Name: 4385-35-7|1,4-Dihydro-3H-2-benzopyran-3-one|98%
Brand: Ambeed
SKU: A186280
Price: 5.0 USD
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1
[ 615-13-4 ]
[ 4385-35-7 ]

Reference： [1]Synthesis,1981,p. 818 - 820
[2]Journal of Heterocyclic Chemistry,1995,vol. 32,p. 73 - 77
[3]Tetrahedron Asymmetry,1996,vol. 7,p. 417 - 420
[4]Organic and biomolecular chemistry,2003,vol. 1,p. 2120 - 2136
[5]Synthesis,1987,p. 497 - 498
[6]Synthesis,1991,p. 739 - 740
[7]Synthetic Communications,1989,vol. 19,p. 829 - 834
[8]Journal of the Chemical Society,1949,p. 1723
Journal of the Chemical Society,1958,p. 2038,2039

2
[ 75-77-4 ]
[ 4385-35-7 ]
[ 87532-04-5 ]

Reference： [1]Organic Letters,2015,vol. 17,p. 5898 - 5901
[2]Journal of Organic Chemistry,1983,vol. 48,p. 4940 - 4944

3
[ 4385-35-7 ]
[ 694-87-1 ]

Reference： [1]Tetrahedron Letters,1982,vol. 23,p. 3665 - 3668

5
[ 4385-35-7 ]
[ 42900-89-0 ]

Reference： [1]Synthesis,1987,p. 497 - 498
[2]Organic and biomolecular chemistry,2003,vol. 1,p. 2120 - 2136
[3]Tetrahedron Asymmetry,1999,vol. 10,p. 3939 - 3949
[4]Journal of the American Chemical Society,2006,vol. 128,p. 12366 - 12367
[5]Chemistry - A European Journal,2008,vol. 14,p. 10762 - 10771

6
[ 4385-35-7 ]
[ 83864-42-0 ]

Yield	Reaction Conditions	Operation in experiment
74%		Example 1 : lsochroman-3,4-dione 4-oxime [identical to 4-(Hydroxyimino)isochroman-3- one] by nitrosation of isochromanoneTo a suspension of isochromanone (99% pure, 149.7g, 1.00 mol) in methanol (280 ml.) was added dropwise over a period of 90 min at 14-16 0C sodium methanolate (30 % in methanol, 270.0 g, 1.50 mol) and the resulting mixture was stirred for 90 min at 15 0C. To this mixture was added dropwise over a period of 6.5 h at 9-13 0C iso-butyl nitrite (94% pure, 137.1 g, 1.25 mol) and the mixture was stirred at 8 0C overnight. The conversion was monitored by HPLC. After completion of the reaction, 4 M hydrochloric acid was added to adjust a pH<;1 before the resulting suspension was stirred for overnight at 4C. The crude product was collected by filtration, washed with cold dist. water (2x 500 ml.) and dried in vacuo at max. 45C. lsochroman-3,4-dione-4-oxime was ob- tained as a colorless solid (145.9 g, 90.4 HPLC-area %, 74% yield).1H-NMR (DMSO-d6): delta = 13.3 (s, 1 H), 8.34 (d, J = 7.4 Hz, 1 H), 7.54-7.41 (m, 3H), 5.46 (s, 2H) ppm; 13C-NMR (DMSO-d6): delta = 162.3, 140.2, 133.2, 130.2, 129.0, 127.9, 125.4, 125.0, 68.3 ppm; mp = 179-182 0C.
		To a suspension of isochromanone (99% pure, 149.7 g, 1.00 mol) in methanol (280 mL) was added dropwise over a period of 90 min at 14-16 C. sodium methanolate (30% in methanol, 270.0 g, 1.50 mol) and the resulting mixture was stirred for 90 min at 15 C. To this mixture was added dropwise over a period of 6.5 h at 9-13 C. iso-butyl nitrite (94% pure, 137.1 g, 1.25 mol) and the mixture was stirred at 8 C. overnight. The conversion was monitored by HPLC. After completion of the reaction, 4 M hydrochloric acid was added to adjust a pH<1 before the resulting suspension was stirred for overnight at 4 C. The crude product was collected by filtration, washed with cold dist. water (2×500 mL) and dried in vacuo at max. 45 C. Isochroman-3,4-dione-4-oxime was obtained as a colorless solid (145.9 g, 90.4 HPLC-area %, 74% yield).1H-NMR (DMSO-d6): delta=13.3 (s, 1H), 8.34 (d, J=7.4 Hz, 1H), 7.54-7.41 (m, 3H), 5.46 (s, 2H) ppm; 13C-NMR (DMSO-d6): delta=162.3, 140.2, 133.2, 130.2, 129.0, 127.9, 125.4, 125.0, 68.3 ppm; mp=179-182 C.

Reference： [1]Patent: WO2010/89267,2010,A2 .Location in patent: Page/Page column 11
[2]Canadian Journal of Chemistry,1982,vol. 60,p. 2678 - 2686
[3]Patent: US2011/295022,2011,A1 .Location in patent: Page/Page column 5

7
[ 941-69-5 ]
[ 14381-41-0 ]
[ 4385-35-7 ]
(3aR,4S,9aR)-1,3-Dioxo-2-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-4-carboxylic acid [ No CAS ]
(3aS,4S,9aS)-1,3-Dioxo-2-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 19% 2: 68% 3: 13%	In benzene-d6 at 140℃; for 3h;

Reference： [1]Jefford, Charles W.; Bernardinelli, Gerald; Wang, Ying; Spellmeyer, David C.; Buda, Andrzej; Houk [Journal of the American Chemical Society, 1992, vol. 114, # 4, p. 1157 - 1165]

8
[ 201230-82-2 ]
[ 74785-02-7 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine;C52H46O2P2Pd2; triphenylphosphine; In toluene; at 60℃; under 760.051 Torr; for 2.16667h;Conversion of starting material;	Example 9: Carbonylation of ortho-bromomethyl benzyl alcohol to form 3-isochromanone using compound 2IA as catalyst; ort.ho-Bromomethyl benzyl alcohol (0.25g, 1.24 mmol),ethyldiisopropylamine (0.24ml, 1.37mmol),triphenylphosphine (16.24mg, 0.06mmol), toluene (20cm3)and compound 2IA (12.14mg, 0.0124 mmol) were reactedaccording to the method of Example 5, except that themixture was allowed to carbonylate for 130 minutes.During the course of the reaction, the colour of thesolution changed from virtually colourless to deep orangeto yellow. G.C.M.S. analysis showed that ortho-bromomethyl benzyl alcohol had been completely consumed,to give 3-isochromanone quantitatively. Crystals of 3-isochromanone appeared in the product mixture uponstanding, due to low solubility in toluene.

Reference： [1]Patent: WO2006/10885,2006,A1 .Location in patent: Page/Page column 27-28
[2]Journal of the American Chemical Society,1980,vol. 102,p. 4193

9
[ 4385-35-7 ]
[ 64-17-5 ]
[ 39191-76-9 ]

Yield	Reaction Conditions	Operation in experiment
	With Acetyl bromide; at 0 - 20℃; for 16.0833h;	Acetyl bromide (1 ml) was added dropwise to ethanol (10 ml) at 0 C. and stirred for 5 min. <strong>[4385-35-7]3-isochromanone</strong> (0.56 g) was added and then allowed to reach RT and stirred for 16 h. The solvents were evaporated under reduced pressure to give the sub-title compound, yield 257 mg.1H NMR (CDCl3) delta 7.40-7.20 (4H, m), 4.60 (2H, s), 4.16 (2H, q), 3.79 (2H, s), 1.26 (3H, t)
	With hydrogen bromide; at 70℃;	An ethanol solution of hydrogen bromide (25%, 10 ml) was added to 1,4-dihydro-3H-isochromene-3-one (500 mg) and stirred at 70 C overnight. After removing the solvent, the residue was roughly purified with a silica gel chromatography (hexane - ethyl acetate) to obtain a crude material of [2-(bromomethyl) phenyl] ethyl acetate. Methyl 3-(4-aminophenyl)-2-[(2,6-dichlorobenzoyl) amino] propionate (520 mg), triethylamine (490 mul) and DMF (5 ml) were added to the crude material and stirred at 125C for six hours. After removing the solvent, the residue was purified with a silica gel chromatography (hexane - ethyl acetate) to obtain methyl 2-[(2,6-dichlorobenzoyl) amino]-3-(4-[2-(2-ethoxy-2-oxoethyl) benzyl] amino} phenyl) propionate (510 mg). MS (ESI MH+) : 542 CHN0 : C28H28C12N205

Reference： [1]Journal of Organic Chemistry,2019,vol. 84,p. 2012 - 2021
[2]Tetrahedron Asymmetry,1996,vol. 7,p. 417 - 420
[3]Organic Letters,2000,vol. 2,p. 2185 - 2187
[4]Patent: US2008/255150,2008,A1 .Location in patent: Page/Page column 16
[5]Patent: EP1454898,2004,A1 .Location in patent: Page 52
[6]Journal of Organic Chemistry,2019,vol. 84,p. 5813 - 5820

10
[ 201230-82-2 ]
[ 612-14-6 ]
[ 4385-35-7 ]
[ 644-36-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 9 % Spectr. 2: 56%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; hydrogen iodide In acetone at 90℃; for 42h;

Reference： [1]Lin, Yong-Shou; Yamamoto, Akio [Tetrahedron Letters, 1997, vol. 38, # 21, p. 3747 - 3750]

11
[ 201230-82-2 ]
[ 612-14-6 ]
[ 4385-35-7 ]
[ 95-47-6 ]
[ 644-36-0 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1998,vol. 71,p. 723 - 734
[2]Bulletin of the Chemical Society of Japan,1998,vol. 71,p. 723 - 734

12
[ 4385-35-7 ]
(Z)-diphenyl[(Z)-2-phenyl-2-(phenylsulfonyl)vinyl]selenonium trifluoromethanesulfonate [ No CAS ]
(Z)-4-(2-benzenesulfonyl-2-phenylethenyl)isochroman-3-one [ No CAS ]

Reference： [1]Organic Letters,2003,vol. 5,p. 565 - 567

13
[ 4385-35-7 ]
[ 1165952-91-9 ]
4-(cyclohex-2-enyl)isochroman-3-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2004,vol. 69,p. 7552 - 7557

14
[ 14736-50-6 ]
[ 4385-35-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7241 - 7257

15
[ 14736-50-6 ]
[ 4385-35-7 ]
[ 63969-91-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7241 - 7257

