[ CAS No. 55745-70-5 ] {[proInfo.proName]}

Name: 55745-70-5|2,3-Dihydrobenzofuran-5-carbaldehyde|97%
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Quality Control of [ 55745-70-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 55745-70-5 ]

Product Details of [ 55745-70-5 ]

CAS No. :	55745-70-5	MDL No. :	MFCD00068058
Formula :	C₉H₈O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WEBVDBDZSOJGPB-UHFFFAOYSA-N
M.W :	148.16	Pubchem ID :	735901
Synonyms :		Chemical Name :	2,3-Dihydrobenzofuran-5-carbaldehyde

Calculated chemistry of [ 55745-70-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	41.17
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.71
Log Po/w (XLOGP3) :	1.6
Log Po/w (WLOGP) :	1.43
Log Po/w (MLOGP) :	1.05
Log Po/w (SILICOS-IT) :	2.65
Consensus Log Po/w :	1.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.1
Solubility :	1.17 mg/ml ; 0.00787 mol/l
Class :	Soluble
Log S (Ali) :	-1.76
Solubility :	2.55 mg/ml ; 0.0172 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.62
Solubility :	0.358 mg/ml ; 0.00242 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.62

Safety of [ 55745-70-5 ]

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

Application In Synthesis of [ 55745-70-5 ]

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

Upstream synthesis route of [ 55745-70-5 ]
Downstream synthetic route of [ 55745-70-5 ]

[ 55745-70-5 ] Synthesis Path-Upstream 1~15

1
[ 496-16-2 ]
[ 68-12-2 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 70 - 90℃; for 9.5 h;	2,3-Dihydrobenzofuran (100 g, 832 mmol) and N,N-dimethylformamide (134 g, 1830 mmol) were mixed and heated, and phosphorus oxychloride (255 g, 1643 mmol) were added thereto at an inner temperature of 70 to 80°C over 2 hrs. The reaction mixture was heated at an inner temperature of 80 to 90°C and stirred for 7.5 hrs. Then, the resulting mixture was added dropwise to water (1000 g) under cooling, and stirred at room temperature for 5 hrs. The resulting mixture was extracted with toluene, and the extract was washed sequentially with water, saturated sodium bicarbonate aqueous solution and water, and the organic layer was concentrated under vacuum to give a toluene solution of the title compound (amount 340 g, apparent yield 100percent).
98%	Stage #1: at 30 - 70℃; Stage #2: With water In N,N-dimethyl-formamide at 20℃; for 1 h;	To a solution of 2,3-dihydrobenzofuran (600.0 g, 4.99 moles) in N,N-dimethylformamide(804 g, 10.98 moles) was added drop-wise phosphorous oxychloride (1530 g, 9.96 moles) over a period of 45 min maintaining the temperature of reaction mixture between 30- 35°C. The mixture was slowly heated to 7O⁰C and stirred for 8 hr. The mixture was cooled to room temperature and poured into 8 lit of ice-cold water and stirred for 1 hr. The reaction mixture was saturated with sodium chloride and then the product was extracted with ethyl acetate (6L). The extract was washed with saturated aqueous solution of sodium bicarbonate (1.5 L) and concentrated under reduced pressure to obtain (725 g, 98percent) of the title compound.
93%	at 85℃; for 12 h; Cooling with ice	(31.4 ml, 0.333πο1) was slowly added dropwise to N, N-dimethylformamide (28.4 ml, 0.366 mol). After 10 minutes of reaction, the mixture was slowly added dropwise , 3-dihydrobenzofuran (1,20.0g, 0.166πο1), remove the ice bath, heating at 85 ° C stirring reaction for 12 hours, the reaction system into the ice water, add sodium hydroxide solution, adjust the PH value The organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), petroleum ether-ethyl acetate ( 5: 1) as eluant, to give 5-aldehyde dihydrobenzofuran (2,22.8 g) in a yield of 93percent.

85%	at 80 - 85℃; for 4 - 5 h;	Example 1; Synthesis of 2,3-dihydrobenzofuran-5-carboxaldehdye:Phosphorous oxychloride (255.58 g, 1.666 mol) was slowly added to a solution of DMF (355.0 ml) and 2, 3-dihydrobenzofuran (100 g, 0.833 mol) maintaining the temperature 80-85⁰C. The reaction mixture was stirred for 4-5 hr and the reaction progress monitored by HPLC. The reaction mixture was then poured into ice water and extracted with toluene (2000 ml). The organic layer was washed with 5percent sodium bicarbonate solution (500 ml) and then 10percent brine solution (500 ml). The organic layer was distilled off under vacuum at 50-60⁰C. A liquid product was isolated. Yield: 85- 90percent, Purity: 90-92 percent
14.5 g	at 70 - 80℃; for 10 h;	Take a 1001 ^ three mouth reaction bottle,2,3-dihydrobenzofuran (128, 0.1111) was dissolved in nitrogen,Nitrogen-dimethylformamide (120 g, 1.64 mil) was placed in a reaction flask,Heated to 70 ° C to 80 ° C in 2 hours with mechanical agitation, In part by adding phosphorus pentachloride / nitrogen,Nitrogen-dimethylformamide mixed formylating reagent (25 g, 0.2 mol).The reaction mixture was incubated for 8 hours.After the reaction,The reaction mixture was added dropwise to ice water (l0 g) and stirred at room temperature for 5 hours.Toluene 50mL extraction,Organic layer followed by water,Saturated aqueous sodium bicarbonate solution and washed with water,Dried over anhydrous sodium sulfate,filter,The organic layer was concentrated to give product 2, 3-dihydrobenzofuran-5-carbaldehyde (14. 5 g, 0.08 mil).This product can be used for the production of lamivudine.

Reference： [1] Patent: EP1792899, 2007, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2010/41271, 2010, A2, . Location in patent: Page/Page column 28
[3] Letters in Drug Design and Discovery, 2013, vol. 10, # 7, p. 561 - 571
[4] Patent: CN102766135, 2017, B, . Location in patent: Paragraph 0035-0036
[5] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[6] Patent: WO2008/151170, 2008, A2, . Location in patent: Page/Page column 45
[7] Patent: CN106554345, 2017, A, . Location in patent: Paragraph 0032-0033
[8] Patent: WO2008/150953, 2008, A1, . Location in patent: Page/Page column 29

2
[ 496-16-2 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With trichlorophosphate In water; N,N-dimethyl-formamide	Reference Example 1: Synthesis of 2,3-dihydrobenzofuran-5-carbaldehyde 2,3-Dihydrobenzofuran (100.0 g, 832.3 mmol) and N,N-dimethylformamide (133.8 g, 1830.6 mmol) were mixed and heated, and phosphorus oxychloride (255.2 g, 1643.0 mmol) was added dropwise thereto at an inner temperature of 70 to 80OEC over 2 hours. The mixture was heated to an inner temperature of 80 to 90OEC, stirred for 7.5 hours, cooled and then added dropwise to 1000 g of water, followed by stirring at room temperature for 5 hours. After extracting with toluene and washing in turn with water, saturated sodium bicarbonate water and water, the organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (yield: 340 g, apparent yield: 100percent)
100%	With trichlorophosphate In water; N,N-dimethyl-formamide	REFERENCE EXAMPLE 1 Synthesis of 2,3-Dihydrobenzofuran-5-carbaldehyde 2,3-Dihydrobenzofuran (100.0 g, 832.3 mmol) and N,N-dimethylformamide (133.8 g, 1830.6 mmol) were mixed and heated, and phosphorus oxychloride (255.2 g, 1643.0 mmol) was added dropwise thereto at an inner temperature of 70 to 80° C. over 2 hours. The mixture was heated to an inner temperature of 80 to 90° C., stirred for 7.5 hours, cooled and then added dropwise to 1000 g of water, followed by stirring at room temperature for 5 hours. After extracting with toluene and washing in turn with water, saturated sodium bicarbonate water and water, the organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (yield: 340 g, apparent yield: 100percent)
94%	With sodium hydrogencarbonate; trichlorophosphate In N,N-dimethyl-formamide	Reference Example 1 2,3-Dihydrobenzofuran-5-carbaldehyde To a solution of 2,3-dihydrobenzofuran (100.0 g, 832 mmols) in N,N-dimethylformamide (134.0 g, 1.83 mols) was added dropwise phosphorus oxychloride (255.1 g, 1.66 mols), then the mixture was stirred at 80-90° C. for 7.5 hours. The mixture was cooled to room temperature, poured into water (1 L) and stirred for 15 hours. The product was extracted with toluene (1.5 L). The extract was washed with water (500 mL) followed by a saturated aqueous solution of sodium bicarbonate (500 mL) and concentrated under reduced pressure to obtain 115.9 g (yield: 94percent) of the title compound.

Reference： [1] Patent: EP1334732, 2003, A1,
[2] Patent: US2004/18239, 2004, A1,
[3] Patent: US10098866, 2018, B2,
[4] Patent: US6348485, 2002, B1,
[5] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 16, p. 4313 - 4336

3
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[ 4885-02-3 ]
[ 55745-70-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[2] Patent: US6034239, 2000, A,
[3] Patent: EP1199304, 2002, A1, . Location in patent: Referential example 1
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 23, p. 3700 - 3706
[5] Patent: US6162927, 2000, A,
[6] Patent: US5767144, 1998, A,
[7] Patent: US5622971, 1997, A,

4
[ 496-16-2 ]
[ 4885-02-3 ]
[ 55745-70-5 ]
[ 196799-45-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 3, p. 322 - 330
[2] Patent: US2005/187282, 2005, A1, . Location in patent: Page/Page column 8

5
[ 66826-78-6 ]
[ 68-12-2 ]
[ 55745-70-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 16, p. 4313 - 4336

6
[ 68-12-2 ]
[ 55745-70-5 ]

Reference： [1] Tetrahedron Letters, 2000, vol. 41, # 14, p. 2269 - 2273

7
[ 76429-73-7 ]
[ 55745-70-5 ]

Reference： [1] Chemical Communications, 2017, vol. 53, # 73, p. 10228 - 10231

8
[ 109-72-8 ]
[ 66826-78-6 ]
[ 55745-70-5 ]

Reference： [1] Patent: US6649643, 2003, B1,

9
[ 496-16-2 ]
[ 542-88-1 ]
[ 55745-70-5 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 3, p. 409 - 413

10
[ 615-58-7 ]
[ 55745-70-5 ]

Reference： [1] Tetrahedron Letters, 2000, vol. 41, # 14, p. 2269 - 2273

11
[ 496-16-2 ]
[ 74-90-8 ]
[ 55745-70-5 ]

Reference： [1] Journal of the Chemical Society, 1956, p. 2455,246

12
[ 55745-70-5 ]
[ 10035-16-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chlorobenzene at 20 - 80℃; for 1 h; Inert atmosphere	NBS (0.656 g, 3.69 mmol) and AIBN (8.10 mg, 49.2 lmol) wereadded to a solution of 107 (0.364 g, 2.46 mmol) in chlorobenzene(7.3 mL) at room temperature under an argon atmosphere. Afterstirring for 1 h at 80 C, the mixture was cooled to room temperatureand diluted with EtOAc. The organic layers were washed withsaturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, andconcentrated in vacuo. The residue was purified by silica gel CC(EtOAc/hexane, 3:97) to afford benzofuran-5-carbaldehyde (108)(0.268 g, 1.84 mmol, 75percent) as a colorless oil: 1H-NMR (CDCl3,400 MHz) d: 6.82 (d, J = 2.0 Hz, 1H, furan-H), 7.54 (d, J = 8.8 Hz,1H, Ar–H), 7.65 (d, J = 2.0 Hz, 1H, furan-H), 7.79 (d, J = 8.8 Hz, 1H,Ar–H), 8.07 (s, 1H, Ar–H), 9.99 (s, 1H, –CHO); spectroscopic datawere consistent with those reported in the literature (van Otterloet al., 2005).
60%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chlorobenzene at 80℃; for 1 h;	To a solution of 2,3-dihydrobenzofuran-5-carbaldehyde (1 g, 6.75 mmol, A) in Chlorobenzene (20 mL), NBS (1.44 g, 8.10 mmol), AIBN (22 mg, 0.13 mmol) were added and the mixture was stirred at 80° C. for 1 h. After cooling the reaction mixture to room temperature, it was washed with aqueous NaHCO₃. The organic layer was separated and the aqueous layer was washed with CH₂Cl₂. The organic layers were combined, dried over Na₂SO₄and concentrated under vacuum on a rotary evaporator. The crude product was purified via gradient column chromatography using hexanes and ethyl acetate (100:1 to 1:1) to obtain the desired aldehyde B as brown syrup (60percent) which solidifies at 0° C. [0076] ¹H NMR (500 MHz, CDCl₃): δ 10.07 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.5, 8.6 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 6.90 (m, 1H). [0077] ¹³C NMR (125 MHz, CDCl₃): δ 191.7, 158.2, 146.7, 132.2, 125.7, 124.6, 112.1, 107.2
55%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chlorobenzene at 80℃; for 4 h; Cooling with ice	To an ice-cold stirred solution of compound A (500 mg, 3.37 mmol, leq) in chlorobenzene (10 ml) were added NBS (721 mg, 4.05 mmol, 1.2 eq) in portions and AIBN (11 mg, 0.07 mmol, 0.02 eq) and the resulting solution was stirred at 80 °C for 4 h. The reaction mixture was cooled to RT, concentrated in vacuo and the residue was washed with saturated aq. NaHCC>3 solution (20 ml). The organic components were extracted with ethyl acetate (50 ml) and the ethyl acetate layer was concentrated in vacuo. The crude material was purified by flash chromatography (Combiflash) using 100-200 mesh silica gel eluting with 5percent ethyl acetate/hexane to obtain the compound B (270 mg, 55percent) as white solid. [0176] ^{FontWeight="Bold" FontSize="10"}H NMR (400 MHz, OMSO-d₆) δ 10.06 (s, 1 H), 8.28 (s, 1 H), 8.16-8.16 (m, 1 H), 7.89-7.87 (m, 1 H), 7.81-7.79 (m, 1 H), 7.16-7.15 (m, 1 H); (0181) [0177] LCMS: m/z = 147.4 [M+H], RT = 2.99 minutes; (Program Rl, Column Y).

