[ CAS No. 865234-02-2 ] {[proInfo.proName]}

Name: 865234-02-2|Methyl 3-(4-hydroxyphenyl)hex-4-ynoate|95%
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SKU: A212378
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Quality Control of [ 865234-02-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 865234-02-2 ]

SDS Specification

Alternatived Products of [ 865234-02-2 ]

Product Details of [ 865234-02-2 ]

CAS No. :	865234-02-2	MDL No. :	MFCD24713927
Formula :	C₁₃H₁₄O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BENPHURJTUUUSX-UHFFFAOYSA-N
M.W :	218.25	Pubchem ID :	57835749
Synonyms :

Calculated chemistry of [ 865234-02-2 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.31
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	61.72
TPSA :	46.53 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) :	-6.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.49
Log Po/w (XLOGP3) :	2.24
Log Po/w (WLOGP) :	2.14
Log Po/w (MLOGP) :	2.43
Log Po/w (SILICOS-IT) :	2.55
Consensus Log Po/w :	2.37

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.62
Solubility :	0.526 mg/ml ; 0.00241 mol/l
Class :	Soluble
Log S (Ali) :	-2.85
Solubility :	0.306 mg/ml ; 0.0014 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.83
Solubility :	0.324 mg/ml ; 0.00148 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.72

Safety of [ 865234-02-2 ]

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

Application In Synthesis of [ 865234-02-2 ]

* 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 [ 865234-02-2 ]
Downstream synthetic route of [ 865234-02-2 ]

[ 865234-02-2 ] Synthesis Path-Upstream 1~5

1
[ 865233-34-7 ]
[ 74-88-4 ]
[ 865234-02-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: With potassium hydrogencarbonate In acetone for 0.25 h; Stage #2: at 40℃;	The acid (23.5 g, 1 15 mmol) was dissolved in acetone (230 mL) and treated with potassium bicarbonate (1 1.5 g, 1 15 mmol). After 15 min, methyl iodide (5 mL, 80 mmol) was added and the reaction stirred at 40°C overnight. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating was continued for 24 h. Insolubles were removed by filtration and rinsed with acetone. The filtrate was concentrated to an oil which was purified on silica gel using 2.5percent methanol in dichloromethane as eluent. This gave 3-(4- hydroxyphenyl)hex-4-ynoic acid methyl ester (21.5 g, 85percent) as a pale yellow oil. ¹H NMR (500 MHz) (acetone-c(₆) δ 8.2 (br, s, 1 H); 7.20 (d, 2H, J = 9.5 Hz); 6.77 (d, 2H, J = 9.0 Hz); 3.98 (m, 1 H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J = 2.5 Hz). MS ESI m/e: 219.1 (M+H); 241 (M+Na).

Reference： [1] Patent: WO2012/97427, 2012, A1, . Location in patent: Page/Page column 40-41

2
[ 67-56-1 ]
[ 865233-34-7 ]
[ 865234-02-2 ]

Yield	Reaction Conditions	Operation in experiment
90.9%	at 65℃; for 2 h;	Intermediate 115: Methyl 3-(4-hydroxyphenyl) hex-4-ynoateTo a 250 mL RB flask fitted with magnetic stirrer was charged with methanol (10 mL). To the stirred solvent was added 3-(4-Hydroxyphenyl) hex-4-ynoic acid (0.62 g, 20.14 mmol) and methane sulfonic acid (3 mL), it was heated at 65 for 2 h. The RM was concentrated, extracted with ethyl acetate (50 mL X 2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na₂S0₄ and the solvent was removed under reduced pressure to obtain the product. (0.4 g, yield: 90.9percent).

Reference： [1] Patent: WO2012/11125, 2012, A1, . Location in patent: Page/Page column 151; 153
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3390 - 3394

3
[ 865233-33-6 ]
[ 865234-02-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3390 - 3394
[2] Patent: WO2012/11125, 2012, A1,
[3] Patent: WO2012/97427, 2012, A1,

4
[ 17474-27-0 ]
[ 865234-02-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3390 - 3394
[2] Patent: WO2012/11125, 2012, A1,
[3] Patent: WO2012/97427, 2012, A1,

5
[ 123-08-0 ]
[ 865234-02-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3390 - 3394
[2] Patent: WO2012/11125, 2012, A1,
[3] Patent: WO2012/97427, 2012, A1,

