[ CAS No. 13391-28-1 ] {[proInfo.proName]}

Name: 13391-28-1|5-Methoxybenzofuran|95%
Brand: Ambeed
SKU: A571992
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Quality Control of [ 13391-28-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 13391-28-1 ]

CAS No. :	13391-28-1	MDL No. :	MFCD00079770
Formula :	C₉H₈O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JJXPTUWJVQUHKN-UHFFFAOYSA-N
M.W :	148.16	Pubchem ID :	25943
Synonyms :

Calculated chemistry of [ 13391-28-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.11
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	42.71
TPSA :	22.37 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.57 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	2.3
Log Po/w (WLOGP) :	2.44
Log Po/w (MLOGP) :	1.23
Log Po/w (SILICOS-IT) :	2.4
Consensus Log Po/w :	2.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.75
Solubility :	0.265 mg/ml ; 0.00179 mol/l
Class :	Soluble
Log S (Ali) :	-2.41
Solubility :	0.579 mg/ml ; 0.00391 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.39
Solubility :	0.0598 mg/ml ; 0.000404 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.06

Safety of [ 13391-28-1 ]

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

Application In Synthesis of [ 13391-28-1 ]

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

Upstream synthesis route of [ 13391-28-1 ]
Downstream synthetic route of [ 13391-28-1 ]

[ 13391-28-1 ] Synthesis Path-Upstream 1~7

1
[ 13391-28-1 ]
[ 58546-89-7 ]

Reference： [1] Synthetic Communications, 2006, vol. 36, # 14, p. 1983 - 1990

2
[ 13391-28-1 ]
[ 40492-52-2 ]

Reference： [1] Patent: US2011/105527, 2011, A1,

3
[ 13391-28-1 ]
[ 13196-10-6 ]

Yield	Reaction Conditions	Operation in experiment
79.6%	With boron tribromide In dichloromethane at 0 - 20℃; for 3 h;	To an ice-cooled solution of 5-methylbenzofuran (0.5 g, 3.37 mmol) in DCM (7 mL) was added boron tribromide (3.4 mL, 3.37 mmol, IM in DCM). The light brown solution was stirred at 0 ⁰C for Ih, another equivalent of boron tribromide (3.4 mL) was then added. The mixture was stirred at room temperature for 2 h. TLC analysis indicated the completion of the reaction. The mixture was poured into ice and the pH was adjusted to 7 with Na₂CO₃. The aqueous was extracted with DCM (x2). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The resulting light brown sold gave the satisfactory purity without further purification for next step: 0.36 g (79.6percent yield), ¹H NMR (400 MHz, CD₃OD) δ 7.59(d, J = 2.0 Hz, IH), 7.35(d, J = 9.2 Hz, IH), 7.01(d, J = 2.4 Hz, IH), 6.82 (dd, J = 8.8 Hz, J = 2.8 Hz, IH), 6.67 (m, IH), 4.73 (s, IH).
77%	With hydrogenchloride; sodium ethanolate; 2-(diethylamine)ethanethiol In 1-methyl-pyrrolidin-2-one; ethanol at 150℃; Inert atmosphere; Dean-Stark	A mixture of 5-methoxybenzofuran (61.6 g, 0.416 mol), 2-(diethylamino)ethanethiol:HC1 (88.4 g, 0.521 mol) and NMP (600 mL) was sparged with nitrogen for 10 mi Sodium ethoxide solution (388 mL, 21 wtpercent in EtOH, 1.04 mol) was added and the resulting solution was heated to 150°C overnight. A Dean-Stark trap was used to distill off ethanol during the reaction. The mixture was cooled to room temperature and acidified with 1.1 L of 1 ON HC1.The solution was then partitioned with 850 mL of ethyl acetate. The layers were separated and the aqueous layer back extracted twice with 300 mL of ethyl acetate. The combined organic extracts were washed twice with 300 mL of water, once with 150 mL of brine and then dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated by rotary evaporation to 72.4 g of a dark oil. This residue was purified on SiliaFlash G-60(2.0 L, 1.0 kg) using 10percent EtOAc/n-heptane as eluant, providing 52.4 g of material as waxy solids, 94.8percent purity by LC with significant non-polar impurities. The material was slurned for one-hour in 200 mL of n-heptane and then filtered. The solids were further washed with 150 mL of n-heptane and air-dried giving 29.7 g of 5-hydroxybenzofuran with an LC purity of 98.9percent. The filtrate was concentrated by rotary evaporation to a residue (16.4 g) which waspurified on SiliaFlash G-60 (0.90 L, 0.45 kg) using a gradient of 10-25percent EtOAc in nheptane as eluant. This provided an additional 13.0 g of with a 99.5percent purity, for a total combined yield of 5-hydroxybenzofuran of 42.7 g (77percent).
51.3%	With boron tribromide In dichloromethane at 0℃;	To an ice-cooled solution of 5-methoxybenzofuran (0.71 g, 4.79 mmol) in dichloromethane (8.0 mL) was added 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol). The mixture was stirred at 0 °C for 1.0 h. HPLC indicated ca 30-40percentstarting material still remaining. Then another portion of 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol) was added and the mixture was stirred from 0 °C to room temperature over an hour. HPLC indicated a complete conversion of starting material. The mixture was poured into ice water, stirred for 15 mm, extracted with dichloromethane. The organic layer was dried over sodium sulfate. After evaporation ofsolvent, Intermediate 44A (0.33 g, 2.460 mmol, 51.3 percent yield) was obtained as slightlybrown oil. It was used for the next step without further purification. ‘H NMR (500MHz,chloroform-d) 7.60 (d, J=2.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H),6.82 (dd, J=8.8, 2.8 Hz, 1H), 6.69-6.67 (m, 1H), 4.78 (s, 1H); LC-MS: Method A, 50 to100percent B. RT = 2.32 mm, MS (ESI) m/z: no (M+H)