Reference： [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 20, p. 6270 - 6286
[2] Phytochemistry, 2013, vol. 96, p. 132 - 147
[3] Patent: US2014/309427, 2014, A1, . Location in patent: Paragraph 0074; 0075; 0076; 0077
[4] Patent: WO2018/64135, 2018, A1, . Location in patent: Paragraph 0174-0177

13
[ 496-16-2 ]
[ 4885-02-3 ]
[ 55745-70-5 ]
[ 196799-45-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 3, p. 322 - 330
[2] Patent: US2005/187282, 2005, A1, . Location in patent: Page/Page column 8

14
[ 55745-70-5 ]
[ 196597-78-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[2] Patent: WO2008/150953, 2008, A1,
[3] Patent: WO2008/150953, 2008, A1,
[4] Patent: WO2008/151170, 2008, A2,

15
[ 55745-70-5 ]
[ 448964-30-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[2] Letters in Drug Design and Discovery, 2013, vol. 10, # 7, p. 561 - 571
[3] Patent: WO2016/131098, 2016, A1,
[4] Patent: CN102766135, 2017, B,

[ 55745-70-5 ] Synthesis Path-Downstream 1~55

1
[ 55745-70-5 ]
[ 103262-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium borohydrid; In methanol;	Reference Example 79 (2,3-dihydrobenzofuran-5-yl)methanol To a solution of 2,3-dihydrobenzofuran-5-carbaldehyde (30.0 g, 0.202 mol) in methanol (150 mL) was added sodium borohydride (3.83 g, 0.101 mol) under ice-cooling. The mixture was stirred for 15 minutes at ambient temperature and then diluted with water. The product was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the title compound (yield 27.6 g, 91%) as an oily product. NMR (CDCl3) delta: 1.67 (1H, s), 3.20 (2H, t, J 8.6 Hz), 4.57 (2H, t, J=8.6 Hz), 4.58 (2H, s), 6.76 (1H, d, J=8.0 Hz), 7.10 (1H, d, J=8.0 Hz), 7.22 (1H, s)

Reference： [1]Patent: EP1199304,2002,A1 .Location in patent: Referential example 79
[2]Journal of the Chemical Society,1956,p. 2455,246
[3]Patent: US6034239,2000,A

2
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[ 4885-02-3 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	titanium chloride; In dichloromethane; water;	Reference Example 1 2,3-Dihydrobenzofuran-5-carbaldehyde Titanium chloride (28 ml) was dropwise added to a dichloromethane (100 ml) solution containing 2,3-dihydrobenzofuran (10.0 g, 83.2 mmols) and dichloromethyl methyl ether (11.3 ml, 0.125 mmols), while cooling with ice. The mixture was stirred for 1 hour, while still cooling with ice, and then water was added thereto. Dichloromethane was removed under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel chromatography (hexane/ethyl acetate=1/1) to obtain 11.4 g (yield: 92%) of the target compound. This was oily. NMR (CDCl3) delta: 3.28 (2H, t, J=8.8 Hz), 4.70 (2H, t, J=8.8 Hz), 6.88 (1H, d, J=8.4 Hz), 7.67 (1H, dd, J=1.0 Hz, 8.4 Hz), 7.75 (1H, d, J=1.0 Hz), 9.83 (1H, s)
60%	tin(IV) chloride; In dichloromethane;	EXAMPLE 52A 2,3-Dihydrobenzofuran-5-carboxaldehyde To a stirred solution of alpha,alpha-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 C. was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2 Cl2 (5 mL) maintaining the temperature at or below -35 C. The mixture was warmed to 0 C., stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 C. at 0.3 mm Hg.
60%	tin(IV) chloride; In dichloromethane;	EXAMPLE 52A 2,3-Dihydrobenzofuran-5-carboxaldehyde To a stirred solution of alpha,alpha-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 C. was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2 Cl2 (5 mL) maintaining the temperature at or below -35 C. The mixture was warmed to 0 C., stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 C. at 0.3 mm Hg.

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4222 - 4239
[2]Patent: US6034239,2000,A
[3]Patent: EP1199304,2002,A1 .Location in patent: Referential example 1
[4]Journal of Medicinal Chemistry,1993,vol. 36,p. 3700 - 3706
[5]Patent: US6162927,2000,A
[6]Patent: US5767144,1998,A

3
[ 496-16-2 ]
[ 4885-02-3 ]
[ 55745-70-5 ]
[ 196799-45-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 2,3-dihydrobenzo[b]furan (9.4 mL, 83.4 mmol) in dichloromethane (250 mL) under Ar at -5 C. was added dropwise titanium(IV) chloride (18 mL, 167.0 mmol) over 15 min, maintaining the temperature below 0 C. After addition was complete, the red-brown reaction mixture was allowed to stir for a further 10 min before alpha,alpha-dichloromethyl methyl ether (8.3 mL, 91.6 mmol) was added dropwise [CAUTION-exotherm] maintaining the temperature below 0 C. Upon complete addition, the vivid crimson reaction mixture was allowed to warm to ambient temperature over 2 h, and was then cautiously poured onto a saturated aqueous solution of sodium bicarbonate (700 mL). The mixture was filtered through a pad of Kieselguhr, which was washed through with dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane (2×400 mL). The combined organic fractions were washed with brine (300 mL), dried (magnesium sulfate) and concentrated in vacuo to afford a mixture [5-CHO:7-CHO (4:1)] of aldehyde products (11.48 g, 93%) as a green-black liquid which as used without further purification.

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 322 - 330
[2]Patent: US2005/187282,2005,A1 .Location in patent: Page/Page column 8

4
[ 496-16-2 ]
[ 68-12-2 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With trichlorophosphate; at 70 - 90℃; for 9.5h;	2,3-Dihydrobenzofuran (100 g, 832 mmol) and N,N-dimethylformamide (134 g, 1830 mmol) were mixed and heated, and phosphorus oxychloride (255 g, 1643 mmol) were added thereto at an inner temperature of 70 to 80C over 2 hrs. The reaction mixture was heated at an inner temperature of 80 to 90C and stirred for 7.5 hrs. Then, the resulting mixture was added dropwise to water (1000 g) under cooling, and stirred at room temperature for 5 hrs. The resulting mixture was extracted with toluene, and the extract was washed sequentially with water, saturated sodium bicarbonate aqueous solution and water, and the organic layer was concentrated under vacuum to give a toluene solution of the title compound (amount 340 g, apparent yield 100%).
100%	With trichlorophosphate; at 70 - 90℃; for 9.5h;	2,3-Dihydrobenzofuran (100.0 g, 832.3 mmol) and N,N-dimethylformamide (133.8 g, 1830.6 mmol) were mixed and heated, and phosphorus oxychloride (255.2 g, 1643.0 mmol) was added dropwise thereto at an inner temperature of 70 to 80 C. over 2 hours. The mixture was heated to an inner temperature of 80 to 90 C., stirred for 7.5 hours, cooled and then added dropwise to 1000 g of water, followed by stirring at room temperature for 5 hours. After extracting with toluene and washing in turn with water, saturated sodium bicarbonate water and water, the organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (yield: 340 g, apparent yield: 100%)
98%		To a solution of 2,3-dihydrobenzofuran (600.0 g, 4.99 moles) in N,N-dimethylformamide(804 g, 10.98 moles) was added drop-wise phosphorous oxychloride (1530 g, 9.96 moles) over a period of 45 min maintaining the temperature of reaction mixture between 30- 35C. The mixture was slowly heated to 7O0C and stirred for 8 hr. The mixture was cooled to room temperature and poured into 8 lit of ice-cold water and stirred for 1 hr. The reaction mixture was saturated with sodium chloride and then the product was extracted with ethyl acetate (6L). The extract was washed with saturated aqueous solution of sodium bicarbonate (1.5 L) and concentrated under reduced pressure to obtain (725 g, 98%) of the title compound.

93%	at 85℃; for 12h;Cooling with ice;	(31.4 ml, 0.333piomicron1) was slowly added dropwise to N, N-dimethylformamide (28.4 ml, 0.366 mol). After 10 minutes of reaction, the mixture was slowly added dropwise , 3-dihydrobenzofuran (1,20.0g, 0.166piomicron1), remove the ice bath, heating at 85 C stirring reaction for 12 hours, the reaction system into the ice water, add sodium hydroxide solution, adjust the PH value The organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), petroleum ether-ethyl acetate ( 5: 1) as eluant, to give 5-aldehyde dihydrobenzofuran (2,22.8 g) in a yield of 93%.
85 - 90%	With trichlorophosphate; at 80 - 85℃; for 4 - 5h;	Example 1; Synthesis of 2,3-dihydrobenzofuran-5-carboxaldehdye:Phosphorous oxychloride (255.58 g, 1.666 mol) was slowly added to a solution of DMF (355.0 ml) and 2, 3-dihydrobenzofuran (100 g, 0.833 mol) maintaining the temperature 80-850C. The reaction mixture was stirred for 4-5 hr and the reaction progress monitored by HPLC. The reaction mixture was then poured into ice water and extracted with toluene (2000 ml). The organic layer was washed with 5% sodium bicarbonate solution (500 ml) and then 10% brine solution (500 ml). The organic layer was distilled off under vacuum at 50-600C. A liquid product was isolated. Yield: 85- 90%, Purity: 90-92 %
14.5 g	With phosphorus pentachloride; at 70 - 80℃; for 10h;	Take a 1001 ^ three mouth reaction bottle,2,3-dihydrobenzofuran (128, 0.1111) was dissolved in nitrogen,Nitrogen-dimethylformamide (120 g, 1.64 mil) was placed in a reaction flask,Heated to 70 C to 80 C in 2 hours with mechanical agitation, In part by adding phosphorus pentachloride / nitrogen,Nitrogen-dimethylformamide mixed formylating reagent (25 g, 0.2 mol).The reaction mixture was incubated for 8 hours.After the reaction,The reaction mixture was added dropwise to ice water (l0 g) and stirred at room temperature for 5 hours.Toluene 50mL extraction,Organic layer followed by water,Saturated aqueous sodium bicarbonate solution and washed with water,Dried over anhydrous sodium sulfate,filter,The organic layer was concentrated to give product 2, 3-dihydrobenzofuran-5-carbaldehyde (14. 5 g, 0.08 mil).This product can be used for the production of lamivudine.
	With trichlorophosphate; at 30 - 98℃; for 5.16667h;	EXAMPLE 1 : Preparation of 2, 3- DIHYDROBENZOFURAN -5- CARBALDEHYDE (FORMULA XII, wherein i1^ represents a single bond); 400 g of 2,3-dihydro benzofuran of Formula XIII (wherein =* represents a single bond) and 566 ml of dimethyl formamide (DMF) were charged into a clean and dry 4 neck round bottom flask followed by stirring for about 5 minutes. 544 ml of phosphorous oxy chloride was slowly added through a dropper for 65 minutes at 3O0C. The reaction solution was heated to 95-98C followed by stirring for 4 hours for the completion of the reaction. The reaction mass was then cooled to 100C and quenched into ice slowly followed by stirring for 20-30 minutes. 1300 ml of caustic lye was added to the solution at 25 - 350C to adjust the pH of the reaction mass to neutral. The reaction mass was extracted with dichloromethane (3X1000 ml) and separated the organic layer and aqueous layer. The combined organic layer was washed with brine solution (2000 ml). The resultant organic layer was distilled completely below 6O0C to afford 497 g of the title compound.

Reference： [1]Patent: EP1792899,2007,A1 .Location in patent: Page/Page column 11
[2]Patent: US10098866,2018,B2 .Location in patent: Page/Page column 38
[3]Patent: WO2010/41271,2010,A2 .Location in patent: Page/Page column 28
[4]Letters in drug design and discovery,2013,vol. 10,p. 561 - 571
[5]Patent: CN102766135,2017,B .Location in patent: Paragraph 0035-0036
[6]Journal of Medicinal Chemistry,2002,vol. 45,p. 4222 - 4239
[7]Patent: WO2008/151170,2008,A2 .Location in patent: Page/Page column 45
[8]Patent: CN106554345,2017,A .Location in patent: Paragraph 0032-0033
[9]Patent: WO2008/150953,2008,A1 .Location in patent: Page/Page column 29

5
[ 55745-70-5 ]
[ 867-13-0 ]
[ 196597-65-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium hydrogencarbonate; acetic acid; In methanol; water; toluene;	Reference Example 2 Ethyl (E)-3-(2,3-Dihydrobenzofuran-5-yl)-2-propenoate To an ice-cooled suspension of sodium t-butoxide (90.4 g, 941 mmols) in toluene (1 L) was added dropwise triethyl phosphonoacetate (211.0 g, 941 mmols) followed by 2,3-dihydrobenzofuran-5-carbaldehyde (115.9 g 782 mmols). The mixture was stirred for 1 hour and then acetic acid (12 g, 200 mmols) and water (604 mL) was added. The separated organic layer was washed with water (525 mL) followed by a saturated aqueous solution of sodium bicarbonate (263 mL) and concentrated under reduced pressure. Methanol (525 mL) and water (525 mL) were added to the residue and the mixture was stirred for 30 minutes. Crystals precipitated were collected by filtration to obtain 161.2 g (yield: 94%) of the title compound.
88%	In tetrahydrofuran; water;	Reference Example 2 Ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)-2-propenoate 60% sodium hydride (3.39 g, 84.6 mmols) was added to a tetrahydrofuran (150 ml) solution of triethyl phosphonoacetate (19.0 g, 84.6 mmols) while cooling with ice, and the mixture was stirred for 20 minutes. To this was dropwise added a tetrahydrofuran (15 ml) solution of 2,3-dihydrobenzofuran-5-carbaldehyde (11.4 g, 76.9 mmols) and stirred further for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (hexane/ethyl acetate=from 95/5 to 9/1) to obtain 14.7 g (yield: 88%) of the target compound. This was oily. NMR (CDCl3) delta: 1.33 (3H, t, J=7.2 Hz), 3.23 (2H, t, J=8.8 Hz), 4.25 (2H, q, J=7.2 Hz), 4.63 (2H, t, J=8.8 Hz), 6.28 (1H, d, J=16.0 Hz), 6.79 (1H, d, J=8.4 Hz), 7.31 (1H, d, J=8.4 Hz), 7.41 (1H, s), 7.64 (1H, d, J=16.0 Hz)
88.1%	With sodium t-butanolate; In toluene; for 1h;Cooling;	To the solution (340 g) of 2,3-Dihydrobenzofuran-5-carbaldehyde (832 mmol) in toluene obtained in the above step was added dropwise triethyl phosphonoacetate (205 g, 916 mmol) under cooling. Then, a suspension of sodium t-butylate (88.0 g, 1187 mmol) in toluene (530 g) was added dropwise, and stirred for 1 hr, and further acetic acid (20 g) and water (500 g) were added dropwise thereto. The reaction mixture was warmed to room temperature, and separated the layers. The organic layer was washed sequentially with saturated sodium bicarbonate aqueous solution and water, and the organic layer was concentrated to below 300 mL under vacuum. Then to the residue was added methanol (396 g) to heat and dissolve. To the solution was added dropwise water (500 g) at room temperature, and stirred to deposit crystals, which was collected by filtration and dried under reduced pressure to give title compound (amount 161 g, yield 88.1%).

88.1%

With sodium t-butanolate; In toluene; for 1h;

To 2,3-dihydrobenzofuran-5-carbaldehyde obtained Reference Example 1 (832.3 mmol)/toluene solution (340 g), triethyl phosphonoacetate (205.3 g, 915.7 mmol) was added dropwise under cooling. Then, t-butoxy sodium (88.0 g, 1187.3 mmol) suspended in toluene (530 g) was added dropwise to the resultant mixture and, after stirring the mixture for one hour, acetic acid (20 g) and water (500 g) were further added dropwise thereto. The reaction mixture was raised to room temperature and partitioned. The organic layer was washed in turn with saturated sodium bicarbonate water and water and concentrated under reduced pressure until the volume is reduced to 300 mL or less. Methanol (396 g) was added and the mixture was heated to dissolve it. Water (500 g) was added dropwise thereto at room temperature and the mixture was stirred to deposit crystals. The crystals were collected by filtration and dried under reduced pressure to obtain the title compound (yield: 161.3 g, 88.1%).