[ 865234-02-2 ] Synthesis Path-Downstream 1~88

1
[ 865234-02-2 ]
[ 5122-94-1 ]
C₂₅H₂₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper diacetate; triethylamine; In dichloromethane; at 25℃; for 16.0h;Molecular sieve 4A;	General procedure for preparation of diaryl ether compounds: A flask is charged with phenol (1.0 equiv.), Cu(OAc)2 (1.0 equiv.), arylboronic acid (1.0-3.0 equiv.), powdered 4 Å molecular sieves. The reaction mixture was diluted with CH2Cl2 to yield a solution approximately 0.1 M in phenol, and Et3N (5.0 equiv.) is added. After stirring the heterogeneous reaction mixture for 16 h at 25 C. under ambient atmosphere, the resulting slurry is filtered and the diaryl ether is isolated from the organic filtrate by flash chromatography. The resulted ester was then hydrolyzed with LiOH (2.0 equiv.) in a 1:1:1 mixture of MeOH, THF, and water for 2 h at 25 C. The reaction mixture was acidified with 1N HCl, extracted with CH2Cl2 and concentrated to give the pure acid. 3-[4-(Biphenyl-4-yloxy)-phenyl]-hex-4-ynoic acid (42.4). MS ESI m/e: 357.0 (M+H). 1H NMR (500 MHz) (CDCl3) δ 7.60-7.57 (4H, m); 7.46 (2H, dd, J=8.0, 8.0 Hz); 7.39 (2H, d, J=8.5 Hz); 7.36 (1H, d, J=7.3 Hz); 7.09 (2H, d, J=8.6 Hz); 7.04 (2H, d, J=8.6 Hz); 4.2-4.1 (1H, m); 2.87 (1H, dd, J=15.8, 8.6 Hz); 2.77 (1H, dd, J=15.8, 6.7 Hz); 1.88 (3H, d, J=2.3 Hz).

Reference： [1]Patent: US2006/4012,2006,A1 .Location in patent: Page/Page column 52

2
[ 865234-02-2 ]
[ 111787-91-8 ]
C₂₅H₂₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 14.0h;	6.5 Example 5 This example illustrates the preparation of 3-[4-(2-Methyl-5-phenyl-furan-3-ylmethoxy)-phenyl]-hex-4-ynoic acid. 3-[4-(2-Methyl-5-phenyl-furan-3-ylmethoxy)-phenyl]-hex-4-ynoic acid (5). The Mitsunobu reaction was carried out according to the method of Mikó et al. (2003) J. Med. Chem.46: 1523-1530. Commercially available 5.1 (37.6 mg, 0.2 mmol), PPh3 (52 mg, 0.2 mmol) and phenol 1.3 (43.6 mg, 0.2 mmol) were added to anhydrous THF (3 mL). DEAD (45 μL, 0.22 mmol) was then added dropwise. The reaction mixture was stirred at room temperature over 14 hours. The reaction was then extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The resulting residue was dissolved in THF/MeOH/10% NaOH(aq) (1:1:1) solution (6 mL). The resulting mixture was stirred at room temperature over 30 minutes. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was acidified with 1N HCl(aq.) until pH=4. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was triturated in 20% ethyl acetate in hexanes (10 mL). The precipitate was filtered and compound 5 was obtained as a white powder (35 mg, 0.9 mmol). MS ESI m/e: 375 (M-H). 1H NMR (500 MHz) (CDCl3) δ 7.65 (2H, d, J=8 Hz); 7.40-7.24 (5H, m); 6.96 (2H, d, J=8.5 Hz); 6.68 (1H, s); 4.88 (2H, s); 4.1 (1H, s); 2.77 (2H, m); 2.4 (3H, s); 1.86 (3H, s).

Reference： [1]Patent: US2006/4012,2006,A1 .Location in patent: Page/Page column 27-28

3
[ 865234-02-2 ]
[ 865233-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid; acetic acid; at 80℃; for 3.0h;	3-[2-(4'-Trifluoromethyl-biphenyl-3-yl)-benzooxazol-5-yl]-hex-4-ynoic acid (43.3). 3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (1.32 g, 6 mmol) was treated with HNO3 (0.30 mL, 7.2 mmol) in AcOH (10 mL) at 80 C. for 3 h. The solvent was concentrated in vacuo and 3-(3-nitro-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (613 mg, 2.3 mmol) was isolated from flash chromatography. MS ESI m/e: 264.0 (M+H). The nitro group was then reduced with SnCl2 (2.62 g, 11.6 mmol) in EtOH (10 mL0 and EtOAc (10 mL) at 70 C. for 3 h. The reaction mixture was cooled to 25 C., washed with saturated aqueous Na2CO3, water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified by reverse phase HPLC to give 3-(3-amino-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol). MS ESI m/e: 234.0 (M+H). 3-(3-amino-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol) and 3-bromobenzaldehyde (278 mg, 1.5 mmol) in DMF (3 mL) was treated with DDQ (204 mg, 0.9 mmol) for 2 h at 25 C. The producted was purified by reverse phase HPLC. MS ESI m/e: 398.0 (M+H). 3-[2-(3-Bromo-phenyl)-benzooxazol-5-yl]-hex-4-ynoic acid methyl ester (19.6 mg, 0.05 mmol) and trifluorophenylboronic acid (38 mg, 0.2 mmol) in DME (1 mL) and 0.2 mL of 2M solution of aqueous Na2CO3 was treated with Pd(PPh3)4 at 80 C. for 14 h. The product was isolated from flash chromatography. MS ESI m/e: 464.0 (M+H). The methyl ester (7.8 mg, 0.017 mmol) was hydrolyzed with LiOH (4 mg, 0.1 mmol) in a 1 mL of 1:1:1 mixture of MeOH, THF, and water for 2 h at 25 C. The reaction mixture was acidified with 1N HCl, extracted with CH2Cl2 and concentrated to give the pure acid (7.6 mg). MS ESI m/e: 450.1 (M+H). 1H NMR (500 MHz) (CDCl3) δ 8.52 (1H, s); 8.30 (1H, d, J=7.8 Hz); 7.91 (1H, s); 7.83 (2H, d, J=8.2 Hz); 7.82 (1H, s); 7.78 (2H, dd, J=8.0, 8.0 Hz); 7.67 (1H, dd, J=7.8, 7.8 Hz); 7.58 (2H, d, J=8.4 Hz); 7.46 (1H, dd, J=8.4, 1.5 Hz); 4.29 (1H, m); 2.94 (1H, dd, J=15.8, 8.1 Hz); 2.84 (1H, dd, J=15.8, 6.9 Hz); 1.89 (3H, d, J=2.3 Hz).

