Name: 1836-62-0|2-(2-Methoxyphenoxy)ethylamine|98%
Brand: Ambeed
SKU: A957783
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1
[ 4463-59-6 ]
[ 1836-62-0 ]
[ 3258-70-6 ]

Reference： [1]Bulletin de la Societe de Chimie Biologique,1945,vol. 27,p. 562,563

2
[ 6974-77-2 ]
[ 18113-18-3 ]
[ 1836-62-0 ]
[ 47553-06-0 ]

Reference： [1]Journal of Medicinal Chemistry,1965,vol. 8,p. 356 - 367

3
[ 764-41-0 ]
[ 18113-18-3 ]
[ 1836-62-0 ]
[ 47553-23-1 ]

Reference： [1]Journal of Medicinal Chemistry,1965,vol. 8,p. 356 - 367

4
[ 26646-63-9 ]
[ 1836-62-0 ]

Yield	Reaction Conditions	Operation in experiment
91.2%	With sodium hydroxide; In water; at 110℃; for 7h;	Take 26.7 g of the intermediate obtained in S3) and 30% of 300 mlThe aqueous sodium hydroxide solution was refluxed at 110 C for 7 h.After the reaction was completed, it was extracted three times with 400 ml of toluene.And dried by anhydrous Na2SO4,The product was isolated by a concentration column to obtain 15.2 g of a product.HPLC content is not less than 99%,The yield of 2-(2-methoxyphenoxy)ethylamine was 91.2%.
	With water; potassium hydroxide; at 130℃; for 13h;	Example 3: Preparation of 2-(2-Methoxy phenoxy) ethylamine50 gm of potassium hydroxide was dissolved in 50 ml of water and 50 gm of Phthalimide derivative of l-(2-Chloroethoxy)-2-methoxy benzene was added to the solution. The contents were heated to about 130 0C and stirred for about 13 hours. The reaction mixture was cooled and ambient temperature and extracted with 2 X 200 ml of dichloromethane (DCM).20 ml of 36% aqueous hydrochloric acid was added to the organic layer and stirred the contents for 15 minutes and separated the layers. The aqueous layer was washed with DCM (2 X 25 ml) and then pH was adjusted to about 8 using aqueous sodium hydroxide solution. The aqueous layer was extracted with toluene (2 XlOO ml) and distilled off the solvent completely to obtain 20 gm of the title compound as residue. Purity by HPLC: 98.05 %

Reference： [1]Patent: CN109206328,2019,A .Location in patent: Paragraph 0017
[2]European Journal of Medicinal Chemistry,2009,vol. 44,p. 809 - 817
[3]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 6496 - 6511
[4]Journal of Medicinal Chemistry,1965,vol. 8,p. 356 - 367
[5]Bioorganic and Medicinal Chemistry,2002,vol. 10,p. 719 - 730
[6]Journal of Medicinal Chemistry,2004,vol. 47,p. 1900 - 1918
[7]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 1130 - 1133
[8]Patent: WO2009/128088,2009,A2 .Location in patent: Page/Page column 10

5
[ 96-21-9 ]
[ 18113-18-3 ]
[ 1836-62-0 ]
[ 47553-07-1 ]

Reference： [1]Journal of Medicinal Chemistry,1965,vol. 8,p. 356 - 367

6
[ 1836-62-0 ]
[ 3245-91-8 ]
[ 47552-77-2 ]

Reference： [1]Augstein,J. et al. [Journal of Medicinal Chemistry, 1965, vol. 8, p. 356 - 367]

7
[ 1836-62-0 ]
[ 4463-59-6 ]
[ 3258-70-6 ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5312 - 5329
[2]Journal of Medicinal Chemistry,1965,vol. 8,p. 356 - 367

8
[ 1836-62-0 ]
[ 4463-59-6 ]
[ 3244-08-4 ]

Reference： [1]Journal of Medicinal Chemistry,1965,vol. 8,p. 356 - 367

9
[ 1836-62-0 ]
[ 116091-63-5 ]
2-Methoxy-5-{2-[(E)-2-(2-methoxy-phenoxy)-ethylimino]-propyl}-benzenesulfonamide [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 1443 - 1451

10
[ 558-42-9 ]
[ 1836-62-0 ]
[ 10587-66-3 ]

Reference： [1]Journal of Medicinal Chemistry,1966,vol. 9,p. 812 - 818

11
[ 4151-97-7 ]
[ 1836-62-0 ]
[ 10461-28-6 ]

Reference： [1]Augstein,J. et al. [Journal of Medicinal Chemistry, 1966, vol. 9, p. 812 - 818]

12
[ 6962-92-1 ]
[ 1836-62-0 ]
[ 10415-33-5 ]

Reference： [1]Journal of Medicinal Chemistry,1966,vol. 9,p. 812 - 818

13
[ 183427-87-4 ]
[ 1836-62-0 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 7851 - 7861
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 1504 - 1511
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2017 - 2020

14
[ 955371-83-2 ]
[ 1836-62-0 ]
4-((9H-carbazol-4-yl)oxy)-1-((2-(2-methoxyphenoxy)ethyl)amino)butan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	lithium bromide; In 1,2-dimethoxyethane; at 60℃; for 24h;	Preparation of 12a and 14a (FIG. 10, Scheme 2): To a solution of epoxide 21 or 6 (1.00 mmol) in anhydrous DME (6 mL) were added amine 7a or 23 (2.00 mmol), respectively, and LiBr (catalytic). The reaction mixtures were stirred for 24 h at 60 C. After removal of the solvent under vacuum, the residues were taken up in ether (10 mL) and washed with water. The aqueous layers were extracted with ether (2×10 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, evaporated under reduced pressure and the residues were purified by flash chromatography over silica gel to obtain pure 12a or 14a as liquids. 12a: yield: 73%; 1H NMR (300 MHz) delta 8.29 (d, J=7.7 Hz, 1H), 8.16 (s, 1H), 7.43-7.30 (m, 3H), 7.26-7.19 (m, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.96-6.82 (m, 4H), 6.71 (d, J=8.2 Hz, 1H), 4.42 (t, J=6.15 Hz, 2H), 4.12 (t, J=5.13 Hz, 2H), 4.08-4.02 (m, 2H), 3.88-3.79 (m, 4H), 3.13-2.93 (m, 3H), 2.72-2.65 (m, 1H), 2.27-2.05 (m, 2H); 13C NMR (75 MHz) delta 155.55, 149.74, 148.30, 141.11, 138.89, 126.85, 125.00, 123.04, 122.79, 121.78, 121.09, 119.68, 114.19, 112.71, 111.97, 110.15, 103.65, 101.27, 69.34, 67.04, 65.07, 55.92, 55.26, 48.54, 34.78; mass spectrum, m/z 420 (M+). Exact mass calcd for C25H28N2O4: 420.20491. Found: 420.20655.
73%	In ethanol; for 24h;Reflux;	General procedure: Compound 5a (100 mg, 0.42 mmol), and 2-(2-methoxyphenoxy)ethanamine (84 mg, 0.50 mmol) were added to ethanol and theresulting heterogeneous solution was reuxed for 24 h. Themixture was cooled to room temperature and ltered through a padof celite and the ltrate was concentrated under reduced pressure.The residue was puried by ash chromatography on silica-gelwith 10% methanol in ethyl acetate. Yielding 83% compound 9a(176 mg) as a white solid. Compound 9b was synthesized followingthe procedure of preparation 9a.

Reference： [1]Patent: US2007/254849,2007,A1 .Location in patent: Page/Page column 18
[2]European Journal of Medicinal Chemistry,2018,vol. 154,p. 253 - 266
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 8626 - 8655
[4]Patent: WO2015/31914,2015,A1 .Location in patent: Sheet 3/7

15
[ 4463-59-6 ]
[ 1836-62-0 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 1900 - 1918
[2]Bioorganic and Medicinal Chemistry,2002,vol. 10,p. 719 - 730

16
[ 1836-62-0 ]
[ 51997-51-4 ]
[ 72956-09-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	In isopropyl alcohol; for 5h;Inert atmosphere; Reflux;	General procedure: Corresponding 2-(aryloxymethyl)oxiranes (5 mmol, 1 equiv) and amines (7.5 mmol, 1.5 equiv) were dissolved in 30 mL i-PrOH. The reaction was purged with argon 3 times and stirred at reflux for 5 h, andthen the mixture was cooled to room temperature and added AcOEt.After washing with brine 3 times, the organic layer was dried overanhydrous Na2SO4, filtered, and evaporated in vacuo. Purification ofthe crude residue by column chromatography on silica gel yielded target compounds.
36.26%	With N-ethyl-N,N-diisopropylamine; In 1,2-dimethoxyethane; at 80 - 85℃;	2-(2-Methoxyphenoxy)ethyl amine (15.09 g), N,N-diisopropylethyl amine (10.8 g), 4-(oxiran-2yl-methoxy)-9H-carbazole (20.0 g) and monoglyme (30 mL) were heated to 80-850C. After 8-12 hours, the reaction mixture was cooled to room temperature and ethyl acetate (40 mL) was added. The contents were cooled to 0-50C. The solid is filtered after slurry in ethylacetate to get crude Carvedilol (100 mL). (Purity: 98.62%; Yield: 36.26 %; Bis-impurity: 0.65%.)
	With sulfuric acid; potassium carbonate; In isopropyl alcohol; at 80℃; for 6h;	A mixture of 9.7 g 4-(OXIRANE-2-YLMETHOXY)-9H-CARBAZOLE (II), 53.7 g of anhydrous hydrogen sulphate of 2-(2-METHOXYPHENOXY) ETHYLAMINE (III) and 28 g of anhydrous potassium carbonate in 200 ML ISOPROPANOL are, with intensive stirring, heated at 80 C for six hours. When the epoxide has reacted, the mixed salts are filtered off from the reaction mixture and isopropanol is distilled off from the filtrate. The obtained honey-like concentrate is diluted with heating in 50 ml of ethylacetate, the solution is cooled to the temperature of 40 C, it is inoculated and stirred at the temperature of 40 C for two hours. After the crystal precipitates, the mixture is cooled to the temperature of 0 C, and is kept like that with stirring for a minimum of four hours. After filtration and washing with cooled ethylacetate, 5.2 g of wet, crude Carvedilol is obtained (HPLC contents 95.2 area %, HPLC contents of the bis-derivative 2.8 area %).

