-1 ]

Reference： [1]Liebigs Annalen der Chemie,1981,vol. No. 12,p. 2247 - 2257

6
[ 14963-96-3 ]
[ 24599-58-4 ]
[ 51837-72-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With aluminium trichloride In dichloromethane Ambient temperature;

Reference： [1]Smith, Colin W.; Ambler, Samantha J.; Steggles, David J. [Tetrahedron Letters, 1993, vol. 34, # 46, p. 7447 - 7450]

7
[ 14963-96-3 ]
[ 13321-74-9 ]
[ 68409-19-8 ]

Reference： [1]Liebigs Annalen der Chemie,1981,vol. No. 12,p. 2247 - 2257

8
[ 14963-96-3 ]
[ 114772-05-3 ]
[ 125665-34-1 ]

Yield	Reaction Conditions	Operation in experiment
	In chloroform for 24h; Ambient temperature;

Reference： [1]Duncia, John V.; Chiu, Andrew T.; Carini, David J.; Gregory, George B.; Johnson, Alexander L.; et al. [Journal of Medicinal Chemistry, 1990, vol. 33, # 5, p. 1312 - 1329]

9
[ 14963-96-3 ]
[ 1779-58-4 ]
[ 122450-52-6 ]
[ 122450-56-0 ]
[4-Methoxy-3-oxo-3H-isobenzofuran-(1E)-ylidene]-acetic acid methyl ester [ No CAS ]
[4-Methoxy-3-oxo-3H-isobenzofuran-(1Z)-ylidene]-acetic acid methyl ester [ No CAS ]

Reference： [1]Synthetic Communications,1994,vol. 24,p. 1179 - 1186

10
[ 14963-96-3 ]
phenylmagnesium bromide [ No CAS ]
[ 96597-77-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃;

Reference： [1]Braun, Manfred; Veith, Reiner; Moll, Gerard [Chemische Berichte, 1985, vol. 118, # 3, p. 1058 - 1070]

11
[ 14963-96-3 ]
[ 100-36-7 ]
[ 77763-85-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	at 170℃; for 1h;

Reference： [1]Da Settimo; Primofiore; Ferrarini; et al. [European Journal of Medicinal Chemistry, 1981, vol. 16, # 1, p. 59 - 64]

12
[ 14963-96-3 ]
[ 86264-61-1 ]
(R)-4-hydroxy-9-acetyl-9-acetamido-6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione [ No CAS ]
(R)-1-hydroxy-9-acetyl-9-acetamido-6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With aluminium trichloride; sodium chloride at 180℃; for 0.116667h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

Reference： [1]Ishizumi, Kikuo; Ohashi, Naohito; Tanno, Norihiko [Journal of Organic Chemistry, 1987, vol. 52, # 20, p. 4477 - 4485]

13
[ 14963-96-3 ]
[ 2605-68-7 ]
2-[7-Methoxy-3-oxo-3H-isobenzofuran-(1E)-ylidene]-propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In chloroform Ambient temperature;

Reference： [1]Kayser, Margaret M.; Hatt, Krista L.; Yu, Heshui; Hooper, Donald L. [Canadian Journal of Chemistry, 1993, vol. 71, # 7, p. 1010 - 1021]

14
[ 14963-96-3 ]
[ 150-78-7 ]
[ 121364-88-3 ]

Yield	Reaction Conditions	Operation in experiment
30%	With aluminium trichloride In nitrobenzene at 20℃; for 18h;

Reference： [1]Gupta, Dahmendra N.; Hodge, Philip; Hurley, Peter N. [Journal of the Chemical Society. Perkin transactions I, 1989, p. 391 - 394]

15
[ 78136-34-2 ]
[ 14963-96-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With acetic anhydride; trifluoroacetic acid for 1h; Heating;

Reference： [1]Rao, A. V. Rama; Chanda, Bhanu M.; Wadekar, Alpana V. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1981, vol. 20, # 3, p. 248 - 249]