Reference： [1]Patent: US2006/4012,2006,A1 .Location in patent: Page/Page column 54

4
[ 865234-02-2 ]
4-phenyl-cyclohexanol [ No CAS ]
[ 929712-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 20℃;	A pear-shaped flask (25 mL) was equipped with a magnetic stir bar, a nitrogen inlet and a nitrogen outlet. The compound (+-)-M1 (0.05 g, 0.229 mmol) was added to the flask and dissolved in 0.6 mL of anhydrous toluene. To this solution, 4-phenylcyclohexanol (0.061 g, 0.344 mmol) and triphenylphosphine (0.078 g, 0.298 mmol) were added. DIAD (0.07 g, 0.344 mmol) was added, and the reaction was allowed to stir at room temperature. When the reaction was complete, the solution was concentrated in vacuo and the residue was dissolved in a minimal amount of DCM. The solution was flash column chromatographed with 0 to 100% EtOAc/hexanes as the eluant. The fractions were combined and concentrated to afford 28 as a viscous oil.

Reference： [1]Patent: US2007/66647,2007,A1 .Location in patent: Page/Page column 63

5
[ 67-56-1 ]
[ 865233-34-7 ]
[ 865234-02-2 ]

Yield	Reaction Conditions	Operation in experiment
90.9%	With methanesulfonic acid; at 65℃; for 2.0h;	Intermediate 115: Methyl 3-(4-hydroxyphenyl) hex-4-ynoateTo a 250 mL RB flask fitted with magnetic stirrer was charged with methanol (10 mL). To the stirred solvent was added 3-(4-Hydroxyphenyl) hex-4-ynoic acid (0.62 g, 20.14 mmol) and methane sulfonic acid (3 mL), it was heated at 65 for 2 h. The RM was concentrated, extracted with ethyl acetate (50 mL X 2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure to obtain the product. (0.4 g, yield: 90.9%).
90.9%	With sulfuric acid; at 75℃; for 2.0h;	Intermediate 10b (6.3 g, 30.9 mmol) was dissolved in methanol (40 mL)Concentrated sulfuric acid (123.6 mmol, 4 equivalents) was added and the reaction was refluxed at 75 C for 2 h. The solvent was evaporated under reduced pressure, and water was added, and the mixture was evaporated.Column chromatography gave intermediate 10 (6 g, colorless oil).The yield was 90.9 %.
86.9%	With sulfuric acid; at 65℃; for 12.0h;	Compound D (0.89 g,4.3mmo)was dissolved in methanol(15 ml),followed by adding concentrated sulfuric acid(1.5 ml) slowly withstirring. The mixture was stirred at 65 C for 12 h. Water was addedafter removing most solvent. The emulsion was extracted by AcOEt,which was washed with saturated brine and dried over anhydrous sodiumsulfate. After concentration in vacuo, it was purified by silica gelcolumn chromatography to afford the desired product E (0.83 g.86.9%)as viscous liquid. 1H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.14 (d,J = 7.9 Hz, 2H), 6.70 (d, J = 7.9 Hz, 2H), 3.92 (s, 1H), 3.57 (s, 3H),2.66 (d, J = 7.1 Hz, 2H), 1.77 (s, 3H).

Reference： [1]Patent: WO2012/11125,2012,A1 .Location in patent: Page/Page column 151; 153
[2]Patent: CN109666027,2019,A .Location in patent: Paragraph 0128; 0129; 0131
[3]Bioorganic and Medicinal Chemistry,2020,vol. 28
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3390 - 3394

6
[ 865233-33-6 ]
[ 865234-02-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3390 - 3394
[2]Patent: WO2012/11125,2012,A1
[3]Patent: WO2012/97427,2012,A1
[4]Patent: CN109666027,2019,A
[5]Bioorganic and Medicinal Chemistry,2020,vol. 28

7
[ 865234-02-2 ]
[ 1312791-61-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3390 - 3394

8
[ 865234-02-2 ]
C₂₁H₁₄F₅NO₅ [ No CAS ]
C₂₁H₁₄F₅NO₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3390 - 3394

9
[ 865234-02-2 ]
C₁₃H₁₁NO₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3390 - 3394