	In ethyl acetate; at 78℃; for 6h;Product distribution / selectivity;	Example 1About 4 parts of ethyl acetate were charged into a reactor, under stirring. About 1.4 parts of MFA, about 0.045 parts of activated carbon and about 1 part of EPOC were added.The mixture was heated to the reflux temperature of ethyl acetate (about 780C).The reaction mixture was stirred at about 780C for about six hours.The progress of the reaction was checked by TLC.When the reaction was completed, the mixture was filtered at a temperature not below 650C in order to separate the activate carbon. EPO <DP n="7"/>The mixture was cooled to room temperature and then to about 0 ÷ -50C and stirred for about1 hour.The resultant crystals were separated by centrifugation and washed with about 1 part of ethyl acetate.The resultant wet crude carvedilol was charged into a stainless steel reactor and about 6 parts of ethyl acetate and 0.045 parts of activated carbon were added.The mixture was heated to the reflux temperature of ethyl acetate (about 780C), until the dissolution of the crystals. The mixture was stirred at about 780C for about 1 hour and then filtered at a temperature not below 650C in order to separate the activate carbon.The mixture was allowed to cool at about 2O0C and then to about 0 ÷ -50C and stirred for about 1 hour.The resultant crystals were separated by centrifugation and washed with about 1 part of ethyl acetate. The wet crystallized carvedilol was charged into a stainless steel reactor and about 4 parts of ethyl acetate were added.The mixture was heated to the reflux temperature of ethyl acetate (about 780C), until dissolution of the crystals.The mixture was stirred at about 780C for about 1 hour and filtered at a temperature not below 650C.The mixture was allowed to cool at about 2O0C and then to about 0 ÷ -50C and stirred for about 1 hour.The resultant crystals were separated by centrifugation and washed with about 1 part of ethyl acetate. The wet product was dried in an air dryer at 5O0C until the residual solvent ethyl acetate was within the specifications.Yield: about 1.05 to 1.10 parts of pure carvedilol for 1 part of EPOC.; Example 2 By repeating the procedure as described in example 1 but carrying out the reaction at a temperature of 7O0C, 6O0C and 5O0C, substantially the same results were obtained with a EPO <DP n="8"/>prolonged reaction time of 8 hours, 10 hours and 16.5 hours, respectively.; Example 3 The procedure as described in example 1 was repeated obtaining substantially similar results by using a molar ratio EPOGMFA of 1 : 1.5, 1 : 1.7, 1 : 1.8 and 1 :2.2.
	With sodium carbonate; In water; ethyl acetate;	Example 1 Preparation of Carvedilol in Neat Conditions 2-(2-Methoxyphenoxy)ethylamine (III) (4.89 g) was heated to about 100 C., after which <strong>[51997-51-4]4-(oxiran-2-ylmethoxy)-9H-carbazole</strong> (II) (3.31 g) was added portionwise. After approximately 20 minutes, the reaction mixture was cooled to about 70 C., after which water (25 ml) and ethyl acetate (15 ml) were added. The pH of the two-phase mixture was then adjusted to 5 with 2 N hydrochloric acid. The solid that formed, Carvedilol hydrochloride hydrate, is filtered, washed with water (20 ml) followed with ethylacetate (15 ml). The resulting material is reslurried in ethylacetate (50 ml) and water (20 ml) containing 5% Sodium carbonate until the pH reached 7.5. The organic phase was separated and dried over sodium sulfate. The dried solution was concentrated to a turbid solution and cooled overnight to about 4 C. Precipitated carvedilol was isolated by filteration and crystallized from isopropanol.
	With sodium carbonate; In water; ethyl acetate;	Example 2 Preparation of Carvedilol in Neat Conditions 2-(2-Methoxyphenoxy)ethylamine (III) (4.89 g) was heated to about 100 C., after which <strong>[51997-51-4]4-(oxiran-2-ylmethoxy)-9H-carbazole</strong> (II) (3.31 g) was added portionwise. After approximately 20 minutes, the reaction mixture was cooled to about 70 C., after which water (25 ml) and ethyl acetate (15 ml) were added. The pH of the two-phase mixture was then adjusted to 5 with 2 N hydrochloric acid. The solid that formed, Carvedilol hydrochloride hydrate, is filtered, washed with water (20 ml) followed with ethylacetate (15 ml). The resulting material is reslurried in ethylacetate (50 ml) and water (20 ml) containing 5% Sodium carbonate until the pH reached 7.5. The organic phase was separated and dried over sodium sulfate. The dried solution was concentrated to a turbid solution and cooled overnight to about 4 C. Precipitated carvedilol was isolated by filteration and crystallized from methanol.
	In dimethyl sulfoxide; at 68 - 72℃; for 18 - 20h;Product distribution / selectivity;	EXAMPLE 1 Preparation of PTSA Salt of Carvedilol a) In a dry reaction flask, 120 gm (0.502 moles) of <strong>[51997-51-4]4-(2,3-epoxypropoxy)carbazole</strong> of Formula II, 188.7 gm (1.13 mole) of 2-(2-methoxy phenoxy)ethylamine, and 1200 ml dimethylsulphoxide (DMSO) were charged under dry nitrogen atmosphere. The reaction mass was heated to about 70 C. till completion of reaction (about 20 hours), and then the reaction mass was cooled to 30 C. and 1200 ml water was added to it. The crude product was extracted with dichloromethane (1200 ml), and the dichloromethane layer was washed with water. The dichloromethane layer was mixed with 240 ml water, followed by the addition of 55.8 gm p-toluene sulphonic acid (PTSA) to attain a pH in the range of 7 to 8. After stirring, the layers were separated and the organic layer was washed with water.; EXAMPLE 4 Preparation of Carvedilol; In a dry reaction flask charged 25.0 g 4-(2,3-epoxy propoxy)carbazole (0.104 moles), 39.35 g of 2-(2-methoxy phenoxy)ethylamine (0.235 moles) in 250 ml dimethyl sulfoxide. The temperature of the reaction mass was raised to about 70 C. under stirring and maintaining the reaction mixture at 68-72 C. for 18-20 hrs. The reaction mass was cooled to about 30 C. and quenched the reaction mass in 250 ml water, stirred and extracted the resultant solution in 250 ml dichloromethane. The organic layer was separated and washed with aqueous sulphuric acid till pH of the washings about 7.0-8.0. The organic layer was separated and further adjusted the pH with the aqueous sulfuric acid to 4.0-4.5 to precipitate carvedilol sulphate salt. The precipitated salt was filtered and taken in 300 ml ethyl acetate and made alkaline with 10% sodium carbonate solution. The reaction mass was stirred and separated the organic layer. The ethyl acetate was distilled under vacuum, and 330 ml toluene was added to it. The solid obtained was filtered and crystallized from ethyl acetate to obtain pure carvedilol (58-62% yield).
	In ethyl acetate; for 24h;Reflux;	In a dry reaction flask, 4-(2,3-epoxy propoxy) carbazole (50 gm.0.21 moles), 2-(2-methoxy phenoxy) ethyl amine (75.5 gm. 0.45 moles) and 500 ml of ethyl acetate were charged and heated to reflux for about 24 hours. After completion of the reaction, solvent was distilled off from the reaction mixture to obtain 125 gm of the residue. Ethyl acetate (312 ml) and water (312 ml) were added to the residue and stirred for about 15 minutes. Reaction mixture pH was adjusted to about 3 with 40 ml (0.68 moles) of phosphoric acid at room temperature. Reaction mixture was stirred for about 11 hours and filtered the solid to obtain carvedilol phosphate. The wet solid thus obtained was slurred in 325 ml of acetone at 26 0C for about 30 minutes. The solid was filtered and dried to obtain the title compound. Yield: 50 gm
	lithium bromide; In 1,2-dimethoxyethane; at 50℃; for 24h;	General Procedure for the Preparation of 1b-1d (FIG. 12, Scheme 4): To a solution of epoxide 6 (1.00 mmol) in anhydrous DME (6 mL) were added amines 7b-7d (2.00 mmol), respectively, and LiBr (catalytic). Each reaction mixture was stirred for 24 h at 50 C. Then the solvent was removed under vacuum, the residues were taken up in ether (10 mL) and washed with water. The aqueous layers were extracted with ether (2×10 mL). The organic layers were washed with brine (25 mL), dried over Na2SO4, evaporated under reduced pressure and the residues were purified by flash chromatography over silica gel to obtain pure 1b-1d.
176 mg	In ethanol; for 24h;Reflux;	Compound 5a (100 mg, 0.42 mmol), and 2-(2-methoxyphenoxy)ethanamine (84 mg, 0.50 mmol) were added to ethanol and theresulting heterogeneous solution was reuxed for 24 h. Themixture was cooled to room temperature and ltered through a padof celite and the ltrate was concentrated under reduced pressure.The residue was puried by ash chromatography on silica-gelwith 10% methanol in ethyl acetate. Yielding 83% compound 9a(176 mg) as a white solid. Compound 9b was synthesized followingthe procedure of preparation 9a.
	In ethyl acetate; for 24h;Reflux;	Example 5: Preparation of Carve dilol using 2-(2-methoxyphenoxy) ethylamine solid: In a dry reaction flask, 4-(2,3-epoxy propoxy) carbazole (50 gm), 27(2- methoxy phenoxy) ethyl amine solid (75.5 gm) and 500 ml of ethyl acetate were charged and heated to reflux for about 24 hours. After completion of the reaction, solvent was distilled off from the reaction mixture to obtain 117 gm of the residue. Ethyl acetate ( 175 ml) was added to the residue and stirred for about 12 hours at room temperature. The suspension was cooled to O0C, filtered and dried to get 65 gm of the title compound. M.R: 115 C- 1 17C Purity by HPLC: 99.74%