16
[ 201230-82-2 ]
[ 612-12-4 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
84.53%	With water; N-ethyl-N,N-diisopropylamine; In tert-Amyl alcohol; at 40 - 70℃; under 3087.28 - 3475.15 Torr;Product distribution / selectivity;	A reactor vessel was purged and vented four times using nitrogen at a pressure of 1 barG. To the reactor vessel was charged tertiary-amyl alcohol (48kg, 0.55kg mol), de-ionised water (92kg, 5kg mol) o-xylene-alpha,alpha'-dichloride (45kg, 0.25kg mol), tertiary-amyl alcohol (10kg, 0.11kg mol) as a line wash for residual o-xylene-alpha,alpha'-dichloride and the palladium chloride-triphenylphosphine catalyst species formed prior to addition using the following method.Preparation of Catalyst Triphenylphosphine (1.50kg, 0.0057kg mol) was charged to a 2-litre reaction vessel and heated to 90C with rapid agitation to produce a melt. Palladium chloride in hydrochloric acid solution (0.125kg, 0.00025kg mol) was added dropwise to the melt and the reaction mixture was agitated until the catalyst was produced as a yellow slurry. The 2-litre reaction vessel was removed from the source of heat and the yellow slurry poured into a pyrex dish. The catalyst readily solidified and was subsequently broken up using a mortar and pestle for use as a powder in the reaction. The above process was repeated for a second charge of triphenylphosphine (1.5kg, 0.0057kg mol), and assuming a quantitative chemical yield of 100% the catalyst had a palladium strength of 1.66%. The reactor vessel was purged and vented four times using nitrogen at a pressure of 1 barG. To the reactor vessel was charged N,N-diisopropylethylamine (99kg, 0.75kg mol) and tertiary-amyl alcohol (10kg, 0.11kg mol) as a line wash for residual N,N-diisopropylethylamine. The reactor vessel was purged and vented four times using nitrogen at a pressure of 1 barG, followed by being purged and vented twice using carbon monoxide at a pressure of 4 barG. The reactor vessel was heated to 40C at a pressure of 3-3.5 barG under carbon monoxide. The exotherm from the reaction raised the batch temperature to 70C. The batch was then controlled at 70C to within +/-5C using pressurised hot water until the carbon monoxide uptake ceased (ca 10kg). The pressure of the reactor vessel was reduced by venting the carbon monoxide to the atmosphere, and the temperature of the reactor vessel was reduced to 40C. The reactor vessel was purged and vented four times using nitrogen at a pressure of 1 barG. The contents of the reactor vessel were analysed for the end of reaction by gc. The reactor vessel was purged and vented twice using carbon monoxide at a pressure of 4 barG and left at a pressure of 1 barG using carbon monoxide. The reactor vessel was heated to 100C and held at this temperature for 1 hour, and the pressure of the reactor vessel was reduced by venting the carbon monoxide to the atmosphere. The reactor vessel was cooled to 55-60C and purged and vented four times using nitrogen at a pressure of 1 barG. To the reactor vessel was charged de-ionised water (108kg, 6kg mol) and 47% sodium hydroxide (87kg, 1.025kg mol). The reactor vessel was held at 55-60C for 30 minutes and the contents then allowed to settle for 1 hour after stirring was stopped. The lower aqueous phase was separated and filtered via a Pall screening cartridge, and after stirring was started the organic phase was discharged to an earthed drum. The aqueous phase distilled under a vacuum of 50mmHg at a temperature of 55C until a change in distillate appearance was apparent. The distillate was then discharged to an earthed drum. To the remaining aqueous phase was charged o-xylene (130kg, 1.28kg mol) and hydrochloric acid (65kg, 0.64kg mol) maintaining the reactor vessel at a temperature of 55-60C throughout the course of the addition. The reactor vessel was stirred for 1 hour at 55-60C and then analysed for pH (<2). The contents were then allowed to settle for 1 hour after stirring was stopped, and the aqueous and o-xylene phases were separated to individual earthed drums. The solution of 3-isochromanone in o-xylene (166.5kg) was analysed as 18.37% w/w/ strength (30.59kg at 100% weight). This represents an isolated yield of 82.58%. The chemical yield for the process was analysed to be 84.53%.
80.95%	With water; N-ethyl-N,N-diisopropylamine; In tert-Amyl alcohol; at 70℃; under 1551.49 Torr;Product distribution / selectivity;	o-Xylene-alpha,alpha'-dichloride (14.24g at 98.3% strength, 80mntol) N,N-diisopropylethylamine (31.33g at 99% strength, 240mmol), t-amyl alcohol (21.37 at 99% strength, 240mmol), water (28.8g, 1600mmol) and catalyst mixture preformed as described below (1.065g to give 3.52mmol triphenylphosphine and 0.16mmol catalyst) were charged to a 310ml Hastelloy autoclave. The autoclave was purged three times with carbon monoxide (premium grade) at 75psi before being finally pressurised to 30 psi. The reaction liquors were agitated at 1 000rpm whilst beating to 70C. The reaction temperature was held at 70C, maintaining the pressure at 30 psi throughout the reaction period. Reaction was deemed to be complete when carbon monoxide uptake ceased. The vessel was vented to ~15psi and the mixture heated to 100C to facilitate the precipitation of palladium. The reaction was stirred at 500 rpm at 100C for one hour before transferring to a nitrogen-blanketed JRV. Aqueous sodium hydroxide (60.59g at 21 % strength) was added to the JRV and stirred at 60C for one hour, maintaining the nitrogen blanket. Separation was carried out to give a lower aqueous layer which was retained for further work-up and an upper organic layer (48.32g). The aqueous layer was recharged to the vessel along with xylene (42.46g) and concentrated hydrochloric acid (20.56g at 35.5% strength). This mixture was stirred at 60C for one hour before separating to give a lower aqueous layer (97.0g; 3-isochromanone strength 0.22%; 1.8% yield) and an upper xylene solution of 3-isochromanone. (52.59g; 3-isochromanone strength 17.84%; 79.15% yield). Total chemical yield by quantative gc analysis, 80.95%.
75.4 - 75.8%	With water; N-ethyl-N,N-diisopropylamine;triphenylphosphine; palladium dichloride; In tert-Amyl alcohol; at 70 - 75℃; under 3863.02 Torr; for 4h;Product distribution / selectivity;	EXAMPLE 1 Palladium chloride (0.043g, 0.24mmol), triphenyl phosphine (0.93g, 4mmol), N,N-diisopropylethylamine (31g, 240mmol), water (14.4g, 800mmol), o-xylene-alpha,alpha' dichloride (14g, 80mmol) and tert-amyl alcohol (33.8g, 384 mmol) were charged to a 310 ml PARR reactor, fitted with an agitator and carbon monoxide charging system. The stirrer was switched on after the temperature was adjusted to 70C and the pressure increased to 4 bar.g (60 psig). The vessel pressure was maintained at 60 psig using carbon monoxide and the temperature between 70-75C by heating/cooling. When the carbon monoxide uptake ceased, the pressure was released back to atmosphere and the 3-isochromanone product was extracted from the organic phase using aqueous sodium hydroxide (12.8g at 100% strength, 320mmol). The 3-isochromanone was regenerated by addition of hydrochloric acid (7.3g at 35.5% strength, 200 mmol) and extracted into o-xylene (42.5g, 400mmol). The resultant solution was analyzed for 3-isochromanone and found to contain 16.8 %w/w. This represents a yield of 75.4% of 3-isochromanone from xylene-alpha alpha'dichloride. o-Xylene-alpha,alpha'-dichloride (14.7g at 95% strength, 80mmol), N,N-diisopropylethylamine (31.4g at 99% strength, 240 mmol, nitrogen degassed), tert-amyl alcohol (33.8g at 100% strength, 384mmol, nitrogen degassed), palladium chloride (PdCl2 catalyst (0.043g at 99% strength, 0.24 mmol), triphenylphosphine (2.12g at 99% strength, 8mmol) and water (14.4g, 800mmol, nitrogen degassed), were charged to a 310 Inconel autoclave. The autoclave was purged three times at 5 bar.g with carbon monoxide (technical grade), before being finally pressurised to 4 bar.g. The reaction liquors were agitated at 1000rm and heated to 70C. The reaction temperature was maintained at 70C for approximately 4 hours maintaining the carbon monoxide pressure at approximately 4 bar.g throughout the reaction period, noting the rate of uptake of carbon monoxide. Reaction was deemed to be complete when no further carbon monoxide was seen to be consumed. A stirred sample of reaction liquors was removed from the autoclave and tested by gc for the presence of o-xylene-alpha,alpha'-dichloride. The autoclave was cooled to 60C, agitation was stopped and the autoclave vented to approximately 1 bar.g. This residual pressure was used to discharge the reaction liquors (clear, amber, single phase) to a jacketed reaction vessel (JRV), which had been previously brought to 60C and purged with nitrogen. A positive flow of nitrogen was maintained throughout the workup in the JRV to eliminate oxygen incursion. Aqueous sodium hydroxide (60.9g at 2 1 % strength, nitrogen degassed) was added to the stirred reaction liquors via a balanced dropping funnel which had been purged with nitrogen. The resulting liquors were stirred for approximately 1 hour then allowed to settle enabling a phase separation to take place. This consisted of an upper clear red organic phase, a lower clear red aqueous base phase and a slight black dispersion located at the interface. The lower aqueous base phase was weighed off and stored for workup later. The black dispersion was seen to adhere to the walls of the JRV on discharge of the lower phase. Air was then blown over the stirred upper organic phase allowing air incursion. Within 1 to 2 minutes severe tarring of the organic phase was seen confirming that oxygen exclusion was in fact needed during workup to avoid tarring. The organic phase was then discharged. The aqueous base phase was reintroduced in air to a clean JRV which had been heated to 60C and agitated at 400rpm. o-Xylene (42.5g at 100 % strength, 400mmol) was introduced to the JRV followed by cautious addition of hydrochloric acid (20.3g at 36% strength, 0.2mmol). Fuming was evident and the liquors were allowed to stir for approximately 1 hour. The liquors were then allowed to stand at 60C enabling two phases to be separated. The lower clear acidic aqueous phase was weighed off, followed by the upper clear red/amber o-xylene solution of 3-isochromanone (approximately 18%w/w). The previously recovered organic phase, acidic aqueous phase and o-xylene solution were analysed by gc for 3-isochromanone; yield: organic phase 0.37%, acidic aqueous phase 1.56%, o-xylene solution 73.9%: total 75.8%.

69.9 - 83.9%

With water; N-ethyl-N,N-diisopropylamine;hydrogen tetrachloropalladate; triphenylphosphine; In tert-Amyl alcohol; at 70℃; under 3102.97 - 3863.02 Torr; for 2 - 4h;Product distribution / selectivity;

o-Xylene-alpha,alpha'-dichloride (14.7g at 95% strength, 80mmol), N,N-diisapropylethylamine (31.4g at 99% strength, 250mmol), an aqueous solution of dihydrotetrachloropalladium (H2PdCl4) catalyst (0.1271g at 53.8% strength, 0.27mmol), tert-amyl alcohol (28.2g at 95% strength, 300mmol), water (14.4g, 800mmol) and triphenylphosphine (0.93g at 99% strength, 3.5mmol) were charged to a 300ml Inconel autoclave. The autoclave was purged three times at 5 bar.g with carbon monoxide gas before being finally pressurised to about 4 bar.g. The reaction mixture was briskly agitated (~ 900rpm) and heated to 70C. Once at temperature, the reaction mixture was stirred at 70C for approximately 4 hours, the pressure being maintained at about 4 bar.g and the rate of uptake of carbon monoxide gas noted. The reaction was adjudged complete when no further carbon monoxide was seen to be consumed. The reaction mixture was then rapidly cooled to below 40C and sampled to test for the presence of starting material by gc. Water (33g) and sodium hydroxide (27.4g at 47% strength) were charged in one portion to the open autoclave, which was then sealed and purged with carbon monoxide gas three times at 5 bar.g before finally being pressurised to 1bar.g. The reaction mixture was then stirred at 60C under 1-2 bar.g (CO pressure) for approximately 1 hour. The two phases were then transferred to a hot separator (in air) and separated at 60C, the aqueous phase being drawn off for further work-up. The aqueous phase was added cautiously to a stored solution of o-xylene (41.4g) and concentrated hydrochloric acid (19.8g at 36% strength) at 60C (in air). The mixture was then stirred for I hour at 60C before being separated to give an aqueous waste stream and a xylene solution containing the product, 3-isochromanone; yield 83.7%. A repeat experiment gave a yield of 83.9%. o-Xylene-alpha,alpha'-dichloride (14.7g at 95% strength, 80mmol), N,N-diisopropylethylamine (25.5g at 99% strength, 200mmol), an aqueous solution of dihydrotetrachloropalladium (H2PdCl4) catalyst (0.0586 at 53.8% strength, 0.126mmol), tert-amyl alcohol (14.1g, 163mmol,) water (28.8g, 1600mmol) and triphenylphosphine (2.1g at 95% strength, 8.0mmol) were charged to 300ml Inconol autoclave. The autoclave was purged three times at 5 bar.g with carbon monoxide gas before finally being pressurised to about 4 bar.g. The reaction mixture was briskly agitated (~ 900rpm) and heated to 70C. Once at temperature, the reaction mixture was stirred at 70C for approximately 4 hours, the pressure being maintained at about 4 bar.g and the rate of uptake of carbon monoxide gas noted. The reaction was adjudged complete when no further carbon monoxide was seen to be consumed. The reaction mixture was then rapidly cooled to below 40C and sampled to test for the presence of starting material by gc. Water (33g) and sodium hydroxide (27.4g at 47% strength) were charged in one portion to the open autoclave, which was then sealed and purged with carbon monoxide gas three times at 5 bar.g before finally being pressurised to 1 bar.g The reaction mixture was then stirred at 60C under 1-2 bar.g (CO pressure) for approximately 1 hour. The two phases were then transferred to a hot separator (in air) and separated at 60C, the aqueous phase being drawn off for further work-up. The aqueous phase was added cautiously to a stirred solution of o-xylene (41.4g) and concentrated hydrochloric acid (19.8g at 36% strength) at 60C (in air). The mixture was then stirred for 1 hour at 60C before being separated to give an aqueous waste stream and a xylene solution containing the product, 3- isochromanone; yield 75.8%; o-Xylene-alpha,alpha'-dichloride (14.7g at 95% strength, 80mmol), N,N-diisopropylethylamine (29.24g at 99% strength, 224 mmol), an aqueous solution of dihydrotetrachloropalladium (H2PdCl4) catalyst (0.075g at 53.8% strength, 0.16mmol), tert-amyl alcohol (21.37g at 99% strength, 240mmol), water (25.2g, 1400mmol) and triphenylphosphine (2.11 g at 99% strength, 8mmol) were charged to a 310ml PARR autoclave fitted with an agitator and carbon monoxide charging system. The autoclave was pressurised to 60 psi with carbon monoxide and this pressure was maintained throughout the reaction, which was carried out at 70C. The reaction was adjudged complete when no further carbon monoxide was seen to be consumed. The contents of the autoclave were transferred to a beaker where a sample of the reaction mixture was withdrawn. The autoclave was evacuated and the reaction mixture recharged to the autoclave by vacuum displacement. Sodium hydroxide solution was prepared in the same beaker with pearl sodium hydroxide (12.8g at 100% strength) and water (22.32g). This was also transferred to the autoclave by vacuum displacement. The mixture was now stirred at 60C for I hour at 15 psi before transferring the contents to a separating funnel. The two phases were separated to give an aqueous layer, which was carried forward to the acid work u...