10
[ 865234-02-2 ]
[ 100-39-0 ]
[ 1312791-71-1 ]

Yield	Reaction Conditions	Operation in experiment
78.35%	With potassium carbonate; In acetonitrile; at 0 - 20℃; for 16.0h;	Intermediate 133: Methyl 3-[4-(benzyloxy) phenyl] hex-4-ynoateTo a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> (3.8 g, 17.4 mmol), potassium carbonate (7.2 g, 52.2 mmol). The reaction mixture was brought to 0 C, was added benzyl bromide (4.47 g, 1.5 mmol) in acetonitrile (20 mL) drop wise and stirred at room temperature for 16 h. The reaction mixture was concentrated to distill off the solvent. Water (20 mL) was added and extracted with ethyl acetate (60 mL). The organic layer was washed with water (20 mL) and saturated brine solution (20 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants to obtain product (4.2 g, yield: 78.35%).

Reference： [1]Patent: WO2012/11125,2012,A1 .Location in patent: Page/Page column 163-164
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3390 - 3394

11
[ 17474-27-0 ]
[ 865234-02-2 ]

12
[ 123-08-0 ]
[ 865234-02-2 ]

13
[ 865234-02-2 ]
[ 142-82-5 ]
[ 1353043-40-9 ]
[ 603-35-0 ]
[ 1972-28-7 ]
[ 1353043-41-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water; ethyl acetate;	Methyl 3-[4-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethoxy)phenyl]hex-4-ynoate 556 mg of 5-bromo-1-hydroxymethyl-3,3-dimethyl-1,3-dihydroindol-2-one, 673 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> and 810 mg of tri-phenylphosphine were dissolved in 100 ml of tetrahydrofuran. While cooling with ice, 538 mg of diethyl azodicarboxylate was added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. Then 5 ml of water were added cautiously and the reaction mixture was concentrated under reduced pressure. The residue was taken up in 50 ml of water and 50 ml of ethyl acetate. The organic phase was removed, dried over MgSO4 and then concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>50% ethyl acetate. This gave 730 mg of methyl 3-[4-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethoxy)phenyl]-hex-4-ynoate.

Reference： [1]Patent: US2012/4165,2012,A1

14
[ 865234-02-2 ]
[ 2857-97-8 ]
[ 1353043-42-1 ]
[ 1353043-43-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In n-heptane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	100 mg of 6-bromo-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl 2,2-dimethylpropionate were dissolved in 2 ml of dichloromethane and cooled in an ice bath to 0 C. Then 71.7 μl of bromotrimethylsilane were slowly added dropwise. The mixture was stirred at 0 C. for 30 minutes while cooling with ice. Then the solvent was removed under reduced pressure. The residue was dissolved in 2 ml of dichloromethane and 5 ml of n-heptane. Then the solvents were removed once again under reduced pressure. The residue and 71 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> were initially charged in 5 ml of dry DMF, 265 mg of cesium carbonate were added and the mixture was stirred at room temperature for 4 hours. The experiment was left to stand at room temperature overnight and was then diluted with 100 ml of ethyl acetate and extracted with 40 ml of water. The organic phase was removed and dried over MgSO4, filtered and then concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture=4:1. This gave 91 mg of methyl 3-[4-(6-bromo-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethoxy)phenyl]hex-4-ynoate.

Reference： [1]Patent: US2012/4165,2012,A1

15
[ 865234-02-2 ]
[ 2163-42-0 ]
[ 1354028-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; In dichloromethane; at 0 - 20℃; for 48.0h;	Methyl 3-[4-(3-hydroxy-2-methylpropoxy)phenyl]hex-4-ynoate 500 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong>, 1.01 ml of 2-methyl-1,3-propanediol and 1.20 g of resin-bound triphenylphosphine were initially charged in a 100 ml round-bottom flask in 30 ml of dichloromethane under argon and cooled to 0 C. At this temperature, 0.91 ml of diisopropyl azodicarboxylate, dissolved in 10 ml of dichloromethane, was slowly added dropwise. The ice cooling was removed and the mixture was stirred at room temperature for two days. The reaction mixture was filtered off from the resin and washed three times with 50 ml each time of dichloromethane. The filtrate was washed with 30 ml of 1N HCl, dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by means of RP-HPLC to obtain 486 mg of methyl 3-[4-(3-hydroxy-2-methylpropoxy)phenyl]hex-4-ynoate. C17H22O4 (290.36), LCMS (ESI-pos): 291.2 (M+H+).