16
[ 38157-42-5 ]
[ 14963-96-3 ]

Yield	Reaction Conditions	Operation in experiment
90 % Turnov.	With boron trifluoride diethyl etherate In 1,2-dichloro-benzene for 10h; Heating;

Reference： [1]Newman, Melvin S.; Kanakarajan, Kuppusamy [Journal of Organic Chemistry, 1980, vol. 45, # 17, p. 3523 - 3524]

17
[ 14963-96-3 ]
[ 2765-77-7 ]
[ 39546-36-6 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminium trichloride; 1,1,2,2-tetrachloroethane at 150 - 155℃;

Reference： [1]Horii,Z. et al. [Chemical and pharmaceutical bulletin, 1972, vol. 20, # 11, p. 2502 - 2506]

18
[ 14963-96-3 ]
[ 22531-27-7 ]
[ 39546-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminium trichloride; 1,1,2,2-tetrachloroethane at 150 - 155℃;

Reference： [1]Horii,Z. et al. [Chemical and pharmaceutical bulletin, 1972, vol. 20, # 11, p. 2502 - 2506]

19
[ 14963-96-3 ]
[ 34954-65-9 ]
[ 67765-42-8 ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 6797 - 6801

20
[ 37418-88-5 ]
[ 74-88-4 ]
[ 14963-96-3 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 3-hydroxyphthalic anhydride With sodium hydride In N,N-dimethyl-formamide for 0.25h; Stage #2: methyl iodide In DMF (N,N-dimethyl-formamide) for 48h;	16 5-(4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid EXAMPLE 16; 5-(4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid To a solution of 4-hydroxy-isobenzofuran-1,3-dione (195 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (4 ml) under nitrogen was added sodium hydride (61 mg, 1.56 mmol). The solution was stirred for 15 minutes and then methyl iodide (0.37 ml, 6.0 mmol) was added. The reaction was stirred for 48 hours and then quenched with saturated ammonium chloride. The mixture was concentrated in vacuo , diluted in ethyl acetate (20 ml) and the organic phase washed with 1 N hydrochloric acid (5 ml) and brine (3 x 5 ml). The organic layer was dried (MgSO4) and concentrated in vacuo . To the crude solid was added methanol causing a precipitate to form. The flask was cooled in an ice bath for 2 hours and the solid filtered off, washed with methanol and dried in vacuo which afforded 0.1 g (47 %) of 4-methoxy-isobenzofuran-1,3-dione as a solid. 1H-NMR (300 MHz, DMSO-d6) δ 7.95 (t, 1H, J = 8 Hz), 7.61 (d, 1H, J = 8 Hz), 7.58 (d, 1H, J = 8 Hz), 3.99 (s, 3H). APCI-MS: m/z: 179 [M+H]+
47%	With sodium hydride In N,N-dimethyl-formamide for 48h;	16 5-(4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; To a solution of 4-hydroxy-isobenzofuran-1,3-dione (195 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (4 ml) under nitrogen was added sodium hydride (61 mg, 1.56 mmol). The solution was stirred for 15 minutes and then methyl iodide (0.37 ml, 6.0 mmol) was added. The reaction was stirred for 48 hours and then quenched with saturated ammonium chloride. The mixture was concentrated in vacuo, diluted in ethyl acetate (20 ml) and the organic phase washed with 1N hydrochloric acid (5 ml) and brine (3×5 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. To the crude solid was added methanol causing a precipitate to form. The flask was cooled in an ice bath for 2 hours and the solid filtered off, washed with methanol and dried in vacuo which afforded 0.1 g (47%) of 4-methoxy-isobenzofuran-1,3-dione as a solid.1H-NMR (300 MHz, DMSO-d6) δ 7.95 (t, 1H, J=8 Hz), 7.61 (d, 1H, J=8 Hz), 7.58 (d, 1H, J=8 Hz), 3.99 (s, 3H).APCI-MS: m/z: 179 [M+H]+