Reference： [1]Patent: US6348485,2002,B1
[2]Journal of Medicinal Chemistry,2002,vol. 45,p. 4222 - 4239
[3]Patent: US6034239,2000,A
[4]Patent: EP1792899,2007,A1 .Location in patent: Page/Page column 11
[5]Patent: EP1199304,2002,A1 .Location in patent: Referential example 2
[6]Patent: US10098866,2018,B2 .Location in patent: Page/Page column 38; 39

6
[ 55745-70-5 ]
[ 141-82-2 ]
[ 203505-84-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With piperidine; pyridine; at 100℃; for 5h;	A solution of 2,3-dihydrobenzofuran-5-carbaldehyde (10 g, 67.6 mmol), malonic acid (10.5 g, 101.35 mmol) and piperidine (0.47 ml_, 4.73 mmol, 0.07 eq) was heated in pyridine (60 ml_) at 100 C for 5 h. The reaction mixture was acidified to ~pH 3 using 1 N HCI and the product extracted using 10% IPA/chloroform (2 x 250 ml_). The combined organic extracts were washed with water (250 ml_), brine (250 ml_), dried (Na2S04) and concentrated in vacuo. The crude product was triturated using diethyl ether to give (E)-3-(2,3-dihydrobenzofuran-5- yl)acrylic acid as a yellow solid (10 g, 78%).1H NMR (300 MHz, Chloroform-a delta = 7.73 (d, J = 15.9 Hz, 1 H), 7.43 (s, 1 H), 7.33 (dd, J = 8.1 , 1 .8 Hz, 1 H), 6.80 (d, J = 8.1 Hz, 1 H), 6.29 (d, J = 15.9 Hz, 1 H), 4.64 (t, J = 8.7 Hz, 2H), 3.24 (t, J = 8.7 Hz, 2H).
78%	With piperidine; pyridine; at 100℃; for 5h;	A solution of 2,3-dihydrobenzofuran-5-carbaldehyde (10 g, 67.6 mmol), malonic acid (10.5 g, 101.35 mmol) and piperidine (0.47 mL, 4.73 mmol, 0.07 eq) was heated in pyridine (60 mL) at 100 C for 5 h. The reaction mixture was acidified to ~pH 3 using lN HC1 and the product extracted using 10% IPA/ chloroform (2 x 250 mL). The combined organic extracts were washed with water (250 mL), brine (250 mL), dried (Na2S04) and concentrated in vacuo. The crude product was triturated using diethyl - 6l - ether to give (E)-3-(2,3-dihydrobenzofuran-5-yl)acrylic acid as a yellow solid (10 g, 78%). NMR (300 MHz, Chloroform-d) delta = 7-73 (d, J = 15-9 Hz, lH), 7.43 (s, lH), 7.33 (dd, J = 8.1, 1.8 Hz, lH), 6.80 (d, J = 8.1 Hz, lH), 6.29 (d, J = 15.9 Hz, lH), 4.64 (t, J = 8.7 Hz, 2H), 3.24 (t, J = 8.7 Hz, 2H). (0296) A solution of (E)-3-(2,3-dihydrobenzofuran-5-yl)acrylic acid (8.0 g, 42.1 mmol) in acetic acid (80 mL) and water (1.0 mL) was treated with 10% palladium on carbon (1.0 g) in two portions. The reaction mixture was stirred under an atmosphere or hydrogen gas (balloon) until completion, typically 4 h. The mixture was diluted using ethyl acetate (100 mL) and filtered through a bed of celite washing through with further ethyl acetate. The solvents were removed in vacuo and the crude residue azeotroped using toluene (2 x 50 mL) to give an off white solid which was triturated using diethyl ether (50 mL) to give 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid as a white solid (6.5 g, 80%). NMR (400 MHz, CDCI3) delta = 7-04 (s, lH), 6.93 (d, J = 8.4, lH), 6.7 (d, J = 8.4 Hz, lH), 4-55 (t, J = 8.4 Hz, 2H), 3.18 (t, J = 8.4 Hz, 2H), 2.89 (t, J = 7-6 Hz, 2H), 2.64 (t, J = 7-6 Hz, 2H). (0297) A solution of 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid (6.0 g, 31 mmol) in thionyl chloride (8 mL) was heated at 80 C for 1 h. On completion of the reaction the thionyl chloride was removed in vacuo and the crude 3-(2,3-dihydrobenzofuran-5- yl)propanoyl chloride dissolved in anhydrous 1,2-dichloroethane (30 mL). In a separate flask aluminium trichloride (2 g, 15 mmol) was added to anhydrous 1,2-dichloroethane (40 mL) at o C followed by the acid chloride solution (10 mL) drop-wise over 5 min and the resulting solution was stirred for 30 min at o C. A further portion of aluminium trichloride (3 g, 22.5 mmol) was added followed by drop-wise addition of the remaining acid chloride solution (20 mL) at o C. The reaction mixture was stirred at room temperature for 1 h or until completion, diluted with water and extracted using EtOAc (2 x 50 mL). The combined organic extracts were washed with lN HC1 (50 mL), lN NaOH (50 mL), water (25 mL), brine (25 mL), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 10% EtOAc-hexanes eluent to give 2,3,5,6-tetrahydro-7H-indeno[5,6-]furan-7-one as a white solid (3.8 g, 70%). NMR (300 MHz, CD3OD) delta = 7-36 (s, lH), 6.91 (s, lH), 4.61 (t, J = 8.6 Hz, 3H), 3.26 (t, J = 8.6 Hz, 2H), 3.05 (t, J = 5-5 Hz, 3H), 2.68 (t, J = 5-5 Hz, 2H). 2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (1.5 g, 8.61 mmol) was dissolved in C.H2SO4 (6.0 mL) at o C followed by drop-wise addition of f.HN03:c.H2S04, 1:1 (1.2 mL) stirring was continued at o C for 1 h. The reaction mixture was added to ice-cold water (60 mL) and stirred for 10 min, the resulting light brown ppt was removed by filtration, washed with ice cold water (20 mL) and dried in vacuo to give 8-nitro- 2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (1.2 g, 64%). NMR (300 MHz, CD3OD) delta = 7-54 (s, lH), 4.80 (t, J = 8.6 Hz, 2H), 3.42 (t, J = 8.6 Hz, 2H), 3.09 (t, J = 5.6 Hz, 2H), 2.74 (t, J = 5-6 Hz, 2H). A solution of 8-nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (1.0 g, 4.57 mmol) in methanol (20 mL) o C was treated with methane sulfonic acid (0.2 mL) followed by 20% palladium hydroxide (0.5 g). The reaction mixture was stirred under an atmosphere or hydrogen gas at 60 psi until completion. The reaction mixture was filtered through a bed of celite washing through with methanol (50 mL) and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed using sat. aq. NaHC03 (50 mL), water (20 mL), brine (20 mL), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 10% EtOAc-hexanes eluent to give 3,5,6,7-tetrahydro-2H-indeno[5,6- b]furan-8-amine as a white solid (0.5 g, 63%). NMR (300 MHz, CDC13) delta = 6.54 (s, lH), 5.30 (s, 2H), 4.61 (t, J = 8.7 Hz, 2H), 3.21 (t, J = 8.7 Hz, 2H), 2.95 (t, J = 5.5 Hz, 2H), 2.66 (t, J = 5-5 Hz, 2H).

Reference： [1]Patent: WO2016/131098,2016,A1 .Location in patent: Page/Page column 149
[2]Patent: WO2018/215818,2018,A1 .Location in patent: Page/Page column 60-62
[3]Letters in drug design and discovery,2013,vol. 10,p. 561 - 571
[4]Journal of Medicinal Chemistry,2002,vol. 45,p. 4222 - 4239

7
[ 55745-70-5 ]
[ 61-54-1 ]
[ 199678-69-8 ]

Yield	Reaction Conditions	Operation in experiment
94%		A solution of tryptamine (0.325 g, 2.03 mmol) and 2,3-dihydro-1 -benzof uran-5-carbaldehyde (0.250 g, 1.69 mmol) in glacial acetic acid (10 mL) was heated to 1000C with stirring. After 2.5 h the solution was treated with an additional portion of 2,3-dihydro-1 -benzofuran-5- carbaldehyde (0.062 g, 0.418 mmol) and stirred at O0C for an additional 3 h. The dark brown solution was cooled to RT and stirred overnight. The solvent was removed by concentration at reduced pressure and the residue dissolved in dichlorom ethane. The solution was washed twice with 10% aqueous sodium bicarbonate followed by aqueous brine. The solution was then treated with magnesium sulfate and a small portion of activated charcoal and heated to boiling for 5 minutes. After cooling to RT, the mixture was filtered through celite and the filtrate evaporated to dryness to afford 0.590 g of a yellow-brown foam. The crude product was purified by flash chromatography (silica gel, 95:5 dichloromethane/2M ammonia in methanol) to give (1 R/1 S)-1-(2,3-dihydro-1 -benzof uran-5-yl)-2,3,4,9-tetrahydro-1 H-beta-carboline (0.460 g, 94%) as a yellow powder. 1H NMR (DMSOd6): delta 10.32 (s, 1 H), 7.36 (d,1 H), 7.20 (d, 1 H), 7.09 (S, 1H), 7.01-6.88 (m, 3H), 6.69 (d, 1H), 4.99 (s, 1H), 4.49 (t, 2H), 3.17-3.00 (m, 3H), 2.90 (m, 1 H), 2.79-2.58 (m, 3H). MS m/z 291 (M+1).
94%	With acetic acid; at 0 - 100℃;	A solution of tryptamine (0.325 g, 2.03 mmol) and 2,3-dihydro-1-benzofuran-5-carbaldehyde (0.250 g, 1.69 mmol) in glacial acetic acid (10 ml_) was heated to 1000C with stirring. After 2.5 h the solution was treated with an additional portion of 2,3-dihydro-1-benzofuran-5- carbaldehyde (0.062 g, 0.418 mmol) and stirred at O0C for an additional 3 h. The dark brown solution was cooled to RT and stirred overnight. The solvent was removed by concentration at reduced pressure and the residue dissolved in dichloromethane. The solution was washed twice with 10% aqueous sodium bicarbonate followed by aqueous brine. The solution was then treated with magnesium sulfate and a small portion of activated charcoal and heated to boiling for 5 minutes. After cooling to RT, the mixture was filtered through celite and the filtrate evaporated to dryness to afford 0.590 g of a yellow-brown foam. The crude product was purified by flash chromatography (silica gel, 95:5 dichloromethane/2M ammonia in methanol) to give (1 R/1S)-1-(2,3-dihydro-1-benzofuran-5-yl)-2,3,4,9-tetrahydro- 1 H-beta-carboline (0.460 g, 94%) as a yellow powder. 1H NMR (DMSOd6): delta 10.32 (s, 1 H), 7.36 (d,1 H), 7.20 (d, 1 H), 7.09 (s, 1 H), 7.01-6.88 (m, 3H), 6.69 (d, 1 H), 4.99 (s, 1 H), 4.49 (t, 2H), 3.17-3.00 (m, 3H), 2.90 (m, 1 H), 2.79-2.58 (m, 3H). MS m/z 291 (M+1).

Reference： [1]Patent: WO2007/2051,2007,A1 .Location in patent: Page/Page column 36
[2]Patent: WO2006/15035,2006,A1 .Location in patent: Page/Page column 36
[3]Journal of Medicinal Chemistry,2002,vol. 45,p. 4094 - 4096
[4]Organic letters,2003,vol. 5,p. 43 - 46
[5]Journal of Medicinal Chemistry,2003,vol. 46,p. 441 - 444
[6]Organic Process Research and Development,2005,vol. 9,p. 640 - 645
[7]Journal of Medicinal Chemistry,2005,vol. 48,p. 2126 - 2133
[8]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 761 - 765

8
[ 66826-78-6 ]
[ 68-12-2 ]
[ 55745-70-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 4313 - 4336

9
[ 55745-70-5 ]
[ 835885-26-2 ]

Yield	Reaction Conditions	Operation in experiment
84%		To a suspension of Part A (1.56 g, 4.5 MMOL) in 20 mL of ethanol was added powdered potassium hydroxide (0.5 g, 9 MMOL), and the mixture was stirred at room temperature for 10 min. 2,3-Dihydro-benzofuran-5- CARBALDEHYDE (1.66 g, 11 MMOL) was added, and the mixture was stirred at room temperature. When TLC showed no remaining ketone (48 h), water was added to quench the reaction. The precipitated solid was collected by filtration, washed with water, dried and RECRYSTALLIZED from ETHANOL/ETHER to give the titled compound (1.80 g, 84%) as yellow crystals.

Reference： [1]Patent: WO2005/11592,2005,A2 .Location in patent: Page/Page column 45

10
[ 496-16-2 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With trichlorophosphate; In water; N,N-dimethyl-formamide;	Reference Example 1: Synthesis of 2,3-dihydrobenzofuran-5-carbaldehyde 2,3-Dihydrobenzofuran (100.0 g, 832.3 mmol) and N,N-dimethylformamide (133.8 g, 1830.6 mmol) were mixed and heated, and phosphorus oxychloride (255.2 g, 1643.0 mmol) was added dropwise thereto at an inner temperature of 70 to 80ØC over 2 hours. The mixture was heated to an inner temperature of 80 to 90ØC, stirred for 7.5 hours, cooled and then added dropwise to 1000 g of water, followed by stirring at room temperature for 5 hours. After extracting with toluene and washing in turn with water, saturated sodium bicarbonate water and water, the organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (yield: 340 g, apparent yield: 100%)
100%	With trichlorophosphate; In water; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 1 Synthesis of 2,3-Dihydrobenzofuran-5-carbaldehyde 2,3-Dihydrobenzofuran (100.0 g, 832.3 mmol) and N,N-dimethylformamide (133.8 g, 1830.6 mmol) were mixed and heated, and phosphorus oxychloride (255.2 g, 1643.0 mmol) was added dropwise thereto at an inner temperature of 70 to 80 C. over 2 hours. The mixture was heated to an inner temperature of 80 to 90 C., stirred for 7.5 hours, cooled and then added dropwise to 1000 g of water, followed by stirring at room temperature for 5 hours. After extracting with toluene and washing in turn with water, saturated sodium bicarbonate water and water, the organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (yield: 340 g, apparent yield: 100%)
94%	With sodium hydrogencarbonate; trichlorophosphate; In N,N-dimethyl-formamide;	Reference Example 1 2,3-Dihydrobenzofuran-5-carbaldehyde To a solution of 2,3-dihydrobenzofuran (100.0 g, 832 mmols) in N,N-dimethylformamide (134.0 g, 1.83 mols) was added dropwise phosphorus oxychloride (255.1 g, 1.66 mols), then the mixture was stirred at 80-90 C. for 7.5 hours. The mixture was cooled to room temperature, poured into water (1 L) and stirred for 15 hours. The product was extracted with toluene (1.5 L). The extract was washed with water (500 mL) followed by a saturated aqueous solution of sodium bicarbonate (500 mL) and concentrated under reduced pressure to obtain 115.9 g (yield: 94%) of the title compound.