Reference： [1] Chemical Communications, 2016, vol. 52, # 16, p. 3348 - 3351
[2] Synthetic Communications, 2006, vol. 36, # 14, p. 1983 - 1990
[3] Patent: WO2007/61458, 2007, A2, . Location in patent: Page/Page column 43; 91
[4] Patent: WO2017/87965, 2017, A1, . Location in patent: Page/Page column 23
[5] Patent: WO2018/13774, 2018, A1, . Location in patent: Page/Page column 379; 380
[6] Patent: US6235771, 2001, B1,
[7] Patent: WO2010/24769, 2010, A1, . Location in patent: Page/Page column 14; 29
[8] Patent: US2006/58361, 2006, A1, . Location in patent: Page/Page column 34
[9] Patent: US2007/112019, 2007, A1, . Location in patent: Page/Page column 21/2
[10] Patent: US2011/105527, 2011, A1, . Location in patent: Page/Page column 18
[11] Patent: WO2014/206343, 2014, A1, . Location in patent: Page/Page column 47; 48
[12] Patent: WO2014/206344, 2014, A1, . Location in patent: Page/Page column 56; 57
[13] Patent: WO2015/95261, 2015, A1, . Location in patent: Page/Page column 97
[14] Patent: WO2015/89842, 2015, A1, . Location in patent: Page/Page column 96
[15] Patent: WO2016/165626, 2016, A1, . Location in patent: Paragraph 0156

4
[ 13391-28-1 ]
[ 551001-79-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -30℃; for 1.5 h; Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -30 - 10℃; for 2.17 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water at 10℃;	Step A: 5-Methoxybenzofuran (1 g, 6.8 mmol) was dissolved in tetrahydrofuran (10 ml) and cooled to -30° C. The solution was treated with n-BuLi (3.5 ml, 8.9 mmol, 2.5 M in hexanes) over 30 minutes, maintaining the internal temperature at -30° C. during the addition to give a red solution. After 1 hour at -30° C., trimethyl borate (1 ml, 8.8 mmol) was added over 10 minutes and the solution became pale brown. The resulting solution was allowed to warm slowly to 10° C. over 2 hours after which it was quenched with 6 M HCl (10 ml) and extracted with ethyl acetate (30 ml). The organics were washed with water (30 ml) and brine (30 ml) and were dried over anhydrous magnesium sulfate. After filtration, the organic solution was concentrated and the boronic acid precipitated by adding hexanes. The crystals were filtered and washed with hexanes to give an off-white solid (983 mg, 76percent): ¹H NMR (500 MHz, DMSO-d6) δ 8.53 (br s, 2H), 4.47 (br d, J=8.8 Hz, 1H), 7.20 (br s, 1H), 6.94 (br dd, J=8.8, 2.5 Hz, 1H), 3.79 (br s, 3H).
37%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane at 20℃;	j0379j 2.5 M n-butyllithium in hexanes (2.8 mE, 7.00 mmol) was added slowly to a solution of 5-methoxy-i-benzofuran(1.0 g, 6.75 mmol) in dry tetrahydrothran (15 mL) at -78 °C under a nitrogen atmosphere. After 1 hour stirring at -78 °C, triisopropylborate (3.12 mL, 13.5 mmol) was added drop-wise and the mixture stirred for 30 minutes at -78 °C. The dry ice bath was removed, 2 M aqueous hydrochloric acid (20 mL) was added and the mixture warmed to room temperature whilst stirring overnight. The reaction mixture was poured into waler (25 mL) and extracted with diethyl ether (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Dichloromethane (20 mL) was added and the mixture sonicated for 10 minutes. The minimum amount of methanol (ca. 1 mL) was added to ffilly dissolve the solids and the solution sonicaled for 10 minutes. Heptane (20 mL) was added and the precipitated solids collected by vacuum filtration and allowed to dry under vacuum for 2 hours to give the title compound 476 mg (37percent yield) as a white solid. On NMR (500 MHz, DMSO) 8.53 (s, 2H), 7.46 (d, J= 8.94 Hz, IH), 7.39 (s, lH), 7.19 (d, J= 2.51 Hz, 1H), 6.93 (dd, J= 2.60,8.92 Hz, 1H), 3.78 (s, 3H).