Reference： [1]Bioorganic and medicinal chemistry,2020,vol. 28
[2]Patent: WO2009/157015,2009,A2 .Location in patent: Page/Page column 6
[3]Patent: WO2004/41783,2004,A1 .Location in patent: Page 4
[4]Patent: WO2006/61364,2006,A1 .Location in patent: Page/Page column 5-7
[5]Patent: US2002/143045,2002,A1
[6]Patent: US2002/143045,2002,A1
[7]Patent: US2007/27202,2007,A1 .Location in patent: Page/Page column 4
[8]Patent: WO2009/122425,2009,A1 .Location in patent: Page/Page column 10
[9]Patent: WO2005/80329,2005,A2 .Location in patent: Page/Page column 4-5
[10]Patent: US2007/254849,2007,A1 .Location in patent: Page/Page column 16
[11]Synthetic Communications,2011,vol. 41,p. 85 - 93
[12]Journal of Medicinal Chemistry,2013,vol. 56,p. 8626 - 8655
[13]Patent: WO2015/31914,2015,A1 .Location in patent: Sheet 1/7
[14]European Journal of Medicinal Chemistry,2018,vol. 154,p. 253 - 266
[15]Patent: WO2009/128088,2009,A2 .Location in patent: Page/Page column 11

17
[ 1836-62-0 ]
[ 144-62-7 ]
[ 72956-09-3 ]

Yield	Reaction Conditions	Operation in experiment
77%		174g (1.04 moles, 2.5 mol equivalents) of 2-(2-methoxy phenoxy) ethylamine is dissolved in 500ML OFMONOCHLOROBENZENE. The temperature is raised to 125C under stirring. 100g (0.42 moles) OF 4- (2, 3-epoxy propoxy) carbazole is slowly added in five lots during 1 hr at reflux temperature. REFLUXING is then carried on for two hrs. The reaction is monitored to completion by thin layer chromatography and then cooled to 90C. 500ML water is then charged followed by cooling to 70C. The pH of reaction mass is adjusted to 2.5-2. 7 with 10% OXALIC acid solution at 60C-70C. STIRRING is done for one hr at 60C-70C. The reaction mass is cooled to room temp and maintained for two hrs. The material is filtered and washed with water and dried at 50C-60C. Yield: 160 g (77% yield) M. P: 186C-188C. (C, 63. 01 : H, 5.72 : N, 5.68 : CALCULATED FOR C2GH28N2OS C, 62.90 :, H, 5.68, N, 5.64 : IR Analysis : CM 3447, 3056,1607, 1456,1264, 1216,1187, and 1024: 1HNMR (300MHZ, DMSO-D6) 5 11.25 (LH, s, COOH), 8.2 (LH, d, Ar-H), 7.44 (LH, d, Ar-H), 7.30 (2H, m, Ar-H), 7.10-7. 15 (2H, d, Ar-H), 6.80-7. 05 (4H, m, Ar-H), 6.66 (LH, d, Ar- H), 4.25 (2H, d, OCH2), 4.15 (2H, t, OCH2), 3.70 (3H, s, OCH3), 3. 13 (2H, t, CH2), 3.11 (LH, m, CH), 3.05 (2H, d, CH2) : T3C NMR (75MHZ, DMSO-D6) 6 66.5, 154. 8, 149.4, 147.6, 141.3, 139, 126. 4, 124.5, 122. 7,121. 7,120. 7, 18. 7, 14. 5,112. 3,111. 6, 110. 5,104. 2,70. 2, 66. 5, 66.4, 55.4, 51.4, and 47. 1)
74.6%		146.4 g (0.875 moles, 2.1 mol equivalents) of 2- (2-methoxy phenoxy) ethylamine is dissolved in 500ML of monochlorobenzene and the temperature is raised 125C under stirring. 100 g (0.42 moles) of 4- (2, 3-epoxy propoxy) carbazole is slowly added in lots over 1 hr at reflux temperature. Reflux is then carried on for two hrs. Distilled of the monochlorobenzene under vacuum followed by cooling of the reaction mass to 50-60C. 1000 ml isopropyl acetate is charged followed by the addition of 1000ML DMwater. pH of reaction mass is adjusted to 2.0-2. 5 with 10% oxalic acid solution at 45C-50C. Stirred for one hr at 45C-50C, the reaction mass is cooled to room temperature and maintained for two hrs. The material is filtered washed with isopropyl acetate and water mixture and then dried at 50C-60C. Yield : 155 g (74. 6% yield) M. P: 184C C (C, 63.01 : H, 5.72 : N, 5. 68 : CALCULATED FOR C26HZBNZOS C, 62. 90:, H, 5.68, N, 5.64 : IR Analysis : CM 3447, 3056,1607, 1456, 1264,1216, 1187, and 1024: 1HNMR (300MHZ, DMSO-D6) 8 11.25 (LH, s, COOH), 8. 2 (LH, d, Ar-H), 7.44 (LH, d, Ar-H), 7.30 (2H, m, Ar-H), 7.10-7. 15 (2H, d, Ar-H), 6.80- 7.05 (4H, m, Ar-H), 6.66 (IH, d, Ar-H), 4.25 (2H, d, OCH2), 4.15 (2H, t, OCH2), 3.70 (3H, s, OCH3), 3.13 (2H, t, CH2), 3. 11 (LH, m, CH), 3.05 (2H, d, CH2) : T3C NME (75MHz, DMSO-d6) 8 66.5, 154. 8, 149.4, 147.6, 141.3, 139, 126. 4,124. 5,122. 7,121. 7,120. 7,18. 7,14. 5, 112.3, 111.6, 110.5, 104.2, 70.2, 66. 5,66. 4,55. 4,51. 4, and 47.1)

Reference： [1]Patent: WO2004/94378,2004,A1 .Location in patent: Page 6-7
[2]Patent: WO2004/94378,2004,A1 .Location in patent: Page 7-8

18
N-[2-(2-methoxyphenoxy)ethyl]acetamide [ No CAS ]
[ 1836-62-0 ]

Yield	Reaction Conditions	Operation in experiment
74.8%		209 g (1 mol) of N-[2-(2-Methoxy-phenoxy)-ethyl]-acetamide are refluxed in 400 mi HCI (5n) for 4h. The pH of the reaction mixture is adjusted to 8-9 with 30% NaOH solution and the oily layer is taken up in toluene, which is evapurated afterwards. The 2-(2-Methoxy-phenoxy) ethylamine is purified by distillation under vacuum. The yield is 125 g 2- (2-Methoxy-phenoxy)- ethylamin (74,8%), the boiling point is 110-115C at 2Torr.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5111 - 5131
[2]Patent: WO2003/95416,2003,A1 .Location in patent: Page/Page column 5

19
[ 1836-62-0 ]
[ 67579-92-4 ]
N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine; In dichloromethane;	(f) A mixture comprising 2-(2-methoxyphenoxy)ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) was cooled to 0 C. and then a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was allowed to warm to 23 C. over two hours, quenched with aqueous hydrochloric acid (3M, 20 mL), washed with water (3*20 mL), dried (Na2SO4) and concentrated in vacuo to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (14 g, 74% yield) an off white solid; MS (PB-PCI) C17H18N2O6 m/e calc 346.34; found 347 (MH+).