Reference： [1]Patent: EP1334732,2003,A1
[2]Patent: US2004/18239,2004,A1
[3]Patent: US6348485,2002,B1
[4]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 4313 - 4336

11
[ 55745-70-5 ]
[ 196597-78-1 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4222 - 4239
[2]Patent: WO2008/150953,2008,A1
[3]Patent: WO2008/150953,2008,A1
[4]Patent: WO2008/151170,2008,A2
[5]Patent: US10098866,2018,B2

12
[ 55745-70-5 ]
[ 448964-30-5 ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4222 - 4239
[2]Letters in drug design and discovery,2013,vol. 10,p. 561 - 571
[3]Patent: WO2016/131098,2016,A1
[4]Patent: CN102766135,2017,B
[5]Patent: WO2018/215818,2018,A1

13
[ 55745-70-5 ]
[ 215057-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 62 percent / pyridine; piperidine / 4 h / 100 °C 2: 90 percent / H₂; AcOH / 10percent Pd/C/H₂₀ / 1 h / 20 °C
	Multi-step reaction with 2 steps 1: piperidine / pyridine / 4 h / Reflux 2: palladium 10% on activated carbon; hydrogen / acetic acid / 1 h / 20 °C
	Multi-step reaction with 2 steps 1: pyridine; piperidine / 5 h / 100 °C 2: acetic acid; palladium 10% on activated carbon; hydrogen / water / 4 h

	Multi-step reaction with 2 steps 1: piperidine / pyridine / 12 h / 100 °C 2: palladium 10% on activated carbon; acetic acid; hydrogen / 4 h / 20 °C
	Multi-step reaction with 2 steps 1.1: piperidine; pyridine; acetic acid / 4 - 5 h / 100 °C 1.2: 2 - 3 h / 20 °C 2.1: sodium hydroxide; hydrogen; ammonium formate / palladium 10% on activated carbon / water / 5 - 6 h / 20 °C
	Multi-step reaction with 2 steps 1: piperidine; pyridine / 5 h / 100 °C 2: palladium 10% on activated carbon; hydrogen / water; acetic acid / 4 h

Reference： [1]Uchikawa, Osamu; Fukatsu, Kohji; Tokunoh, Ryosuke; Kawada, Mitsuru; Matsumoto, Kiyoharu; Imai, Yumi; Hinuma, Shuji; Kato, Koki; Nishikawa, Hisao; Hirai, Keisuke; Miyamoto, Masaomi; Ohkawa, Shigenori [Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239]
[2]Chen, Wen; Yang, Li-Juan; Li, Yan; Wang, Xue-Quan; Wang, Shao-Jie; Wan, Wei-Chao; Zhang, Hong-Bin; Yang, Xiao-Dong [Letters in drug design and discovery, 2013, vol. 10, # 7, p. 561 - 571]
[3]Current Patent Assignee: THE UNIVERSITY OF QUEENSLAND; UNIVERSITY OF DUBLIN - WO2016/131098, 2016, A1
[4]Current Patent Assignee: YUNNAN UNIVERSITY - CN102766135, 2017, B
[5]Current Patent Assignee: KANSAL VINOD KUMAR DR; LIFSHITZ REVITAL; TEVA PHARMACEUTICAL INDUSTRIES LTD.; MISTRY DHIRENKUMAR - WO2008/151170, 2008, A2
[6]Current Patent Assignee: UNIVERSITY OF DUBLIN - WO2018/215818, 2018, A1

14
[ 55745-70-5 ]
[ 16647-80-6 ]
(2S,3R,4R,5S)-1-[(2,3-dihydrobenzofuran-5-yl)methyl]-2-hydroxymethyl-3,4,5-piperidinetriol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; (polystyrylmethyl)trimethylammonium cyanoborohydride; In methanol; at 20℃; for 48.0833h;pH 5.0;	To a solution of 3, 4,5-piperidinetriol, 2- (hydroxymethyl)-, (2S, 3R, 4R, [5S)] [(50MG,] 0. [31MMOL)] in methanol [(2ML)] was added 2, [3-DIHYDROBENZOFURAN-5-CARBOXALDEHYDE] (250mg, 1. [69MMOL).] The mixture was stirred for 5 min until fully dissolved. The pH was adjusted to 5 by addition [OF METHANOLIC HCI (1M),] then (polystyrylmethyl) trimethylammonium cyanoborohydride (180mg, 0. [78MMOL)] was added. The resultant mixture was stirred at room temperature for 48 h. The crude reaction mixture was purified using a plug of acidic Dowex 50X4-200 resin (1.5g), which had been pre-washed with 10% aqueous hydrochloric acid, followed by water then methanol. The resin was eluted with methanol [(25ML)] to remove all non-basic side products. The desired compound was then eluted using a solution of 2: 2: 1 [METHANOL/WATER/AMMONIUM] hydroxide (50ml). The solution was concentrated to a small volume [(-1MOL)] and freeze dried to give title product (83mg, [90%).'H] NMR (d4-methanol) 8 2.55 [(1H,] dd, J = 9.9, 12.2 Hz), 2.71 [(1H,] dd, J = 5. 1,12. [2 HZ),] 3.06 [(1H,] m), 3.17 (2H, t, [J = 8. 7 HZ),] 3.39 [(1H,] t, [J=8. 7HZ),] 3.50 [(1H,] m), 3.72-3. 89 (5H, m), 4.51 (2H, t, J = 8.7 Hz), 6.65 [(1H,] d, J = 7.9 Hz), 7.04 [(1H,] d, J = 7.9 Hz), 7.20 [(1H,] s). MS [M/Z] 296.3 (M+H) +.

Reference： [1]Patent: WO2004/7453,2004,A1 .Location in patent: Page 17

15
[ 55745-70-5 ]
[ 1816-92-8 ]
[ 196799-45-8 ]
[ 327185-08-0 ]
[ 170728-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In methanol; at -13 - -10℃; for 1.66667h;	To a stirred solution of potassium tert-butoxide (31.0 g, 0.26 mol) in anhydrous methanol (220 mL) under Ar at -13 C. was added dropwise a mixture of methyl azidoacetate (31.7 g, 0.27 mol), and 2,3-dihydrobenzo[b]furan-5-carboxaldehyde and <strong>[196799-45-8]2,3-dihydrobenzo[b]furan-7-carboxaldehyde</strong> (4:1 mixture; 10.15 g, 69 mmol) over 40 min. After complete addition, the reaction mixture was stirred at -10 C. for 1 h, then stored at 0 C. overnight (with a vent needle in place). The reaction mixture was partitioned between ethyl acetate (750 mL) and water (1 L) and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic fractions were washed with brine (300 mL), dried (magnesium sulfate) and concentrated in vacuo to afford a crude oil. Purification by flash column chromatography [SiO2; dichloromethane-heptane (1:1)] afforded a mixture [5-substituted: 7-substituted (4:1)] of products (11.4 g, 68%) as a pale yellow solid which was used without further purification.

Reference： [1]Patent: US2005/187282,2005,A1 .Location in patent: Page/Page column 8

16
[ 55745-70-5 ]
[ 875551-14-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With bromine; sodium acetate; acetic acid; at 10 - 20℃; for 1h;	2,3-Dihydrobenzofuran-5-carbaldehyde (2.96 g, 2.0 mmol), sodium acetate (1.97 g, 24 mmol) and acetic acid (40 mL) were added to a 100 mL single neck flask, then bromine (6.39 g, 40 mmol) was added at 10 C. The reaction mixture was stirred for 1 h at rt. To the mixture was added ice water (100 mL) and saturated aqueous sodium thiosulfate (10 mL). The resulting mixture was extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) = 1/20) to give the title compound as a pale yellow solid (4.36 g, 96%).?H NIVIR (400 IVIHz, CDC13) : 9.78 (s, 1H), 7.82 (s, 1H), 7.66 (d, J 0.8 Hz, 1H), 4.79 (t, J 8.8 Hz, 2H), 3.38 (t, J 8.8 Hz, 2H).
91%	With bromine; sodium acetate; acetic acid; at 10 - 20℃; for 2h;	(a) 7-bromo-2,3-dihydro-l-benzofuran-5-carbaldehydeTo a solution of 2,3-dihydro-l-benzofuran-5-carbaldehyde (1.0 g, 6.75mmol) in glacial aGetic acid (8 ml) was added sodium acetate (664mg, 8.1mmol) and bromine (0.7ml, 13.5mmol) at 10C slowly. The reaction was stirred for 2h at room temperature. The reaction was diluted with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. Organics were combined, dried over sodium sulfate and dried in vacuo to give the desired compound (1.4 g, 91%). MS (+ve ion electrospray): m/z 227 (M+H)+.
91%	With bromine; sodium acetate; acetic acid; at 10 - 20℃; for 2h;	(a) 7-bromo-2,3-dihydro- 1 -benzofuran-5-carbaldehydeTo a solution of 2,3 -dihydro- l-benzofuran-5-carbaldehyde (1.0 g, 6.75mmol) in glacial acetic acid (8 mL) was added sodium acetate (664mg, delta. lmmol) and bromine (0.7ml, 13.5mmol) at 1O0C slowly. The reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with a saturated aqueous solution of sodium thiosulfate (10 mL), washed with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. Organics were combined, dried over sodium sulfate and dried in vacuo to give the desired compound (1.4 g, 91%). MS (+ye ion electrospray): m/z 227 (M+H)+.

91%	With bromine; sodium acetate; acetic acid; at 10 - 20℃; for 2h;	To a solution of 2,3-dihydro-l-benzofuran-5-carbaldehyde (1.0 g, 6.75 mmol) in glacial acetic acid (8 mL) was added sodium acetate (664 mg, 8.1mmol) and bromine (0.7 ml, 13.5 mmol) slowly at 1O0C . The reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with a saturated aqueous solution of sodium thiosulfate (10 mL), washed with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. Organics were combined, dried over sodium sulfate and dried in vacuo to give the desired compound (1.4 g, 91%). MS (+ve ion electrospray): m/z 227 (M+H)+.
91%	With bromine; sodium acetate; In acetic acid;	Preparation 14; Preparation of 5-formvl-2.3-dihvdro-1-benzofuran-7-carbonitrile; (a) 7-bromo-2,3-dihydro-1 -benzofuran-5-carbaldehyde; To a solution of 2,3-dihydro-1-benzofuran-5-carbaldehyde (1 g, 6.75 mmol) inacetic acid (8 ml) was added sodium acetate (664 mg, 8.1 mmol) followed by bromine(0.7 ml, 13.5 mmol). After stirring at room temperature for 2 h, the mixture was dilutedwith the aqueous solution of NaHCO3. The aqueous solution was extracted several timeswith ethyl acetate. The organic fractions were combined, washed with saturated NaHCO3,brine and then concentrated to afford the desired compound (1.4 g, 91 %) which was usedwithout further purification: LC/ MS (ES) m/z 228 (M + H)+ .

Reference： [1]Patent: WO2017/36404,2017,A1 .Location in patent: Page/Page column 65
[2]Patent: WO2007/71936,2007,A1 .Location in patent: Page/Page column 83
[3]Patent: WO2007/122258,2007,A1 .Location in patent: Page/Page column 86
[4]Patent: WO2008/6648,2008,A1 .Location in patent: Page/Page column 35
[5]Patent: WO2006/14580,2006,A1 .Location in patent: Page/Page column 51

17
[ 55745-70-5 ]
NaOH (aq.) [ No CAS ]
[ 96042-30-7 ]
[ 465529-65-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; In water; ethyl acetate; acetone; pentane;	Preparation 139 (3E)-4-(2,3-Dihydro-1-benzofuran-5-yl)-3-buten-2-one 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde (Aldrich Chemicals) (2g, 13.5 mmol), acetone (2.73 ml, 37.1 mmol), water (1.35 ml) and 10% NaOH (aq.) (0.34 ml) were added together and the whole stirred at room temperature for 16 h. The yellow solid was redissolved in approx. 15 ml DCM and 2N HCl added to achieve a solution of pH 2. Water (10 ml) was added and the organic layer was extracted with DCM (220 ml). The aqueous layers were separated, and re-extracted with DCM (215 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to a yellow solid which was purified by column chromatography using 15-30% EtOAc in pentane as eluant to provide the title product (2.13 g, 84%); 1H-NMR (400 MHz, CDCl3) delta: 2.3 (s, 3H), 3.2 (t, 2H), 4.6 (t, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.45 (d, 1H); LRMS: M+H, 189. (ES+).

Reference： [1]Patent: US2003/105132,2003,A1

18
[ 109-72-8 ]
[ 66826-78-6 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; hexane; water; N,N-dimethyl-formamide;	(i) Production of Ethyl 2,3-Dihydronaphtho[2,3-b]furan-6-carboxylate 5-Bromo-2,3-dihydrobenzofuran (38.86 g), which was prepared according to the literature (Alabaster, Ramon J. et al., Synthesis, 1988, vol. 12, pp950.), was dissolved in THF (300 mL) and cooled to -78 C. n-Butyl-lithium in hexane (1.6M; 160 mL) was added to the solution and stirred for 30 min. DMF (40 mL) was added to the mixture and was allowed to warm to room temperature. Water was added to the mixture and the solvent was evaporated. The residue was diluted with ethyl acetate, washed with water and brine, dried and concentrated to give crude product of 5-formyl-2,3-dihydrobenzofuran (28.47 g) as an oil.

Reference： [1]Patent: US6649643,2003,B1

19
[ 55745-70-5 ]
[ 372-09-8 ]
(RS)-3-[1-(4-Ethyl-5-methoxybenzocyclobuten-1-ylmethyl)-4-piperidyl]-6-fluoro-1,2-benzisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With ammonium acetate; In pyridine; hydrogenchloride; benzene;	EXAMPLE 21 (RS)-3-[1-(4-Ethyl-5-methoxybenzocyclobuten-1-ylmethyl)-4-piperidyl]-6-fluoro-1,2-benzisoxazole STAGE A: 2-Cyano-3-(2,3-dihydro-5-benzofuranyl)acrylic acid 39.5 g of 2,3-dihydro-5-benzofurancarbaldehyde (prepared according to the process described in J. Org. Chem. (1984), 49, p. 409), 22.7 g of 2-cyanoacetic acid and 4.08 g of ammonium acetate are mixed in 37 ml of pyridine and 210 ml of benzene. The mixture is brought to reflux for 6 hours 30 minutes. The precipitate formed is isolated and then suspended in 600 ml of 6N hydrochloric acid. The solid isolated is filtered off and washed with water and dried in the air. Yield: 48%. Melting point: 234 C. Proton nuclear magnetic resonance spectrum (solvent CDCl3 +DMSO-d6): 3.3 ppm, t, 2H; 4.7 ppm, t, 2H; 6.9 ppm, d, 1H; 7.7 ppm, dd, 1H; 8.05 ppm, s, 1H; 8.15 ppm, s, 1H.