Reference： [1]Patent: US2012/4166,2012,A1 .Location in patent: Page/Page column 55-56

16
[ 865234-02-2 ]
[ 1354028-26-4 ]

Reference： [1]Patent: US2012/4166,2012,A1

17
[ 865234-02-2 ]
[ 142-82-5 ]
1-(3-tert-butylphenoxymethyl)cyclopropyl]methanol [ No CAS ]
[ 1972-28-7 ]
[ 1353893-57-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; In dichloromethane; water; ethyl acetate;	Methyl 3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoate 537 mg of 1-(3-tert-butylphenoxymethyl)cyclopropyl]methanol, 500 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> and 600 mg of triphenylphosphine were dissolved in 80 ml of dichloromethane. While cooling with ice, 0.31 ml of diethyl azodicarboxylate were added dropwise. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 hours. Then 5 ml of water were added cautiously and the reaction mixture was concentrated under reduced pressure. The residue was taken up in 50 ml of water and 50 ml of ethyl acetate. The organic phase was removed, dried over MgSO4 and then concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 410 mg of methyl 3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoate. C28H34O4 (434.58), LCMS (ESI-pos): 435.3 (M+H+).

Reference： [1]Patent: US2012/4187,2012,A1

18
[ 865234-02-2 ]
1,1-bis(hydroxymethylcyclopropane) [ No CAS ]
[ 1353893-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropyl (E)-azodicarboxylate; triphenylphosphine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	Methyl 3-[4-(1-hydroxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate 300 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> were dissolved in 10 ml of DCM and used to charge a microwave vessel, then 234 mg of 1,1-bis(hydroxymethylcyclopropane) and 541 mg of triphenylphosphine (polymer-bound, Reagentplus 99%) were added, and the mixture was stirred for 10 min to swell the resin. Subsequently, 0.41 ml of diisopropyl azodicarboxylate was added and the mixture was stirred at 120 C. under microwave irradiation for 15 min. The cooled reaction mixture was filtered and the filtercake was washed 3* with 10 ml each time of DCM. The combined filtrates were washed with 30 ml of water, then dried using a ChemElut cartridge and concentrated under reduced pressure. The residue was purified by means of RP-HPLC. This gave 200 mg of methyl 3-[4-(1-hydroxymethylcyclopropylmethoxy)phenyl]hex-4-ynoate. C18H22O4. (302.37), LCMS (ESI-pos): 285.1 (M-H2O+H+).

Reference： [1]Patent: US2012/4187,2012,A1

19
[ 865234-02-2 ]
[ 1354027-76-1 ]

Reference： [1]Patent: US2012/4166,2012,A1

20
[ 865234-02-2 ]
[ 145073-39-8 ]
[ 1354028-05-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃; for 15.0h;Cooling with ice;	Methyl 3-{4-[3-(3-tert-butylphenoxy)propoxy]phenyl}hex-4-ynoate 525 mg of 3-(3-tert-butylphenoxy)propan-1-ol, 500 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> and 600 mg of triphenylphosphine were dissolved in 100 ml of dichloromethane. While cooling with ice, 0.31 ml of diethyl azodicarboxylate were added dropwise. Thereafter, the ice bath was removed and the reaction mixture was stirred at room temperature for three hours. A further 600 mg of triphenylphosphine and 0.31 ml of diethyl azodicarboxylate were added and the reaction mixture was left to stand at room temperature for 12 hours. 50 ml of water and 50 ml of ethyl acetate were added to the reaction mixture. The organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 280 mg of methyl 3-{4-[3-(3-tert-butylphenoxy)propoxy]phenyl}hex-4-ynoate. C26H32O4 (408.54), LCMS (ESI-pos): 409.3 (M+H+).

Reference： [1]Patent: US2012/4166,2012,A1 .Location in patent: Page/Page column 43-44

21
[ 865234-02-2 ]
[ 1354028-06-0 ]
[ 1354028-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In tetrahydrofuran; at 60℃; for 1.0h;	Methyl 3-{4-[3-(4-trifluoromethylphenoxy)propoxy]phenyl}hex-4-ynoate In a 100 ml 3-neck flask, 1.0 g of 3-(4-trifluoromethylphenoxy)propan-1-ol and 1.35 ml of diisopropylethylamine were initially charged in 80 ml of methylene chloride and cooled to 0 C. Subsequently, 0.71 ml of methanesulfonyl chloride was added dropwise. Thereafter, the ice bath was removed and the reaction mixture was stirred at room temperature for one hour, 50 ml of water and 50 ml of ethyl acetate were added to the reaction mixture. The organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. This gave 1.3 g of 3-(4-trifluoromethylphenoxy)propyl methanesulfonate; this material was converted further without further purification. In a 50 ml three-neck flask, 1.23 g of 3-(4-trifluoromethylphenoxy)propyl methanesulfonate, 300 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> and 1.34 g of cesium carbonate were suspended in 25 ml of acetonitrile. The reaction mixture was stirred at 60 C. for one hour. 50 ml of water and 50 ml of ethyl acetate were added to the cooled reaction mixture. The organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 45 mg of methyl 3-{4-[3-(4-trifluoromethylphenoxy)propoxy]phenyl}hex-4-ynoate. C23H23F3O4 (420.43), LCMS (ESI-pos): 421.1 (M+H+).