Reference： [1]Patent: EP1114042,2007,B1 .Location in patent: Page/Page column 7
[2]Patent: EP1114042,2007,B1 .Location in patent: Page/Page column 6; 7
[3]Patent: EP1114042,2007,B1 .Location in patent: Page/Page column 4; 5
[4]Patent: EP1114042,2007,B1 .Location in patent: Page/Page column 4-5

17
[ 63321-79-9 ]
[ 4385-35-7 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1985,vol. 24,p. 360 - 362

18
[ 88550-19-0 ]
[ 4385-35-7 ]

Reference： [1]Journal of the Chemical Society,1954,p. 2819,2824

19
[ 91-13-4 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
95.1%	In tert-butyl alcohol;	EXAMPLE 8 The procedure of Example 6 was repeated, except for replacing alpha,alpha'-o-xylene dichloride with 13.2 g (0.05 mol) of alpha,alpha'-o-xylene dibromide and replacing butyl alcohol with 20 g of t-butyl alcohol. As a result, 2.9 g (yield: 39.2%) of 3-isochromanone was obtained. The purity of the product was 95.1% as measured by gas chromatographic analysis.

Reference： [1]Patent: US5886211,1999,A
[2]Scientific Papers of the Institute of Physical and Chemical Research (Japan),1936,vol. 30,p. 180,188

20
[ 98590-71-7 ]
[ 4385-35-7 ]
[ 67519-22-6 ]

Reference： [1]Patent: US6372921,2002,B1 .Location in patent: Example 11

21
[ 612-12-4 ]
[ 603-35-0 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
24%	In water; <i>tert</i>-butyl alcohol	2 Preparation of isochroman-3-one with Addition of Calcium Hydroxide as a Hydrogen Halide Absorbent Comparative Example 2 Preparation of isochroman-3-one with Addition of Calcium Hydroxide as a Hydrogen Halide Absorbent. 52.5 g of 1,2-bischloromethylbenzene, 1.05 g of bis(triphenylphosphine)palladium(II) chloride and 0.87 g of triphenylphosphine are mixed in 100 ml of tert-butanol and suspended in a 500 ml glass autoclave under a protective gas atmosphere (argon) with 48.0 g of water and 46.8 g of calcium hydroxide. The temperature is subsequently increased to 700 C. under a carbon monoxide atmosphere. The carbon monoxide absorption begun with vigorous stirring at 600 C. is complete after 2 hours and a viscous magma is obtained. The addition of a further 1.05 g of bis(triphenylphosphine)palladium(II) chloride and 0.87 g of triphenylphosphine does not lead to any further absorption of carbon monoxide. After cooling, the mixture is acidified to pH 1 using hydrochloric acid and extracted with diethyl ether. 383 g of aqueous phase and 299 g of organic phase are obtained. According to gas-chromatographic analysis, the aqueous phase contains no isochroman-3-one, and according to gas-chromatographic analysis the organic phase contains 10.5 g of isochroman-3-one (Yield =24%; TON=46; TOF=15.4?h?1).

Reference： [1]Current Patent Assignee: CLARIANT AG - US6348603, 2002, B1 Location in patent: Page column 7

22
[ 612-12-4 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
72.9%	With hydrogenchloride; calcium hydroxide; carbon monoxide; triphenylphosphine; In water; dichlorobis(triphenylphosphine)palladium[II]; tert-butyl alcohol;	EXAMPLE 23 In a 300 cc stainless steel-made autoclave were put 350 mg (0.500 mmol) of dichlorobis(triphenylphosphine)palladium, 290 mg (1.11 mmol) of triphenylphosphine, 8.75 g (50.0 mmol) of alpha,alpha'-o-xylene dichloride, 7.80 g (105 mmol) of calcium hydroxide, 15.0 ml of water, and 150 g of t-butyl alcohol. After displacing the atmosphere with carbon monoxide three times, the mixture was stirred at 70 C. for 5 hours under 2 atm of carbon monoxide (gauge pressure: 1 kg/cm2). The reaction mixture was cooled to room temperature, and 100 ml of water and 30 ml of concentrated hydrochloric acid were added thereto. Analysis of the reaction mixture by gas chromatography revealed production of 3-isochromanone at a yield of 72.9%.
66.4%	palladium(II) chloride; In 1-methyl-pyrrolidin-2-one; water; tert-butyl alcohol;	Example 1 Preparation of isochroman-3-one 299 g of 1,2-bischloromethylbenzene and 75 mg of palladium(II) chloride are dissolved in 725 g of N-methylpyrrolidone and mixed under a protective gas atmosphere (argon) in a 2000 ml autoclave made of HC 4 steel. Carbon monoxide is subsequently added at a pressure of 2 MPa and the temperature is increased to 1500 C. At 1500 C. and 2.5 MPa, 1.7 g of a mixture of water/N-methylpyrrolidone (weight ratio 1:1) is metered in in the course of 2 minutes and subsequently 415 g of a mixture of tert-butanol/N-methylpyrrolidone (weight ratio 2:1) is metered in in the course of 165 minutes. The reaction pressure is kept constant at 4 MPa during the addition. After the addition, the mixture is allowed to react for 60 minutes with stirring, and the autoclave is cooled and emptied. 1445 g of reaction mixture are obtained. Gas-chromatographic analysis shows that the reaction mixture contains 168 g of isochroman-3-one, corresponding to a yield of 66.4% of isochroman-3-one, based on 1,2-bischloromethylbenzene employed (TON=2649; TOF=706?h?1).
	With hydrogenchloride; sodium hydroxide; carbon monoxide; N-ethyl-N,N-diisopropylamine; triphenylphosphine;palladium chloride (PdCl2); In o-xylene; water; tert-butyl alcohol;	EXAMPLE 1 o-Xylene-alpha,alpha'-dichloride (7.0 g, 39.9 mmol) N,N-diisopropylethylamine (15.63 g, 119.7 mmol) palladium chloride (PdCl2) catalyst (0.021 g, 0.1197 mmol), water (7.18 g, 399 mmol) and triphenylphosphine (0.47 g, 1.76 mmol) and tert-butanol (11.9 g, 159.6 mmol) were charged to a 100 ml round bottom flask and carbon monoxide bubbled through via a syringe needle. The reaction mixture was heated to 70 C. with fast agitation while bubbling carbon monoxide through. A sample tested by qualitative gc analysis after 3 hours showed the reaction to be complete. Sodium hydroxide (6.38 g at 100% strength) and water (16.5 g) were added to the reaction mixture, which was then stirred at 60 C. for 1 hour before separating an organic layer A (26.66 g) and an aqueous layer. Concentrated hydrochloric acid (12.31 g at 35.5% strength) and o-xylene (21 g) were added to the aqueous layer, which was stirred at 60 C. for 1 hour before separating a xylene solution B (26.94 g) and an aqueous layer C (40.35 g). Quantitative gc analysis showed 3-isochromanone present as follows: Organic layer A 0.04% (0.18% yield) Xylene solution B 15.01% (68.48% yield) Aqueous layer C 0.2% (1.4% yield) Total yield of 3-isochromanone 70.06%

Reference： [1]Patent: US5886211,1999,A
[2]Patent: US6348603,2002,B1 .Location in patent: Page column 7
[3]Patent: US2002/143193,2002,A1

23
[ 644-36-0 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
68%		EXAMPLE 1 o-Tolylacetic acid (346. 5g, 2.307moles) was charged to a glass reactor fitted with stirrer, thermometer condenser and vented to a caustic scrubber. Fluorobenzene (476.2g, 4.96moles) was added and the contents heated to 75-80C with stirring. To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (8.9g, 0.046moles) in fluorobenzene (79.7g, 0.83moles). Sulphuryl chloride (311.4g, 2.307moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for lhour at 75-80C. The temperature was adjusted to 60C and 50% potassium hydroxide (180. 9g, 1.615moles) added, followed by potassium iodide (1.53g, 0. 009moles). The pH was then adjusted to 6.3 using 20% potassium bicarbonate. After settling, the aqueous phase was separated from the organic phase. The aqueous phase was held for extraction and re-cycle of the o-tolylacetic acid. The organic phase was distilled to remove the fluorobenzene and leave the crude 3-isochromanone 286.6g at 81% strength w/w (equivalent to 232g (Z100% wt, 1.568moles) representing a yield of 68% from o-tolylacetic acid. The aqueous phase (1042g) was charged to a reaction vessel containing fluoro- benzene (524g, 5.458moles) and 36% hydrochloric acid (55g, 0.542moles) was added to reduce the pH to 1.0. The organic and aqueous phases were stirred, allowed to settle and separated. Analysis of the upper fluorobenzene layer (642.2g) showed it contained 3. 1% o- tolylacetic acid (19.9g, 0.13moles) equivalent to 6% of the original charge. This layer was recycled for use in a subsequent preparation.
61.5%		EXAMPLE 12 This Example illustrates a distillative work-up of 3-isochromanone Chlorobenzene (481 g, 4.27 moles) and o-Tolylacetic acid (350g, 2.33moles) were charged to a glass reactor fitted with stirrer, thermometer condenser and vented to a caustic scrubber. Additional chlorobenzene (102.4g, 0.91 moles) was added and the contents azeotropically dried under vacuum at 75-80C with stirring (100.4 g removed). To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (8.95g, 0.046moles) in chlorobenzene (80g, 0.71 moles). Sulphuryl chloride (389.2g, 2.80moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for 1 hour at 75-80C. The temperature was adjusted to 60C and water (121g) charged. A 50% potassium hydroxide solution (182g, 1.625moles) added, followed by potassium iodide solution (1.5g, 0. 009moles in water (3.5g)). The pH was adjusted to pH 6.5 using 20% potassium bicarbonate (768g of 20% solution). Additional water (81g) was added and, after settling, the aqueous phase was separated from the organic phase. The chlorobenzene was removed in vacuo and the remaining melt (310g at 81% strength, 72.5% yield) distilled at 145-155C and 9 mbar to give the final product (222g at 95.5% strength, 1.43 moles, 61.5% yield).
48%	With ammonium iodide; Oxone; potassium bromide; In 2,2,2-trifluoroethanol; acetonitrile; at 20℃; for 12h;Green chemistry;	General procedure: To a mixture of MeCN and CF3CH2OH (6:4) (5.0 mL), carboxylic acid 1 (0.5 mmol), NH4I (0.25mmol), KBr (0.4 mmol) and Oxone? (0.75 mmol) were added. The resulting solution was stirred at room temperature for 12 h and then solvents were removed under reduced pressure. Water (10mL), sat. aq Na2S2O3 (4 mL) and sat. aq Na2CO3 (4 mL) were added to the residue and the mixture was stirred for another 5 min. The mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gelusing (hexane-AcOEt 3:1) as eluant to give the pure product of aryl lactone 2.