Reference： [1]Patent: US5100902,1992,A

20
[ 55745-70-5 ]
[ 84944-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; In formic acid; ethyl acetate;	REFERENCE EXAMPLE 64 2,3-Dihydro-5-benzofurancarbonitrile A solution of 2,3-dihydro-5-benzofurancarboxaldehyde (5.00 g, 33.7 mmol) and hydroxylamine hydrochloride (3.52 g, 50.6 mmol) in formic acid (70 mL) was heated under reflux for 2 hours. The reaction mixture was poured into ice water, and neutralized with potassium hydroxide to recover precipitated crystals. The resultant crystals were dissolved in ethyl acetate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the title compound (3.03 g, yield: 62%). Melting point: 69-70 C 1H NMR (CDCl3) delta 3.26 (2H, d, J = 8.8 Hz), 4.67 (2H, d, J = 8.8 Hz), 6.82 (1H, dd, J = 8.8, 1.0 Hz), 7.42-7.46 (2H, m).

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 1840 - 1840
[2]Patent: EP1270577,2003,A1
[3]Organic and Biomolecular Chemistry,2015,vol. 13,p. 8322 - 8329

21
[ 55745-70-5 ]
[ 882287-07-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine; sodium carbonate; In ethanol; at 20℃; for 2h;	[00338] To a solution of 2,3-dihydrobenzofuran 5-carboxaldehyde (Ig, 6.75 mmol) in ethanol (5 mL) was added a 2.4 M OfNH2OH (3.3 mL, 8.1 mmol) solution and then 1.2 M of Na2CO3 (3.3 mL, 4.05 mmol). The resulting solution was stirred for 2 hours at room temperature (HPLC showed no starting material left). The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated under vacuum. This afforded 1.0 g of the product as a white solid. ES-MS 164 as M+l peak.
	With hydroxylamine; sodium carbonate; In ethanol; water; at 20℃; for 2h;	[0374] To a solution of 2,3-dihydrobenzofuran 5-carboxaldehyde (Ig, 6.75 mmol) in ethanol (5 mL) was added a 2.4 M OfNH2OH (3.3 mL, 8.1 mmol) solution and then 1.2 M of Na2CO3 (3.3 mL, 4.05 mmol). The resulting solution was stirred for 2 hours at room temperature (HPLC showed no starting material left). The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated under vacuum. This afforded 1.0 g of the product as a white solid. ES-MS 164 as M+l peak.

Reference： [1]Patent: WO2007/25307,2007,A2 .Location in patent: Page/Page column 312
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 8145 - 8159
[3]Patent: WO2008/106139,2008,A1 .Location in patent: Page/Page column 481

22
[ 55745-70-5 ]
[ 937594-61-1 ]

Yield	Reaction Conditions	Operation in experiment
43%		ft-Butyl lithium (0.94 niL, 2.5 M) was added dropwise to a cooled (-78 C) solution of 2- (3'-methoxybiphenyl-3-yl)-l,3-dithiane (327.4 mg, 2.21 mmol) in dry tetrahydrofuran (5 niL) under an atmosphere of argon. The solution was stirred at -78 C for 20 min and was then treated with 4-methyl-3,4-dihydro-2H-l54-benzoxazine-7-carbaldehyde (500 mg, 2.82 mmol). The reaction was stirred for another 20 min and then allowed to reach room temperature. Silica gel was added and the solvent was evaporated and the residue was purified by column chromatography, using a gradient of 0 to 30% ethyl acetate in n- heptane as the eluent, to give 426 mg (43% yield) the title compound: 1H NMR (CDCl3) 67.88 - 7.79 (m, 2 H) 7.55 - 7.49 (m, 1 H) 7.43 (t, J=7.71 Hz5 1 H) 7.34 (t, J=7.96 Hz5 1 H) 7.03 (d, J-7.83 Hz5 1 H) 6.99 - 6.93 (m, 1 H) 6.89 (dd5 J=7.83, 2.27 Hz5 1 H) 6.70 (dd5 J=8.34, 1.52 Hz5 1 H) 6.64 (s, 1 H) 6.59 (d, J=8.34 Hz5 1 H) 4.98 (d, J=3.54 Hz5 1 H) 4.49 (t, J=8.72 Hz5 2 H) 3.86 (s, 3 H) 3.02 (t, J=8.59 Hz, 2 H) 2.88 (d, J=3.28 Hz5 1 H) 2.77 - 2.67 (m, 4 H); MS (ES) m/z 433 [M-water]+

Reference： [1]Patent: WO2007/58602,2007,A2 .Location in patent: Page/Page column 225

23
[ 55745-70-5 ]
[ 17696-64-9 ]
C₁₁H₉O₄^(1-)*K⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 18; 2,3-Dihvdrobenzofura-5-yl, acetaldehvde; [00170] In a four necked round bottomed flask equipped with thermometer, mechanical stirrer and condenser, was charged under N2, 2,3-Dihydrobenzofura-5-yl, carboxaldehyde (50 g, 0.33moles) and 2-butylchloroacetate (66.5 g, 0.4415 moles). The solution was warmed to 40-450C, followed by a dropwise addition (in about 1 hour) of 288 ml of 17%(w/v) potassium 2-butylate solution in 2-butyl alcohol (0.43 moles). The reaction was maintained at a temperature of 40-45C, and after 1 hour at 40-450C, HPLC analysis revealed almost complete transformation of carboxaldehyde. The suspension was slowly added to a solution of KOH 90% (24.5 g, 0.3937 moles) in water (47 ml), followed by maintaining at 45-500C. After lhour at 45C, TLC analysis revealed complete hydrolysis, and a thick suspension was obtained. At this point toluene (120 ml) and water (180 ml) were <n="49"/>added, and the suspension was cooled to 1-5C. Then, 75% H3PO4 (about 50 g) was added drop-wise to obtain a pH in range of 5.4-5.8. During acidification CO2 evolves and almost complete solid dissolution is observed. After the phases are separated, the organic phase was washed with water (200 ml) and then with sat NaCl, (100 ml). After solvent elimination under vacuum, a residual oil (47 g) of the title compound was obtained. (GC purity 91%.)

Reference： [1]Patent: WO2007/76157,2007,A2 .Location in patent: Page/Page column 47-48

24
[ 141-84-4 ]
[ 55745-70-5 ]
(Z)-5-[(2,3-dihydrobenzofuran-5-yl)methylene]-2-thioxothiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.7%	With ammonium acetate; acetic acid; In acetonitrile; for 3.5h;Inert atmosphere; Reflux;	Synthesis of (Z)-5-[(2,3-dihydrobenzofuran-5-yl)methylene]-2-thioxothiazolidin-4-one (compound 4) Under the argon atmosphere, acetic acid (AcOH) (120 muL, 2.10 mmol, commercial product) was added at room temperature to an acetonitrile (MeCN) (2 mL, dehydrated, commercial product) solution of 2,3-dihydrobenzofuran-5-carbaldehyde (296 mg, 2.00 mmol, commercial product), ammonium acetate (NH4OAc) (77.0 mg, 1.00 mmol, commercial product), and rhodanine (266 mg, 2.00 mmol, commercial product). The mixture was heated to reflux for 3.5 hours. After the mixture was allowed to cool to room temperature, the precipitated crystal was filtered off with a Hirsch funnel. The crystal was washed with water (3 mL * 4) and diethyl ether (3 mL * 2), and thus (Z)-5-[(2,3-dihydrobenzofuran-5-yl)methylene]-2-thioxothiazolidin-4-one (compound 4) (488 mg, 1.86 mmol, 92.7%) was obtained as a yellow solid. mp 247-248C 1H NMR (400 MHz, DMSO-d6) delta 13.70 (brs, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.63 (t, J = 8.4 Hz, 2H), 3.25 (t, J = 8.4 Hz, 2H)
20%	With sodium acetate; acetic acid; at 110℃;	Dissolve the rhodanine (0.09 g, 0.675 mmol), 3-dihydrobenzo-furan-5-carboxaldehyde (0.100 g, 0.675 mmol) and sodium acetate (0.166 g, 2.025 mmol) in 5 mL of acetic acid and cook the solution at 110C, if necessary under microwave conditions (130W for ~10 minutes). Cool down and collect the precipitate via filtration. Wash with an appropriate solvent to remove all the acetic acid. Dry in vacuo.Yield: 20%. mp: >300C. 1H NMR (300 MHz, chloroform-d) delta ppm 3.30 (s, 2 H) 3.30 (t, j=8.75 Hz, 2 H) 4.70 (t, j=8.75 Hz, 2 H) 6.90 (d, j=8.29 Hz, 1 H) 7.30 - 7.34 (m, 1 H) 7.35 (s, 1 H) 7.63 (s, 1 H) 8.90 - 9.40 (br, 1 H). 13C NMR (126 MHz, DMSO-d6) delta ppm 28.49 (s, 1 C) 72.13 (s, 1 C) 109.02 (s, 1 C) 110.06 (s, 1 C) 121.35 (s, 1 C) 125.57 (s, 1 C) 127.32 (s, 1 C) 129.47 (s, 1 C) 132.42 (s, 1 C) 132.63 (s, 1 C) 162.31 (s, 1 C) 195.48 (s, 1 C). LC-MS (ESI): m/z MH+= 264.
	With sodium acetate; In acetic acid; at 110℃; for 48h;	A mixture of aldehyde of formula Va (10 mmol), Rhodanine Via (10 mmol), sodium acetate (30 mmol), and 10 ml. of acetic acid was heated at 110C0 for 48 h. The reaction mixture was cooled to room temperature and filtered to collect the precipitate formed. The precipitate was washed with acetic acid (1 ml_), methanol (1 ml.) and dried in vaccuo to give compound Vila 3.9g (14.81 mmol).To room a temperature suspension of Vila (14.81 mmol) in 100 ml. ethanol was added Hunig's base (5.2 ml_, 29.85 mmol) followed by iodomethane (4.6 ml_, 73.9 mmol).After stirring the resultant suspension at room temperature for 3.5 h, the precipitate was filtered and washed with water to afford compound Villa 3.12g (11.25 mmol) as a first crop. After evaporating the filtrate, to the residue was added methanol (10 ml.) and water (10 ml_), and the resultant mixture was subjected to sonication for 1 min. The process yielded the second crop which was filtered. 0.8g (2.89 mmol).To a mixture of Villa (0.3 mmol) and MS4A (molecular sieve 4 Angstrom powder) (250 mg) was added dimethylaminoethylamine (0.45 mmol) and ethanol (1 mL, dehydrated). The mixture was heated by microwave (SmithSynthesizer-Personal Chemistry) at 1 10 C0 for 1200 seconds. The corresponding product was obtained in 65% yield after purification on SCX column.1H NMR (400MHz, DMSOd6) ppm 2.18 (s, 6H), 2.44 (t, 2H, J = 6.6 Hz), 3.24 (t, 2H, J = 8.6 Hz), 3.58 (t, 2H, J = 6.6 Hz), 4.60 (t, 2H, J = 8.6 Hz), 6.90 (d, 1 H, J = 8.3 Hz), 7.30-7.48 (m, 3H). LC/MS: m/z 318 (M+1 )+, 316 (M-1 ) -.

Reference： [1]Patent: EP2881397,2015,A1 .Location in patent: Paragraph 0106; 0107; 0108
[2]European Journal of Medicinal Chemistry,2016,vol. 112,p. 209 - 216
[3]Patent: WO2007/103754,2007,A2 .Location in patent: Page/Page column 87-88

25
[ 55745-70-5 ]
C₉H₆ClFN₂OS [ No CAS ]
2-(2-chloro-5-fluoro-phenylimino)-5-(2,3-dihydro-benzofuran-5-ylmethylene)-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; In acetic acid; at 120℃; for 48h;Heating / reflux;	A mixture of 2-chloro-5-fluoroaniline Na (2.0 g, 13.7 mmol) and 1.7 g of NH4SCN in 4N-HCI (20 ml.) was heated to reflux at 1 10C for 6 hours. After cooling, it was treated with H2O to form a solid, followed by desiccation in vacuo to give thiourea Ilia (870 mg, 4.3 mmol). A mixture of Ilia (870 mg, 4.3 mmol), CICH2CO2H (400 mg), and AcONa (350 mg) in AcOH (5 ml.) was heated to reflux at 110 C0 for 4 h. The mixture was poured onto water and the formed solid was isolated by filtration. It was washed with MeOH to give imino thiazolidinone IVa (456 mg, 1.9 mmol). A mixture of IVa (98 mg, 0.4 mmol), aldehyde Va (60 mg, 0.4 mmol), AcONa (100 mg) in AcOH (2 ml.) was heated to reflux at 120 degree for 48 hours. After cooling, a small portion of water was added until the solid forms. It was filtered and washed with MeOH, followed by desiccation in vacuo to afford a target product Ia (61 mg, 0.16 mmol). <n="65"/>1HNMR: (DMSO-Cl6) delta 3.21 (t, 2H), 4.58 (t, 2H), 6.87 (d, 1 H), 7.06 (sbr, 2H), 7.30 (d, 1H), 7.39 (s, 1H), 7.58 (sbr, 2H), 12.60 (sbr, 1H) : LC/MS: m/z 375 (M+1), 377 (M+3)

Reference： [1]Patent: WO2007/103754,2007,A2 .Location in patent: Page/Page column 63-64

26
[ 109-80-8 ]
[ 55745-70-5 ]
[ 1034669-88-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With boron trifluoride diethyl etherate; In diethyl ether; dichloromethane; at 0℃; for 2h;	Example 19; 5-(l,3-Dithian-2-yI)-2,3-dihydro-l-benzofuran; Boron trifluoride-diethyl etherate (9.0 mL, 70.1 mmol) was added dropwise to a cooled (0 C) solution of 2,3-dihydrobenzofuran-5-carboxaldehyde (2,3 mL, 18.2 mmol) and 1, 3- propanedithiol (5.1 mL, 18.2 mmol) in dichloromethane (40 mL). The resulting mixture was stirred at 0 C for 2 h. Saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, aqueous potassium hydroxide (10%) and water, dried over magnesium sulfate and the solvent was evaporated to give 4.4 g (100% yield) of the crude title compound: 1HNMR (CDCl3) delta 7.33 (s, 1 H), 7.20 (dd, J= 8.2, 1.9 Hz, 1 H), 6.73 (d, J= 8.3 Hz, 1 H), 4.57 (t, J= 8.7 Hz, 2 H), 3.20 (t, J= 8.7 Hz, 2 H), 3.00 - 3.11 (m, 2 H), 2.86 - 2.94 (m, 2 H), 2.11 - 2.22 (m, 1 H), 1.84 - 1.98 (m, 1 H); HR MS (ES) m/z 239.0559 [M+H]+.