Reference： [1]Patent: US2001/53779,2001,A1

20
[ 214778-48-0 ]
[ 1836-62-0 ]

Yield	Reaction Conditions	Operation in experiment
90%		b) 2-(2-Methoxy-phenoxy)-ethylamine Under an atmosphere of Nitrogen, 3N HCl (3 ml) was added to a solution of [2-(2-methoxy-phenoxy)-ethyl]-carbamic acid tert-butyl ester (320 mg, 1.20 mmol) in dioxane (3 ml). The mixture was heated to reflux (2 h). Upon cooling, the reaction mixture was taken up in ethyl acetate, and extracted several times with H2O. The combined H2O extracts were then made alkaline by addition of NaOH 2N, and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4), and the solvent was evaporated. The obtained product (180 mg, 90%) was used in the next step without further purification. 1H NMR (CDCl3): delta 1.65 (2H, bs), 3.11 (2H, t), 3.86 (3H, s), 4.05 (2H, t), 6.88-6.94 (4H, m).
88%	With trifluoroacetic acid; In dichloromethane;	(d) tert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) was cooled to 0 C. and stirred as a mixture of trifluoroacetic acid:dichloromethane (1: 1, 40 mL) was added dropwise. The mixture was allow to warm to 23 C., stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 mL) and the solution was washed with saturated aqueous sodium hydrogen carbonate (320 mL) and aqueous sodium hydroxide (10%, 320 mL), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88% yield) a light yellow solid; MS (PB-PCI) C9H13NO2 m/e calc 167.21; found 168 (MH+).

Reference： [1]Patent: US2006/252779,2006,A1 .Location in patent: Page/Page column 7
[2]Patent: US2001/53779,2001,A1

21
[ 1836-62-0 ]
[ 185383-64-6 ]
[(cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-[2-(2-methoxy-phenoxy)-ethyl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane;	EXAMPLE 1a [(cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-[2-(2-methoxy-phenoxy)-ethyl]-amine A solution of 4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.38 g, 1.6 mmol), [2-(2-methoxy-phenoxy)-ethyl]-amine (0.27 g, 1.6 mmol), sodium triacetoxyborohydride (0.5 g, 2.2 mmol) and acetic acid (0.06 ml, 1.8 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 4 hours. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (360 ml) and washed with brine (360 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.43 g (71%) of product as a white solid. The HCl salt was prepared in ethyl acetate: mp 186-188 C. Elemental analysis for C23 H27 FN2 O2.HCl.0.06C4 H8 O2 Calc'd: C, 65.80; H, 6.77; N, 6.60 Found: C, 65.59; H, 6.69; N, 6.44
	With sodium hydroxide; sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane;	EXAMPLE 1a [(cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-[2-(2-methoxy -phenoxy)-ethyl]-amine A solution of 4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.38 g,1.6 mmol), [2-(2-methoxy-phenoxy)-ethyl]-amine (0.27 g, 1.6 mmol), sodium triacetoxyborohydride (0.5 g, 2.2 mmol) and acetic acid (0.06 ml, 1.8 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 4 hours. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and washed with brine (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.43 g(71%) of product as a white solid. The HCl salt was prepared in ethyl acetate: mp 186-188C.

Reference： [1]Patent: US6110956,2000,A
[2]Patent: EP1068184,2002,B1

22
acetic acid 1-hydroxy-propyl ester [ No CAS ]
trans-4-(5-Fluoro-1H-indol-3-yl)cyclo-hexanecarbaldehyde [ No CAS ]
[ 1836-62-0 ]
[ 246028-79-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; sodium hydroxide; sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane;	EXAMPLE 10a [(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexylmethyl]-[2-(2-methoxy-phenoxy)-ethyl]-amine A solution of 4-(5-fluoro-1H-indol-3-yl)cyclohexanecarbaldehyde (0.25 g, 1.02 mmol), <strong>[1836-62-0]2-(2-methoxy-phenoxy)ethylamine</strong> (0.17 g, 1.02 mmol), sodium triacetoxyborohydride (0.32 g, 1.4 mmol) and acetic acid (0.06 ml) in 1,2-dichloroethane (5 ml) was allowed to stir at room temperature for 16 hours. The reaction was quenched with 0.5 N sodium hydroxide (100 ml), extracted with methylene chloride (2100 ml) and washed with brine (2100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum. Chromatography (2% methanol-ethyl acetate plus 0.2% ammonium hydroxide) afforded 0.1 g (25%) of product. The HCl salt was prepared in ethyl acetate: mp 157-159 C. Elemental analysis for C24 H29 FN2 O2.HCl Calc'd: C, 65.22; H, 7.07; N, 6.34 Found: C, 65.10; H, 6.84; N, 6.25
	With ammonium hydroxide; sodium hydroxide; sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane;	EXAMPLE 10a [(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexylmethyl]-[2-(2 -methoxy-phenoxy)-ethyl]-amine A solution of 4-(5-fluoro-1H-indol-3-yl)cyclohexanecarbaldehyde (0.25 g, 1.02 mmol), <strong>[1836-62-0]2-(2-methoxy-phenoxy)ethylamine</strong> (0.17 g, 1.02 mmol), sodium triacetoxyborohydride (0.32 g, 1.4 mmol) and acetic acid (0.06 ml) in 1,2-dichloroethane (5 ml) was allowed to stir at room temperature for 16 hours. The reaction was quenched with 0.5 N sodium hydroxide (100 ml), extracted with methylene chloride (2 x 100 ml) and washed with brine (2 x 100 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum. Chromatography (2% methanol-ethyl acetate plus 0.2% ammonium hydroxide) afforded 0.1 g (25%) of product. The HCl salt was prepared in ethyl acetate: mp 157-159C.

Reference： [1]Patent: US6110956,2000,A
[2]Patent: EP1068184,2002,B1

23
[ 1836-62-0 ]
[ 52147-11-2 ]
(3,4-dihydro-quinazolin-2-yl)-[2-(2-methoxy-phenoxy)-ethyl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	In acetonitrile; at 80℃;screw-capped vial;	d) (3,4-Dihydro-quinazolin-2-yl)-[2-(2-methoxy-phenoxy)-ethyl]-amine 2-(2-Methoxy-phenoxy)-ethylamine (42 mg, 0.25 mmol) was added to a solution of 2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (70 mg, 0.23 mmol) in acetonitrile (1 ml), and the mixture was heated overnight (80 C.) in a screw-capped vial. The title compound (42 mg, 62%) was then isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, lambda=230 nm, flow rate 40 ml/min). MS: m/e=298.2 [M+H+]. 1H NMR (CDCl3): delta 3.71 (3H, s), 3.91 (2H, t), 4.16 (2H, t), 4.57 (2H, s), 6.85-7.01 (8H, m), 7.80 (1H, bs), 8.63 (1H, s).

Reference： [1]Patent: US2006/252779,2006,A1 .Location in patent: Page/Page column 8

24
[ 58421-79-7 ]
[ 1836-62-0 ]
[ 69324-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In chloroform; benzene;	Preparation 2. Compound No. 31 To a solution of 1.8 g (0.01 mol) of <strong>[58421-79-7]4-chloro-6-methylquinazoline</strong> in 50 ml of benzene were added 1.0 g (0.01 mol) of triethylamine and 1.7 g (0.01 mol) of 2-(O-methoxyphenoxy)ethylamine, and the mixture was heated, with stirring, at 60~70 C. for 5 hours. After completion of the reaction, the benzene was evaporated under reduced pressure and the residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure to leave crystals, which were recrystallized from ethanol, giving 0.9 g of 6-methyl-4-[2-(2-methoxyphenoxy)ethyl]-aminoquinazoline in the form of colorless plates. m.p. 167~169 C. Elementary analysis (%): Calcd: C, 69.88; H, 6.19; N, 13.58 Found: C, 69.86; H, 6.15; N, 13.60

Reference： [1]Patent: US4213987,1980,A

25
[ 1836-62-0 ]
[ 51997-51-4 ]
[ 918903-20-5 ]
[ 72956-09-3 ]

Yield	Reaction Conditions	Operation in experiment
58 - 62%	In dimethyl sulfoxide; at 68 - 72℃; for 18 - 20h;	Example -4: Preparation of carvedilol In a dry reaction flask charged 25.0 g 4 - (2,3-epoxy propoxy) carbazole (0.104 moles), 39.35 g of 2 - (2- methoxy phenoxy) ethylamine (0.235moles) in 250 ml dimethyl sulfoxide. The temperature of the reaction mass was raised to about 70C under stirring and maintaining the reaction mixture at 68 - 72C for 18 - 20 hrs. The reaction mass was cooled to about 30C and quenched the reaction mass in 250 ml water, stirred and extracted the resultant solution in 250 ml dichloromethane. The organic layer was separated and washed with aqueous sulphuric acid till pH of the washings about 7.0 - 8.0. The organic layer was separated and further adjusted the pH with the aqueous sulfuric acid to 4.0 - 4.5 to precipitate carvedilol sulphate salt. The precipitated salt was filtered and taken in 300 ml ethyl acetate and made alkaline with 10% sodium carbonate solution. The reaction mass was stirred and separated the organic layer. The ethyl acetate was distilled under vacuum, and 330 ml toluene was added to it. The solid obtained was filtered and crystallized from ethyl acetate to obtain pure carvedilol. Yield = 58 - 62%.