41 - 57.3%		EXAMPLE 2 o-Tolylacetic acid (3.96kg, 26.36moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene (6kg, 53.3moles) was added and the contents heated to 78-79C with stirring. To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (0. 103kg, 0.54moles) in chlorobenzene (0.93kg, 8.3moles). Sulphuryl chloride (2.86kg, 21.34moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for lhour at 78-80C. The temperature was adjusted to 60C and 50% potassium hydroxide (1. 4kg, 12. 5moles) was added, followed by 30% potassium iodide (0. 05kg, 0.09moles). The pH was then adjusted to 6.8 using 20% potassium bicarbonate (11. 2kg, 22. 4moles). After settling, the aqueous layer was separated from the organic phase. The organic phase was given a further aqueous potassium bicarbonate wash at pH 6.8 (4.8kg containing 0.06kg, 0.6moles potassium bicarbonate). The two aqueous washes were combined for recycling. The organic phase was distilled to remove some of the chlorobenzene and water. Methylcyclohexane was added (6kg, 61.2moles). The solution of 3-isochromanone was cooled to-5C and the 3-isochromanone isolated by filtration followed by washing with methylcyclohexane. The isolated 3-isochromanone weighed 1.8 kg (12.2 moles), at 98% strength w/w and contained less than 1% o-tolylacetic acid. The isolated yield was 45% from the o-tolylacetic acid charged (60% from the o-tolylacetic acid consumed taking into account the o-tolylacetic acid recovered). The combined aqueous washes saved for recycling (ca. 15.9kg) were charged to a reaction vessel containing chlorobenzene (4kg, 35.6moles). Hydrochloric acid 32% strength (l. lkg, 9.6moles) was added to reduce the pH to 3.5. The phases were then settled and separated. Analysis of the upper chlorobenzene layer showed it contained o-tolylacetic acid (0.96kg, 6.4moles) equivalent to 24.2% of the original charge. This layer was re-cycled in a subsequent preparation as part of the batch charge. EXAMPLE 3 o-Tolylacetic acid (3.04kg, 20.3moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene containing re-cycled o-tolylacetic acid (5.23kg at 18.3% equivalent to 0.96kg 100%, 6.4moles) recovered from Example 2 was added followed by a make up charge of chlorobenzene (1. 5kg/13. 3moles) to give a total chlorobenzene charge of 6kg (53.3moles). The contents were heated to 78-79C with stirring. To the mixture was added 2, 2'-azobis (2- methylbutyronitrile) (0.103kg, 0.54moles) in chlorobenzene (0.93kg, 8.3moles). Sulphuryl chloride (3.28kg, 24.2moles) was added over 3 hours maintaining the temperature at 75-80 C. After the addition was complete, the mixture was held for 1 hour at 78-80C. The temperature was adjusted to 60C and 2kg of water were added followed by 50% potassium hydroxide (2kg, 17.8moles). Potassium iodide 30% (0. 05kg, 0.09moles) was added and the pH was then adjusted to 6.8 using 20% potassium bicarbonate (10.7kg, 21. 5moles). After settling, the aqueous phase was separated from the organic phase for extraction and recycling of the o-tolylacetic acid : The organic phase was distilled to remove some of the chlorobenzene and water. Methylcyclohexane was added (6kg, 61.2moles). The solution of 3-isochromanone was cooled to-5C, the 3-isochromanone isolated by filtration and washed with methylcyclohexane. The isolated 3-isochromanone weighed 1.65 kg (98% strength w/w, 11.15 moles). The isolated yield was 41% from o-tolylacetic acid charged (58% from o- tolylacetic acid consumed taking into account the o-tolylacetic acid recovered). The aqueous phase saved for recycling (ca. 17. 1kg) was charged to a reaction vessel containing chlorobenzene (4kg, 35.6moles). Hydrochloric acid 32% strength (1.36kg, 11. 9moles) was added to reduce the pH to 3.5. The phases were then settled and separated. Analysis of the upper chlorobenzene layer showed it to contain o-tolylacetic acid (1.19kg, 7.9moles) equivalent to 29.6% of the original charge. This layer was held for re-cycling in a subsequent preparation as part of the batch charge. EXAMPLE 4 o-Tolylacetic acid (3.96 kg, 26.4moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer, condenser and scrubber. Chlorobenzene (6 kg) was charged to the reaction vessel and the contents heated to 78-79C. A solution of 2, 2'-azobis (2- methylbutyronitrile) (103g) in chlorobenzene (930g) was added to the vessel. This was followed by sulphuryl chloride (2.86 kg, 22.19 moles) added at a steady rate over 3 hours. After complete addition, the reaction mixture was held for an hour. Potassium hydroxide (50% w/w solution, 1.4kg) was dosed to the reactor to control an exotherm. Potassium iodide (30% aqueous solution, 50g) was then added. The pH was finally adjusted to 6.8 with 20% potassium bicarbonate...
41.8 - 42.7%		EXAMPLE 10 o-Tolylacetic acid (199.5 g, 1.33moles) was charged to a 1 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene was added (275 g, 2.44moles). The contents were heated to 78-79C with stirring. To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (5.15g, 0.027moles) in chlorobenzene (46. 5g, 0.41moles). Chlorine (75. 5g, 1.06moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for lhour at 78-80C. The temperature was adjusted to 60C and water (67 g) was added followed by 50% potassium hydroxide (77.2g, 0.69moles) Potassium iodide 30% (2. 5g, 0.0045moles) was added and the pH was adjusted to 6.4 using 20% potassium bicarbonate (448.8g, 0.897moles). After settling, the aqueous phase was separated from the organic phase for extraction and re-cycling of the o-tolylacetic acid. The organic phase was distilled to remove some of the chlorobenzene/water. Methylcyclo- hexane was added (300g, 3.06moles), the chlorobenzene/methylcyclohexane ratio being 50/50% w/w. The solution was cooled to-5C and the 3-isochromanone isolated by filtration followed by methylcyclohexane washing. The isolated 3-isochromanone (85g at 99.0% strength w/w, 0.57 mol) contained less than 0. 1% o-tolylacetic acid. The isolated yield was 42.7% from the o-tolylacetic acid charged, or 58.3% from the o-tolylacetic acid consumed taking into account the o-tolylacetic acid recovered, (63.8% including recovered 3- isochromanone). The aqueous phase (ca. 686g) was charged to a reaction vessel containing chlorobenzene (275g, 2.44moles). Hydrochloric acid 32% strength (59. 5g, 0.52moles) was added to reduce the pH to 3.5. The phases were then settled and separated. The organic layer contained o- tolylacetic acid (55.3g, 0.37moles), and 3-isochromanone (10.8g, 0.07moles). This layer was held for re-cycling in Example 11 as part of the batch charge. EXAMPLE 11 o-Tolylacetic acid (145.2, 0.967moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene containing the re-cycled o-tolylacetic acid from Example 10 (345g at 15.8% o-tolylacetic acid; 54. 5g, 0.37 moles) was added. The contents were heated to 78-79C with stirring. To the mixture was added 2, 2'-azobis (2-methylbutyronitrile) (5. 15g, 0.027moles) in chlorobenzene (46. 5g, 0.41moles). Chlorine (75. 5g, 1.063moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for 1 hour at 78-80C. The temperature was adjusted to 60C and water (67g) was added followed by 50% potassium hydroxide (100g, 0.89moles). Potassium iodide 30% (2. 5g, 0.0045moles) was added and the pH was adjusted to 6.4 using 20% potassium bicarbonate (442g, 0.88moles). After settling, the aqueous phase was separated from the organic phase for extraction and re-cycling of the o-tolylacetic acid. The organic phase was distilled to remove some of the chlorobenzene/water. Methylcyclo- hexane was added (250g, 2. 55moles), the chlorobenzene/methylcyclohexane ratio being 51/49% w/w. The solution was cooled to-5C, the 3-isochromanone isolated by filtration and washed with methylcyclohexane. The isolated 3-isochromanone (61. Og at 98.3% strength w/w) contained less than 0. 1% o-tolylacetic acid. The isolated yield was 41.8% from the o- tolylacetic acid charged, or 69.9% from the o-tolylacetic acid consumed taking into account the o-tolylacetic acid recovered. The aqueous phase (ca. 739g) was charged to a reaction vessel containing chlorobenzene (275g, 2.44moles). Hydrochloric acid 32% strength (84.2g, 0.74moles) was added to reduce the pH to 3.5. The phases were settled and separated. The organic layer contained o- tolylacetic acid (55.3g, 0.373moles) equivalent to 28. 1% of the original charge.
	With trichlorophosphate; In benzene; at 55℃;	At 500 ml round bottom flask was added 100g o-tolylacetic acid (1), 150g benzene, heating to 55 C. Under stirring, slowly drop phosphorus oxychloride (122.4 g). Reaction to disappearance of the raw material. Stop the reaction. Cool to room temperature, the organic uses 30% NaOH is washed to neutral, take off the dry solvent to obtain product 103.0 g, yield 99.1%, purity 93.0%.

Reference： [1]Patent: WO2003/95442,2003,A2 .Location in patent: Page/Page column 6
[2]Helvetica Chimica Acta,2014,vol. 97,p. 854 - 860
[3]Patent: WO2003/95442,2003,A2 .Location in patent: Page/Page column 14-15
[4]Synthetic Communications,2014,vol. 44,p. 1608 - 1613
[5]Patent: WO2003/95442,2003,A2 .Location in patent: Page/Page column 6-13
[6]Patent: WO2003/95442,2003,A2 .Location in patent: Page/Page column 13-14
[7]Patent: CN105061375,2017,B .Location in patent: Paragraph 0019-0033

24
[ 67-56-1 ]
[ 4385-35-7 ]
[ 95360-33-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; at 20 - 26℃; for 2.5h;	Gaseous hydrogen chloride (HC1) was bubbled through a solution of <strong>[4385-35-7]3-isochromanone</strong> (2.0 g, 13.5 mmol) in methanol (30 mL) for 0.5 hours at room temperature. The solution was further stirred for an additional 2 hours. Methanol was removed under reduced pressure and the resultant residue was dissolved in dichloromethane. Any insoluble material present was removed by filtration, after which the solution was dried by percolating over calcium carbonate, to remove water. Finally, the solvent was removed to give methyl 2-chloromethylphenylacetate (2.62 g, 98%) as an oil which was used in the following step without further purification.
90%	With hydrogenchloride; at 20℃; for 8.05h;	Methyl 2-(2-(chloromethyl)phenyl)acetate. Hydrogen chloride gas was bubbled though a solution of <strong>[4385-35-7]3-isochromanone</strong> (1.2 g, 8.1 mmol) in methanol (30 mL) for 3 minutes. Reaction stirred at room temperature for 8 hours. Mixture was diluted with water (70 mL). Mixture was extracted with dichloromethane (2×40 mL). Combined organic layers were washed with brine (20 mL). Mixture was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as clear colorless oil in 90% yield. 1H NMR (300 MHz, CDCl3): delta=7.40-7.26 (m, 4H), 4.67 (s, 2H), 3.80 (s, 2H), 3.69 (s, 3H).
90%	With hydrogenchloride; at 20℃; for 8.05h;	Methyl 2-(2-(chloromethyl)phenyl)acetate; Hydrogen chloride gas was bubbled though a solution of <strong>[4385-35-7]3-isochromanone</strong> (1.2 g, 8.1 mmol) in methanol (30 mL) for 3 minutes. Reaction stirred at room temperature for 8 hours. Mixture was diluted with water (70 mL). Mixture was extracted with dichloromethane (2×40 mL). Combined organic layers were washed with brine (20 mL). Mixture was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as clear colorless oil in 90% yield. 1H NMR (300 MHz, CDCl3): delta=7.40-7.26 (m, 4H), 4.67 (s, 2H), 3.80 (s, 2H), 3.69 (s, 3H).