Reference： [1]Patent: WO2008/76043,2008,A1 .Location in patent: Page/Page column 63

27
[ 55745-70-5 ]
(1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride [ No CAS ]
[ 1075236-86-0 ]

Yield	Reaction Conditions	Operation in experiment
34.5%		Example 36; (lR)-l-({4-[(2,3-Dihydro-l-benzofuran-5-ylmethyl)amino]-l- piperidinyl} methyl)- 1 ,2-dihydro-4H,9H-imidazo [ 1 ,2,3-//] - 1 ,8-naphthyridine-4,9- dione hydrochloride; A suspension of (li?)-l-({4-[(l,2,3-benzothiadiazol-5-ylmethyl)amino]-l- piperidinyl} methyl)- 1 ,2-dihydro-4eta,9eta-rmidazo[l ,2,3-ij]-l ,8-naphthyridine-4,9-dione dihydrochoride(for a preparation see Example 5A(j)) (60mg, 0.161 mmol) in chloroform (2 ml) and methanol (0.100 ml) at rt under nitrogen was treated with triethylamine (0.067 ml, 0.482 mmol) and stirred at rt for 15min. The solution was then treated with 2,3- dihydro-l-benzofuran-5-carbaldehyde (commercially available) (0.020 ml, 0.161 mmol) and stirred for a further 30min. The solution was then treated with sodium triacetoxyborohydride (102 mg, 0.482 mmol) and stirred at rt for 45min. This was then treated with saturated aqueous NaHCO3 (10ml) and extracted with 20% methanol/DCM (3 x 25ml). The combined organic fractions were dried (NaSO4), filtered, evaporated and chromatographed (5-25% methanol/DCM) to give the free base of the title compound (24mg, 34.5%) as a white solid.1H NMR deltaH CDCl3, (400MHz) 1.22-1.49 (m, 2H), 1.79-2.10 (m, 2H), 2.21-2.40 (m, 2H), 2.45-2.58 (m, IH), 2.61-2.72 (m, 2H), 2.90-3.01 (m, IH), 3.05-3.15 (m, IH), 3.21 (t, 2H), 3.72 (s, 2H), 4.32-4.42(m, IH), 4.51-4.62 (m, 3H), 4.95-5.05 (m, IH), 6.22-6.33 (m, 2H), 6.72(d, IH), 7.14 (d, IH), 7.19 (s, IH), 7.45-7.52 (2H, m), MS (ES+) m/z 433 (MH+). <n="92"/>The free base of the title compound was dissolved in a small amount of DCM, treated with one equivalent of IM HCl in diethyl ether and then evaporated to give the title compound as the mono-HCl salt (22.7mg, 28.6%). LCMS consistent with product.

Reference： [1]Patent: WO2008/128942,2008,A1 .Location in patent: Page/Page column 90-91

28
[ 55745-70-5 ]
[ 141-82-2 ]
[ 198707-57-2 ]

Yield	Reaction Conditions	Operation in experiment
92 - 95%		Example 2:Synthesis of Intermediate IV; A mixture of 2,3-dihydrobenzofuran-5-carbaldehdye (100.0 g, 0.6756 mol) and Malonic acid (175.67 g, 1.6891 mol) in pyridine (200ml) containing piperidine (11.5 g, 0.135 mol) and acetic acid (4.05 g, 0.0676 mol) was heated at 1000C for 4-5 hr. The reaction progress was checked by TLC and HPLC monitoring. The cooled reaction mixture was poured into aqueous HCl and stirred for 2-3 hr at room temperature. The solid mass was isolated by filtration and dried under the vacuum at 60-70 C. Yield: 92- 95%, Purity: 95%
74%	With piperidine; In pyridine; at 100℃; for 12h;	5- aldehyde dihydrobenzofuran (2,4.99g, 33.7mmol), malonic acid (5.27g, 50.6mmol) and piperidine (192mg, 2.25mmol) was added pyridine (30ml), the heating at 100 deg.] C The reaction was stirred for 12 hours, the reaction was poured into water, and 6N hydrochloric acid solution was added, adjusting the PH value of 3-4, the precipitated solid was filtered, washed with water and the solid was washed several times with petroleum ether and dried to give 5-prepared acrylic dihydrobenzofuran (3,4.73g), yield 74%;
	With piperidine; pyridine; at 120℃; for 6h;	EXAMPLE 2: Preparation of 3-(2,3-dihydrobenzofuran-5-yl)-2-propenoic acid (FORMULA Xl, wherein ^^^ represents a single bond); 202 g of 2, 3- dihydrobenzofuran -5- carbaldehyde of Formula XII (wherein 1^" represents a single bond), 400 ml of pyridine, 17.4 g of piperidine and 197.18 g of malonic acid were charged into a clean and dry 4 neck round bottom flask followed by stirring given. The reaction mass was heated to 1200C and stirred for about 6 hours up to completion of the reaction. The reaction mass was cooled to 260C and quenched into ice slowly (2000 g). The resultant reaction solution was extracted with ethyl acetate (3x800 ml) and the organic and the aqueous layer were separated. The combined organic layer was washed with water (5 X <n="31"/>1000ml) brine solution (2 X 750 ml). The resultant organic layer was distilled completely below 5O0C under vacuum. Diisopropyl ether 600 ml was added to the obtained crude followed by stirring for 30 minutes at 260C. The separated solid was filtered and washed with 100 ml diisopropyl ether solvent. The obtained solid was dried under vacuum at 580C to afford 175.4 g of the title compound.

Reference： [1]Patent: WO2008/151170,2008,A2 .Location in patent: Page/Page column 5; 6; 14; 20; 35; 45; 63; 68
[2]Patent: CN102766135,2017,B .Location in patent: Paragraph 0037-0038
[3]Patent: WO2008/150953,2008,A1 .Location in patent: Page/Page column 29-30

29
[ 66826-78-6 ]
[ 55745-70-5 ]
[ 87901-66-4 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 4162 - 4166

30
[ 55745-70-5 ]
[ 10035-16-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene; at 20 - 80℃; for 1h;Inert atmosphere;	NBS (0.656 g, 3.69 mmol) and AIBN (8.10 mg, 49.2 lmol) wereadded to a solution of 107 (0.364 g, 2.46 mmol) in chlorobenzene(7.3 mL) at room temperature under an argon atmosphere. Afterstirring for 1 h at 80 C, the mixture was cooled to room temperatureand diluted with EtOAc. The organic layers were washed withsaturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, andconcentrated in vacuo. The residue was purified by silica gel CC(EtOAc/hexane, 3:97) to afford benzofuran-5-carbaldehyde (108)(0.268 g, 1.84 mmol, 75%) as a colorless oil: 1H-NMR (CDCl3,400 MHz) d: 6.82 (d, J = 2.0 Hz, 1H, furan-H), 7.54 (d, J = 8.8 Hz,1H, Ar-H), 7.65 (d, J = 2.0 Hz, 1H, furan-H), 7.79 (d, J = 8.8 Hz, 1H,Ar-H), 8.07 (s, 1H, Ar-H), 9.99 (s, 1H, -CHO); spectroscopic datawere consistent with those reported in the literature (van Otterloet al., 2005).
60%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene; at 80℃; for 1h;	To a solution of 2,3-dihydrobenzofuran-5-carbaldehyde (1 g, 6.75 mmol, A) in Chlorobenzene (20 mL), NBS (1.44 g, 8.10 mmol), AIBN (22 mg, 0.13 mmol) were added and the mixture was stirred at 80 C. for 1 h. After cooling the reaction mixture to room temperature, it was washed with aqueous NaHCO3. The organic layer was separated and the aqueous layer was washed with CH2Cl2. The organic layers were combined, dried over Na2SO4 and concentrated under vacuum on a rotary evaporator. The crude product was purified via gradient column chromatography using hexanes and ethyl acetate (100:1 to 1:1) to obtain the desired aldehyde B as brown syrup (60%) which solidifies at 0 C. [0076] 1H NMR (500 MHz, CDCl3): delta 10.07 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.5, 8.6 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 6.90 (m, 1H). [0077] 13C NMR (125 MHz, CDCl3): delta 191.7, 158.2, 146.7, 132.2, 125.7, 124.6, 112.1, 107.2
55%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene; at 80℃; for 4h;Cooling with ice;	To an ice-cold stirred solution of compound A (500 mg, 3.37 mmol, leq) in chlorobenzene (10 ml) were added NBS (721 mg, 4.05 mmol, 1.2 eq) in portions and AIBN (11 mg, 0.07 mmol, 0.02 eq) and the resulting solution was stirred at 80 C for 4 h. The reaction mixture was cooled to RT, concentrated in vacuo and the residue was washed with saturated aq. NaHCC>3 solution (20 ml). The organic components were extracted with ethyl acetate (50 ml) and the ethyl acetate layer was concentrated in vacuo. The crude material was purified by flash chromatography (Combiflash) using 100-200 mesh silica gel eluting with 5% ethyl acetate/hexane to obtain the compound B (270 mg, 55%) as white solid. [0176] FontWeight="Bold" FontSize="10" H NMR (400 MHz, OMSO-d6) delta 10.06 (s, 1 H), 8.28 (s, 1 H), 8.16-8.16 (m, 1 H), 7.89-7.87 (m, 1 H), 7.81-7.79 (m, 1 H), 7.16-7.15 (m, 1 H); (0181) [0177] LCMS: m/z = 147.4 [M+H], RT = 2.99 minutes; (Program Rl, Column Y).

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 6270 - 6286
[2]Phytochemistry,2013,vol. 96,p. 132 - 147
[3]Patent: US2014/309427,2014,A1 .Location in patent: Paragraph 0074; 0075; 0076; 0077
[4]Patent: WO2018/64135,2018,A1 .Location in patent: Paragraph 0174-0177

31
[ 55745-70-5 ]
[ 867-13-0 ]
[ 217483-05-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium tert-butylate; In toluene; at 20℃;Cooling with ice;	To an ice-cooled suspension of potassium t-butoxide (658 g, 5.SB moles) in toluene (6.24 lit) was added drop-wise triethyl phosphonoacetate (1318 g, 5.88 moles). 2,3- dihydrobenzofuran-5-carbaldehyde (725 g, 4.90 moles) was added drop-wise to the obtained reaction mixture followed by stirring at room temperature for 1 hour. Acetic acid (75 ml) and water (3.5 lit) were then added to the reaction mixture. The separated toluene layer was washed with water (1.5 lit) and the solvent was distilled out from the reaction mixture under reduced pressure to get the residue. To the obtained residue hexane (1 lit) was added and stirred to obtain crystals (1007 g, 94%) of the title compound.

Reference： [1]Patent: WO2010/41271,2010,A2 .Location in patent: Page/Page column 28

32
[ 55745-70-5 ]
[ 873942-91-7 ]
[ 1346226-39-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With acetic acid; In ethanol; at 26℃; for 0.5h;	General procedure: To a suspension of compound 4 (1 mmol) in dry ethanol (8 mL) were added substituted aldehydes (1 mmol) and catalytic amount of acetic acid (2 drops). The reaction mixture was stirred at 26 C for 30 min and was monitored by TLC. When the reaction was completed, it was concentrated under reduced pressure. The solid separated was filtered, dried and recrystallized from diethyl ether. Some of the final compounds were purified by Biotage column chromatography using pet ether:ethyl acetate (40:60) as eluant.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 5283 - 5292

33
[ 55745-70-5 ]
[ 188945-44-0 ]
[ 1221160-65-1 ]
[ 196597-65-6 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Triton B (40% in MeOH, 7.30 mL, 17.5 mmol) was added dropwise to a solution of ethyl 2-[bis(2-isopropylphenoxy) phosphoryl]acetate (5.30 g, 13.1 mmol) in THF (150 mL) at -78 C under Ar. After 15 min of stirring, a solution of 2-methylbenzaldehyde (59) (1.50 g, 12.5 mmol) in THF (50 mL) was added dropwise to the solution. After 10 h of stirring, the mixture was quenched with satd. aq. NH4Cl (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed successively with H2O, satd. aq. (20 mL) NaHCO3 (20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentratedin vacuo.; Z-selective olefination of 2,3-dihydrobenzofuran-5-carbaldehyde(107) was performed using the procedure described aboveto provide (Z)-ethyl 3-(2,3-dihydrobenzofuran-5-yl)acrylate (cis-163) (78%, Z:E = 93:7, determined by 1H-NMR spectrum) (silicagel CC, EtOAc/hexane, 3:97) as a colorless oil: 1H-NMR (CDCl3,400 MHz) d: 1.26 (t, J = 7.4 Hz, 3H, -CH3), 3.22 (t, J = 8.8 Hz, 2H,dihydrofuran-H), 4.19 (q, J = 7.4 Hz, 2H, -CH2-), 4.60 (t, J = 8.8 Hz,2H, dihydrofuran-H), 5.78 (d, J = 12.8 Hz, 1H, CH-CO2-), 6.75 (d,J = 8.4 Hz, 1H, Ar-H), 6.82 (d, J = 12.8 Hz, 1H, Ar-CH), 7.42 (d,J = 8.4 Hz, 1H, Ar-H), 7.79 (s, 1H, Ar-H).

Reference： [1]Phytochemistry,2013,vol. 96,p. 132 - 147

34
[ 55745-70-5 ]
C₁₈H₁₉F₂NO₂ [ No CAS ]
(2S,4R,5R)-2-(bis(4-fluorophenyl)methyl)-5-(((2,3-dihydrobenzofuran-5-yl)methyl)amino)tetrahydro-2H-pyran-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium cyanoborohydride; acetic acid; In methanol; 1,2-dichloro-ethane;	Amine 5 (50 mg, 0.16 mmol) was reacted with 2,3-dihydrobenzofuran-5-carbaldehyde (28 mg, 0.19 mmol), glacial acetic acid (13 muL, 0.21 mmol), and NaCNBH3 (17 mg, 0.27 mmol) in a mixture of 1,2-dichloroethane (4.5 mL) and methanol (1.5 mL). The residue was purified by gradient silica gel column chromatography using a mixture of dichloromethane and methanol (100:1 to 6:1) to afford corresponding compound 6c (D-507) (56 mg, 79%) as a light yellow syrup. [0071] 1H NMR (400 MHz, CDCl3): delta 7.23-7.31 (m, 2H), 7.10-7.19 (m, 3H), 6.89-7.03 (m, 5H), 6.71 (d, J=8.1 Hz, 1H), 4.55 (t, J=8.8 Hz, 2H), 4.33-4.47 (m, 1H), 3.95-4.03 (m, 1H), 3.85-3.94 (m, 2H), 3.74-3.83 (m, 2H), 3.63 (d, J=12.7 Hz, 1H), 3.17 (t, J=8.8 Hz, 2H), 2.46 (s, 1H), 1.63-1.74 (m, 1H), 1.36-1.46 (m, 1H). [0072] 13C NMR (100 MHz, CDCl3): delta 162.7, 162.6, 160.3, 160.2, 159.3, 137.8, 137.7, 137.5, 137.4, 131.8, 129.9, 129.8, 129.7, 129.6, 127.9, 127.2, 124.9, 115.6, 115.4, 115.3, 115.1, 108.9, 73.5, 71.3, 67.2, 64.7, 56.3, 54.9, 51.0, 33.2, 29.7. [0073] [alpha]25D=(-)39.8, c=1 in CH2Cl2.
79%		General procedure: To a stirred solution of amine 1 (60 mg, 0.22 mmol) and 1-benzofuran-5-carbaldehyde (35 mg, 0.24 mmol) in 1,2-dichloroethane (6 mL) was added glacial acetic acid (13 muL, 0.22 mmol). After being stirred for 30 min, NaCNBH3 (28 mg, 0.44 mmol) was added portion wise followed by methanol (1 mL). The reaction mixture was stirred for overnight. The reaction mixture was quenched with saturated NaHCO3 solution at 0 C and extracted with dichloromethane (3 * 75 mL). The combined organic layer was washed with water, brine, dried over Na2SO4, and the solvent was removed under reduced pressure. Crude product was purified by column chromatography using 70% ethyl acetate in hexanes to give compound 2a (D-484) (60 mg, 67%) as thick syrup.