Reference： [1]Patent: EP1741700,2007,A1 .Location in patent: Page/Page column 2-3; 6

26
[ 1836-62-0 ]
trans-5-phenyl-1,4-dioxane-2-carboxylic acid [ No CAS ]
trans-N-(2-(2-methoxyphenoxy)ethyl)-5-phenyl-1,4-dioxane-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6359 - 6370

27
[ 1836-62-0 ]
cis-5-phenyl-1,4-dioxane-2-carboxylic acid [ No CAS ]
cis-N-(2-(2-methoxyphenoxy)ethyl)-5-phenyl-1,4-dioxane-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6359 - 6370

28
[ 1836-62-0 ]
trans-6-phenyl-1,4-dioxane-2-carboxylic acid [ No CAS ]
trans-N-(2-(2-methoxyphenoxy)ethyl)-6-phenyl-1,4-dioxane-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6359 - 6370

29
[ 1836-62-0 ]
cis-6-phenyl-1,4-dioxane-2-carboxylic acid [ No CAS ]
cis-N-(2-(2-methoxyphenoxy)ethyl)-6-phenyl-1,4-dioxane-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6359 - 6370

30
[ 1836-62-0 ]
[ 1187921-94-3 ]
[ 72956-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In isopropyl alcohol at 60℃;	2 Example-2 Preparation of Carvedilol; 48 % HBr solution [35 ml] was added to 4-(2,3-Epoxy propoxy)carbazole (25 gm) in lsopropyl alcohol (50 ml ) at 25-300C and heated to 600C and maintained for about one hour with stirring. The solvent was distilled under reduced pressure and allow the reaction mass to cool at room temperature. Triethyl amine (16 gm) and 2-(2-methoxyphenoxy)-ethylamine (35 gm) were added to reaction mass and heated to 600C and maintained for about 2 hours with stirring. Traces of lsopropyl alcohol was distilled under reduced pressure at 45-500C. Water (50 ml), Toluene (100 ml) and 50 ml ethyl acetate were added at 500C1 and stirred for 15 minutes. The organic layer was allowed to separate and washed with water at 500C then dried with sodium sulfate (10 gm). Solvent was distilled under reduced pressure up to 550C. Ethyl acetate (55 ml) was added to residue and stirred for 30 minutes. The reaction mass was cooled to 0-50C and filtered to get Carvedilol (12 gm). The product was dried to give Carvedilol (>97% HPLC purity). Carvedilol obtained by the present invention is indicated for the treatment of mild-to- severe heart failure of ischemic or cardiomyopathic origin. It is also indicated to reduce cardiovascular mortality during the acute phase of myocardial infarction and for the management of essential hypertension. Since Carvedilol is multiple action drug, its β- adrenoreceptor blocking activity affects the response to certain nerve impulses in parts of the body. Carvedilol is known to be vasodilator resulting primarily from α-adrenoceptor blockade. The multiple drug actions of Carvedilol are responsible for the antihypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.

Reference： [1]Current Patent Assignee: CADILA PHARMACEUTICALS LIMITED - WO2009/115906, 2009, A2 Location in patent: Example 2

31
[ 1836-62-0 ]
[ 1187921-93-2 ]
[ 72956-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In toluene at 80 - 85℃; for 13h;	1 Example 1 : Preparation of Carvedilol; 4-(2,3-Epoxypropoxy)carbazole (10 gms) was added to a solution of hydrochloric acid [25 ml] at 25-300C. The reaction mass was stirred for 5 hours at 25 - 30°C, then the reaction mass was heated to 75-80°C. Water was distilled out at 75 - 85°C and then Toluene was added to remove water under reduced pressure at 75-800C. The residue was cooled to 25-30°C. Toluene (100 ml) and 2-(2-methoxyphenoxy)-ethylamine (10.45 gm) was added followed by addition of K2CO3 (9.45 gm). The reaction mass was heated to 80 - 85°C and maintained for about 13 hours. Water (100 ml) was added and stirred for 5 - 10 minutes. Toluene layer was separated and distilled out under reduced pressure at 65 - 700C. Ethyl acetate was added to the residue and stirred at ambient temperature for half an hour. The reaction mass was gradually cooled to 0-5°C and stirred for 2 hrs. The reaction mass was filtered, washed with chilled ethyl acetate to obtain Carvedilol (5.5 gm). The product was dried under reduced pressure to give Carvedilol (>97% HPLC purity).

Reference： [1]Current Patent Assignee: CADILA PHARMACEUTICALS LIMITED - WO2009/115906, 2009, A2 Location in patent: Example 1

32
[ 87-69-4 ]
[ 1836-62-0 ]
[ 51997-51-4 ]
[ 863664-91-9 ]

Yield	Reaction Conditions	Operation in experiment
56.89%		A mixture of <strong>[51997-51-4]4-(oxiran-2-ylmethoxy)-9H-carbazole</strong> (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70C to 80C. To this 2- (2- methoxyphenoxy) ethylamine (III) (25.33 g, 151.67 mmole) is added in one lot. The temperature of reaction mass is raised to reflux (80C to 85C) and maintained at this temperature for 2 hour. After that, this reaction mass is added to the pre-heated (80C to 85C) solution of L (+) tartaric acid (24. 32 g) (162.1 mmole) in 2-propanol (287.5 ml) and continued the reflux for next 1 hour, cooled to 50C to 55C and maintained for 1 hour. The product is filtered at the same temperature (50C to 55C) followed by three 33.5 ml wash with hot (50C to 55C) 2-Propanol. The wet product dried at 60C to 65C for 6-8 hours or till constant weight gave 33.0 g of Carvedilol tartarate (Yield = 56. 89%).

Reference： [1]Patent: WO2005/80329,2005,A2 .Location in patent: Page/Page column 8

33
[ 1836-62-0 ]
[ 65-85-0 ]
[ 51997-51-4 ]
[ 852995-81-4 ]

Yield	Reaction Conditions	Operation in experiment
66%		A mixture of <strong>[51997-51-4]4-(oxiran-2-ylmethoxy)-9H-carbazole</strong> (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70C to 80C. To this 2- (2- methoxyphenoxy) ethylamine (III) (25.33 g, 151.67 mmole) is added in one lot. The temperature of reaction mass is raised to reflux (80C to 85C) and maintained at this temperature for 1 hour. After that, this reaction mass was added to the pre-heated (80C to 85C) solution of benzoic acid (18.5 g) in 2-propanol (287.5 ml) and continued the reflux for next 2-hour, cooled to 50C to 55C and maintained the same temperature for 1 hr. The product filtered at same temperature followed by three 33.5 ml wash with hot (50C to 55C) 2-propanol. The wet product dried at 60C to 65C for 6-8 hours or till constant weight gives 36.5 g of Carvedilol benzoate (Yield = 66 %).

Reference： [1]Patent: WO2005/80329,2005,A2 .Location in patent: Page/Page column 7-8

34
[ 1836-62-0 ]
[ 144-62-7 ]
[ 51997-51-4 ]
[ 72956-09-3 ]

Yield	Reaction Conditions	Operation in experiment
80.95%		A mixture of <strong>[51997-51-4]4-(oxiran-2-ylmethoxy)-9H-carbazole</strong> (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70C to 80C. To this 2- (2- methoxyphenoxy) ethylamine (III) (25.33 g, 151.67 mmole) is added in one lot. The temperature of reaction mass is raised to reflux (80C to 85C) and maintain at this reaction temperature for one hour. After that, this reaction mass is added to the pre- heated (80C to 85C) solution of oxalic acid (14.6 g) (162.13 mmole) in 2-propanol (287.5 ml) and continued the reflux for next one-hour, cooled to 50C to 55C and maintain for 1 hour. The product is filtered at the same temperature followed by three 33.5 ml wash with hot (50C to 55C) 2-propanol. The wet product dried at 60C to 65C for 6-8 hours or till constant weight gives 42.0 g of Carvedilol Oxalate (Yield = 80.95%).