	With thionyl chloride; at 0 - 20℃; for 48h;	Intermediate 33. (2-Chloromethyl-phenyl)-acetic acid methyl ester.[0029J Isochromanone 32 (1.9 g, 13 mmol) is dissolved in MeOH (15 mL) and cooled to 0C. Thionyl chloride (2 mL, 27.3 mmol) is added and the solution is stirred at rt for 48 h. The solvent is removed in vacuo, the remainder is dissolved in DCM and washed with water and saturated aqueous NaHCO3. The organic layer is dried (MgSO4), filtered and concentrated. Purification by flash chromatography (EtOAc/Hexanes gradient) affords the (2-chloromethyl-phenyl)-acetic acid methyl ester 33 as a colorless oil: 1H-NMR (400MHz, CDCl3) delta = 7.39-7.26 (m, 4H), 4.68 (s, 2H), 3.82 (s, 2H), 3.70 (s, 3H). MS calcd. for CiOH1 1O2 (M-Cl+) 163.1, found 163.1.
	With thionyl chloride; for 2h;Cooling with ice;	Preparation of methyl 2-chloromethylphenylacetate:Take a clean and dry 250 mL round bottom flask.An analytical balance weighed isochromone (5g, 33.75mmoL) in a bottle,Add 13 mL of methanol,The round bottom flask was then placed in an ice water bath.Slowly add dropwise thionyl chloride (be careful with SOCl2 exothermic splash)A total of 15 mL was added and the reaction was continued for 2 h.Weigh K2CO3 (15g, 108.5mmoL),Add distilled water to make a 10% K2CO3 solution.Add dropwise to the reaction solution to adjust pH>6,The organic layer was extracted with ethyl acetate.Add anhydrous magnesium sulfate overnight,Filtering,Concentrate by rotary evaporation to give a colorless oily liquid.

Reference： [1]Patent: WO2017/125010,2017,A1 .Location in patent: Page/Page column 13
[2]Chemistry - A European Journal,2010,vol. 16,p. 8439 - 8445
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 865 - 880
[4]Patent: US2006/94707,2006,A1 .Location in patent: Page/Page column 45
[5]Patent: US2007/259850,2007,A1 .Location in patent: Page/Page column 81
[6]Asian Journal of Chemistry,2014,vol. 26,p. 2381 - 2388
[7]Patent: WO2007/87448,2007,A1 .Location in patent: Page/Page column 34
[8]Patent: CN108276374,2018,A .Location in patent: Paragraph 0045

25
[ 75-85-4 ]
[ 612-12-4 ]
[ 7087-68-5 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
75.8%	With hydrogenchloride; sodium hydroxide; triphenylphosphine;dihydrotetrachloropalladium (H2PdCl4); In o-xylene; water;	EXAMPLE 4 o-Xylene-alpha,alpha'-dichloride (14.7 g at 95% strength, 80 mmol), N,N-diisopropyl-ethylamine (25.5 g at 99% strength, 200 mmol), an aqueous solution of dihydrotetrachloropalladium (H2PdCl4) catalyst (0.0586 at 53.8% strength, 0.126 mmol), tert-amyl alcohol (14.1 g, 163 mmol,) water (28.8 g, 1600 mmol) and triphenylphosphine (2.1 g at 95% strength, 8.0 mmol) were charged to 300 ml Inconol autoclave. The autoclave was purged three times at 5 bar.g with carbon monoxide gas before finally being pressurised to about 4 bar.g. The reaction mixture was briskly agitated (~900 rpm) and heated to 70 C. Once at temperature, the reaction mixture was stirred at 70 C. for approximately 4 hours, the pressure being maintained at about 4 bar.g and the rate of uptake of carbon monoxide gas noted. The reaction was adjudged complete when no further carbon monoxide was seen to be consumed. The reaction mixture was then rapidly cooled to below 40 C. and sampled to test for the presence of starting material by gc. Water (33 g) and sodium hydroxide (27.4 g at 47% strength) were charged in one portion to the open autoclave, which was then sealed and purged with carbon monoxide gas three times at 5 bar.g before finally being pressurised to 1 bar.g The reaction mixture was then stirred at 60 C. under 1-2 bar.g (CO pressure) for approximately 1 hour. The two phases were then transferred to a hot separator (in air) and separated at 60 C., the aqueous phase being drawn off for further work-up. The aqueous phase was added cautiously to a stirred solution of o-xylene (41.4 g) and concentrated hydrochloric acid (19.8 g at 36% strength) at 60 C. (in air). The mixture was then stirred for 1 hour at 60 C. before being separated to give an aqueous waste stream and a xylene solution containing the product, 3-isochromanone; yield 75.8%.

Reference： [1]Patent: US2002/143193,2002,A1

26
[ 75-85-4 ]
[ 612-12-4 ]
[ 603-35-0 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
75.4%	With hydrogenchloride; sodium hydroxide; carbon monoxide; N-ethyl-N,N-diisopropylamine;palladium(II) chloride; In water;	EXAMPLE 2 Palladium chloride (0.043 g, 0.24 mmol), triphenyl phosphine (0.93 g, 4 mmol), N,N-diisopropylethylamine (31 g, 240 mmol), water (14.4 g, 800 mmol), o-xylene-alpha,alpha' dichloride (14 g, 80 mmol) and tert-amyl alcohol (33.8 g, 384 mmol) were charged to a 310 ml PARR reactor, fitted with an agitator and carbon monoxide charging system. The stirrer was switched on after the temperature was adjusted to 70 C. and the pressure increased to 4 bar.g (60 psig). The vessel pressure was maintained at 60 psig using carbon monoxide and the temperature between 70-75 C. by heating/cooling. When the carbon monoxide uptake ceased, the pressure was released back to atmosphere and the 3-isochromanone product was extracted from the organic phase using aqueous sodium hydroxide (12.8 g at 100% strength, 320 mmol). The 3-isochromanone was regenerated by addition of hydrochloric acid (7.3 g at 35.5% strength, 200 mmol) and extracted into o-xylene (42.5 g, 400 mmol). The resultant solution was analyzed for 3-isochromanone and found to contain 16.8% w/w. This represents a yield of 75.4% of 3-isochromanone from xylene-alphaalpha' dichloride.

Reference： [1]Patent: US2002/143193,2002,A1

27
[ 75-85-4 ]
[ 612-12-4 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
83.9%	With hydrogenchloride; sodium hydroxide; N-ethyl-N,N-diisopropylamine; triphenylphosphine;dihydrotetrachloropalladium (H2PdCl4); In o-xylene; water;	EXAMPLE 3 o-Xylene-alpha,alpha'-dichloride (14.7 g at 95% strength, 80 mmol), N,N-diisopropylethylamine (31.4 g at 99% strength, 250 mmol), an aqueous solution of dihydrotetrachloropalladium (H2PdCl4) catalyst (0.1271 g at 53.8% strength, 0.27 mmol), tert-amyl alcohol (28.2 g at 95% strength, 300 mmol), water (14.4 g, 800 mmol) and triphenylphosphine (0.93 g at 99% strength, 3.5 mmol) were charged to a 300 ml Inconel autoclave. The autoclave was purged three times at 5 bar.g with carbon monoxide gas before being finally pressurised to about 4 bar.g. The reaction mixture was briskly agitated (~900 rpm) and heated to 70 C. Once at temperature, the reaction mixture was stirred at 70 C. for approximately 4 hours, the pressure being maintained at about 4 bar.g and the rate of uptake of carbon monoxide gas noted. The reaction was adjudged complete when no further carbon monoxide was seen to be consumed. The reaction mixture was then rapidly cooled to below 40 C. and sampled to test for the presence of starting material by gc. Water (33 g) and sodium hydroxide (27.4 g at 47% strength) were charged in one portion to the open autoclave, which was then sealed and purged with carbon monoxide gas three times at 5 bar.g before finally being pressurised to 1 bar.g. The reaction mixture was then stirred at 60 C. under 1-2 bar.g (CO pressure) for approximately 1 hour. The two phases were then transferred to a hot separator (in air) and separated at 60 C., the aqueous phase being drawn off for further work-up. The aqueous phase was added cautiously to a stored solution of o-xylene (41.4 g) and concentrated hydrochloric acid (19.8 g at 36% strength) at 60 C. (in air). The mixture was then stirred for 1 hour at 60 C. before being separated to give an aqueous waste stream and a xylene solution containing the product, 3-isochromanone; yield 83.7%. A repeat experiment gave a yield of 83.9%.

Reference： [1]Patent: US2002/143193,2002,A1

28
[ 75-85-4 ]
N,N-diisopropyl-ethyllamine [ No CAS ]
[ 612-12-4 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; carbon monoxide; triphenylphosphine;dihydrotetrachloropalladium (H2PdCl4); In 5,5-dimethyl-1,3-cyclohexadiene; water;	EXAMPLE 7 o-Xylene-alpha,alpha'-dichloride (7.35 g at 95% strength, 40 mmol), N,N-diisopropyl-ethyllamine (15.7 g at 99% strength, 120 mmol), an aqueous solution of dihydrotetrachloropalladium (H2PdCl4) catalyst (0.0651 g at 53.8% strength, 0.14 mmol), tert-amyl alcohol (14.1 g at 95% strength, 150 mmol), water (14.4 g, 800 mmol) and triphenylphosphine (1.1 g at 99% strength, 4 mmol) were charged to a 100 ml round bottom flask. The vessel was sealed and vacuum purged with carbon monoxide gas three times. The contents of the reaction vessel were briskly agitated (~900 rpm) and heated to 70 C., with a steady bubbling of carbon monoxide through the mixture. Once at temperature, the reaction mixture was stirred at 70 C. for approximately 2.25 hours, maintaining the steady bubbling. The reaction mixture was sampled to test for the presence of starting material by gc. Sodium hydroxide solution (30.2 g at 21% strength) was charged in one portion to the flask, which was sealed. Carbon monoxide was then bubbled through the mixture again. The reaction mixture was stirred at 60 C., with steady bubbling for approximately 1 hour. The two phases were transferred to a hot separator (in air) and separated at 60 C., the aqueous phase being drawn off for fisher work-up. The organic phase was retained for a recycle reaction (see Recycle 1). The aqueous phase was added cautiously to a stirred solution of xylene (20.7 g) and concentrated hydrochloric acid (9.9 g at 36% strength) at 60 C. (in air). The mixture was stirred for 1 hour at 60 C. before separating to give an aqueous waste stream and a xylene solution containing the product, 3-isochromanone.

Reference： [1]Patent: US2002/143193,2002,A1

29
[ 4385-35-7 ]
[ 95360-33-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; In methanol; dichloromethane;	EXAMPLE 4 This Example illustrates the preparation of methyl 2-chloromethylphenylacetate used in Example 2. Gaseous hydrogen chloride was bubbled through a solution of <strong>[4385-35-7]3-isochromanone</strong> (2.0 g, 13.5 mmol) in methanol (30 ml) for 0.5 hour at room temperature and the reaction stirred for a further 2 hours. The methanol was removed under reduced pressure and the residue was dissolved in dichloromethane and dried. Removal of the solvent gave methyl 2-chloromethylphenylacetate (2.62 g, 98%) as an oil which was used without further purification; 1 H NMR (270 MHz)delta: 3.70(3H,s), 3.81(2H,s), 4.68(2H,s), 7.22-7.40(4H,m) ppm.
	With thionyl chloride; potassium hydrogencarbonate; In methanol; toluene;	Temperature: ambient 3-Isochromanone (15 g, 0.099 mol) was charged to methanol (30.2 g, 0.9 mol) in a 100 ml round bottom flask and the temperature lowered to <10 C. Thionyl chloride (25 g, 0.21 mol) was added dropwise maintaining the temperature at -5 C. to 0 C. The reaction mixture was stirred, allowing the temperature to rise to ambient for 2 hours then tested for completion of reaction by GC analysis (completed when <1% <strong>[4385-35-7]3-isochromanone</strong> left). The product was extracted with toluene and washed with water followed by dilute potassium bicarbonate solution until pH>6. The toluene was removed by vacuum distillation to ca. 10% toluene by area % GC analysis. The final product, methyl 2-(chloromethyl)phenylacetate, was weighed and analyzed by GC: 16.9 g (18.2 g at 93.03% strength), 85% yield; 2.23% methyl 2-(methoxymethyl) phenylacetate impurity; no <strong>[4385-35-7]3-isochromanone</strong> starting material detected.