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1976 - 1980
[2] Patent: US2006/52378, 2006, A1, . Location in patent: Page/Page column 96
[3] Patent: WO2016/33445, 2016, A1, . Location in patent: Paragraph 0379

5
[ 13391-28-1 ]
[ 5419-55-6 ]
[ 551001-79-7 ]

Yield	Reaction Conditions	Operation in experiment
69.8%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333 h; Stage #2: at -78 - 20℃; for 2 h;	To 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL) at -78 °C wasadded 1.6 N n-BuLi in hexanes (1.190 mL, 1.903 mmol) dropwise. The solution became slightly yellow. The reaction mixture was stirred at -78 °C for 20 mm, followed by addition of triisopropyl borate (0.737 mL, 3.17 mmol). After 30 mm stirring at -78 °C, the cooling bath was removed and the stirring was continued at room temperature for 1.5h. The reaction mixture was diluted with EtOAc, quenched with 3.0 mL of 1.0 N HC1.After stirring at room temperature for 25 mm, the organic layer was collected, washedwith brine and dried over sodium sulfate. After evaporation of solvent, the cmde product was dissolved in a small amount of chloroform/a drop of MeOH and charged to a 4 g silica gel cartridge which was eluted with hexanes for 2 mm., then a 10 mm gradient from 0percent to 60percent. The desired fractions were combined, concentrated and lyophilized to giveIntermediate 2A (170 mg, 0.886 mmol, 69.8 percent yield) as a white solid. ‘H NMR (500MHz, methanol-d4) ö 7.41 (d, J=9. 1 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J2.5 Hz, 1H), 6.96 (dd, J=8.9, 2.6 Hz, 1H), 3.84 (s, 3H); LC-MS: method A, RT = 1.45 mm, MS (ESI) m/z: 149.0 (M-B(OH)2)t
37%	With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h; Inert atmosphere	Step 1, Method 3: (5-Methoxy-l-benzofuran-2-yl)boronic acid[0149] 2.5 M M-butyllithium in hexanes (2.8 mL, 7.00 mmol) was added slowly to a solution of 5-methoxy-l-benzofuran (1.0 g, 6.75 mmol) in dry tetrahydrofuran (15 mL) at -78 °C under a nitrogen atmosphere. After 1 hour stirring at -78 °C, triisopropylborate (3.12 mL, 13.5 mmol) was added drop-wise and the mixture stirred for 30 minutes at -78 °C. The dry ice bath was removed, 2 M aqueous hydrochloric acid (20 mL) was added and the mixture allowed to warm to room temperature whilst stirring overnight. The reaction mixture was poured into water (25 mL) and extracted with diethyl ether (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over magnesium sulphate, filtered and concentrated. Dichloromethane (20 mL) was added and the mixture sonicated for 10 minutes. The minimum amount of methanol (circa 1 mL) was added to fully dissolve the solids and the solution sonicated for a 10 minutes. Heptane (20 mL) was added and the precipitated solids collected by vacuum filtration and allowed to dry under vacuum for 2 hours to give the title compound 476 mg (37percent yield) as a white solid. 5H NMR (500 MHz, DMSO) 8.53 (s, 2H), 7.46 (d, J= 8.94 Hz, 1H), 7.39 (s, 1H), 7.19 (d, J= 2.51 Hz, 1H), 6.93 (dd, J= 2.60, 8.92 Hz, 1H), 3.78 (s, 3H).

Reference： [1] Patent: WO2018/13774, 2018, A1, . Location in patent: Page/Page column 292; 397
[2] Patent: WO2016/33460, 2016, A1, . Location in patent: Paragraph 0149
[3] Journal of Biological Inorganic Chemistry, 2018, vol. 23, # 7, p. 1139 - 1151

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[ 13391-28-1 ]
[ 5419-55-6 ]
[ 7732-18-5 ]
[ 551001-79-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: With n-butyllithium In tetrahydrofuran at -60 - -10℃; for 1.25 h; Inert atmosphere Stage #2: at -60 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran at 20℃; for 1 h;	Step 1. 5-Methoxybenzofuran-2-ylboronic acidThe solution of 5-methoxybenzofuran (1.0 g, 6.76 mmol) in dry tetrahydrofuran (50 mL) was kept below -60°C under nitrogen, while BuLi (8.10 mmol, 2.5M solution in hexane) was added dropwise. It was warmed to -10°C during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below -60°C, followed by dropwise addition of triisopropyl borate (3.8 g, 20.21 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (30 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3 x 80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5- methoxybenzofuran-2-ylboronic acid (986 mg, 76percent), which was used for the next step without further purification.'H-NMR (300 MHz, CDC1₃): δ 8.52 (s, 2H), 7.45 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 0.9 Hz, 1H), 7.18 (d, / = 2.7 Hz, 1H), 6.91 - 6.95 (m, 1H), 3.78 (s, 3H)

Reference： [1] Patent: WO2012/119046, 2012, A2, . Location in patent: Page/Page column 63

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[ 13391-28-1 ]
[ 688-74-4 ]
[ 551001-79-7 ]

Yield	Reaction Conditions	Operation in experiment
48%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -30℃; for 1 h; Stage #2: at 14℃; for 12 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water	5-Methoxybenzofuran (5.3 g, 35.8 mmol) was dissolved in anhydrous THF (120 mL) and cooled to −30° C. The solution was treated with n-BuLi (18 mL, 45 mmol, 2.5 M in hexanes) over 30 min, maintaining the internal temperature at −30° C. during the addition to give a yellow solution. After 1 h at −30° C., tributyl borate (12.2 mL, 45.1 mmol) was added over 10 min and the solution became pale yellow. The resulting solution was allowed to warm slowly to 14° C. over 12 h, then was quenched with 6 M HCl (50 mL) and extracted with EtOAc (150 mL). The organics were washed with water, then brine and dried over MgSO₄. After filtration, the organic solution was concentrated and the boronic acid precipitated by the addition of hexanes. The solid was filtered and washed with hexanes to give an off-white solid (3.95 g, 48percent).