Reference： [1]Patent: US2012/4166,2012,A1 .Location in patent: Page/Page column 47

22
[ 865234-02-2 ]
[ 1354028-30-0 ]
[ 1354028-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,4-diaza-bicyclo[2.2.2]octane; 1-methyl-pyrrolidin-2-one; at 80℃; for 20.0h;	Meth 3-{4-[3-(2-chloro-4-trifluoromethylphenoxy)-2-hydroxypropoxy]phenyl}hex-4-ynoate 434 mg of 2-(2-chloro-4-trifluoromethylphenoxymethyl)oxirane, 250 mg of <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> and 0.19 ml of 1,4-diazabicyclo[2.2.2]octane were dissolved in 10 ml of N-methylpyrrolidone and heated to 80 C. for twenty hours. Subsequently, 50 ml of water were added cautiously to the cooled reaction mixture, and the mixture was extracted three times with portions each of 80 ml of ethyl acetate. The combined organic phases were washed with 100 ml of water, dried over MgSO4 and then concentrated under reduced pressure. The residue was purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 90 mg of methyl 3-{4-[3-(2-chloro-4-trifluoromethylphenoxy)-2-hydroxypropoxy]phenyl}hex-4-ynoate. C23H22ClF3O5 (470.88), LCMS (ESI-pos): 471.1 (M+H+), 493.1 (M+Na+).

Reference： [1]Patent: US2012/4166,2012,A1 .Location in patent: Page/Page column 64

23
[ 865234-02-2 ]
[ 1356599-47-7 ]

Reference： [1]Patent: WO2012/11125,2012,A1

24
[ 865234-02-2 ]
[ 1356601-60-9 ]

Reference： [1]Patent: WO2012/11125,2012,A1

25
[ 865234-02-2 ]
[ 1356601-63-2 ]

Reference： [1]Patent: WO2012/11125,2012,A1

26
[ 865234-02-2 ]
[ 1356599-86-4 ]
[ 1356599-41-1 ]

Reference： [1]Patent: WO2012/11125,2012,A1

27
[ 865234-02-2 ]
[ 1356599-86-4 ]
[ 1356601-16-5 ]

Yield	Reaction Conditions	Operation in experiment
42.86%	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In toluene; at 0 - 20℃; for 4.0h;	Intermediate 116: Methyl 3-{4-[(4-[(2Z)-2-(methoxyimino)-2-phenylethyl] oxy} benzyl) oxy] phenyl} hex-4-ynoateTo a 50 mL RB flask fitted with magnetic stirrer was charged with 15 mL of toluene. To the stirred solvent were added (4-[(2E, 2Z)-2-(methoxyimino)-2-phenylethyl]oxy} phenyl)methanol (0.2 g, 0.74 mmol), <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> (0.16 g, 0.74 mmol). The reaction mixture was cooled to 0 C; tributylphosphine (0.195 g, 0.96 mmol) was added and stirred for 10 minutes. To the stirring solution, 1 ,1'-(azodicarbonyl) dipiperidine (0.242 g, 0.96 mmol) in toluene (2 mL) was added drop wise at the same temperature and stirred at room temperature for 4 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL X 2). The organic layer was washed with water (10 mL), followed by brine solution (10 mL). The organic layer was dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutant. The product was obtained as colorless oil (0.15 g, yield: 42.86%).

Reference： [1]Patent: WO2012/11125,2012,A1 .Location in patent: Page/Page column 151; 153

28
[ 865233-34-7 ]
[ 74-88-4 ]
[ 865234-02-2 ]

Yield	Reaction Conditions	Operation in experiment
85%		The acid (23.5 g, 1 15 mmol) was dissolved in acetone (230 mL) and treated with potassium bicarbonate (1 1.5 g, 1 15 mmol). After 15 min, methyl iodide (5 mL, 80 mmol) was added and the reaction stirred at 40C overnight. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating was continued for 24 h. Insolubles were removed by filtration and rinsed with acetone. The filtrate was concentrated to an oil which was purified on silica gel using 2.5% methanol in dichloromethane as eluent. This gave 3-(4- hydroxyphenyl)hex-4-ynoic acid methyl ester (21.5 g, 85%) as a pale yellow oil. 1H NMR (500 MHz) (acetone-c(6) δ 8.2 (br, s, 1 H); 7.20 (d, 2H, J = 9.5 Hz); 6.77 (d, 2H, J = 9.0 Hz); 3.98 (m, 1 H); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J = 2.5 Hz). MS ESI m/e: 219.1 (M+H); 241 (M+Na).

Reference： [1]Patent: WO2012/97427,2012,A1 .Location in patent: Page/Page column 40-41

29
[ 865234-02-2 ]
[ 4039-92-3 ]
3-[4-(4-methoxybenzyloxy)phenyl]hex-4-ynoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With caesium carbonate; In acetone; at 20℃;	The phenol (0.96 g, 4.4 mmol) and 4-methoxybenzyl chloride (0.72 mL, 5.3 mmol) were dissolved in acetone (9 mL) and treated with cesium carbonate (1.45 g, 4.4 mmol). The reaction mixture was stirred at room temperature overnight. Insolubles were filtered and the solution was evaporated under reduced pressure. This gave 3-[4-(4-methoxybenzyloxy)-phenyl]-hex-4-ynoic acid methyl ester (1.67 g, 95%) as a white powder which was used without further purification.