Reference： [1]Patent: US6015905,2000,A
[2]Patent: US6048998,2000,A
[3]Patent: CN109748792,2019,A

30
[ 95335-46-9 ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium hydrogencarbonate; In fluorobenzene; cyclohexane;	2-Chloromethylphenylacetic acid (97.75% strength; 10 g) was dissolved in fluorobenzene (20.6 g) at 70 C. over ~20 minutes. The pH of the reaction mixture was found to be 7-8 during the course of the addition. The mixture was then separated at 60 C., the lower aqueous layer being back-extracted with fluorobenzene (10 ml). The combined fluorobenzene phases were then dried by azeotropic distillation at 85-90 C. Slow addition of cyclohexane (20 g) at 80 C. gave a colourless solution which was then slowly cooled to ambient temperature. Further cooling to 0-5 C. gave a white precipitate which was filtered, washed with n-hexane (11.5 g), pulled dry on the filter and dried in air to constant weight (6.60 g); 1 H NMR (CDCl3)delta 3.7 (s,2H); 5.3(s,2H); 7.2-7.6 (m,4H) ppm; quantitative yield 83.9%; chemical yield 94.8%; % strength 99.7% by quantitative HPLC. Acid Drown-out Work-up 2-Chloromethylphenylacetic acid (97.75% strength; 10 g) was dissolved in fluorobenzene (12.6 g) at 70 C., and aqueous hydrochloric acid (18% strength; 6.45 g) added in one portion. The reaction mixture was stirred at 70-80 C. for 30 minutes. Potassium bicarbonate solution (20% strength; 10.15 g) was then added slowly followed by portionwise addition of solid potassium bicarbonate (6.7 g). The mixture was then separated at 60 C., the lower aqueous layer being back-extracted with fluorobenzene (10 ml). The combined fluorobenzene phases were then dried by azeotropic distillation at 85-90 C. Slow addition of cyclohexane (20 g) at 80 C. gave a colourless solution which was then slowly cooled to ambient temperature. Further cooling to 0-5 C. gave a white precipitate which was filtered, washed with n-hexane (11.5 g), pulled dry on the filter and dried in air to constant weight (6.45 g); 1 H NMR (CDCl3)delta3.7 (s,2H); 5.3 (s,2H); 7.2-7.6 (m,4H)ppm; quantitative yield 81.9%; chemical yield 99.1%; % strength 99.61% by quantitative HPLC.
39 g	With potassium hydrogencarbonate; In water; at 50℃;pH 7.2;	50 grams of o-methylphenylacetic acid and50 grams of sulfonyl chloride are configured separately250 ml of tetrachloroethylene solution,Set the microchannel reactor temperature to 120 C to 5 mL / minThe flow rate of the two raw materials of tetrachloroethylene into the microchannel reactor for reaction;After collecting the reaction solution, wash it once in cold water.Adjust the pH to 7.2 with a saturated aqueous solution of potassium hydrogencarbonate, and keep the reaction at 50 C.The reaction system was detected by HPLC without change, washed with 100 ml of water and dried with an organic phase.The solvent was removed by concentration, and the residue was recrystallized from methanol.Drying gave 39 g of 3-isochromanone in a yield of 79% and a purity of 99.5%.

Reference： [1]Patent: US6008381,1999,A
[2]Patent: CN109456295,2019,A .Location in patent: Paragraph 0026-0035

31
[ 4385-35-7 ]
disobutyl aluminum hydride [ No CAS ]
[ 42900-89-0 ]

Yield	Reaction Conditions	Operation in experiment
2.8 g (91%)	With hydrogenchloride In dichloromethane	2 3,4-Dihydro-1H-2-benzopyran-3-ol. EXAMPLE 2 3,4-Dihydro-1H-2-benzopyran-3-ol. To a solution of 3.00 g (0.020 mol) of 1,4-dihydro-3H-2-benzopyran-3-one in 100 mL of dry dichloromethane, cooled to -78° C., was added dropwise, over 1 hour, 24 mL (0.022 mol) of a 1M solution of disobutyl aluminum hydride in dichloromethane. After stirring at -78° C. for 2 hours and at 0° C. for 15 minutes, 100 mL of ether was added, followed by dropwise addition of 1.2N HCl until a pH of 1-2 was reached. Separation of the organic phase, extraction of the aqueous phase with ether and concentration of the combined dried (MgSO4) extracts provided 2.8 g (91%) of 3,4-dihydro-1H-2-benzopyran-3-ol. This product decomposes on standing or on chromatography on silica gel and consequently was used directly for the next reaction step. TLC Rf 0.13 (SiO2, CH2 Cl2, brown-orange CAS and heat).

Reference： [1]Current Patent Assignee: UNIVERSITY OF VERMONT - US4935509, 1990, A

32
[ 4385-35-7 ]
[ 1738-36-9 ]
[ 1179322-20-3 ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 10824 - 10825

33
[ 4385-35-7 ]
[ 107-31-3 ]
[ 77-78-1 ]
(E)-4-(methoxymethylene)isochroman-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0360] Methyl formate in an amount of 3.61 g was added to 60 ml chlorobenzene solution of <strong>[4385-35-7]3-isochromanone</strong> in an amount of 2.96 g, and the resulting slurry was gradually added with sodium methylate in powder in an amount of 2.16 g at 0-5 C. while spending 5 minutes. The reacted slurry was stirred for 1 hour at 0-5 C. and then added with 59% aqueous solution of benzyltributylammonium chloride in an amount of 0.37 g, 10 ml of water and dimethyl sulfate in an amount of 5.04 g in order of precedence. During 2 hours stirring at 25 C., the slurry was gradually dissolving to form a bilayer solution comprising water and chlorobenzene. After completion of the reaction, the organic solvent layer was separated and dried with anhydrous magnesium sulfate. The obtained filtrate was quantitatively analyzed by means of high pressure liquid chromatography, and it is noted that the desired (E)-4-methoxymethylene-<strong>[4385-35-7]3-isochromanone</strong> is contained in the filtrate at a content of 89.6%.
83 - 85.5%Chromat.		[0361] Methyl formate in an amount of 7.21 g was added to 120 ml toluene solution of <strong>[4385-35-7]3-isochromanone</strong> in an amount of 5.92 g, and the resulting slurry was added with sodium methylate in powder in an amount of 4.32 g while spending 5 minutes. The reacted slurry was stirred for 1 hour at 0-5 C. and then added with 50% aqueous solution of benzyltributylammonium chloride in an amount of 0.75 g, 25% aqueous solution of sodium hydroxide in an amount of 8.32 g, 20 ml of water and dimethyl sulfate in an amount of 7.57 g in oreder of precedence. During stirring the slurry for 2 hours at 21-28 C., the slurry was gradually dissolving to form a bilayer solution comprising water and chlorobenzene. After confirming the completion of the reaction by using high pressure liquid chromatography, the temperature of the reaction system was raised to 50 C. and the reaction system was stirred for 1 hour. By analysis of the reacted solution by means of gas chromatography, it is confirmed that no un-reacted dimethyl sulfate is remained in the reacted solution. [0362] After cooling the reacted solution, the organic solvent layer was taken out by separation and was washed with 20 ml of water. The separated organic solvent layer was added with 40 ml of toluene and condensed by dehydration under reduced pressure to obtain toluene solution containing (E)-4-methoxymethylene-<strong>[4385-35-7]3-isochromanone</strong>. The toluene solution was quantitatively analyzed by means of high pressure liquid chromatography, and it is noted that the desired (E)-4-methoxymethylene-<strong>[4385-35-7]3-isochromanone</strong> is contained in the toluene solution at a concentration of approximately 21%. (Yield 85.5%) REFERENCE EXAMPLE 3; Preparation of methyl (E)-3-methoxy-2-(2-chloromethylphenyl)acrylate [0370] Methyl formate in an amount of 7.21 g was added to 120 ml toluene solution of <strong>[4385-35-7]3-isochromanone</strong> in an amount of 5.93 g, and the resulting slurry was added with sodium methylate in powder in an amount of 4.32 g at a temperature ranging from -2 to 5 C. while spending 5 minutes. The reacted slurry was stirred at 0-5 C. for 3 hours and added with 50% aqueous solution of benzyltributylammonium chloride in an amount of 0.75 g, 25% aqueous solution of sodium hydroxide in an amount of 7.04 g, 20 ml of water and dimethyl sulfate in an amount of 11.10 g in order of precedence. During stirring the slurry at 25 C. for 2 hours, the slurry was gradually dissolved to produce a bilayer solution of water and chlorobenzene. The toluene layer obtained by separation was washed with 20 ml of water, and the resulting organic layer was added with 40 ml of toluene, condensed by dehydration under reduced pressure to obtain a toluene solution containing (E)-4-methoxymethylene-<strong>[4385-35-7]3-isochromanone</strong>. The toluene solution was quantitatively analyzed by means of high pressure liquid chromatography, and it is noted that the solution contains (E)-4-methoxymethylene-<strong>[4385-35-7]3-isochromanone</strong> at a concentration of 24% (Yield 83%). Further, by conducting analysis by means of gas chromatography, it is noted that approximately 40% of the used dimethyl sulfate was remained as un-reacted in the solution.
92%Chromat.		[0365] Titanium tetrachloride in an amount of 2.09 g and 15 ml of chloroform were added to the reaction system while flowing nitrogen gas into a 100 ml volume two-inlets type flask and then cooling the reaction system to -5 C. Then, methyl formate in an amount of 0.69 g was gradually added to the reaction system while stirring and added with <strong>[4385-35-7]3-isochromanone</strong> in an amount of 1.48 g at one go-off. The resulting solution was stirred at -5 C. for 30 minutes, and triethylamine in an amount of 2.53 g was fed dropwise into to the solution while spending 10 minutes. After the dropping, the solution was stirred at 0 C. for 1 hour to complete the reaction. The reacted solution was then gradually fed dropwise with 5 ml aqueous solution of 35% hydrochloric acid in an amount of 1.04 g to discontinue the reaction. The resulting organic solvent layer was taken out by separation and washed with 5 ml aqueous solution of 35% hydrochloric acid in an amount of 1.04 g, and the obtained chloroform solution was dried with anhydrous magnesium sulfate and then condensed under reduced pressure to obtain reddish oily substance in an amount of 1.6 g. [0366] The obtained reddish oily substance was dissolved in 20 ml of toluene, and the resulting solution was added with 50% aqueous solution of benzyltributylammonium chloride in an amount of 0.20 g, 15% aqueous solution of sodium hydroxide in an amount of 2.1 g and dimethyl sulfate in an amount of 1.90 g in order of precedence, then stirred at an ambient temperature for 2 hours. After checking the completion of the reaction by means of high speed liquid chromatography, the reaction system was heated to 50 C. and then stirred for 1 hour. The reacted solution was analyzed by means of gas chromatography, and it is noted that no un-reacted dimethyl sulfate was remained therein. [0367] The reacted solution was cooled down to an ambient temperature, and the organic solvent layer was separated and then washed with 20 ml of water. Then the separated organic solvent layer was added with 40 ml of toluene and condensed by dehydration under reduced pressure to obtain the toluene solution containing (E)-4-methoxymethylene-<strong>[4385-35-7]3-isochromanone</strong>. The toluene solution was quantitatively analyzed by means of high pressure liquid chromatography, and it is noted that the desired (E)-4-methoxymethylene-<strong>[4385-35-7]3-isochromanone</strong> is contained in the toluene solution at a concentration of 21%. (Yield 92%)

Reference： [1]Patent: US2004/152894,2004,A1 .Location in patent: Page 36
[2]Patent: US2004/152894,2004,A1 .Location in patent: Page 36; 37-38
[3]Patent: US2004/152894,2004,A1 .Location in patent: Page 37