Reference： [1]Patent: WO2005/80329,2005,A2 .Location in patent: Page/Page column 8-9

35
[ 1836-62-0 ]
[ 69-72-7 ]
[ 51997-51-4 ]
[ 787598-91-8 ]
[ 918903-20-5 ]

Yield	Reaction Conditions	Operation in experiment
57 - 70%		A mixture of <strong>[51997-51-4]4-(oxiran-2-ylmethoxy)-9H-carbazole</strong> (II) (25.0 g, 104.60 mmole) and 62. 5 ml-2-propanol is heated to 70C to 80C. To this 2- (2- methoxyphenoxy) ethylamine (III) (20.96 g, 125.52 mmole) is added in one lot. The temperature of the reaction mass is raised to 80C to 85C and refluxed for 1.0 hour. The reaction mixture is added into the preheated (80C to 85C) solution of salicylic acid (18.77 g, 135.98 mmoles) in 187.5 ml 2-propanol. This reaction mass is further refluxed for 2.0 hours, cooled to 50C to 55C and stirred for one hour at this temperature. The solid is filtered followed by three 33 ml wash with hot (50C to 55C) 2-propanol. The wet product dried at 60C to 65C for 6 hours or till constant weight gives 32.5 g (Yield=57%) of Carvedilol salicylate, which contains about 2-2.5 % of compound (IV) as an impurity. HPLC Purity = 92. 5-95. 0 % Melting point. = 164C-166C; Example: 2; Preparation of Carvedilol salicylate : A mixture of 4- (oxiran-2-ylmethoxy)-9H-carbazole (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70C to 80C. To this 2- (2- methoxyphenoxy) ethylamine (III) (25.33 g, 151. 67 mmole) is added in one lot. The temperature of the reaction mass is then raised to 80C to 82C and refluxed for 1 hour. The reaction mixture is added into the preheated (80C to 85C) solution of salicylic acid (18.77 g, 135.98 mmoles) in 187.5 ml of 2-propanol. The reaction mass is further refluxed for 2 hours, cooled to 50C to 55C and stirred for 1 hour at this temperature. The solid is filtered, followed by three 33 ml wash with hot (50C to 55C) 2-propanol. The wet product dried at 60C to 65C for 6 hours or till constant weight gives 39.75 g (Yield 70%) of Carvedilol salicylate, which contains about 2-2.5 % of compound (IV) as an impurity. HPLC purity = 92. 5-95% Melting point = 164C-166C; Example: 3; Process of purification for Carvedilol salicylate : A mixture of Carvedilol salicylate (39.0 g 39.81 mmole) and ethyl acetate (312 ml) is stirred at 70C to 75C for 30 minutes then cooled to 50C to 55C and stirred at that temperature for 1 hour. The content is filtered at same temperature and washed with hot (50C to 55C) ethyl acetate, the product is dried at 60C to 65C for 6 hours or till constant weight to afford 37.0 g of pure Carvedilol salicylate (Recovery=94.87%), which contains about 1.0-2. 0 % of compound (IV) as an impurity. HPLC purity = 94-97 % Melting point = 165C-167

Reference： [1]Patent: WO2005/80329,2005,A2 .Location in patent: Page/Page column 6-7

36
[ 64464-07-9 ]
[ 1836-62-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydroxide; In water; at 0℃;pH 12 - 14;	To a solution of 2-(2-methoxyphenoxy) ethylamine hydrochloride (100 g) in water (200 mL), was added 10% aqueous NaOH at 00C till the pH of the solution is 12-14 and then extracted into dichloromethane (3 x 100 mL). The organic layer was washed with brine (2 X 100 mL). The organic layer was dried over Na2SO4 and concentrated to obtain 2-(2-methoxyphenoxy) ethylamine (97%).

Reference： [1]Patent: WO2009/157015,2009,A2 .Location in patent: Page/Page column 6

37
[ 1836-62-0 ]
[ 1151808-88-6 ]
[ 1151809-17-4 ]

Yield	Reaction Conditions	Operation in experiment
7.5%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	Step 2: Synthesis of 2-{4-[3-(2-methoxyphenoxyethylamino)propoxy]phenyl}3- (3,5-dimethoxyphenyl)acrylic acid methyl esterA suspension of 2-[4-(3-bromopropoxy)phenyl]-3-(3,5-dimethoxyphenyI) acrylic acid methyl ester (0.56 g, 1.3 mmol), 2-(2-methoxyphenoxy)ethylamine (0.23 mL, 1.5 mmol) and potassium carbonate (0.53 g, 3.8 mmol) in DMF (8 mL) was heated to 80 0C for 4 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (2 x 100 mL). The ethyl acetate layer was washed with water (100 mL x 3), dried over anhydrous Na2SO4 and concentrated to afford the crude compound, which was purified by column chromatography using 2% methanol in dichloromethane as the eluent, to furnish the title compound (0.05 g, 7.5 % yield). 1H NMR (DMSO-d6) delta (ppm): 1.86-1.90 (2H, m, -CH2), 2.72-2.76 (2H, t, - CH2), 2.87-2.90 (2H, t, -CH2), 3.53 (6H, s, -OCH3), 3.70 (3H, s, -OCH3), 3.73 (3H, s, - OCH3), 3.99-4.02 (2H, t, -CH2), 4.04-4.07 (2H, t, -CH2), 6.27-6.28 (2H, d, Ar-H), 6.38- 6.39 (IH, m, Ar-H), 6.87-6.89 (2H, m, Ar-H), 6.94-6.97 (4H, m, Ar-H), 7.07-7.09 (2H, d, Ar-H), 7.67 (IH, s, =CH). MS m/z: 522.2 (M+l).
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;	Step 2: Synthesis of 2-{4-[3-(2-methoxyphenoxyethylamino)propoxy]phenyl}3-(3,5-dimethoxyphenyl)acrylic acid methyl esterA suspension of 2-[4-(3-bromopropoxy)phenyl]-3-(3,5-dimethoxyphenyl)acrylic acid methyl ester (0.56 g, 1.3 mmol), 2-(2-methoxyphenoxy)ethylamine (0.23 mL, 1.5 mmol) and potassium carbonate (0.53 g, 3.8 mmol) in DMF (8 mL) was heated to 80 C. for 4 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The ethyl acetate layer was washed with water (100 mL×3), dried over anhydrous Na2SO4 and concentrated to afford the crude compound, which was purified by column chromatography using 2% methanol in dichloromethane as the eluent, to furnish the title compound (0.05 g, 7.5% yield). 1H NMR (DMSO-d6) delta (ppm): 1.86-1.90 (2H, m, -CH2), 2.72-2.76 (2H, t, -CH2), 2.87-2.90 (2H, t, -CH2), 3.53 (6H, s, -OCH3), 3.70 (3H, s, -OCH3), 3.73 (3H, s, -OCH3), 3.99-4.02 (2H, t, -CH2), 4.04-4.07 (2H, t, -CH2), 6.27-6.28 (2H, d, Ar-H), 6.38-6.39 (1H, m, Ar-H), 6.87-6.89 (2H, m, Ar-H), 6.94-6.97 (4H, m, Ar-H), 7.07-7.09 (2H, d, Ar-H), 7.67 (1H, s, CH). MS m/z: 522.2 (M+1).

Reference： [1]Patent: WO2009/60282,2009,A2 .Location in patent: Page/Page column 43
[2]Patent: US2010/298402,2010,A1 .Location in patent: Page/Page column 26

38
[ 1836-62-0 ]
[ 244123-12-4 ]
[ 1255188-26-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 7065 - 7077

39
[ 1836-62-0 ]
[ 104-15-4 ]
[ 51997-51-4 ]
[ 1016214-10-0 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE IV; Preparation of Carvedilol tosylate; To a solution of lOOg of 4-(2,3-qpoxypropoxy) carbazole (III) in monoglyme (200 ml) at 10-300C, 2-(2-methoxyphenoxy) ethylamine (125 g) was added and the reaction mixture was refluxed for reaction completion. Monoglyme was recovered and mass was diluted with isopropyl alcohol. Reaction mass is cooled and added to a solution of p-toluene sulfonic acid in IPA. Mass is refluxed for 2 hrs. Mass is cooled to 15-20 C for complete crystallization. Product is filtered and washed with isopropyl alcohol. Solid is dried to get 180 g Carvedilol tosylate which can be optionally recrystallized.

Reference： [1]Patent: WO2008/38301,2008,A1 .Location in patent: Page/Page column 11

40
[ 1836-62-0 ]
[ 69-72-7 ]
[ 51997-51-4 ]
[ 787598-91-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE Il; Preparation of Carvedilol salicylate; To a solution of lOOg of 4-(2,3-epoxypropoxy) carbazole (III) in isopropyl alcohol (200 ml) at 10-300C, 2-(2-methoxyphenoxy) ethylamine (125 g) was added and the reaction mixture is stirred at 75-800C for reaction completion. Reaction mass is cooled and <n="12"/>added to a solution of salicylic acid (90- g) in isopropyl alcohol. Mass is refluxed to get ?precipitation. Mass is cooled and product is filtered and washed with isopropyl alcohol. Solid is dried to get 160 g Carvedilol salicylate which can be optionally recrystallized.

Reference： [1]Patent: WO2008/38301,2008,A1 .Location in patent: Page/Page column 10-11

41
[ 1836-62-0 ]
[ 100-39-0 ]
[ 3246-03-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In toluene; at 0 - 25℃; for 8h;	To a solution of benzyl bromide (4100 mg, 23.92 mmol) in toluene(15 ml) was added triethylamine (6051 mg, 59.80 mmol)the temperature was lowered to 0 C .Toluene (10 ml) in which 2-(2-methoxyphenoxy)ethanamine (5000 mg, 29.90 mmol) was slowly added dropwise at 0 C,The temperature was increased to 25 C . After the reaction mixture was stirred at room temperature for 8 hours, water (25 ml) was added dropwise to the reaction mixture, and the mixture was stirred for 15 minutes. The organic layer was then separated, washed with water (15 ml), dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was then purified by column chromatography on silica gel, 15-80% ethyl acetate / hexane to give the final compound as the final product.