Reference： [1]Patent: WO2012/97427,2012,A1 .Location in patent: Page/Page column 40-41

30
[ 865234-02-2 ]
(+/-)3-{4-[(3-phenoxyphenyl)methoxy]phenyl}hex-4-ynoic acid [ No CAS ]

Reference： [1]Patent: WO2012/97427,2012,A1

31
[ 865234-02-2 ]
[ 929713-77-9 ]
[ 865233-36-9 ]

Yield	Reaction Conditions	Operation in experiment
	With OJ-H column; In isopropyl alcohol;Resolution of racemate;	Preparation of racemic <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> was performed as described in the procedure in Bioorganic & Medicinal Chemistry Letters 21(11) 3390, 2011. Separation of the enantiomers was performed by SFC (OJ-H column, 6% IPA/CO2) to give the (R) (faster peak) and (S) (slower peak) enantiomers. 1H NMR (500 MHz, acetone-^) 8.2 (br, 1H), 7.20 (d, 2H), 6.77 (d, 2H), 3.98 (m, 1H), 3.60 (s, 3H), 2.65 (m, 2H), 1.78 (s, 3H).

Reference： [1]Patent: WO2014/130608,2014,A1 .Location in patent: Page/Page column 103; 145

32
[ 865234-02-2 ]
[ 865233-35-8 ]

Reference： [1]Patent: WO2014/130608,2014,A1

33
[ 865234-02-2 ]
methyl 3-(2-(3-bromophenyl)chroman-6-yl)hex-4-ynoate [ No CAS ]

Reference： [1]Patent: WO2014/130608,2014,A1

34
[ 865234-02-2 ]
methyl 3-(4-hydroxy-3-(hydroxymethyl)phenyl)hex-4-ynoate [ No CAS ]

Reference： [1]Patent: WO2014/130608,2014,A1

35
[ 865234-02-2 ]
methyl 3-(2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)chroman-6-yl)hex-4-ynoate [ No CAS ]

Reference： [1]Patent: WO2014/130608,2014,A1

36
[ 865234-02-2 ]
3-(2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)chroman-6-yl)hex-4-ynoic acid [ No CAS ]

Reference： [1]Patent: WO2014/130608,2014,A1

37
[ 50-00-0 ]
[ 865234-02-2 ]
methyl 3-(3-formyl-4-hydroxyphenyl)hex-4-ynoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; magnesium chloride; In acetonitrile; for 3.0h;Reflux;	To a solution of acetonitrile (305 ml) and <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> (2.00 g, 9.16 mmol), magnesium chloride (1.31 g, 13.8 mmol), and paraformaldehyde (1.38 g, 45.8 mmol) was added TEA (4.79 mL, 34.4 mmol). The resulting slurry was heated to reflux. After 3 h, the homogenous yellow solution was cooled to room temperature and poured into 5% HC1 (200 mL). The mixture was then extracted with ethyl acetate (2 x 250 mL). The combined organic layers were dried (MgS04) and concentrated. The resulting residue was purifed by HPLC (ISCO 120g, 0 to 50% EA/Hex) to give the title compound. 1H NMR (500 MHz, CDCI3) 10.98 (s, 1H), 9.90 (s, 1H), 7.60 (s, 1H), 7.59 (d, 1H), 6.99 (d, 1H), 4.15 (m, 1H), 3.68 (s, 3H), 2.68 (ddd, 2H), 1.85 (s, 3H).

Reference： [1]Patent: WO2014/130608,2014,A1 .Location in patent: Page/Page column 104; 145

38
[ 865234-02-2 ]
5-(chloromethyl)-3-(2-methylphenyl)benzo[b]thiophene [ No CAS ]
(3RS)-methyl 3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 40℃; for 16.0h;	(A) Methyl 3-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4- ynoate was prepared from 5-(chloromethyl)-3-(2-methylphenyl)benzo[b]thiophene (Example 2a, Step F) and <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> (available from Oxchem Corporation, Irwindale, CA; Cat. AX8267763) following General Procedure E, at a reaction temperature of 40 C. LC/MS: mass calcd. for C29H26O3S: 454.16, found: 477.1 [M+Na]+. General Procedure E: A mixture of the benzylic chloride (0.11 mmol), the phenol (0.14 mmol) and Cs2CO3 (0.17 mmol) in MeCN (2 mL) was stirred at rt for 16 h. EtOAc (50 mL) was then added and the organic layer was successively washed with water and brine, dried (Na2SO4), filtered and concentrated to afford the crude corresponding benzylic phenyl ether, which was purified by silica gel chromatography (EtOAc/heptanes).