47%	In N,N-dimethyl-formamide for 48h;	16 Example 16 5-(4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; To a solution of 4-hydroxy-isobenzofuran-1,3-dione (195 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (4 ml) under nitrogen was added minutes and then methyl iodide (0.37 ml, 6.0 mmol) was added. The reaction was stirred for 48 h. and then quenched with saturated ammonium chloride. The mixture was concentrated in vacuo, diluted in ethyl acetate (20 ml) and the organic phase washed with 1N hydrochloric acid (5 ml) and brine (3×5 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. To the crude solid was added methanol causing a precipitate to form. The flask was cooled in an ice bath for 2 h. and the solid filtered off, washed with methanol and dried in vacuo which afforded 0.1 g (47%) of 4-methoxy-isobenzofuran-1,3-dione as a solid.1H NMR (300 MHz, DMSO-d6) δ 7.95 (t, J=8, 1H), 7.61 (d, J=8, 1H), 7.58 (d, J=8, 1H), 3.99 (s, 3H).APCI-MS: [M+H]+=179.1A solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (122 mg, 0.43 mmol, prepared as described in Example 17) and 4-methoxy-isobenzofuran-1,3-dione (92 mg, 0.52 mmol) was prepared in distilled tetrahydrofuran (4 ml) under nitrogen. 1-hydroxybenzotriazole (87 mg, 0.65 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg, 0.65 mmol), and triethylamine (0.29 ml, 2.15 mmol) were added. The reaction was stirred at ambient temperature for 18 h., then concentrated in vacuo. The crude mixture was diluted with ethyl acetate (25 ml) and washed with 1N hydrochloric acid (5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 0.18 g (94%) of 2-amino-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester.1H NMR (300 MHz, CDCl3) δ 7.66 (t, J=7, 1H), 7.43 (d, J=7, 1H), 7.19 (d, J=7, 1H), 4.59-4.46 (m, 2H), 4.06-3.72 (m, 3H), 4.00 (s, 3H), 2.87-2.81 (m, 1H), 2.60-2.51 (m, 1H), 1.48 (s, 9H).To a solution of the above 2-amino-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.18 g, 0.42 mmol) in distilled dichloromethane (5 ml) under nitrogen was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.25 g, 1.26 mmol) and triethylamine (0.23 ml, 1.68 mmol). The reaction was stirred for 12 h., concentrated in vacuo and reconstituted in ethyl acetate (25 ml). The organic layer was washed with 1N hydrochloric acid (2×5 ml), saturated sodium bicarbonate (5 ml), and brine (5 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude material was purified by silica gel chromatography using a gradient of ethyl acetate/dichloromethane (0 to 10% gradient). Pure fractions were collected and the solvent evaporated in vacuo to give 195 mg (81%) of 2-(tert-butoxyoxalyl-amino)-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.1H NMR (300 MHz, CDCl3) δ 12.48 (s, 1H), 7.65 (t, J=7, 1H), 7.43 (d, J=7, 1H), 7.19 (d, J=7, 1H), 4.77 (d, J=15, 1H), 4.63 (d, J=15, 1H), 4.04-3.75 (m, 3H), 4.00 (s, 3H), 2.94 (d, J=17, 1H), 2.65 (dd, J=17, 10, 1H), 1.58 (s, 9H), 1.53 (s, 9H).LC-MS: Rt=4.17 min, [M+H]+=573.2The above 2-(tert-butoxyoxalyl-amino)-5-(4-methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.15 g, 0.26 mmol) was dissolved in a mixture of 50% trifluoroacetic acid/dichloromethane (5 ml). The reaction was stirred at ambient temperature for 7 h., concentrated in vacuo and the residue evaporated in vacuo from dichloromethane (3×10 ml). The resulting precipitate was washed with dichloromethane and dried in vacuo to give 100 mg (83%) of the title compound as a solid.1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.79 (t, J=8, 1H), 7.48 (d, J=8, 1H), 7.42 (d, J=8, 1H), 4.74 (d, J=15, 1H), 4.56 (d, J=15, 1H), 3.95 (s, 3H), 3.91-3.79 (m, 2H), 3.69-3.63 (m, 1H), 2.98 (d, J=17, 1H), 2.57 (dd, J=17, 10, 1H).LC-MS: Rt=1.26 min, [M+H]+=461.0HPLC (254.4 nm): Rt=3.10 min, 100%

