Name: 46112-46-3|4-(2-Hydroxyethyl)benzoic acid|95%
Brand: Ambeed
SKU: A101353
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1
[ 4654-39-1 ]
[ 46112-46-3 ]

Reference： [1]Journal of the American Chemical Society,1948,vol. 70,p. 4177

2
[ 76527-25-8 ]
[ 46112-46-3 ]
4-[2-(2-hydroxy-2-methoxycarbonyl-1,1-diphenyl-ethoxy)-ethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032

3
[ 109-72-8 ]
[ 60-29-7 ]
[ 124-38-9 ]
[ 4654-39-1 ]
[ 46112-46-3 ]

Reference： [1]Journal of the American Chemical Society,1948,vol. 70,p. 4177

4
diazotized 2-<4-amino-phenyl>-ethanol [ No CAS ]
CuCN [ No CAS ]
[ 46112-46-3 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 4303

5
[ 6066-82-6 ]
[ 46112-46-3 ]
[ 920006-92-4 ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 16020 - 16021

6
[ 46190-45-8 ]
[ 46112-46-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		A solution of 13 (174 mg, 0.96 mmol) in methanol (3 mL) and water (1 mL) was added NaOH (58 mg, 1.43 mmol) at ambient temperature. The mixture was stirred for 2 days at ambient temperature,water (5 mL) was then added, and extracted with ether (3*20 mL). The aqueous layer was acidified with HCl (1:1) to pH = 1, the white solid was filtered out to afford 158 mg (100%)of 14 which was used directly in the next step. 1H NMR(300 MHz, CDCl3) d 7.97 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H),3.83 (t, J = 6.3 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2988 - 2998
[2]Journal of the American Chemical Society,2006,vol. 128,p. 16020 - 16021

7
[ 1076-96-6 ]
[ 46112-46-3 ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 16020 - 16021
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2988 - 2998

8
[ 46112-46-3 ]
4-(2-undec-10-enoyloxy-ethyl)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 16020 - 16021

9
[ 46112-46-3 ]
4-[2-(10-oxo-undecanoyloxy)-ethyl]-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 16020 - 16021

10
[ 46112-46-3 ]
4-[2-(2-carboxy-2-hydroxy-1,1-diphenyl-ethoxy)-ethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032

11
[ 46112-46-3 ]
3-<2-(4-carboxyphenyl)ethoxy>-2-<(4,6-dimethylpyrimidin-2-yl)oxy>-3,3-diphenylpropionic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3026 - 3032

12
[ 18620-02-5 ]
[ 46112-46-3 ]

Reference： [1]Journal of the American Chemical Society,1948,vol. 70,p. 4177

13
[ 869294-96-2 ]
[ 46112-46-3 ]
4-[2-({2-[([3-(methyloxy)phenyl]methyl}amino)carbonyl]-4-oxo-3,4-dihydroquinazolin-5-yl}oxy)ethyl]benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With sodium hydride; In N,N-dimethyl acetamide; at 20 - 90℃; for 2.5h;	Example 281; 4-[2-({2-[([3-(methyloxy)phenyl]methyl}amino)carbonyl]- 4-oxo-3,4-dihydroquinazolin-5-yl}oxy)ethyl]benzoic acid A solution of 5-fluoro-N-[3- (methyloxy) phenyl]methyl}-4-oxo-3,4-dihydroquinazoline- 2-carboxamide (1.00 g, 3.06 mmol) obtained in Example 110 and 4- (2-hydroxyethyl)benzoic (0.508 g, 3.06 mmol) in DMA (20 mL) was added dropwise to a suspension of 60% sodium hydride (0.466 g, 12.2 mmol) in DMA (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min. and the mixture was stirred with heating at 90C for 2 hrs. The mixture was allowed to cool to room temperature, water (60 mL) was added, and the aqueous layer was washed with ethyl acetate (60 mLx3). The aqueous layer was acidified with 1N hydrochloric acid (ca. 18 mL), and the object product was extracted withethyl acetate (60 mLx2). The organic layers were combined, washed with 0.1N hydrochloric acid (60 mLx2) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the concentrated residue was crystallized from methanol to give the title compound as a white powder (170 mg, 12%). melting point: 228-230C
12%	With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 10 - 90℃; for 2.5h;	Example 281 4-[2-({2-[([3-(methyloxy)phenyl]methyl}amino)carbonyl]-4-oxo-3,4-dihydroquinazolin-5-yl}oxy)ethyl]benzoic acid A solution of 5-fluoro-N-[3-(methyloxy)phenyl]methyl}-4-oxo-3,4-dihydroquinazoline-2-carboxamide (1.00 g, 3.06 mmol) obtained in Example 110 and <strong>[46112-46-3]4-(2-hydroxyethyl)benzoic acid</strong> (0.508 g, 3.06 mmol) in DMA (20 mL) was added dropwise to a suspension of 60% sodium hydride (0.466 g, 12.2 mmol) in DMA (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min. and the mixture was stirred with heating at 90 C. for 2 hrs. The mixture was allowed to cool to room temperature, water (60 mL) was added, and the aqueous layer was washed with ethyl acetate (60 mL3). The aqueous layer was acidified with 1N hydrochloric acid (ca. 18 mL), and the object product was extracted with ethyl acetate (60 mL2). The organic layers were combined, washed with 0.1N hydrochloric acid (60 mL*2) and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the concentrated residue was crystallized from methanol to give the title compound as a white powder (170 mg, 12%). melting point: 228-230 C.