Reference： [1]Patent: US2014/309427,2014,A1 .Location in patent: Paragraph 0069; 0070; 0071; 0072
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 821 - 828

35
[ 55745-70-5 ]
[ 1118-71-4 ]
[ 109-77-3 ]
2-amino-6-tert-butyl-4-(2',3'-dihydrobenzofuran-5-yl)-5-pivaloyl-4H-pyran-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With iodine; In water; at 25℃; for 0.166667h;Sonication; Green chemistry;	General procedure: A 50mL flask was charged with aldehyde (1 mmol), malononitrile (1 mmol), 1,3-diketone (1 mmol) and iodine (0.2 mmol) in water (3 mL). The mixture was sonicated (35 kHz, constant frequency) at 25 C for 10 min. After completion of the reaction [monitored by TLC, using hexane:ethyl acetate (9:1) as eluent], the reaction mixture was quenched with ice and the precipitate formed was filtered, washed, dried and recrystallized from ethanol to get the pure product. The structures of all the products were confirmed by IR, 1H NMR, 13C NMR, ESI-MS and CHN analysis.

Reference： [1]Ultrasonics Sonochemistry,2015,vol. 24,p. 1 - 7

36
[ 55745-70-5 ]
[ 614-27-7 ]
[ 109-77-3 ]
2-amino-5-benzoyl-4-(2',3'-dihydrobenzofuran-5-yl)-6-methoxy-4H-pyran-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With iodine; In water; at 25℃; for 0.166667h;Sonication; Green chemistry;	General procedure: A 50mL flask was charged with aldehyde (1 mmol), malononitrile (1 mmol), 1,3-diketone (1 mmol) and iodine (0.2 mmol) in water (3 mL). The mixture was sonicated (35 kHz, constant frequency) at 25 C for 10 min. After completion of the reaction [monitored by TLC, using hexane:ethyl acetate (9:1) as eluent], the reaction mixture was quenched with ice and the precipitate formed was filtered, washed, dried and recrystallized from ethanol to get the pure product. The structures of all the products were confirmed by IR, 1H NMR, 13C NMR, ESI-MS and CHN analysis.

Reference： [1]Ultrasonics Sonochemistry,2015,vol. 24,p. 1 - 7

37
[ 55745-70-5 ]
[ 367-57-7 ]
[ 109-77-3 ]
2-amino-4-(2′,3′-dihydrobenzofuran-5-yl)-6-methyl-5-(2″,2″,2″-trifluoroacetyl)-4H-pyran-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With iodine; In water; at 25℃; for 0.166667h;Sonication; Green chemistry;	General procedure: A 50mL flask was charged with aldehyde (1 mmol), malononitrile (1 mmol), 1,3-diketone (1 mmol) and iodine (0.2 mmol) in water (3 mL). The mixture was sonicated (35 kHz, constant frequency) at 25 C for 10 min. After completion of the reaction [monitored by TLC, using hexane:ethyl acetate (9:1) as eluent], the reaction mixture was quenched with ice and the precipitate formed was filtered, washed, dried and recrystallized from ethanol to get the pure product. The structures of all the products were confirmed by IR, 1H NMR, 13C NMR, ESI-MS and CHN analysis.

Reference： [1]Ultrasonics Sonochemistry,2015,vol. 24,p. 1 - 7

38
[ 55745-70-5 ]
[ 1522-22-1 ]
[ 109-77-3 ]
2-amino-4-(2′,3′-dihydrobenzofuran-5-yl)-5-(2″,2″,2″-trifluoroacetyl)-6-(trifluoromethyl)-4H-pyran-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With iodine; In water; at 25℃; for 0.166667h;Sonication; Green chemistry;	General procedure: A 50mL flask was charged with aldehyde (1 mmol), malononitrile (1 mmol), 1,3-diketone (1 mmol) and iodine (0.2 mmol) in water (3 mL). The mixture was sonicated (35 kHz, constant frequency) at 25 C for 10 min. After completion of the reaction [monitored by TLC, using hexane:ethyl acetate (9:1) as eluent], the reaction mixture was quenched with ice and the precipitate formed was filtered, washed, dried and recrystallized from ethanol to get the pure product. The structures of all the products were confirmed by IR, 1H NMR, 13C NMR, ESI-MS and CHN analysis.

Reference： [1]Ultrasonics Sonochemistry,2015,vol. 24,p. 1 - 7

39
[ 55745-70-5 ]
[ 556-90-1 ]
(Z)-5-[(2,3-dihydrobenzofuran-5-yl)methylene]-2-iminothiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.1%	With ammonium acetate; acetic acid; In acetonitrile; for 6h;Inert atmosphere; Reflux;	Synthesis of (Z)-5-[(2,3-dihydrobenzofuran-5-yl)methylene]-2-iminothiazolidin-4-one (compound 7) Under the argon atmosphere, acetic acid (AcOH) (120 muL, 2.10 mmol, commercial product) was added at room temperature to an acetonitrile (MeCN) (2 mL, dehydrated, commercial product) solution of 2,3-dihydrobenzofuran-5-carbaldehyde (296 mg, 2.00 mmol, commercial product), ammonium acetate (NH4OAc) (77.0 mg, 1.00 mmol, commercial product), and <strong>[556-90-1]pseudothiohydantoin</strong> (232 mg, 2.00 mmol, commercial product). The mixture was heated to reflux for 6 hours. After the mixture was allowed to cool to room temperature, the precipitated crystal was filtered off with a Hirsch funnel. The crystal was washed with water (3 mL * 4) and diethyl ether (3 mL * 2), and thus (Z)-5-[(2,3-dihydrobenzofuran-5-yl)methylene]-2-iminothiazolidin-4-one (compound 7) (468 mg, 1.90 mmol, 95.1%) was obtained as a light yellow solid. mp 280C (dec) 1H NMR (400 MHz, DMSO-d6) delta 9.33 (brs, 1H), 9.07 (brs, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.36 (dd, J = 7.2, 0.8 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 4.62 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 7.2 Hz, 2H)

Reference： [1]Patent: EP2881397,2015,A1 .Location in patent: Paragraph 0115; 0116; 0117

40
[ 55745-70-5 ]
[ 98-86-2 ]
[ 1401797-84-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With boric acid; In neat (no solvent); at 160℃; for 0.666667h;Microwave irradiation; Sealed tube; Green chemistry;	General procedure: A mixture of substrate (1 mmol), aldehyde (1.2 mmol) and boric acid (0.2 mmol) was placed in a cylindrical quartz reactor ( theta = 4 cm). The reactor was introduced into an Explorer24 CEM apparatus. The stirred mixture was heated at 160 C (P = 300 W) for 40 min, except for 3c (180 C). After microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature and ethanol (10 mL) or mixture of H2O/EtOH (10 mL) was directly added in the cylindrical quartz reactor. The resulting precipitated product was filtered off and was purified by recrystallization from ethanol if necessary.

Reference： [1]Molecules,2015,vol. 20,p. 11617 - 11631

41
[ 55745-70-5 ]
[ 108-29-2 ]
(E)-3-((2,3-dihydrobenzofuran-5-yl)methylene)-5-methyldihydrofuran-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%		To a solution of NaH in dry toluene (0.162 g, 4.05 mmol), a solution of the delta-valerolactone (0.324 g, 3.24 mmol, 0.309 mL) was added, and the mixture stirred overnight at room temperature. On the next day, the mixture was cooled in an ice bath and 2,3-dihydrobenzo-furan-5-carboxaldehyde (0.300 g, 2.025 mmol) dissolved in dry toluene was added dropwise. The temperature was slowly increased to reflux until the starting materials were consumed. After cooling down, a solution of 10% H2SO4 was added and the solution stirred at room temperature for few minutes. Then 10 mL of water were added and the mixture extracted 3 times with ethyl acetate (10 mL). The organic phase was washed with brine and dried over Na2SO4. After evaporating the solvent in vacuo, crude product was purified the column chromatography. Yield: 31%. Mp: 131 C. 1H NMR (500 MHz, DMSO-d6) delta ppm 1.36 (d, J = 6.31 Hz, 3H) 2.72-2.84 (m, 1H) 3.23 (t, J = 8.67 Hz, 2H) 3.33-3.40 (m, 1H) 4.60 (t, J = 8.67 Hz, 2H) 4.69-4.79 (m, 1H) 6.87 (d, J = 8.20 Hz, 1H) 7.35 (s, 1H) 7.37-7.41 (m, 1H) 7.51 (s, 1H). 13C NMR (126 MHz, DMSO-d6) delta ppm 22.03 (s, 1C) 28.66 (s, 1C) 34.63 (s, 1C) 71.66 (s, 1C) 73.64 (s, 1C) 109.37 (s, 1C) 122.20 (s, 1C) 126.72 (s, 1C) 127.18 (s, 1C) 128.47 (s, 1C) 131.34 (s, 1C) 135.15 (s, 1C) 161.17 (s, 1C) 171.65 (s, 1C). LC-MS (ESI): m/z MH+ = 231.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 112,p. 209 - 216

42
[ 96-48-0 ]
[ 55745-70-5 ]
(E)-3-((2,3-dihydrobenzofuran-5-yl)methylene)dihydrofuran-2(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4%	With sodium ethanolate; In ethanol; at 50℃;Cooling with ice;	The solution of 2,3-dihydro-benzofuran-5-carboxaldehyde (0.300 g, 0.255 ml, 2.02 mmol) and gamma-butyrolactone (0.174 g, 0.156 ml, 2.02 mmol) in ethanol was added drop by drop to a solution of NaOEt (0.275 g, 4.04 mmol) in ethanol in a ice-cooled bath. The mixture was stirred increasing slowly the temperature to 50C, if necessary under microwave conditions (130W for ~10 minutes). Cool down and filter the precipitate, washing 3 times with ethanol. Purify by chromatography, if necessary.Yield: 4%. Mp: n.d. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 3.15 (td, J=7.39, 2.89 Hz, 2 H) 3.19 (t, J=8.68 Hz, 2 H) 4.39 (t, J=7.31 Hz, 2 H) 4.58 (t, J=8.83 Hz, 2 H) 6.78 (d, J=8.22 Hz, 1 H) 7.24 (d, J=8.22 Hz, 1 H) 7.29 (s, 1 H) 7.45 (t, J=2.89 Hz, 1 H). 13C NMR (126 MHz, CHLOROFORM-d) delta ppm 27.52 (s, 1 C) 29.34 (s, 1 C) 65.26 (s, 1 C) 71.88 (s, 1 C) 109.88 (s, 1 C) 119.83 (s, 1 C) 126.90 (s, 1 C) 127.58 (s, 1 C) 128.11 (s, 1 C) 131.24 (s, 1 C) 136.90 (s, 1 C) 161.59 - 161.91 (m, 1 C) 172.98 (s, 1 C). LC-MS (ESI): m/z MH+= 217.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 112,p. 209 - 216

43
[ 55745-70-5 ]
5-(2,6-dichlorobenzyl)-4-phenylthiazol-2-amine [ No CAS ]
C₂₅H₁₈Cl₂N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In toluene; at 130℃;	General procedure: The 4,5-disubstituted thiazol-2-amine (1 equivalent) obtained from theprevious step, a substituted aryl aldehyde (1 equivalent) and a catalyticamount of p-toluenesulfonic acid were added to a 50mL round-bottomflask, and the mixture was refluxed in toluene for 24h. Then, the solventwas removed, and sodium borohydride (5 equivalents) in ethanol was added. Themixture was stirred for 2-3h and monitored by TLC. After the solvent wasremoved and the mixture was extracted, washed and concentrated, columnchromatography was performed for further purification. 5-(2,6-Dichlorobenzyl)-N-((2,3-dihydrobenzofuran-5-yl)methyl)-4-phenylthiazol-2-amine (9) was obtained as a slight yellow in 76.0% yield. 1H NMR (DMSO-d6, 600 MHz) delta 3.13 (t, J = 8.4 Hz, 2H, CH2), 4.29 (d, J = 5.4 Hz, 2H, CH2), 4.36 (s, 2H, CH2), 4.48 (t, J = 8.4 Hz, 2H, CH2), 6.68 (d, J = 7.8 Hz, 1H, ArH), 7.04 (d, J = 7.8 Hz, 1H, ArH), 7.19 (s, 1H, ArH), 7.30 (t, J = 7.8 Hz, 1H, ArH), 7.34 (t, J = 7.8 Hz, 1H, ArH), 7.44 (t, J = 6.6 Hz, 4H, ArH), 7.64 (d, J = 7.8 Hz, 2H, ArH), 7.76 (t, J = 5.4 Hz, 1H, NH); 13C NMR (151 MHz, CDCl3) delta 166.62, 159.66, 147.66, 136.59, 135.73, 135.54, 129.74, 128.70, 128.45, 128.25, 127.70, 127.43, 124.55, 117.61, 109.14, 77.22, 77.01, 76.80, 71.32, 49.61, 29.63, 29.30; ESI-MS m/z: 467 [M+H]+; m.p. 147.2-148.9 C.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 123,p. 309 - 316

44
[ 55745-70-5 ]
[ 1779-49-3 ]
[ 633335-97-4 ]

Yield	Reaction Conditions	Operation in experiment
98%		General procedure: n-Butyl lithium (1 equiv., 2.5 M in THF) was added dropwise to a 0.12 M solution of methyltriphenylphosphonium bromide (1 equiv.) in THF. The yellow solution was allowed to stir for 15 minutes before addition of aldehyde (1 equiv.), upon which, the mixture turned white or pale yellow. After 2 hours (or observed completion of the reaction by TLC), saturated ammonium chloride was added and the mixture extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification of the crude residue with column chromatography (ethyl acetate/petroleum ether or petroleum ether only was used as the eluent) afforded the substituted styrene.