Reference： [1] Patent: US2014/256936, 2014, A1, . Location in patent: Paragraph 0347

[ 13391-28-1 ] Synthesis Path-Downstream 1~88

1
[ 39581-55-0 ]
[ 13391-28-1 ]

Reference： [1]Journal of the Chemical Society,1953,p. 3602,3605
[2]Patent: WO2015/95261,2015,A1
[3]Patent: WO2015/89842,2015,A1

2
[ 10242-08-7 ]
[ 13391-28-1 ]

Reference： [1]Biochemical Journal,1957,vol. 66,p. 188,191

3
[ 13391-28-1 ]
[ 122-78-1 ]
[ 139201-44-8 ]

Yield	Reaction Conditions	Operation in experiment
243 gm (90%)	With n-butyllithium; In tetrahydrofuran; hexane; water; ethyl acetate;	Step (A) Preparation of 2-(1-hydroxy-2-phenyl)ethyl-5-methoxy-benzofuran, E2 To a solution of <strong>[13391-28-1]5-methoxybenzofuran</strong>, E1, (148 gm; 1 mole) in tetrahydrofuran (2 L) at -78 C. was added dropwise 2.5 molar n-butyllithium in hexane (420 mL; 1.05 moles). The mixture was stirred at -78 C. for 1.5 hours and then phenyl acetaldehyde (144 gm; 1.2 moles) was added over 15 minutes. The cooling bath was removed and the mixture permitted to gradually rise to 0 C. Water (600 mL) was added. The ether layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The crude was chromatographed in silica gel (2 Kg) using a solvent mixture of increasing polarity of 5%, 10%, 20% and 30% ethylacetate in hexane to obtain 243 gm (90%) of 2-(1-hydroxy-2-phenyl)ethyl-<strong>[13391-28-1]5-methoxybenzofuran</strong>, E2 m.p. 69-70 C. Anal. Calc'd. for C17 H16 O3: C, 76.09; H, 6.01. Found: C, 76.17; H, 6.12.

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 1299 - 1318
[2]Patent: US5091533,1992,A

4
[ 13391-28-1 ]
[ 13391-30-5 ]

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 4417 - 4429
[2]ACS Catalysis,2020,p. 2124 - 2130
[3]Journal of Heterocyclic Chemistry,1985,vol. 22,p. 1389 - 1393

5
[ 13391-28-1 ]
[ 100586-82-1 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 749 - 754

6
[ 13391-28-1 ]
[ 77440-98-3 ]
[ 77440-95-0 ]
[ 77440-97-2 ]
[ 77440-96-1 ]

Reference： [1]Bulletin de la Societe Chimique de France,1980,vol. 2,p. 601 - 608
[2]Bulletin de la Societe Chimique de France,1980,vol. 2,p. 601 - 608
[3]Bulletin de la Societe Chimique de France,1980,vol. 2,p. 601 - 608

7
[ 69034-13-5 ]
[ 13391-28-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With tin-exchanged H-b zeolite (Sn-b); for 0.5h;Reflux;	General procedure: A 25 mL round-bottomed flask was charged with 2-aryloxyacetaldehyde diethyl acetals (1 mmol), Sn-b (0.1 g), andtrifluorotoluene (10 mL). The mixture was stirred under refluxingcondition and monitored by GC. Upon completion, the mixture wascooled to room temperature, and the catalyst Sn-b was filtrate off.The filter cake was washed with trifluorotoluene (10 mL3). Thecombined filtratewas concentrated under vacuum. The residuewaspurified by flash column chromatography on SiO2 (petroleumether/ethyl acetate) to afford the desired 2,3-unsubstituted benzo[b]furans.
78%	With Amberlyst-15; In chlorobenzene; at 120℃; for 3h;	General procedure: To a solution of 13a (or 13b) (3 mmol) in 30 mL of chlorobenzene was added Amberlyst-15 (10 wt%). The mixture was heated at 120C for 3h. After cooling down to room temperature, the mixture was filtered and the solvent was removed under reduced pressure. The residue were purified on silica gel (EP/Et2O 8/2) to give compound 14a (or 14b) as yellow oil with 78% (or 75%) yield. 1H and 13C spectra of compounds 14a-b were in agreement with literature data.
33%	With Amberlyst 15; In toluene; for 6h;Reflux;	The mixture of the product of Step A(420 g, 1.87 mmol) and Amberlyst 15(42 g) in toluene (2 L) was stirred at reflux for 6hrs with concomitant azeotrope removal of EtOH generated in the reaction (keep the solvent more than 1.5 L). The resulting reaction mixture was filtered and the resin was washed with an excess of toluene. The combined filtrates were concentrated to dryness under reduced pressure. The crude product was distilled at 100 C underreduced pressure through a lab oil pump to afford (105 g, 74 C fraction). The solid was dilutedwith 1000 mL of PE and washed with NaOH (3 M, 200 mL x 2), brine (500 mL x 3), dried overanhydrate sodium sulfate and concentrated under reduced pressure to give the title compounds(85 g, 33%) as a white solid. ?HNMR (400 IVIHz, CDC13) 7.59 (d, J 2.0 Hz, 1H), 7.39 (d, J9.0 Hz, 1H), 7.05 (d, J 2.4 Hz, 1H), 6.90 (dd, J= 9.0, 2.4 Hz, 1H), 6.73 - 6.68 (m, 1H), 3.84 (s,3H)ppm.