Reference： [1]Patent: WO2005/105760,2005,A1 .Location in patent: Page/Page column 211-212
[2]Patent: US2015/329556,2015,A1 .Location in patent: Paragraph 1029-1031

14
[ 869295-00-1 ]
[ 46112-46-3 ]
[ 869295-71-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydride; In N,N-dimethyl acetamide; at 20 - 80℃; for 2h;	Example 179; 4-[2-({6-fluoro-2-[([3-(methyloxy)phenyl]methyl}amino)carbonyl]- 4-oxo-3,4-dihydroquinazolin-5-yl}oxy)ethyl]benzoic acid; A solution of 5,6-difluoro-N-[3- (methyloxy) phenyl]methyl}-4-oxo-3,4-dihydroquinazoline- 2-carboxamide (500 mg, 1.45 mmol) obtained in Example 113 and 4- (2-hydroxyethyl)benzoic (241 mg, 1.45 mmol) in DMA (5 mL) was added dropwise to a suspension of 60% sodium hydride (165 mg, 4.34 mmol) in DMA (2.5 mL) at room temperature and the mixture was stirred at room temperature for 30 min. and then at 80C for 1.5 hrs with heating. The reaction mixture was ice-cooled, and water (5 mL), ethyl acetate (10 mL), IN hydrochloric acid (6 mL) and hexane (10 mL) were successively added dropwise. The precipitated solid was collected by filtration, and washed with water and methanol. The obtained solid was suspended in methanol, and the mixture was stirred with heating at 70C for 30 min. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration, and washed with methanol to give the title compound as a pale-yellow powder (501 mg, 70%). melting point: 227-229C ?H NMR (300 MHz, DMSO-d6) 8: 3.18 (2H, t, J = 6.9 Hz) , 3.73 (3H, s), 4.32 (2H, t, J 6.9 Hz) , 4.44 (2H, d, J = 6. 0 Hz) , 6. 81-6.84 (1H, m) , 6. 89-6.92 (2H, m) , 7.46 (2H, d, J = 8.4 Hz) , 7.24 (1H, t, J = 8.1 Hz), 7.53 (1H, dd, J = 6.3,4.8 Hz), 7.79 (1H, t, J = 9.6 Hz), 7.87 (2H, d, J = 8.1 Hz), 9.50 (1H, t, J = 6.3 Hz), 12.20 (1H, bs), 12.87 (1H, bs).

Reference： [1]Patent: WO2005/105760,2005,A1 .Location in patent: Page/Page column 128-129