Reference： [1]Synthetic Communications,2011,vol. 41,p. 85 - 93
[2]Patent: KR2018/125090,2018,A .Location in patent: Paragraph 0282; 0284-0291

42
[ 1836-62-0 ]
[ 4463-59-6 ]
[ 51997-51-4 ]
[ 1059573-45-3 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 85 - 93

43
[ 1836-62-0 ]
[ 51997-51-4 ]
[ 918903-20-5 ]

Reference： [1]Synthetic Communications,2011,vol. 41,p. 85 - 93

44
[ 1836-62-0 ]
[ 72956-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dmap / N,N-dimethyl-formamide / 15 - 30 °C / Inert atmosphere 2: 100 - 110 °C / Inert atmosphere 3: ethanol; sodium hydroxide / Inert atmosphere; Reflux
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 10 h / 100 °C / Inert atmosphere 2: 100 - 110 °C / Inert atmosphere 3: ethanol; sodium hydroxide / Inert atmosphere; Reflux

Reference： [1]Kumar, B. Anand; Ashrafuddin; Rajesh; Parveen, Sadhika; Madhusudhan [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 780 - 784]
[2]Kumar, B. Anand; Ashrafuddin; Rajesh; Parveen, Sadhika; Madhusudhan [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 780 - 784]

45
[ 1836-62-0 ]
[ 1429014-66-3 ]
[ 148890-53-3 ]
C₂₄H₂₆FN₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%		General procedure: Primary amine (0.55 mmol), oxo ester 9-12 (0.50 mmol) and TMS-N3 (0.55 mmol)were dissolved in EtOH (3.0 ml) in a vial. Isocyanide (0.60 mmol) was added and the mixture was stirred at room temperature for 12 h, then evaporated in vacuo. Subsequently, 10% TFA solution in DCE (3.0 ml) was added and the reaction mixture was heated at 70-75 C for 8-10 h.The mixture was treated with saturated aqueous K2CO3, the organic layer was separated, the aqueous one was extracted with EtOAc (2 × 2ml). The combined organic extracts were washed with water (2 × 5 ml). The organicl ayer was dried over Na2SO4 and then concentrated in vacuo. The residue was treated with 10% EtOAc in Et2O (to cause crystallization of the product) or purified on silica gel (EtOAc : hexane = 1 : 10 1: 2). For characteristics of compounds 13-16, see Online Supplementary Materials.

Reference： [1]Mendeleev Communications,2013,vol. 23,p. 108 - 109

46
[ 2461-42-9 ]
[ 1836-62-0 ]
[ 1479050-16-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	In isopropyl alcohol; for 5h;Inert atmosphere; Reflux;	General procedure: Corresponding 2-(aryloxymethyl)oxiranes (5 mmol, 1 equiv) and amines (7.5 mmol, 1.5 equiv) were dissolved in 30 mL i-PrOH. The reaction was purged with argon 3 times and stirred at reflux for 5 h, andthen the mixture was cooled to room temperature and added AcOEt.After washing with brine 3 times, the organic layer was dried overanhydrous Na2SO4, filtered, and evaporated in vacuo. Purification ofthe crude residue by column chromatography on silica gel yielded target compounds.

Reference： [1]Bioorganic and medicinal chemistry,2020,vol. 28
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 8626 - 8655

47
[ 1836-62-0 ]
[ 51997-51-4 ]
1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propanol phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90 g		Example 1 : Preparation of carvedilol phosphate 4-(Oxiranylmethoxy)-9H-carbazole (75 gm) was added to 2-(2- methoxyphenoxy)ethylamine (140 gm) at room temperature, followed by stirring the reaction mixture for 37 hours at room temperature. Ethyl acetate (385 ml) was added to the reaction mass, followed by maintaining the resulting mass at room temperature for 1 hour 30 minutes. The resulting mass was cooled to 0 to 5C and then maintained at the same temperature for 1 hour 30 minutes. The separated solid was filtered, washed with chilled ethyl acetate and then dried to obtain carvedilol. To the carvedilol obtained was added acetone (300 ml) and water (100 ml) at room temperature. To the reaction mixture was added phosphoric acid (5 ml), followed by stirring the reaction mixture at room temperature. The separated solid was filtered and then dried to obtain 90 gm of carvedilol phosphate.

Reference： [1]Patent: WO2014/108921,2014,A2 .Location in patent: Page/Page column 7-8

48
[ 1836-62-0 ]
[ 141109-47-9 ]
C₁₇H₂₆N₂O₄ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 9884 - 9888,5
Angew. Chem.,2014,vol. 126,p. 10042 - 10046,5
Angewandte Chemie,2014,vol. 126,p. 10042 - 10046,5
[2]Chemical Communications,2015,vol. 51,p. 12103 - 12106

49
[ 1836-62-0 ]
[ 6160-65-2 ]
1-(2-isothiocyanatoethoxy)-2-methoxybenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.2%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	General procedure: Triethylamine (3 or 6.25 equiv.) was added to a solution of the amine (1 equiv. in dimethylformamide at RT under N2). To the resultant solution, 1,1?-thiocarbonyldiimidazole (2 equiv. in DMF at RT under N2) was added in a dropwise fashion over 15min, with continued stirring at RT for 18h. The solution was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried (magnesium sulfate) and concentrated. The crude material was purified using silica gel chromatography (ethyl acetate-hexanes) to afford the desired isothiocyanate.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 93,p. 501 - 510

50
[ 1836-62-0 ]
C₁₅H₁₃NO₃ [ No CAS ]
1-[3-hydroxycarbazolyl-⁽⁴⁾-oxy]-3-[2-(2-methoxyphenoxy)ethylamino]propanol-⁽²⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	In isopropyl alcohol; at 20℃; for 18h;	The above product 7 (50 mg, 0.20 mmol), and commercially available 2-(2-methoxyphenoxy)ethanamine (49 mg, 0.29 mmol) were added to isopropanol (1 mL). The mixture was stirred at room temperature for 18 h and concentrated under reduced pressure. The crude product was subjected to flash chromatography over silica gel (dichloromethane-methanol, 95:5) to obtain 2 (44 mg, 53%) as a beige solid: mp 145-147 oC;

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 149 - 153

51
[ 1836-62-0 ]
[ 105-56-6 ]
N-(2-(2-methoxyphenoxy)ethyl)-2-cyanoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In ethanol; at 20℃;	General procedure: In a simply obtainable screw cap bottle, a mixture of ethylcyanoacetate6 (1.2 mmol) and the suitable amine (1 mmol) in EtOH (10 mL)was stirred at RT for 4-8 h. After completion as indicated by TLC, thereaction liquid was refrigerated down to 4 C in an ice bath. In severalcases, the precipitation of amide usually took later than some minutesto hours [12]. Filtered off the formed solid, rinsed with ether numeroustimes to obtain pure 7(a-q) in corresponding yield.
	In ethanol;Reflux;	General procedure: To a solution of different amines (1 mmol) in ethanol (10 mL), ethylcyanoacetate (1.2 mmol) was added. The reaction mixture was stirred for 5-8 h under reflux. Progress of the reaction was monitoredby TLC. After completion of the reaction, the resulting mixture was cooled to 0-5 C in an ice bath and the solid separated was filtered off.

Reference： [1]Bioorganic Chemistry,2019,vol. 88
[2]European Journal of Medicinal Chemistry,2016,vol. 107,p. 219 - 232
[3]Chemical Biology and Drug Design,2016,p. 43 - 53
[4]Molecular Pharmaceutics,2018,vol. 15,p. 2206 - 2223

52
[ 5503-32-2 ]
[ 1836-62-0 ]
N-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-2-(2-methoxyphenoxy)ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With potassium iodide; In 2-methoxy-ethanol; at 160℃; under 5171.62 Torr; for 0.5h;Microwave irradiation;	General procedure: A 10mL microwave vial was charged with 4 or 5 or 6 (1.0 mmol), a small excess (1.2 mmol) of 2-phenoxy- or (2-methoxyphenoxy)-or (2,6-dimethoxyphenoxy)-ethanamine and a catalytic amount ofpotassium iodide in 1 mL of 2-methoxyethanol. The reaction wasstirred under microwave irradiation at 160 C (pressure 100 PSI, power 50 W) for 30 min. Then the solvent was evaporated under reduced pressure. The residue was taken up with EtOAc, basified with 5% NaOH. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 435 - 452

53
[ 1836-62-0 ]
1-oxa-4-thiaspiro[4.5]decan-2-ylmethyl 4-methylbenzenesulfonate [ No CAS ]
N-(1-oxa-4-thiaspiro[4.5]decan-2-ylmethyl)-2-(2-methoxyphenoxy)ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With potassium iodide; In 2-methoxy-ethanol; at 160℃; under 5171.62 Torr; for 0.5h;Microwave irradiation;	General procedure: A 10mL microwave vial was charged with 4 or 5 or 6 (1.0 mmol), a small excess (1.2 mmol) of 2-phenoxy- or (2-methoxyphenoxy)-or (2,6-dimethoxyphenoxy)-ethanamine and a catalytic amount ofpotassium iodide in 1 mL of 2-methoxyethanol. The reaction wasstirred under microwave irradiation at 160 C (pressure 100 PSI, power 50 W) for 30 min. Then the solvent was evaporated under reduced pressure. The residue was taken up with EtOAc, basified with 5% NaOH. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 435 - 452

54
[ 1836-62-0 ]
2-(chloromethyl)-1,4-dithiaspiro[4.5]decane [ No CAS ]
{1,4-dithiaspiro[4.5]decan-2-ylmethyl}[2-(2-methoxyphenoxy)ethyl]amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With potassium iodide; In 2-methoxy-ethanol; at 160℃; under 5171.62 Torr; for 0.5h;Microwave irradiation;	General procedure: A 10mL microwave vial was charged with 4 or 5 or 6 (1.0 mmol), a small excess (1.2 mmol) of 2-phenoxy- or (2-methoxyphenoxy)-or (2,6-dimethoxyphenoxy)-ethanamine and a catalytic amount ofpotassium iodide in 1 mL of 2-methoxyethanol. The reaction wasstirred under microwave irradiation at 160 C (pressure 100 PSI, power 50 W) for 30 min. Then the solvent was evaporated under reduced pressure. The residue was taken up with EtOAc, basified with 5% NaOH. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 435 - 452

55
[ 1836-62-0 ]
[ 51997-51-4 ]
carvedilol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 6h;Reflux;	To a 1000 mL three-necked flask with mechanical stirring was added absolute ethanol (800 mL), 4- (2,3-epoxypropoxy) carbazole , 2-(2-methoxyphenoxy) ethylamine was refluxed for 6 hours to obtain a reaction solution, which was then used in the next step.