33%	With Amberlyst 15; In toluene; for 6h;Reflux;	The mixture of the product of Step A (420 g, 1.87 mmol) and Amberlyst 15 (42 g) intoluene (2 L) was stirred at reflux for 6hrs with concomitant azeotrope removal of EtOHgenerated in the reaction (keep the solvent more than 1.5 L). The resulting reaction mixture was filtered and the resin was washed with an excess of toluene. The combined filtrates were concentrated to dryness under reduced pressure. The crude product was distilled at 100 C under reduced pressure through a lab oil pump to afford (105 g, 74 C fraction). The solid wasdiluted with 1000 mL of PE and washed with NaOH (3 M, 200 mL x 2), brine (500 mL x 3), dried over anhydrate sodium sulfate and concentrated under reduced pressure to give the title compounds (85 g, 33%) as a white solid. ?H NIVIR (400 IVIHz, CDC13) 7.59 (d, J= 2.0 Hz, 1H), 7.39 (d, J= 9.0 Hz, 1H), 7.05 (d, J= 2.4 Hz, 1H), 6.90 (dd, J 9.0, 2.4 Hz, 1H), 6.73 -6.68 (m, 1H), 3.84 (s, 3H) ppm.
	With Amberlyst-15 resin; In toluene; at 20℃; for 7h;Reflux; Dean-Stark;	To a solution of 2-(4-methoxyphenoxy)-1,1-diethoxyethane (166.9 g, 0.695 mol) in toluene (835 mL) was added Amberlyst-15 resin (16.7 g, 10 wt%). The reaction mixture was heated at reflux for a total of 7 h while ethanol was removed via azeotropic distillation with a Dean-Stark trap. The mixture was then cooled to room temperature, filtered and concentratedat the rotary evaporator. The resulting dark oil was twice reconstituted in 200 mL of methanoland concentrated to 96.1 g of residue. The cmde product was chromatographed on 1.5 kg ofSiliaFlash G-60 using 10% MTBE in n-heptane. 5-methoxybenzofuran was isolated as 40.6 g(39%) of a clear oil.

Reference： [1]Tetrahedron,2015,vol. 71,p. 4835 - 4841
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1863 - 1870
[3]Synthetic Communications,1989,vol. 19,p. 257 - 266
[4]European Journal of Organic Chemistry,2018,vol. 2018,p. 2774 - 2779
[5]Synthetic Communications,2006,vol. 36,p. 1983 - 1990
[6]Patent: WO2014/206343,2014,A1 .Location in patent: Page/Page column 47
[7]Patent: WO2014/206344,2014,A1 .Location in patent: Page/Page column 56; 57
[8]European Journal of Organic Chemistry,2016,vol. 2016,p. 2268 - 2273
[9]Angewandte Chemie - International Edition,2018,vol. 57,p. 15204 - 15208
Angew. Chem.,2018,vol. 130,p. 15424 - 15428,5
[10]New Journal of Chemistry,2016,vol. 40,p. 6564 - 6567
[11]Organic Letters,2016,vol. 18,p. 5624 - 5627
[12]Patent: WO2017/87965,2017,A1 .Location in patent: Page/Page column 23
[13]Chemical Communications,2019,vol. 55,p. 11187 - 11190

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[ 111437-45-7 ]
[ 13391-28-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 3029 - 3036

9
[ 13391-28-1 ]
[ 454182-00-4 ]
3-methoxy-6-(5-methoxy-benzofuran-2-sulfonyl)-pyridazine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6326 - 6339