15
5,6-difluoro-N-[(4-fluoro-3-methylphenyl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide [ No CAS ]
[ 46112-46-3 ]
4-(2-[6-fluoro-2-([(4-fluoro-3-methylphenyl)methyl]amino}carbonyl)-4-oxo-3,4-dihydroquinazolin-5-yl]oxy}ethyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With sodium hydride; In N,N-dimethyl acetamide; at 20 - 70℃; for 2.5h;	Example 359; 4-(2-[6-fluoro-2-([(4-fluoro-3- methylphenyl) methyl]amino}carbonyl)-4-oxo-3,4- dihydroquinazolin-5-ylloxylethyl) benzoic acid; A solution of 5,6-difluoro-N-[(4-fluoro-3- methylphenyl) methyl]-4-oxo-3,4-dihydroquinazoline-2- carboxamide (500 mg, 1.44 mmol) obtained in Example 357 and 4- (2-hydroxyethyl)benzoic (263 mg, 1.58 mmol) in DMA (10 mL) was added dropwise to a suspension of 60% sodium hydride (202 mg, 5.04 mmol) in DMA (6 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. and then at 70C for 2 hrs with heating. The reaction mixture was ice-cooled and water (4 mL), ethyl acetate (8 mL), 1N hydrochloric acid (7 mL) and hexane (8 mL) were successively added dropwise. The precipitated solid was collected by filtration, and washed with ethanol and water. The obtained solid was dissolved in 0.2N aqueous sodium hydroxide solution (40 mL) and washed with ethyl acetate (50 mLx2). The aqueous layer was acidified with 2N hydrochloric acid. The precipitated solid was collected by filtration and washed with water. The obtained solid was suspended in methanol and the mixture was stirred with heating at 70C for 20 min. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with methanol to give the title compound as a white powder (182 mg, 26%). melting point: 267-268C ¹H-NMR (300MHz, DMSO-d6) 8: 2.21 (3H, d, J = 1.9 Hz), 3.17 (2H, t, J = 6.9 Hz), 4.31 (2H, t, J = 6.8 Hz), 4.41 (2H, d, J = 6.4 Hz), 7.04-7.13 (lH, m), 7.15 - 7.28 (2H, m, J = 21.0, 5.6 Hz), 7.45 (2H, d, J = 8.3 Hz), 7.52 (1H, dd, J = 8.9,4.6 Hz), 7.78 (lH, dd, J = 10.4, 9.0 Hz), 7.86 (2H, d, J = 8.1 Hz), 9.51 (lH, t, J = 6.3 Hz), 11.86-12.94 (2H, m) .
26%	With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 10 - 70℃; for 2.5h;	Example 359 4-(2-[6-fluoro-2-([(4-fluoro-3-methylphenyl)methyl]amino}carbonyl)-4-oxo-3,4-dihydroquinazolin-5-yl]oxy}ethyl)benzoic acid A solution of 5,6-difluoro-N-[(4-fluoro-3-methylphenyl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide (500 mg, 1.44 mmol) obtained in Example 357 and <strong>[46112-46-3]4-(2-hydroxyethyl)benzoic acid</strong> (263 mg, 1.58 mmol) in DMA (10 mL) was added dropwise to a suspension of 60% sodium hydride (202 mg, 5.04 mmol) in DMA (6 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. and then at 70 C. for 2 hrs with heating. The reaction mixture was ice-cooled and water (4 mL), ethyl acetate (8 mL), 1N hydrochloric acid (7 mL) and hexane (8 mL) were successively added dropwise. The precipitated solid was collected by filtration, and washed with ethanol and water. The obtained solid was dissolved in 0.2N aqueous sodium hydroxide solution (40 mL) and washed with ethyl acetate (50 mL*2). The aqueous layer was acidified with 2N hydrochloric acid. The precipitated solid was collected by filtration and washed with water. The obtained solid was suspended in methanol and the mixture was stirred with heating at 70 C. for 20 min. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with methanol to give the title compound as a white powder (182 mg, 26%). melting point: 267-268 C. 1H-NMR (300 MHz, DMSO-d6) delta: 2.21 (3H, d, J=1.9 Hz), 3.17 (2H, t, J=6.9 Hz), 4.31 (2H, t, J=6.8 Hz), 4.41 (2H, d, J=6.4 Hz), 7.04-7.13 (1H, m), 7.15-7.28 (2H, m, J=21.0, 5.6 Hz), 7.45 (2H, d, J=8.3 Hz), 7.52 (1H, dd, J=8.9, 4.6 Hz), 7.78 (1H, dd, J=10.4, 9.0 Hz), 7.86 (2H, d, J=8.1 Hz), 9.51 (1H, t, J=6.3 Hz), 11.86-12.94 (2H, m).