34
[ 4385-35-7 ]
[ 74-89-5 ]
[ 218131-53-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran; at 20℃; for 8h;	To a stirred solution of <strong>[4385-35-7]isochroman-3-one</strong> (316 mg, 2.13 mmol) in THF (10 mL) was added NH2Me (662 mg, 21.35 mmol). The above mixture was stirred at rt for 8 h and excess THF was removed under reduced pressure. The residue was diluted with DCM (10 mL) and the organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated under vacuum. The residue was chromatographied using PE/EA = 1:1 to provide 9 (377 mg, 99% yield) as colorless oil. 1H NMR (300 MHz, CDCl3): delta 7.39-7.37 (m, 1H), 7.29-7.24 (m, 3H), 6.37 (br, 1H), 4.66 (s, 2H), 4.38 (br, 1H), 3.62 (s, 2H), 2.74 (d, J = 4.8 Hz, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 4935 - 4952

35
[ 4385-35-7 ]
[ 6346-00-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;	The suspension of lithium aluminum hydride (1.03 g, 27.0 mmol) in THF was cooled to 0 C, to which was added dropwise a solution of <strong>[4385-35-7]3-isochromanone</strong> S50 (2.0 g, 13.5 mmol) in 25 mL of THF under argon atmosphere. The reaction mixture was warmed to room temperature and further stirred for 3 hours. The suspension was cooled to 0 C again by ice bath, quenched with saturated Na2S04 solution, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The crude mixture was diluted with 100 mL of ethyl acetate, washed sequentially by saturated NaHC03 solution (20.0 mL) and brine (20.0 mL), and dried over anhydrous Na2S04. The solvent was evaporated in vacuo to get intermediate S51 as a colorless oil (2.01 g, 99% yield), which was used directly in the next step without further purification. H NMR (500MHz): 57.34-7.22 (m, 4H), 4.65 (s, 2H), 3.89 (t, J 6.0 Hz, 2H), 2.96 (t, J 6.0 Hz, 2H)
99%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere;	The suspension of lithium aluminum hydride (1 .03 g, 27.0 mmol) in THF was cooled to 0 C, to which was added drop wise a solution of <strong>[4385-35-7]3-isochromanone</strong> S50 (2.0 g, 13.5 mmol) in 25 mL of THF under argon atmosphere. The reaction mixture was warmed up to room temperature and further stirred for 3 hours. The suspension was cooled to 0 C again by ice bath, quenched with saturated Na2S04 solution and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The crude mixture was diluted with 1 00 mL of ethyl acetate, washed sequentially with saturated NaHC03 solution (20.0 mL) and brine (20.0 mL), and dried over anhydrous Na2S04. The solvent was evaporated in vacuo to get intermediate S51 as a colorless oil (2.01 g, 99% yield), which was used directly in the next step without further purification. 1 H NMR (500MHz) : 57.34-7.22 (m , 4H), 4.65 (s, 2H), 3.89 (t, J 6.0 Hz, 2H), 2.96 (t, J 6.0 Hz, 2H)
60%	With phenylsilane; potassium hydroxide; In tetrahydrofuran; for 4h;Schlenk technique; Inert atmosphere; Reflux;	General procedure: Isobenzofuran-1(3H)-one (0.4 mmol), KOH (0.4 mmol), PhSiH3 (1.2 mmol), dried THF (2 mL) were charged in a Schlenk tube(15 mL) under N2 atmosphere. The mixture was refluxed for 4 h. After cooling to rt, the reaction was quenched with EtOH(0.5-1 mL). Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel with petroleum ether-ethyl acetate as the eluent to afford the desired product.

Reference： [1]Patent: WO2015/69932,2015,A1 .Location in patent: Page/Page column 101
[2]Patent: WO2015/188197,2015,A2 .Location in patent: Page/Page column 89
[3]Chinese Chemical Letters,2019,vol. 30,p. 725 - 728
[4]Journal of Organic Chemistry,2012,vol. 77,p. 3049 - 3059

36
[ 4385-35-7 ]
[ 303065-25-0 ]
[ 1439391-28-2 ]

Yield	Reaction Conditions	Operation in experiment
78 mg	With trimethylaluminum; In toluene; at 75℃; for 15h;	To a suspension of 1002 (288 mg, 1.00 mmol) in toluene (9 mL) was added 3- isochromanone (311 mg, 2.10 mmol) followed by trimethyl aluminum (2M in toluene, 1.0 mL, 2.00 mmol). The resulting mixture was stirred at 75C for 15 h, cooled to room temperature and diluted with ethyl acetate (50 mL). The organic layer was washed with water (3x20 mL), 10% sodium chloride solution (10 mL), dried (magnesium sulfate) and concentrated under reduced pressure. The crude product was purified by HPLC to afford N,N-(5,5-(thiobis(ethane-2,l-diyl))bis(l,3,4- thiadiazole-5,2-diyl))bis(2-(2-(hydroxymethyl)phenyl)acetamide) (181, 78 mg). 1H NMR (300 MHz, DMSO-d6) delta 7.42(d, J=6.84 Hz, 2H), 7.26(bs, 6H), 4.57(s, 4H), 3.90(s, 4H), 3.27(t, J =6.62 Hz, 4H), 2.94(t, J =6.44 Hz, 4H)

Reference： [1]Patent: WO2013/78123,2013,A1 .Location in patent: Page/Page column 78; 79

37
[ 4385-35-7 ]
[ 98558-04-4 ]
[ 1439391-57-7 ]

Yield	Reaction Conditions	Operation in experiment
62 mg	With trimethylaluminum; In toluene; at 75℃; for 15h;	To a suspension of 1001 (256 mg, 1.00 mmol) in toluene (8 mL) was added 3- isochromanone (311 mg, 2.10 mmol) followed by trimethyl aluminum (2M in toluene, 1.0 mL, 2.00 mmol). The resulting mixture was stirred at 75C 15 h, cooled to room temperature and diluted with ethyl acetate (50 mL). The organic layer was washed with water (3x20 mL), 10% sodium chloride solution (10 mL), dried (magnsesium sulfate) and concentrated under reduced pressure. The crude product was purified by HPLC to afford N,N-(5,5-(thiobis(ethane-2,l-diyl))bis(l,3,4-thiadiazole-5,2- diyl))bis(2-(2-(hydroxymethyl)phenyl)acetamide) (208, 62 mg). 1H NMR (300 MHz, DMSO-d6) delta 7.4 l(s, 2H), 7.26(s, 6H), 4.56(s, 4H), 3.01(bs, 4H), 1.76(bs, 4H)

Reference： [1]Patent: WO2013/78123,2013,A1 .Location in patent: Page/Page column 79

38
[ 4385-35-7 ]
[ 493-05-0 ]
[ 42900-89-0 ]

Yield	Reaction Conditions	Operation in experiment
1: 55 %Chromat. 2: 20 %Chromat.	With aluminium(III) triflate; tris(2,4-pentanedionato)ruthenium(III); hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In tetrahydrofuran at 130℃; for 4h; Autoclave;

Reference： [1]Li, Yuehui; Topf, Christoph; Cui, Xinjiang; Junge, Kathrin; Beller, Matthias [Angewandte Chemie - International Edition, 2015, vol. 54, # 17, p. 5196 - 5200][Angew. Chem., 2015, vol. 127, # 17, p. 5285 - 5289,5]

39
[ 4385-35-7 ]
C₉H₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		To a only 50mL Schlenk bottles for oxygen-free processing, then adding 1.48g (10mmol) neighbouring hydroxy methyl acetic acid lactone, 1.236g (12mmol) and TBN 25 ml anhydrous methanol, ice-bath stirring 10 min, then dropping sodium methoxide (0.756g, 14mmol) methanol (5 ml) solution, stirring the mixture at room temperature for 24h. After the reaction is ended, revolving off a methanol, water and ethyl acetate each 20 ml, then using dilute hydrochloric acid to pH in the system is about 7, ethyl acetate extraction three to four times, combined with the phase, drying, turns on lathe does, then purified by silica gel column chromatography, to obtain 1.15g product, yield 65%.

Reference： [1]Patent: CN105294490,2016,A .Location in patent: Paragraph 0003; 0004

40
[ 4385-35-7 ]
[ 107-31-3 ]
[ 117428-51-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With acetic acid;Heating;	In a 1000 ml round-bottom flask is added in 3- different chromone (1) 100 g, the methyl formate 400 g and glacial acetic acid 120 g, heating reflow to 3- different chromone (1) disappears, to remove liquid, got the midbody (2) the crude product, then adding thionyl chloride 1000 g, reflux reaction to intermediate (2) the reaction is complete, add methanol 500 g, room temperature 25 C reaction to produce the product completely, stopping reaction, filtration dried to get the product (3) 156 g, yield 96%, purity 97%.

Reference： [1]Patent: CN104250213,2016,B .Location in patent: Paragraph 0032

41
[ 4385-35-7 ]
[ 2937-50-0 ]
allyl 3-oxoisochroman-4-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 5472 - 5475

42
[ 4385-35-7 ]
[ 69739-34-0 ]
((1H-isochromen-3-yl)oxy)(tert-butyl)dimethylsilane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylamine; In dichloromethane; at 23℃; for 0.5h;	General procedure: To a solution of the corresponding lactone (1.0 mmol) and trimethylamine (1.3 equiv.) in anhydrous CH2Cl2 (10 mL) was added silyltriflate (1.2 equiv.) at room temperature. The mixture was stirred at 23 C for 30 min. The reaction mixture was diluted by hexane (5 mL), and organic layer was extracted with saturated water (5 mL). The aqueous layer was extracted with hexane (5 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo. The resulting residue was used next step without further purification. ((1H-Isochromen-3-yl)oxy)(tert-butyl)dimethylsilane (1a): 1H NMR (CDCl3, 500 MHz): d 7.16-7.12 (m, 1H), 6.99-6.95 (m, 2H), 6.86 (d, J = 7.5 Hz, 1H), 5.13 (s, 2H), 5.03 (s, 1H), 0.96 (s, 9H), 0.24 (s, 6H).

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2944 - 2947

43
[ 4385-35-7 ]
[ 79271-56-0 ]
((1H-isochromen-3-yl)oxy)triethylsilane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylamine; In dichloromethane; at 23℃; for 0.5h;	General procedure: To a solution of the corresponding lactone (1.0 mmol) and trimethylamine (1.3 equiv.) in anhydrous CH2Cl2 (10 mL) was added silyltriflate (1.2 equiv.) at room temperature. The mixture was stirred at 23 C for 30 min. The reaction mixture was diluted by hexane (5 mL), and organic layer was extracted with saturated water (5 mL). The aqueous layer was extracted with hexane (5 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo. The resulting residue was used next step without further purification.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2944 - 2947

44
[ 4385-35-7 ]
[ 80522-42-5 ]
((1H-isochromen-3-yl)oxy)triisopropylsilane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylamine; In dichloromethane; at 23℃; for 0.5h;	General procedure: To a solution of the corresponding lactone (1.0 mmol) and trimethylamine (1.3 equiv.) in anhydrous CH2Cl2 (10 mL) was added silyltriflate (1.2 equiv.) at room temperature. The mixture was stirred at 23 C for 30 min. The reaction mixture was diluted by hexane (5 mL), and organic layer was extracted with saturated water (5 mL). The aqueous layer was extracted with hexane (5 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo. The resulting residue was used next step without further purification.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2944 - 2947

45
[ 4385-35-7 ]
[ 644-36-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; W(OTf)6; hydrogen; acetic acid; at 50℃; under 760.051 Torr; for 12h;	General procedure: Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10%, 26.5mg, 0.025mmol, 0.5mol%) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2mol%). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, gamma- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699% yield measured propionic acid, purity of the product was 99%. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and operation method were the same as in Example 27 except that the substrate used was 2 mmol and lmL of acetic acid was added as a solvent at a reaction temperature of 50 C, a yield of 98% and a purity of 99%. The product was subjected to nuclear magnetic identification using the manner described in the present invention, and the NMR data of the product were as follows

Reference： [1]Patent: CN106831389,2017,A .Location in patent: Paragraph 0113; 0226-00228
[2]ACS Catalysis,2017,vol. 7,p. 7520 - 7528

46
[ 4385-35-7 ]
[ 187327-30-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: hydrogenchloride / 2.5 h / 20 - 26 °C 2.1: sodium hydroxide; 15-crown-5 / toluene / 2 h / Reflux 2.2: 2 h / 75 °C

Reference： [1]Current Patent Assignee: ROTAM GLOBAL AGROSCIENCES LIMITED - WO2017/125010, 2017, A1