Reference： [1]Current Patent Assignee: NOVO NORDISK A/S; ONTOGEN CORP - EP1214325, 2005, B1 Location in patent: Page/Page column 36
[2]Current Patent Assignee: NOVO NORDISK A/S; ONTOGEN CORP - US7019026, 2006, B1 Location in patent: Page/Page column 53
[3]Current Patent Assignee: ONTOGEN CORP; NOVO NORDISK A/S - US7115624, 2006, B1 Location in patent: Page/Page column 67-69
[4]Dang, Qun; Brown, Brian S.; Van Poelje, Paul D.; Colby, Timothy J.; Erion, Mark D. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1505 - 1510]

21
[ 14963-96-3 ]
3-methoxy-N-hydroxyphthalimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With pyridine; hydroxylamine hydrochloride for 0.00833333h; microwave irradiation;

Reference： [1]Sugamoto, Kazuhiro; Matsushita, Yoh-Ichi; Kameda, Yu-Hei; Suzuki, Masahiko; Matsui, Takanao [Synthetic Communications, 2005, vol. 35, # 1, p. 67 - 70]

22
[ 14963-96-3 ]
[ 135217-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / Heating 2: H⁽¹⁺⁾ 3: AlCl₃ / CH₂Cl₂

Reference： [1]Luethy, Christoph; Zondler, Helmut; Rapold, Thomas; Seifert, Gottfried; Urwyler, Bernhard; Heinis, Thomas; Steinruecken, Hans Christian; Allen, James [Pest Management Science, 2001, vol. 57, # 3, p. 205 - 224]

23
[ 14963-96-3 ]
7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-methoxy-3-methyl-phthalide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine / Heating 2: H⁽¹⁺⁾ 3: AlCl₃ / CH₂Cl₂ 4: K₂CO₃

24
[ 14963-96-3 ]
[ 139360-85-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium borohydride 2: NBS / CCl₄ / Irradiation

Reference： [1]Dang, Qun; Brown, Brian S.; Van Poelje, Paul D.; Colby, Timothy J.; Erion, Mark D. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1505 - 1510]

25
[ 14963-96-3 ]
[ 70767-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium borohydride 2: NBS / CCl₄ / Irradiation

Reference： [1]Dang, Qun; Brown, Brian S.; Van Poelje, Paul D.; Colby, Timothy J.; Erion, Mark D. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1505 - 1510]

26
[ 14963-96-3 ]
naphthalen-1-ylmethyl-phosphonic acid bis-(7-methoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl) ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium borohydride 2: NBS / CCl₄ / Irradiation 3: 33 percent / Hunig's base / acetonitrile / 24 h / 25 °C

Reference： [1]Dang, Qun; Brown, Brian S.; Van Poelje, Paul D.; Colby, Timothy J.; Erion, Mark D. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1505 - 1510]

27
[ 14963-96-3 ]
naphthalen-1-ylmethyl-phosphonic acid bis-(4-methoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl) ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium borohydride 2: NBS / CCl₄ / Irradiation 3: 41 percent / Hunig's base / acetonitrile / 24 h / 25 °C

Reference： [1]Dang, Qun; Brown, Brian S.; Van Poelje, Paul D.; Colby, Timothy J.; Erion, Mark D. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1505 - 1510]

28
[ 14963-96-3 ]
[ 130662-53-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 37 percent / NaBH₄ / acetic acid; tetrahydrofuran / 2 h / 50 °C 2: 100 percent / DIBAH / toluene / 0.5 h / -70 °C