Reference： [1]Patent: WO2005/105760,2005,A1 .Location in patent: Page/Page column 276-277
[2]Patent: US2015/329556,2015,A1 .Location in patent: Paragraph 1282-1286

16
6-chloro-5-fluoro-N-[3-(methyloxy)phenyl]methyl}-4-oxo-3,4-dihydroquinazoline-2-carboxamide [ No CAS ]
[ 46112-46-3 ]
4-[2-({6-chloro-2-[([3-(methyloxy)phenyl]methyl}amino)carbonyl]-4-oxo-3,4-dihydroquinazolin-5-yl}oxy)ethyl]benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With sodium hydride; In N,N-dimethyl acetamide; at 20 - 70℃; for 2h;	Example 360; 4-[2-({6-chloro-2-[([3- (methyloxy) phenyl]methyl}amino)carbonyl]-4-oxo-3,4- dihydroquinazolin-5-yl} oxy)ethyl]benzoic acid; The compound was synthesized by a method similar to that of Example 15'9 from 6-chloro-5-fluoro-N-[3- (methyloxy) phenyl]methyl}-4-oxo-3,4-dihydroquinazoline- 2-carboxamide obtained in Example 358 and 4-(2- hydroxyethyl) benzoic acid. A solution of 6-chloro-5-fluoro-N-[3- (methyloxy) phenyl]methyl}-4-oxo-3,4-dihydroquinazoline- 2-carboxamide (500 mg, 1.38 mmol) obtained in Example 358 and 4- (2-hydroxyethyl)benzoic (253 mg, 1.52 mmol) in DMA (10 mL) was added dropwise to a suspension of 60% sodium hydride (193 mg, 4.84 mmol) in DMA (6 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. and then at 70C for 1.5 hr with heating. The reaction mixture was ice-cooled, and water (4 mL), ethyl acetate (8 mL), 1N hydrochloric acid (7 mL) and hexane (8 mL) were successively added dropwise. The precipitated solid was collected by filtration, and washed with ethanol and water. The obtained solid was dissolved in 0.2N aqueous sodium hydroxide solution (40 mL) and washed with ethyl acetate (50 mLx2). The aqueous layer was acidified with 2N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water. The obtained solid was suspended in methanol, and the mixture was stirred with heating at 70C for 20 min. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with methanol to give the title compound as a white powder (222 mg, 32%). melting point: 226-227C ¹H-NMR (300MHz, DMSO-d6) No.: 3.24 (2H, t, J = 6.8 Hz), 3.74 (3H, s) , 4.27 (2H, t, J = 6.9 Hz) , 4.44 (2H, d, J = 6.4 Hz), 6.80 - 6.86 (lH, m), 6.88 - 6.94 (2H, m), 7.25 (lH, t, J = 8.1 Hz), 7.47 (2H, d, J = 8.3 Hz), 7.52 (lH, d, J = 8.7 Hz), 7.88 (2H, d, J 8.3 Hz), 7.92 (1H, d, J = 8.9 Hz), 9.53 (1H, t, J = 6.4 Hz) , 12.51 (2H, s) .
32%	With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 10 - 70℃; for 2h;	Example 360 4-[2-({6-chloro-2-[([3-(methyloxy)phenyl]methyl}amino)carbonyl]-4-oxo-3,4-dihydroquinazolin-5-yl}oxy)ethyl]benzoic acid The compound was synthesized by a method similar to that of Example 159 from 6-chloro-5-fluoro-N-[3-(methyloxy)phenyl]methyl}-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Example 358 and <strong>[46112-46-3]4-(2-hydroxyethyl)benzoic acid</strong>. A solution of 6-chloro-5-fluoro-N-[3-(methyloxy)phenyl]methyl}-4-oxo-3,4-dihydroquinazoline-2-carboxamide (500 mg, 1.38 mmol) obtained in Example 358 and <strong>[46112-46-3]4-(2-hydroxyethyl)benzoic acid</strong> (253 mg, 1.52 mmol) in DMA (10 mL) was added dropwise to a suspension of 60% sodium hydride (193 mg, 4.84 mmol) in DMA (6 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. and then at 70 C. for 1.5 hr with heating. The reaction mixture was ice-cooled, and water (4 mL), ethyl acetate (8 mL), 1N hydrochloric acid (7 mL) and hexane (8 mL) were successively added dropwise. The precipitated solid was collected by filtration, and washed with ethanol and water. The obtained solid was dissolved in 0.2N aqueous sodium hydroxide solution (40 mL) and washed with ethyl acetate (50 mL*2). The aqueous layer was acidified with 2N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water. The obtained solid was suspended in methanol, and the mixture was stirred with heating at 70 C. for 20 min. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with methanol to give the title compound as a white powder (222 mg, 32%). melting point: 226-227 C. 1H-NMR (300 MHz, DMSO-d6) delta: 3.24 (2H, t, J=6.8 Hz), 3.74 (3H, s), 4.27 (2H, t, J=6.9 Hz), 4.44 (2H, d, J=6.4 Hz), 6.80-6.86 (1H, m), 6.88-6.94 (2H, m), 7.25 (1H, t, J=8.1 Hz), 7.47 (2H, d, J=8.3 Hz), 7.52 (1H, d, J=8.7 Hz), 7.88 (2H, d, J=8.3 Hz), 7.92 (1H, d, J=8.9 Hz), 9.53 (1H, t, J=6.4 Hz), 12.51 (2H, s).