47
[ 4385-35-7 ]
[ 117428-22-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / 2.5 h / 20 - 26 °C 2.1: sodium hydroxide; 15-crown-5 / toluene / 2 h / Reflux 2.2: 2 h / 75 °C 3.1: sodium methylate / toluene / 6 h / 20 - 26 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 20 - 26 °C

Reference： [1]Current Patent Assignee: ROTAM GLOBAL AGROSCIENCES LIMITED - WO2017/125010, 2017, A1

48
(±)-2-((3aR,6R,7aR)-1-oxo-6,7-dihydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)acetic acid [ No CAS ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
65%	With trifluorormethanesulfonic acid; In chloroform;	Preparation of 3-isochromanone (18) Method A: Lactone acid 14 (1.0 g, 4.7 mmol) was suspended in chloroform-d (10 mL) in a 50 mL two-neck round-bottom flask. Trifluoromethanesulfonic acid (TfOH, 37 muL, 10 mol %) was added. A brown-black color was immediately observed. This solution was stirred overnight at room temp or heated to 80 C. at which time the color had become somewhat darker and a black solid material had precipitated. The chloroform supernatant was decanted and the black residue was washed with a portion of fresh chloroform. The combined chloroform layers were concentrated in vacuo and the residue was purified by flash column chromatography on SiO2 (hexanes/EtOAc, 3:1) to give 3-isochromanone 18 (0.45 g, 65%) as white crystalline solid. Method B: (0290) The lactone methyl ester 14Me (0.5 g, 2.2 mmol) was dissolved in chloroform-d (10 mL) in a 50 mL two-neck round-bottom flask. Trifluoromethanesulfonic acid (TfOH, 20 muL, 10 mol %) was added. A brown-black color was immediately observed. This solution was stirred at 80 C. for 2 hours, at which time the color had become somewhat darker. The chloroform was concentrated in vacuo and the residue was purified by flash column chromatography on SiO2 (hexanes/EtOAc, 3:1) to give the 3-isochromanone 18 (0.23 g, 70%) as a white crystalline solid. (0291) 1H NMR (500 MHz, CDCl3) delta 7.44-7.21 (m, 4H), 5.40 (s, 2H, CH2O), and 3.79 (s, 2H, CH2CO). (0292) mp: 80-83 (lit. 80-81 C.; Li T., et al., Helv. Chim. Acta 2014, 97, 854)

Reference： [1]Patent: US2017/291906,2017,A1 .Location in patent: Paragraph 0286-0292

49
(±)-methyl 2-((3aR,6R,7aR)-1-oxo-6,7-dihydro-3H-3a,6-epoxyisobenzofuran-7a(1H)-yl)acetate [ No CAS ]
[ 4385-35-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With trifluorormethanesulfonic acid; In chloroform; at 80℃; for 2h;	Method B: (0290) The lactone methyl ester 14Me (0.5 g, 2.2 mmol) was dissolved in chloroform-d (10 mL) in a 50 mL two-neck round-bottom flask. Trifluoromethanesulfonic acid (TfOH, 20 muL, 10 mol %) was added. A brown-black color was immediately observed. This solution was stirred at 80 C. for 2 hours, at which time the color had become somewhat darker. The chloroform was concentrated in vacuo and the residue was purified by flash column chromatography on SiO2 (hexanes/EtOAc, 3:1) to give the 3-isochromanone 18 (0.23 g, 70%) as a white crystalline solid. (0291) 1H NMR (500 MHz, CDCl3) delta 7.44-7.21 (m, 4H), 5.40 (s, 2H, CH2O), and 3.79 (s, 2H, CH2CO). (0292) mp: 80-83 (lit. 80-81 C.; Li T., et al., Helv. Chim. Acta 2014, 97, 854)

Reference： [1]Patent: US2017/291906,2017,A1 .Location in patent: Paragraph 0289-0292

50
[ 4385-35-7 ]
[ 87216-46-4 ]

Yield	Reaction Conditions	Operation in experiment
50%	With indium(III) triflate; hexamethyldisilathiane; In 1,2-dichloro-benzene; at 80℃; for 24h;Sealed tube; Glovebox;	General procedure: To a screw-capped tube, lactone or the derivative 1 (0.50 mmol) was added. The tube was sealedand moved into a glovebox, then In(OTf)3 (2.8 mg, 0.0050 mmol) was added. The tube was sealedagain and removed from the glovebox. 1,2-Dichlorobenzene (0.5 mL) and hexamethyldisilathiane(98.1 mg, 0.550 mmol) were successively added, and after the tube was sealed, the mixture was heatedat 80 C for 24 h. The resulting mixture was cooled to room temperature and chloroform was added.The mixture was transferred into a round-bottom flask, which was then evaporated under reducedpressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc)followed by gel permeation chromatography (GPC) in some cases.
23%	With sulfur; indium(III) chloride; phenylsilane; In 1,2-dichloro-benzene; for 24h;Inert atmosphere; Sealed tube;	General procedure: To a screw-capped tube were successively added InCl3 (5.5 mg, 0.025 mmol), o-dichlorobenzene (0.5 mL), the appropriate lactone (0.50 mmol), S8 (17.6 mg, 0.550 mmol) or Se (43.4 mg, 0.550 mmol), and PhSiH3 (36.1 mg, 0.333 mmol). After the tube was sealed with a cap that contained a PTFE septum, the mixture was heated for 24 h at 120 C for thiolactones and at 120 C for selenolactones. After the reaction, the mixture was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc) to afford either the desired thiolactone or selenolactone derivative.

Reference： [1]Molecules,2018,vol. 23
[2]Synthesis,2018,vol. 50,p. 565 - 574

51
[ 4385-35-7 ]
[ 107-31-3 ]
(E)-4-(hydroxymethylene)isochroman-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		adding toluene to the condensation vessel, stirring is started, solid sodium methoxide is added, and the jacket is cooled by water, and the kettle is controlled.At a temperature of 28 to 30 C, methyl formate was added dropwise to the kettle of the reaction kettle, and the mixture was dropped for about 0.5 h, and the mixture was stirred at the end for 30 min;Mix the hand hole, add <strong>[4385-35-7]3-isochromanone</strong> to the kettle, close the hand hole, and heat up the reaction to 30 C to maintain the same temperature. 12Hour, sampling analysis, chroman <100 is acceptable; if not, continue to respond to pass;

Reference： [1]Patent: CN107266316,2017,A .Location in patent: Paragraph 0033; 0043; 0051; 0053

52
[ 4385-35-7 ]
C₃H₈NO⁽¹⁺⁾*CH₃O₄S^(1-) [ No CAS ]
4-methylaminomethyliden-3-isochromanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In methanol; at 30℃; for 2h;	In a four-necked bottle equipped with a mechanical stirrer, thermometer, and condenser tube,Add 148 g (1 mol) of 3-isochromone and 203.5 g of formula (IIC)The complex (1.1 mol) shown and 800 mL of methanol are stirred and thoroughly mixed,Then 2.5 mol of sodium carbonate solid was added to the mixture in portions at 30 C,After the addition was completed, the reaction was carried out at 30 C for 2 hours to obtain the target product, 4-methylaminomethylenyl-3-isochromone. The conversion of the reaction was measured to be 99% and the selectivity was 97%.

Reference： [1]Patent: CN110294727,2019,A .Location in patent: Paragraph 0064-0067

53
[ 4385-35-7 ]
N_.N-Diethylformamid-dimethylsulfat-addukt [ No CAS ]
4-diethylaminomethyliden-3-isochromanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In methanol; at 30℃; for 2h;	In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 148 g (1 mol) of 3-isochromone, 249.7 g of the complex (1.1 mol) represented by formula (IId), and 500 mL of methanol were added and stirred to perform Mix well, and then add 2.5 mol of sodium carbonate solids to the mixture in batches at 30 C. After the addition is complete, react at 30 C for 2 hours to obtain the target product 3-diethylaminemethylenyl-2-isochromone. The conversion of the reaction was measured to be 99% and the selectivity was 98%.

Reference： [1]Patent: CN110294727,2019,A .Location in patent: Paragraph 0068-0071

54
[ 4385-35-7 ]
[ 21511-55-7 ]
4-dimethylaminomethyliden-3-isochromanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In methanol; at 30℃; for 2h;	In a four-necked bottle equipped with a mechanical stirrer, thermometer, and condenser tube,Was added 148g (1mol) 3- isochromanone, 219g of formula (IIa) as shown complex (1.1 mol) and 800mL of methanol,Stir to thoroughly mix, and then add 2.5 mol of sodium carbonate solids to the mixture in batches at 30 C. After the addition is complete, react at 30 C for 2 hours.To give the desired product 4-dimethylaminopyridine methylene-<strong>[4385-35-7]3-isochromanone</strong>. The conversion of the reaction was measured to be 99% and the selectivity was 98%.

Reference： [1]Patent: CN110294727,2019,A .Location in patent: Paragraph 0056-0059

55
[ 4385-35-7 ]
N,N-Dimethylformimidiniumsaeureethylesterethylsulfat [ No CAS ]
4-dimethylaminomethyliden-3-isochromanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In methanol; at 30℃; for 2h;	In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 148 g (1 mol) of 3-isochromone, 249.7 g of the complex (1.1 mol) represented by formula (IIb), and 800 mL of methanol were added and stirred to perform Mix well, and then add 2.5 mol of sodium carbonate solids to the mixture in batches at 30 C. After the addition is complete, react at 30 C for 2 hours to obtain the target product 4-dimethylaminemethenyl-3-isochromone. The conversion of the reaction was measured to be 99% and the selectivity was 98%.

Reference： [1]Patent: CN110294727,2019,A .Location in patent: Paragraph 0060-0063

56
[ 4385-35-7 ]
[ 742099-40-7 ]
(E)-4-(5-bromo-2-(pyrrolidin-1-yl)benzylidene)isochroman-3-one [ No CAS ]
(Z)-4-(5-bromo-2-(pyrrolidin-1-yl)benzylidene)isochroman-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.946 % de	With piperidine In ethanol at 80℃; for 24h; Inert atmosphere; Overall yield = 94 percent; Overall yield = 145 mg; stereoselective reaction;

Reference： [1]Bhowmik, Arup; Das, Sumit; Sarkar, Writhabrata; Saidalavi; Mishra, Aniket; Roy, Anupama; Deb, Indubhusan [Advanced Synthesis and Catalysis, 2021, vol. 363, # 3, p. 826 - 832]

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	4385-35-7	MDL No. :	MFCD00043005
Formula :	C₉H₈O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ILHLUZUMRJQEAH-UHFFFAOYSA-N
M.W :	148.16	Pubchem ID :	78092
Synonyms :

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.35
TPSA :	26.3 Å²

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) :	-6.29 cm/s

Log Po/w (iLOGP) :	1.61
Log Po/w (XLOGP3) :	1.28
Log Po/w (WLOGP) :	1.13
Log Po/w (MLOGP) :	1.59
Log Po/w (SILICOS-IT) :	2.46
Consensus Log Po/w :	1.61

[ CAS No. 4385-35-7 ] {[proInfo.proName]}

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[ 4385-35-7 ] Synthesis Path-Downstream 1~56

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[ 4385-35-7 ]

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[ 4385-35-7 ]

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

Log S (ESOL) :	-1.97
Solubility :	1.59 mg/ml ; 0.0107 mol/l
Class :	Very soluble
Log S (Ali) :	-1.43
Solubility :	5.48 mg/ml ; 0.037 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.84
Solubility :	0.216 mg/ml ; 0.00146 mol/l
Class :	Soluble

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

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

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P378
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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.
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P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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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:
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[ CAS No. 4385-35-7 ] {[proInfo.proName]}

Quality Control of [ 4385-35-7 ]

Related Doc. of [ 4385-35-7 ]

Product Details of [ 4385-35-7 ]

Calculated chemistry of [ 4385-35-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 4385-35-7 ]

Application In Synthesis of [ 4385-35-7 ]

[ 4385-35-7 ] Synthesis Path-Downstream 1~56

Related Functional Groups of [ 4385-35-7 ]

Esters

Related Parent Nucleus of [ 4385-35-7 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

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Inquiry

Related Functional Groups of
[ 4385-35-7 ]

Related Parent Nucleus of
[ 4385-35-7 ]