Reference： [1]Synthesis,2017,vol. 49,p. 3962 - 3967

45
[ 76429-73-7 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With dipotassium hydrogenphosphate; fac-tris(2-phenylpyridinato-N,C₂')iridium(III); tris-(trimethylsilyl)silane; dimethyl dicarbonate In acetonitrile at 20℃; for 6h; Schlenk technique; Inert atmosphere; Sealed tube; Irradiation;

Reference： [1]Zhang, Muliang; Li, Nan; Tao, Xingyu; Ruzi, Rehanguli; Yu, Shouyun; Zhu, Chengjian [Chemical Communications, 2017, vol. 53, # 73, p. 10228 - 10231]

46
[ 1024-30-2 ]
[ 55745-70-5 ]
[ 762-04-9 ]
diethyl ((2,3-dihydrobenzofuran-5-yl)((4-(morpholinosulfonyl)phenyl)amino)methyl)phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium dithionite; In dimethyl sulfoxide; at 120℃;	General procedure: Typical procedure for one-pot synthesis of alpha-aminophosphonates: A mixture of nitro compound (1.0 mmol), aldehyde (1.0 mmol), DEP (1.0 mmol), and sodium dithionite (1.0 mmol) in DMSO (1.0 mL) were stirred at 120 C for the appropriate amount of time (3-4 h). After completion of the reaction as indicated by the TLC and LCMS, the reaction mixture was poured into water (5 mL), and then extracted with ethyl acetate (2 10 mL). The combined organic extracts were washed with saturated brine solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from diethyl ether (solid products) or purified by column chromatography using silica gel (100-200 mesh size) and eluting with hexane/ethyl acetate of increasing polarity to obtain the pure compound. When the above reaction was performed with 5-nitrobenzofuran (entry 16 in Table 2), the double bond between 2 and 3 carbons gets reduced by the sodium dithionite.

Reference： [1]Synthetic Communications,2018,vol. 48,p. 638 - 649

47
[ 55745-70-5 ]
[ 196597-26-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: sodium methylate / toluene / 0.25 h / 0 - 30 °C 2.1: hydrogen / nickel / methanol / 4 h / 50 °C 3.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 4.2: 1 h / -5 - 5 °C 5.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C 6.1: sodium methylate / 5 - 25 °C 7.1: ammonia / nickel / ethanol / 3 - 4 h / 50 °C / 14711.4 Torr 8.1: isopropyl alcohol / 24 h / 26 °C 9.1: dichloromethane 9.2: 26 °C 10.1: toluene / -5 - 0 °C 10.2: 0.25 - 0.33 h
	Multi-step reaction with 11 steps 1.1: piperidine; pyridine / 6 h / 120 °C 2.1: thionyl chloride / 0.67 h / 26 - 73 °C / Heating / reflux 3.1: hydrogen / nickel / methanol / 4 h / 50 °C 4.1: bromine; sodium acetate; acetic acid / 14 h / 20 - 28 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 1,2-dichloro-benzene / 2 h / 28 - 60 °C 5.2: 1 h / -5 - 5 °C 6.1: hydrogen; sodium acetate / raney chloride / methanol / 50 °C 7.1: sodium methylate / 5 - 25 °C 8.1: ammonia / nickel / ethanol / 3 - 4 h / 50 °C / 14711.4 Torr 9.1: isopropyl alcohol / 24 h / 26 °C 10.1: dichloromethane 10.2: 26 °C 11.1: toluene / -5 - 0 °C 11.2: 0.25 - 0.33 h
	Multi-step reaction with 14 steps 1.1: piperidine; pyridine; acetic acid / 4 - 5 h / 100 °C 1.2: 2 - 3 h / 20 °C 2.1: sodium hydroxide; hydrogen; ammonium formate / palladium 10% on activated carbon / water / 5 - 6 h / 20 °C 3.1: bromine; sodium acetate; acetic acid / 2 - 3 h / 0 - 45 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 1 - 2 h / 20 °C 4.2: 1 - 2 h / 0 - 5 °C 5.1: hydrogen; sodium acetate; acetic acid / palladium 10% on activated carbon / 1471.14 - 2206.72 Torr 6.1: sodium hydride / toluene / 2 h / 0 - 5 °C 6.2: 15 - 18 h / 90 - 100 °C 7.1: hydrogen / palladium 10% on activated carbon / methanol; water / 2 - 3 h / 20 °C 8.1: methanol; sodium hydroxide; water / 2 - 3 h / 20 °C 9.1: water; isopropyl alcohol / 0.5 - 0.75 h / 60 - 65 °C / Resolution of racemate 10.1: hydrogenchloride; water / pH 2.0 11.1: thionyl chloride / 3 h / 20 °C 12.1: ammonia / dichloromethane; water 13.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 16 - 26 h / -10 - 20 °C 14.1: sodium hydroxide; water / toluene / 0.5 h / 20 °C 14.2: 0.67 h

Multi-step reaction with 14 steps 1.1: piperidine; pyridine; acetic acid / 4 - 5 h / 100 °C 1.2: 2 - 3 h / 20 °C 2.1: sodium hydroxide; hydrogen; ammonium formate / palladium 10% on activated carbon / water / 5 - 6 h / 20 °C 3.1: bromine; sodium acetate; acetic acid / 2 - 3 h / 0 - 45 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 1 - 2 h / 20 °C 4.2: 1 - 2 h / 0 - 5 °C 5.1: hydrogen; sodium acetate; acetic acid / palladium 10% on activated carbon / 1471.14 - 2206.72 Torr 6.1: sodium hydride / toluene / 2 h / 0 - 5 °C 6.2: 15 - 18 h / 90 - 100 °C 7.1: hydrogen / palladium 10% on activated carbon / methanol; water / 2 - 3 h / 20 °C 8.1: methanol; sodium hydroxide; water / 2 - 3 h / 20 °C 9.1: water; isopropyl alcohol / 0.5 - 0.75 h / 60 - 65 °C / Resolution of racemate 10.1: hydrogenchloride; water / pH 2.0 11.1: triethylamine / dichloromethane / 1 - 2 h / -10 - 0 °C 12.1: ammonia / dichloromethane / 0.5 - 0.75 h / -10 - 0 °C 13.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 16 - 26 h / -10 - 20 °C 14.1: sodium hydroxide; water / toluene / 0.5 h / 20 °C 14.2: 0.67 h

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2008/150953, 2008, A1
[2]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2008/150953, 2008, A1
[3]Current Patent Assignee: KANSAL VINOD KUMAR DR; LIFSHITZ REVITAL; TEVA PHARMACEUTICAL INDUSTRIES LTD.; MISTRY DHIRENKUMAR - WO2008/151170, 2008, A2
[4]Current Patent Assignee: KANSAL VINOD KUMAR DR; LIFSHITZ REVITAL; TEVA PHARMACEUTICAL INDUSTRIES LTD.; MISTRY DHIRENKUMAR - WO2008/151170, 2008, A2

48
[ 55745-70-5 ]
[ 95-54-5 ]
2-(2,3-dihydrobenzofuran-5-yl)-1H-benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With Cobalt Nanocomposite on N-Doped Carbon-800; In tetrahydrofuran; at 100℃; for 8h;Sealed tube; Inert atmosphere; Schlenk technique; Glovebox;	General procedure: A 25 mL sealed tube equipped with a magnetic stirrer bar was charged with catalyst CoOxNC-800 (20 mg, 10 mol%) then sealed with a rubber septum and evacuated to remove air.Benzene-1,2-diamine (0.2 mmol), PhCHO (0.24 mmol), and THF(5 mL) were injected into the tube from a syringe, and the tube was placed in a preheated oil bath at 100 C for 8 h. When the reaction was complete, the mixture was filtered and the organic layers were collected, combined, dried (Na2SO4), and concentrated under vacuum. The residue was purified by passage through a column of silica gel (200-300 mesh) to give a white solid; yield: 38.1 mg (98%).

Reference： [1]Synlett,2019,vol. 30,p. 319 - 324

49
[ 55745-70-5 ]
[ 494854-41-0 ]
(E)-methyl 3-(4-((E)-2-(2,3-dihydrobenzofuran-5-yl)vinyl)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.7%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;	To a stirred solution of compound I (1.0 eq) and compound II or IV (1.05 eq) in dryDMF was added t-BuOK (3.0 eq) at 0. Then, the above reaction mixture was stirredfor 0.5 h at room temperature. The mixture was poured into cold water, the resultantprecipitate was filtered, washed with water, dried and purified by recrystallization fromethyl acetate to afford the pure product III or V.

Reference： [1]Molecules,2019,vol. 24

50
[ 55745-70-5 ]
[ 14295-52-4 ]
(E)-methyl 4-(2-(2,3-dihydrobenzofuran-5-yl)vinyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.6%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;	To a stirred solution of compound I (1.0 eq) and compound II or IV (1.05 eq) in dryDMF was added t-BuOK (3.0 eq) at 0. Then, the above reaction mixture was stirredfor 0.5 h at room temperature. The mixture was poured into cold water, the resultantprecipitate was filtered, washed with water, dried and purified by recrystallization fromethyl acetate to afford the pure product III or V.

Reference： [1]Molecules,2019,vol. 24

51
[ 55745-70-5 ]
[ 1514-82-5 ]
5-(2,3-dihydrobenzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazole [ No CAS ]

Reference： [1]Organic Letters,2020,vol. 22,p. 809 - 813

52
[ 55745-70-5 ]
[ 1560-54-9 ]
(E)-5-(buta-1,3-dien-1-yl)-2,3-dihydrobenzofuran [ No CAS ]
5-(buta-1,3-dien-1-yl)-2,3-dihydrobenzofuran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33.333 % de	In tetrahydrofuran at 0 - 20℃;
25.926 % de	Stage #1: triphenyl(prop-2-en-1-yl)phosphonium bromide With potassium-t-butoxide In tetrahydrofuran at 0℃; for 0.333333h; Inert atmosphere; Stage #2: 2,3-dihydro-benzofuran-5-carbaldehyde In tetrahydrofuran Inert atmosphere; Overall yield = 49percent;
28.571 % de	Stage #1: triphenyl(prop-2-en-1-yl)phosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2,3-dihydro-benzofuran-5-carbaldehyde In tetrahydrofuran; hexane at 20℃; for 1h; Inert atmosphere; Overall yield = 76 percent; Overall yield = 707 mg;

16.667 % de	Stage #1: triphenyl(prop-2-en-1-yl)phosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.666667h; Inert atmosphere; Stage #2: 2,3-dihydro-benzofuran-5-carbaldehyde In tetrahydrofuran; hexane at 20℃; for 3h; Inert atmosphere; Overall yield = 76 percent;
	Stage #1: triphenyl(prop-2-en-1-yl)phosphonium bromide With n-butyllithium In tetrahydrofuran at -78 - 0℃; Inert atmosphere; Stage #2: 2,3-dihydro-benzofuran-5-carbaldehyde In tetrahydrofuran at 0℃; Inert atmosphere; Overall yield = 78 percent; Overall yield = 1.81 g;

Reference： [1]Gevorgyan, Vladimir; Kurandina, Daria; Shing Cheung, Kelvin Pak; Yata, Tetsuji [Journal of the American Chemical Society, 2020, vol. 142, # 22, p. 9932 - 9937]
[2]Ji, Ding-Wei; He, Gu-Cheng; Zhang, Wei-Song; Zhao, Chao-Yang; Hu, Yan-Cheng; Chen, Qing-An [Chemical Communications, 2020, vol. 56, # 54, p. 7431 - 7434]
[3]Zhang, Penglin; Zhou, Zhanglang; Zhang, Rumeng; Zhao, Qian; Zhang, Chun [Chemical Communications, 2020, vol. 56, # 77, p. 11469 - 11472]
[4]Zhang, Rumeng; Li, Qifan; Zhang, Min; Chai, Sida; Duan, Yuqi; Su, Jingfei; Zhao, Qian; Zhang, Chun [Chemical Communications, 2020, vol. 56, # 88, p. 13551 - 13554]
[5]Vaith, Jakub; Rodina, Dasha; Spaulding, Gregory C.; Paradine, Shauna M. [Journal of the American Chemical Society, 2022, vol. 144, # 15, p. 6667 - 6673]

53
[ 350-03-8 ]
[ 55745-70-5 ]
C₁₆H₁₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide In ethanol; water at 20℃; for 0.583333h; Sonication; Green chemistry; stereoselective reaction;	2.2. General Procedure for the Synthesis of (E)-3-(2,3-dihydrobenzofuran-5-yl)-1-(aryl)prop-2-en-1-one Derivatives General procedure: 2,3-Dihydrobenzofuran-5-carbaldehyde (1 mmol), substitutedacetophenones (1 mmol), absolute ethanol (5 mL), and 40 %sodium hydroxide (20 mmol diluted up to 2 mL) were added in aPyrex flask (25 mL). The alkaline mixture was then exposed toultrasound irradiation at room temperature for the period as indicated in Table 5. The reaction was monitored by thin-layerchromatography (eluent 20:80: ethyl acetate: hexane). Thereaction mixture was quenched by pouring on ice. After this, theresulting mixture was acidified by using dilute HCl and theresulting precipitate was then filtered and dried to give thedesired product. The obtained product was recrystallized fromhot ethanol. The synthesized pure products were characterizedby FT-IR, 1HNMR, 13C NMR and HRMS analytical methods.

Reference： [1]Adole, Vishnu A.; Jagdale, Bapu S.; Pawar, Thansing B.; Sagane, Abhishek A. [South African Journal of Chemistry, 2020, vol. 73, p. 35 - 43]

54
[ 55745-70-5 ]
[ 1778-09-2 ]
(E)-3-(2,3-dihydrobenzofuran-5-yl)-1-(4-(methylthio)phenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydroxide In methanol at 20℃; for 24h; Inert atmosphere;	4.1.2. General produce A for the preparation of 2-4, 16 General procedure: To a solution of 1a-c (1.0 equiv.) and 2a or 2c (1.0 equiv.) in methanol was added sodium hydroxide (10.0 equiv.). The solution was stirred at room temperature for 24 h. The forming precipitate was filtered and recrystallized in methanol to give title compounds 2-4.

Reference： [1]Zhang, Cheng; Yue, Hu; Sun, Ping; Hua, Lei; Liang, Shuli; Ou, Yitao; Wu, Dan; Wu, Xinyi; Chen, Hao; Hao, Ying; Hu, Wenhui; Yang, Zhongjin [European Journal of Medicinal Chemistry, 2021, vol. 219]

55
[ 103262-35-7 ]
[ 55745-70-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With acetic anhydride; acetic acid; In dimethyl sulfoxide; at 60℃; for 0.25h;Microwave irradiation; Green chemistry;	7a (0.67mmol, 0.1g), DMSO 2.05mL, Ac2O 1.43mL, AcOH 0.26mL were successively added to a 15mL microwave reaction tube, the microwave power was 150w, the heating temperature was 60C, and the reaction time was 15min.After cooling, NaHCO3 solution was added and stirred at room temperature for 30 min. Extract with ethyl acetate, collect the organic phase, and extract the aqueous phase with ethyl acetate 2-3 times.The organic phases were combined, washed with water in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 7b (yield: 65%).

Reference： [1]Patent: CN114149297,2022,A .Location in patent: Paragraph 0007; 0044-0046

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P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 55745-70-5 ] {[proInfo.proName]}

Quality Control of [ 55745-70-5 ]

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Product Details of [ 55745-70-5 ]

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Lipophilicity

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[ 55745-70-5 ] Synthesis Path-Upstream 1~15

[ 55745-70-5 ] Synthesis Path-Downstream 1~55

Pharmaceutical Intermediates of [ 55745-70-5 ]

Ramelteon Intermediates

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Aldehydes

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Benzofurans

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[ 55745-70-5 ]

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[ 55745-70-5 ]

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[ 55745-70-5 ]