Reference： [1]Patent: WO2005/105760,2005,A1 .Location in patent: Page/Page column 277-278
[2]Patent: US2015/329556,2015,A1 .Location in patent: Paragraph 1287-1292

Yield	Reaction Conditions	Operation in experiment
		4-(2-Hydroxyethyl)benzoic acid To a solution of 0.5 g (3.40 mmol) of the nitrile and 20 mL ethanol was added 7 mL of 2N NaOH. The solution was heated at 98 C. for 18 h., cooled, then evaporated. The remaining oil was dissolved into EtOAc and aqueous sodium bicarbonate. The organic layer was discarded. The aqueous layer was acidified with 6N HCl, extracted into EtOAc, dried over Na2SO4, filtered and evaporated to yield the hydroxy acid as a white solid.

18
[ 46112-46-3 ]
[ 145941-92-0 ]
[ 145941-84-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; potassium carbonate; In acetonitrile;	EXAMPLE 2 2-Chloro-5{5-[4-(ethoxycarbonyl)phenoxy]pentanoyl}thiophene (5c) A mixture consisting of 2-chloro-5-(5-chloropentanoyl)thiophene (3c) (2.13 g, 0.009 mol), sodium iodide (1.1 g, 0.0073 mol), <strong>[46112-46-3]4-hydroxyethylbenzoate</strong> (1.7 g, 0.010 mol), and anhydrous potassium carbonate (6.2 g, 0.045 mol) in acetonitrile (50 ml) was refluxed for 24 hrs., cooled, and filtered. The resulting solution was deprived of the solvent and the residue was taken up with dichloromethane (100 ml). After washing with water and subsequent drying on anydrous sodium sulfate the solution was evaporated to dryness. The resulting solid was crystallized via cyclohexane to pure 5c (2.5 g; 76%). M.p. 87-89 C. Anal. (C18 H19 ClO4 S).
	With sodium iodide; potassium carbonate; In acetonitrile;	EXAMPLE 2 2-Chloro-5{5-[4-(ethoxycarbonyl)phenoxy]pentanoyl]thiophene (5c). A mixture consisting of 2-chloro-5-(5-chloropentanoyl)thiophene (3c) (2.13 g, 0,009 mol), sodium iodide (1.1 g, 0,0073 mol), <strong>[46112-46-3]4-hydroxyethylbenzoate</strong> (1.7 g, 0.010 mol), and anhydrous potassium carbonate (6.2 g, 0.045 mol) in acetonitrile (50 ml) was refluxed for 24 hrs., cooled, and filtered. The resulting solution was deprived of the solvent and the residue was taken up with dichloromethane (100 ml). After washing with water and subsequent drying on anydrous sodium sulfate the solution was evaporated to dryness. The resulting solid was crystallized via cyclohexane to pure 5c (2.5 g; 76%). M.p. 87-89C. Anal. (C18H19ClO4S).