10
[ 13391-28-1 ]
[ 13196-10-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With boron tribromide-dimethyl sulfide complex; In dichloromethane; chlorobenzene; at 0 - 120℃;Inert atmosphere;	General procedure: To a solution of 14a (or 14b) (2 mmol) in anhydrous chlorobenzene (20 mL) a solution of BBr3SMe2 1M in CH2Cl2 (4 mL, 4 mmol) was added dropwise at 0C and under Ar atmosphere. The reaction was kept stirring at reflux for 10h. After cooling down, the reaction was quenched with water and extracted with CH2Cl2 (three times). The organic layers were collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The crude was purified on silica gel to afford compounds 9a (or 9b) with 80% (or 81%) yield. 1H and 13C spectra of compounds 9a-b were in agreement with literature data.[1]
79.6%	With boron tribromide; In dichloromethane; at 0 - 20℃; for 3h;	To an ice-cooled solution of 5-methylbenzofuran (0.5 g, 3.37 mmol) in DCM (7 mL) was added boron tribromide (3.4 mL, 3.37 mmol, IM in DCM). The light brown solution was stirred at 0 0C for Ih, another equivalent of boron tribromide (3.4 mL) was then added. The mixture was stirred at room temperature for 2 h. TLC analysis indicated the completion of the reaction. The mixture was poured into ice and the pH was adjusted to 7 with Na2CO3. The aqueous was extracted with DCM (x2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The resulting light brown sold gave the satisfactory purity without further purification for next step: 0.36 g (79.6% yield), 1H NMR (400 MHz, CD3OD) delta 7.59(d, J = 2.0 Hz, IH), 7.35(d, J = 9.2 Hz, IH), 7.01(d, J = 2.4 Hz, IH), 6.82 (dd, J = 8.8 Hz, J = 2.8 Hz, IH), 6.67 (m, IH), 4.73 (s, IH).
77%	With hydrogenchloride; sodium ethanolate; 2-(diethylamine)ethanethiol; In 1-methyl-pyrrolidin-2-one; ethanol; at 150℃;Inert atmosphere; Dean-Stark;	A mixture of <strong>[13391-28-1]5-methoxybenzofuran</strong> (61.6 g, 0.416 mol), 2-(diethylamino)ethanethiol:HC1 (88.4 g, 0.521 mol) and NMP (600 mL) was sparged with nitrogen for 10 mi Sodium ethoxide solution (388 mL, 21 wt% in EtOH, 1.04 mol) was added and the resulting solution was heated to 150C overnight. A Dean-Stark trap was used to distill off ethanol during the reaction. The mixture was cooled to room temperature and acidified with 1.1 L of 1 ON HC1.The solution was then partitioned with 850 mL of ethyl acetate. The layers were separated and the aqueous layer back extracted twice with 300 mL of ethyl acetate. The combined organic extracts were washed twice with 300 mL of water, once with 150 mL of brine and then dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated by rotary evaporation to 72.4 g of a dark oil. This residue was purified on SiliaFlash G-60(2.0 L, 1.0 kg) using 10% EtOAc/n-heptane as eluant, providing 52.4 g of material as waxy solids, 94.8% purity by LC with significant non-polar impurities. The material was slurned for one-hour in 200 mL of n-heptane and then filtered. The solids were further washed with 150 mL of n-heptane and air-dried giving 29.7 g of 5-hydroxybenzofuran with an LC purity of 98.9%. The filtrate was concentrated by rotary evaporation to a residue (16.4 g) which waspurified on SiliaFlash G-60 (0.90 L, 0.45 kg) using a gradient of 10-25% EtOAc in nheptane as eluant. This provided an additional 13.0 g of with a 99.5% purity, for a total combined yield of 5-hydroxybenzofuran of 42.7 g (77%).