Reference： [1]Patent: WO2016/57731,2016,A1 .Location in patent: Page/Page column 87; 226

39
[ 865234-02-2 ]
tert-butyl 5-(bromomethyl)thiophene-2-carboxylate [ No CAS ]
tert-butyl 5-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.3%		General procedure: To a solution of 16-20 (1 equiv) in DMF was added K2CO3 (2 equiv), stirred for 5min then add the intermediates 9a-d (1.1 equiv), then the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate, then washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was purified with column chromatography (petroleum ether/ethyl acetate=8:1) to yield intermediate 10a-i. 5.1.3.1 tert-butyl 5-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)thiophene-2-carboxylate (10a) Intermediate 10a was prepared with general procedure C using 9a and <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> (16) to afford a yellow oil in 78.3%. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 3.7 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 3.8 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 5.20 (s, 2H), 4.11-4.05 (m, 1H), 3.68 (s, 3H), 2.81-2.63 (m, 2H), 1.85 (d, J = 2.4 Hz, 3H), 1.59 (s, 9H).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 152,p. 175 - 194

40
[ 865234-02-2 ]
tert-butyl 5-(bromomethyl)thiazole-2-carboxylate [ No CAS ]
tert-butyl 5-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)thiazole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.1%		General procedure: To a solution of 16-20 (1 equiv) in DMF was added K2CO3 (2 equiv), stirred for 5min then add the intermediates 9a-d (1.1 equiv), then the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate, then washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was purified with column chromatography (petroleum ether/ethyl acetate=8:1) to yield intermediate 10a-i.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 152,p. 175 - 194

41
[ 865234-02-2 ]
tert-butyl 5-(bromomethyl)furan-2-carboxylate [ No CAS ]
tert-butyl 5-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)furan-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.1%		General procedure: To a solution of 16-20 (1 equiv) in DMF was added K2CO3 (2 equiv), stirred for 5min then add the intermediates 9a-d (1.1 equiv), then the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate, then washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was purified with column chromatography (petroleum ether/ethyl acetate=8:1) to yield intermediate 10a-i.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 152,p. 175 - 194

42
[ 865234-02-2 ]
[ 108052-76-2 ]
tert-butyl 4-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.5%		General procedure: To a solution of 16-20 (1 equiv) in DMF was added K2CO3 (2 equiv), stirred for 5min then add the intermediates 9a-d (1.1 equiv), then the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate, then washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was purified with column chromatography (petroleum ether/ethyl acetate=8:1) to yield intermediate 10a-i.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 152,p. 175 - 194

43
[ 2242-32-2 ]
[ 865234-02-2 ]
methyl 3-(4-((7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methoxy)phenyl)hex-4-ynoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In toluene; at 40℃; for 5.0h;	To a solution of compound 23b (120 mg, 0.60 mmol) and <strong>[865234-02-2]methyl 3-(4-hydroxyphenyl)hex-4-ynoate</strong> (100 mg, 0.46 mmol) in dry toluene (50 mL) was added tributyl phosphine (0.23 mL, 0.92 mmol) and azodicarboxylic acid dipiperidide (232 mg, 0.92 mmol). The mixture was stirred at 40C for 5 hr, then filtrated. The residue was concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether =1:10) to give compound 31a (138 mg, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.33 - 7.27 (m, 2 H), 6.94 - 6.90 (m, 1 H), 6.90 - 6.83 (m, 2 H), 6.81 (d, J = 1.4 Hz, 2 H), 4.58 - 4.48 (m, 1 H), 4.37 (dd, J = 11.5, 2.4 Hz, 1 H), 4.25 - 4.15 (m, 2 H), 4.15 - 4.02 (m, 2 H), 3.66 (s, 3 H), 2.76 (dd, J = 15.3, 8.2 Hz, 1 H), 2.65 (dd, J = 15.3, 7.0 Hz, 1 H), 1.83 (d, J = 2.5 Hz, 3 H).

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5780 - 5791

44
[ 865234-02-2 ]
tert-butyl 5-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.4%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	The intermediate 10 was dissolved in dimethylformamide, potassium carbonate was added thereto, and the mixture was stirred at room temperature for 5 minutes, and the intermediate 10 was added thereto, and the mixture was reacted at room temperature overnight. add water,Extracted three times with ethyl acetate, washed three times with saturated brine, combined organics and dried.Evaporate the solvent under reduced pressure.Column chromatography gave 69 (1.3 g, pale yellow oil).The yield was 26.4%.

Reference： [1]Patent: CN109666027,2019,A .Location in patent: Paragraph 0178; 0179; 0180

45
[ 865234-02-2 ]
5-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)thiophene-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: CN109666027,2019,A

46
[ 865234-02-2 ]
C₁₄H₁₁ClN₂ [ No CAS ]
C₂₇H₂₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-benzyl-N,N,N-triethylammonium chloride; caesium carbonate; potassium iodide; In acetonitrile; at 65℃; for 8.0h;	General procedure: To a solution of J (0.45 g, 1.57 mmol) and E (0.22 g, 1.01 mmol) inacetonitrile, Cs2CO3 (0.82 g, 2.53 mmol), catalytic amount of KI andbenzyltriethylammonium chloride were added. The mixture was stirredat 65 C for 8 h. The solid was removed by suction filtration, and thefilter cake was washed with AcOEt. The filtrates were combined and concentrated by rotary evaporator. The residue was purified by silicagel column chromatography. Finally, a transparent viscous liquid K(83.2 mg, 17.52%) was obtained.