Reference： [1]Patent: US5278184,1994,A
[2]Patent: EP509469,1992,A1

19
[ 935758-91-1 ]
[ 46112-46-3 ]
C₄₈H₃₉FN₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 46 4-(2-[6-fluoro-4-oxo-2-([(3-[2-(1H-1,2,4-triazol-3-yloxy)ethyl]oxy}phenyl)methyl]amino}carbonyl)-3,4-dihydroquinazolin-5-yl]oxy}ethyl)benzoic acid A solution of 5,6-difluoro-4-oxo-N-({3-[(2-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide obtained in Step 1 of Example 44 (150 mg, 0.219 mmol) and <strong>[46112-46-3]4-(2-hydroxyethyl)benzoic acid</strong> (40 mg, 0.241 mmol) in DMA (4 mL) was added dropwise to a suspension of 60% sodium hydride (oil dispersion, 0.031 mg, 0.767 mmol) in DMA (2 mL) at room temperature, and the mixture was stirred at room temperature for 20 min, and then stirred at 80C under heating for 3 hr. After the reaction mixture was allowed to cool to room temperature, water (50 mL) was added thereto, and the mixture was washed with ethyl acetate (50mL2). The aqueous layer was neutralized with 0.1N hydrochloric acid, and the objective compound was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in dichloromethane (2 mL) were added trifluoroacetic acid (0.47 mL) and triethylsilane (0.037 mL, 0.235 mmol) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mm phi 50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/10 ? 0/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from ethanol-diethyl ether to give the title compound as a yellow powder (36 mg, 28% in two steps). melting point: 122-124C

Reference： [1]Patent: EP1953148,2008,A1 .Location in patent: Page/Page column 76

20
[ 1435684-52-8 ]
[ 46112-46-3 ]
[ 1435685-66-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 15h;	General procedure: A mixture of compound 10 (135 mg, 0.49 mmol) and 4-(thiophen-3-yl)benzoic acid (99.4 mg, 0.49 mmol) in dichloromethane (10 mL) was stirred at 0 C (ice-water bath). Dicyclohexylcarbodiimide(DCC) (121 mg, 0.59 mmol) and hydroxybenzotriazole(HOBt) (80 mg, 0.59 mmol) were added to the above solution.The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 15 h. Dichloromethane (20 mL) was added into the reaction mixture, and the solution was washed with saturated aqueous NaHCO3 solution (3*10 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using dichloromethane-methanol (20:1) as the mobile phase to give 11a as a white solid (194 mg, 86%). TLC Rf 0.20 (dichloromethane-methanol 20:1); mp 125.5-126.6 C. 1H NMR(300 MHz, CDCl3) delta 7.75 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H),7.43 (s, 1H), 7.33 (s, 2H), 7.19 (s, 1H), 6.81-6.94 (m, 4H), 3.85 (s,3H), 3.44 (q, J = 5.1 Hz, 2H), 3.25-3.20 (m, 4H), 2.83-2.76 (m,4H), 2.57 (t, J = 5.2 Hz, 2H), 1.93 (t, J = 4.2 Hz, 2H), 1.61-1.69 (m,4H). 13C NMR (CDCl3, 300 MHz): 167.4, 151.4, 142.1, 141.2,138.8, 133.4, 127.5, 126.6, 126.3, 126.1, 121.3, 121.0, 120.7,117.9, 111.6, 57.1, 56.1, 55.3, 54.3, 52.5, 51.8, 39.4, 27.7, 27.3,25.5. HRMS (ESI) Calcd for C27H33N3O2S (M+H)+: 464.2372. Found:464.2379. Anal. (C27H33N3O2S 1.5H2C2O4) C, H, N.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2988 - 2998

21
[ 1075-49-6 ]
[ 46112-46-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 2988 - 2998

22
[ 67-56-1 ]
[ 46112-46-3 ]
[ 46190-45-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sulfuric acid; at 120℃; for 1h;Microwave irradiation;	4-(2-Hydroxyethyl)benzoic acid (2.41 g, 14.5 mmol) was dissolved in MeOH (5 mL) and H2S04 (0.06 mL, 1.13 mmol) added. The reaction was heated in a microwave at 120 C for 1 h and was then evaporated in vacuo. The residue was dissolved in EtOAc (150 mL), washed with 8% NaHC03 (aq) (150 mL), brine (50 mL), dried with a phase separator and evaporated in vacuo to yield methyl 4-(2-hydroxyethyl)benzoate (2.41 g, 92%) as a pale oil. LC/MS: m/z: 181.0 [M+H]+ 1H MR (500 MHz, CDC13) delta 2.94 (t, 2H), 3.88 - 3.94 (m, 5H), 7.32 (d, 2H), 7.97 - 8.02 (m, 2H).

Reference： [1]Patent: WO2015/140527,2015,A1 .Location in patent: Page/Page column 104-105

23
[ 46112-46-3 ]
3,5-diamino-6-chloro-N-((R)-3-((4-((2-(hexyl((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)ethyl)carbamoyl)phenethyl)amino)-2-(2-methylbenzyl)propyl)pyrazine-2-carboxamide [ No CAS ]