51.3%	With boron tribromide; In dichloromethane; at 0℃;	To an ice-cooled solution of <strong>[13391-28-1]5-methoxybenzofuran</strong> (0.71 g, 4.79 mmol) in dichloromethane (8.0 mL) was added 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol). The mixture was stirred at 0 C for 1.0 h. HPLC indicated ca 30-40%starting material still remaining. Then another portion of 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol) was added and the mixture was stirred from 0 C to room temperature over an hour. HPLC indicated a complete conversion of starting material. The mixture was poured into ice water, stirred for 15 mm, extracted with dichloromethane. The organic layer was dried over sodium sulfate. After evaporation ofsolvent, Intermediate 44A (0.33 g, 2.460 mmol, 51.3 % yield) was obtained as slightlybrown oil. It was used for the next step without further purification. ?H NMR (500MHz,chloroform-d) 7.60 (d, J=2.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H),6.82 (dd, J=8.8, 2.8 Hz, 1H), 6.69-6.67 (m, 1H), 4.78 (s, 1H); LC-MS: Method A, 50 to100% B. RT = 2.32 mm, MS (ESI) m/z: no (M+H)
	With lithium iodide; In 2,3,5-trimethyl-pyridine;	Reference Example 202 To a solution of <strong>[13391-28-1]5-methoxybenzofuran</strong> (3.6 g) in collidine (20 ml) was added lithium iodide (6.5 g), and the mixture was refluxed, under argon atmosphere, overnight, cooled, made acidic (pH=4) with hydrochloric acid and extracted with ethyl acetate (three times). The organic layer was washed with 1N hydrochloric acid (twice) and then washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give yellow oil of 5-hydroxybenzofuran (1.6 g). 1H-NMR (200 MHz, CDCl3) delta 6.61 (dd, 1H, J=2.2, 0.6 Hz), 6.82 (dd, 1H, J=8.8, 2.6 Hz), 7.01 (d, 1H, J=2.6 Hz), 7.34 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=2.2 Hz).
	With boron tribromide; In dichloromethane; at 0 - 20℃;	To a stirred solution of <strong>[13391-28-1]5-methoxybenzofuran</strong> (1) (0.50 g, 3.38 mmol) in dichloromethane (15 mL), boron tribromide (16.87 mL, 16.87 mmol, IM solution in dichloromethane) was added slowly at O0C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was then cooled to O0C, quenched with aqueous saturated NaHCO3 solution and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound (2) as an off white solid (300 mg) which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-J) delta: 7.59 (d, J=I.95 Hz, 1 H), 7.35 (d, J=8.59 Hz, IH), 7.00 (d, J=2.73 Hz, IH), 6.80 (dd, 8.59, 2.74 Hz, IH), 6.67 (m, IH), 4.66 (s, IH)
	With boron trichloride; tetra-(n-butyl)ammonium iodide; In dichloromethane; at -78 - 20℃; for 16h;	Preparation 15 Benzofuran-5-ol To a mixture of <strong>[13391-28-1]5-methoxybenzofuran</strong> (10.0 g, 67.5 mmol) and tetrabutylammonium iodide (31.2 g, 84.4 mmol) in CH2Cl2 (100 mL) at -78 C. was added BCl3 (169 mL of a 1 M solution in CH2Cl2, 169 mmol) dropwise over 1 h. The reaction mixture was stirred for 1 h, warmed to rt, stirred for 14 h, poured slowly into sat. NaHCO3 and ice, and extracted with CH2Cl2 (2*). The combined extracts were dried (MgSO4), filtered, concentrated, and chromatographed (20% EtOAc in hexanes) to provide 9.16 g of benzofuran-5-ol as an orange solid. 1H NMR (400 MHz, CDCl3): delta 7.57 (d, 1, J=2.1), 7.34 (d, 1, J=8.7), 7.03 (d, 1, J=2.7), 6.84 (dd, 1, J=8.8, 2.6), 6.64 (dd, 1, J=2.2, 0.9), 6.20 (s, 1). Previously synthesised but data are not provided. Rene, L.; Royer, R. Bull. Soc. Chim. France, 1973, 7-8 (Pt. 2), 2355-6. The TBAl/BCl3 procedural reference is Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.; Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64, 9719-9721.
		prepared from <strong>[13391-28-1]5-methoxybenzo[b]furan</strong> according to a similar demethylation method as described in WO 04/043904).
		To a solution of BBr3-SMe2 (9.45 g; 30.22 mmol) in dichloroethane (50 mL) was added 5-Methoxy-benzofuran (1.28 g; 8.64 mmol), and the mixture was refluxed for 4 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. To the resultant mixture was added water carefully, and the reaction mixture was stirred for 20 minutes. The resultant mixture was diluted with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford the title compound. 1H NMR (400 MHz, CDCl3) delta: 7.60 (d, J=2.3 Hz, 1H), 7.37 (d, 1H), 7.02 (d, 1H), 6.82 (dd, 1H), 6.68 (dd, 1H), 4.59 (s, 1H).
		To a solution of the product of Step B (50 g, 0.34 mol) in CH2C12 (1200 mL) was addedBBr3 (32.5 mL, 0.34 mol) in drops at -20C under N2. After the addition, the mixture waswarmed to 20C and stirred for 2 hrs. The reaction mixture was cooled to 0 C and added into a solution of NH3/MeOH (3 mol/L, 500 mL) using a canula at -20 C over a period of 15 mm carefully. The mixture was concentrated and the residue was added EA (500 mL). The solid was filtered off through a silica pad and the filtrate was concentrated under reduced pressure to give the crude product (crude, 48 g) as a oil which was used for the next step directly. ?H NIVIR (400MHz, DMSO-d6) 9.14 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.36 (d, J 8.8 Hz, 1H), 6.94 (d, J2.4 Hz, 1H), 6.79 (dd, J= 2.0, 0.9 Hz, 1H), 6.74 (dd, J= 8.8, 2.4 Hz, 1H) ppm. MS: IVJIe 135 (M+1).
		To a solution of the product of Step B (50 g, 0.34 mol) in CH2C12 (1200 mL) was added BBr3 (32.5 mL, 0.34 mol) in drops at -20 C under N2. After the addition, the mixture waswarmed to 20C and stirred for 2 hrs. The reaction mixture was cooled to 0 C and added into a solution of NH3/MeOH (3 mol/L, 500 mL) using a canula at -20 C over a period of 15 mm carefully. The mixture was concentrated and the residue was added EA (500 mL). The solid was filtered off through a silica pad and the filtrate was concentrated under reduced pressure to give the crude product (crude, 48 g) as a oil which was used for the next step directly. ?H NMR(400 IVIFIz, DMSO-d6) 9.14 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.36 (d, J 8.8 Hz, 1H), 6.94 (d, J 2.4 Hz, 1H), 6.79 (dd, J 2.0, 0.9 Hz, 1H), 6.74 (dd, J= 8.8, 2.4 Hz, 1H) ppm. MS:IVJIe 135 (M+1).
	With boron tribromide; In dichloromethane; at -60 - 0℃; for 2h;Inert atmosphere;	Step 5: BBr3 (2.6 mL, 13.5 mmol) was added dropwise to S22-4 (2.0 g, 13.Smmol) in DCM (20mL) at -60 C under N2. The solution was stirred at 0C for 2h. The mixture was poured into iceand adjusted the pH to 1213. The inorganic phase was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S22-5.
	With boron tribromide; In dichloromethane; at -60 - 0℃; for 2h;Inert atmosphere;	Step 5: BBr3 (2.6 mL, 13.5 mmol) was added dropwise to S22-4 (2.0 g, 13.5mmol) in DCM (20 mL) at -60 C under N2. The solution was stirred at 0C for 2h. The mixture was poured into ice and adjusted the pH to 12-13. The inorganic phase was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S22- 5.
	With sodium ethanolate; ethanethiol; In N,N-dimethyl-formamide; at 110 - 130℃; for 45h;Inert atmosphere; Large scale;	To a stirred solution of EtONa (154 kg) in DMF (989 kg) was added EtSH (68.6 kg) at an inner temperature ?35 under nitrogen protection. The mixture was stirred for 6090min at the inner temperature ?35. 5-Methoxybenzofuran (58.75 kg) in DMF (55.0 kg) was added. The mixture was heated to 110-130, stirred for 45hrs, and then concentrated under vacuum below 90. After the mixture was cooled to 1020, 2N HCl (1326 kg) was added dropwise, followed by addition of EtOAc (531 kg) and H2O2(129 kg) at the inner temperature ?35. The mixture was stirred for 3060min. After separation of the organic layer, the aqueous phase was extracted with EtOAc. The combined organic phase was washed with saturated brine twice, and then the solvent was evaporated to dryness. MeOH and a solution of NaOH (44.5 kg) in water (185 kg) were added dropwise into the residue below 40. The mixture was stirred for 5-7 hrs at 3040. Active carbon (74 kg) wet up with water (77 kg) was added. The mixture was stirred for 4-6 hrs at 3040 and filtered and the filter cake was washed with MeOH and water. DCM was charged into the filtrate and pH was adjusted to 1 with 35aq. HCl below 40. The aqueous phase was extracted with DCM, and the organic phase was washed with 25NaCl and concentrated below 40 . The residue was used in the next step directly.1H NMR (400 MHz, DMSO-d6) delta 9.14 (s, 1H) , 7.86 (d, J 2.0 Hz, 1H) , 7.36 (d, J 8.8 Hz, 1H) , 6.94 (d, J 2.4 Hz, 1H) , 6.79 (dd, J 2.0, 0.9 Hz, 1H) , 6.74 (dd, J 8.8, 2.4 Hz, 1H) ppm. MS: M/e 135 (M+1)+.
	With sodium ethanolate; ethanethiol; In N,N-dimethyl-formamide; at 110 - 130℃; for 45h;Inert atmosphere; Large scale;	To a stirred solution of EtONa (154 kg) in DMF (989 kg) was added EtSH(68.6 kg) at an inner temperature ^35C under nitrogen protection. The mixture was stirred for 60~90min at the inner temperature ^35C. 5-Methoxybenzofuran (58.75 kg) in DMF (55.0 kg) was added. The mixture was heated to 110-130C, stirred for 45 hours, and then concentrated under vacuum below 90C. After the mixture was cooled to 10~20C, 2N HCl (1326 kg) was added dropwise, followed by addition of EtOAc (531 kg) and H202 (129 kg) at the inner temperature ^35C. The mixture was stirred for 30~60min. After separation of the organic layer, the aqueous phase was extracted with EtOAc. The combined organic phase was washed with saturated brine twice, and then the solvent was evaporated to dryness. MeOH and a solution of NaOH (44.5 kg) in water (185 kg) were added dropwise into the residue below 40C. The mixture was stirred for 5-7 hours at (0191) 30~40C. Active carbon (74 kg) wet up with water (77 kg) was added. The mixture was stirred for 4-6 hours at 30~40C and filtered; and the filter cake was washed with MeOH and water. DCM was charged into the filtrate and pH was adjusted to 1 with 35% aq. HCl below 40C. The aqueous phase was extracted with DCM, and the organic phase was washed with 25% NaCl and (0192) concentrated below 40 C. The residue was used in the next step directly. 1H MR (400 MHz, DMSO-^6) delta 9.14 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.36 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 2.4 Hz, 1H), 6.79 (dd, J= 2.0, 0.9 Hz, 1H), 6.74 (dd, J= 8.8, 2.4 Hz, 1H) ppm. MS: M/e 135 (M+l)+.

Reference： [1]Chemical Communications,2016,vol. 52,p. 3348 - 3351
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[3]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1863 - 1870
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[5]Patent: WO2017/87965,2017,A1 .Location in patent: Page/Page column 23
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11
[ 13391-28-1 ]
[ 909398-11-4 ]

Reference： [1]Synthetic Communications,2006,vol. 36,p. 1983 - 1990

12
[ 13391-28-1 ]
[ 909398-09-0 ]

Reference： [1]Synthetic Communications,2006,vol. 36,p. 1983 - 1990

13
[ 13391-28-1 ]
[ 58546-89-7 ]

Reference： [1]Synthetic Communications,2006,vol. 36,p. 1983 - 1990

14
[ 150-76-5 ]
[ 13391-28-1 ]

Reference： [1]Synthetic Communications,2006,vol. 36,p. 1983 - 1990
[2]Journal of the Chinese Chemical Society,2004,vol. 51,p. 1307 - 1318
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[4]Journal of the Chemical Society. Perkin transactions I,1988,p. 3029 - 3036
[5]Journal of Organic Chemistry,2013,vol. 78,p. 5530 - 5543
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[8]Patent: WO2014/206344,2014,A1
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[18]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1863 - 1870
[19]Chemical Communications,2019,vol. 55,p. 11187 - 11190

15
[ 13391-35-0 ]
[ 13391-28-1 ]

Reference： [1]Journal of the Chinese Chemical Society,2004,vol. 51,p. 1307 - 1318

16
[ 584-82-7 ]
[ 13391-28-1 ]

Reference： [1]Journal of the Chinese Chemical Society,2004,vol. 51,p. 1307 - 1318

17
[ 865759-99-5 ]
[ 13391-28-1 ]

Reference： [1]Journal of the Chinese Chemical Society,2004,vol. 51,p. 1307 - 1318

18
[ 672-13-9 ]
[ 13391-28-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1997,p. 2483 - 2493
[2]Biochemical Journal,1957,vol. 66,p. 188,191

19
[ 93198-67-5 ]
[ 13391-28-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1997,p. 2483 - 2493

20
[ 13391-28-1 ]
[ 139201-45-9 ]