Reference： [1]Patent: CN106045900,2016,A .Location in patent: Paragraph 0011; 0044; 0047; 0048; 0053; 0055; 0056

56
[ 141-30-0 ]
[ 1836-62-0 ]
C₁₃H₁₄ClN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.3%	In ethanol;	(4) Add 31.2 g of compound A ^ 28.2g of 3.6-dichloropyridazine in ethanol, heated to reflux, TLC monitoring reaction, after the end of the reaction, the product was distilled off under reduced pressure and recrystallized to give a yellow solid A244g, Yield 84.3%. 50 g of the compound A2 obtained above was washed with acetic acid / sodium acetate, stirred under reflux and TLC. After the completion of the reaction, sodium acetate was removed, acetic acid was removed under reduced pressure, and the pale yellow solid compound A3 was recrystallized from ethanol in 92% yield.

Reference： [1]Patent: CN106632070,2017,A .Location in patent: Paragraph 0028

57
[ 1836-62-0 ]
[ 25888-01-1 ]
N-[2-(2-methoxyphenoxy)ethyl]-1,2-dimethyl-5-hydroxy-1H-indole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.2%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h;	General procedure: Synthetic method: 1-alkyl-2-methyl-5-hydroxy-1H-indole-3-carboxylic acid 0.020 mol, O-methoxyphenoxyethylamine (12.16 g, 0.060 mol), N, N-dimethylformamide 10 mL and dichloromethane 100 mL were placed in a 250 mL eggplant flask, The HOBt (4.05 g, 0.030 mol), Triethylamine (6.07 g, 0.060 mol) EDCI (5.75 g, 0.030 mol) were added thereto, respectively, The reaction was stirred at room temperature for 16 h, The reaction solution was washed with a 2 mol / L aqueous hydrochloric acid solution and a saturated sodium bicarbonate solution, Add a large amount of water to stir the precipitated solid, Filter, Product crude ethanol recrystallization.

Reference： [1]Patent: CN106946761,2017,A .Location in patent: Paragraph 0071-0074

58
[ 1836-62-0 ]
C₁₆H₂₀N₂O₄ [ No CAS ]
C₂₅H₃₃N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	In isopropyl alcohol; at 60℃; for 12h;	Reaction scheme: Step-1 (0492) Procedure: To a solution of Oxirane intermediate (0.44 g, 1.44mmol) in iPrOH (10 ml_), was added 2-methoxy phenoxyethylamine (0.24 g, 1.44 mmol). The reaction mixture was stirred under 60 C for 12 h, concentrated under reduced pressure and purified by silica column chromatography using 1 % methanol in ethyl acetate as eluent to give (0.35 g, 51 % ) as a thick liquid.

Reference： [1]Patent: WO2017/197324,2017,A1 .Location in patent: Page/Page column 82-83

59
[ 1836-62-0 ]
[ 122797-04-0 ]
(S)-1-(4-(benzyloxy)phenoxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.52 g	In isopropyl alcohol; at 50℃; for 5h;	To a solution of (S)-2-((4-(benzyloxy)phenoxy)methyl)oxirane(1.0 g, 3.9mmol) in iPrOH (40 ml), was added 2-(2-methoxyphenoxy)ethanamine (0.98 g,5.8mmol) in iPrOH dropwise under 50C for 5h. The reaction mixture was cooled to roomtemperature, and removed the solution, water was added, extracted with EA. The organic layerwas washed with water, brine, dried over Na2SO4, concentrated under reduced pressure andpurified by silica column, to give (S)-1-(4-(benzyloxy)phenoxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol (0.52 g, 1.228mmol).

Reference： [1]PLoS ONE,2017,vol. 12

60
[ 1028168-97-9 ]
[ 1836-62-0 ]
2-[2-(2-methoxyphenoxy)ethylamino]-3-(4-methylphenyl)-4-quinazolinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.95%	With triethylamine; In butan-1-ol; for 6h;Reflux;	0.27 g of 2-chloro-3-(4-methylphenyl)-4-quinazolinone,0.17 g 2-(2-methoxyphenoxy)ethanamine,0.303g triethylamine,3mL n-butanol,It was added to an eggplant-shaped flask and refluxed for 6 hours. Naturally, solids precipitated. The mixture was filtered off with suction, washed and dried to give 2-[2-(2-methoxyphenoxy)ethylamino]-3-(4-methylphenyl)-4-quinazolinone, 0.20 g of white powder. , Yield 49.95%

Reference： [1]Patent: CN107793369,2018,A .Location in patent: Paragraph 0047; 0055

61
[ 1836-62-0 ]
2-(2-(4-ethoxyphenoxy)ethyl)oxirane [ No CAS ]
1-(4-ethoxyphenoxy)-4-((2-(2-methoxyphenoxy)ethyl)amino)butan-3-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	In ethanol; for 24h;Reflux;	General procedure: Compound 2a (100 mg, 0.52 mmol), and 2-(2-methoxyphenoxy)ethanamine (150 mg, 0.62 mmol) were added to ethanol and theresulting heterogeneous solution was reuxed for 24 h. Themixture was cooled to room temperature and ltered through a padof celite and the ltrate was concentrated under reduced pressure.The residue was puried by ash chromatography on silica-gelwith 10% methanol in ethyl acetate. Yielding 68% compound 6a(128 mg) as a white solid. Compound 6b was synthesized followingthe procedure of preparation 6a.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 154,p. 253 - 266

62
[ 1836-62-0 ]
[ 100-52-7 ]
[ 3246-03-5 ]

Yield	Reaction Conditions	Operation in experiment
		2- (2-methoxyphenoxy) ethanamine (851 mg, 5.1 mmol),Benzaldehyde (540 mg, 5.1 mmol),Para-Toluenesulfonic acid (PTSA, 105 mg, 0.55 mmol) was dissolved in 5 mL of toluene.The mixed solution was refluxed, maintained and stirred.TLC (Thin Layer Chromatography) was used to confirm the completion of the reaction, and then the temperature was lowered to room temperature.The mixture was separated using water and ethyl acetate, and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulphate and concentrated in vacuo to give crude product.The crude product prepared from the above was dissolved again in methanol (10 ml) at 0 C. Sodium borohydride (250 mg, 6.6 mmol) was slowly added dropwise and the temperature was raised to room temperature. After 24 hours of reaction, the mixture was diluted with dichloromethane and water. The diluted solution was extracted, separated and washed with a saturated aqueous sodium chloride solution three times. It was then dried over magnesium sulfate, concentrated in vacuo, and purified by flash column chromatography on silica gel, 10-50% ethyl acetate / hexane to finally yield the desired compound.

Reference： [1]Patent: KR2018/125090,2018,A .Location in patent: Paragraph 0282; 0293-0297

63
[ 1836-62-0 ]
trans-3-phenyl-1,4-dioxane-2-carboxylic acid [ No CAS ]
trans-N-(2-(2-methoxyphenoxy)ethyl)-3-phenyl-1,4-dioxane-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: Et3N (4.3 mmol) and 97% EtOCOCl (4.3 mmol) in dry CHCl3(25 mL) were added to a solution of the suitable carboxylic acid 24a,24b or 25 (4.3 mmol) at 0 C. After 30 min at 0 C under stirring asolution of the suitable amine (2-phenoxyethanamine, 2-(2-methoxyphenoxy)ethanamine [37], 2-(2,6-dimethoxyphenoxy)ethanamine [38], or 1-(2-methoxyphenyl)piperazine) (4.3 mmol)in dry CHCl3 (10 mL) was added and the reaction mixture was left atroom temperature for 3 h. The solution was washed with 2 N HCl and 2 N NaOH. The organic layer was dried over Na2SO4. After evaporation of the solvent the residue was purified by column chromatography eluting with cyclohexane/EtOAc (7:3).

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 461 - 473

64
[ 1836-62-0 ]
cis-3-phenyl-1,4-dioxane-2-carboxylic acid [ No CAS ]
cis-N-(2-(2-methoxyphenoxy)ethyl)-3-phenyl-1,4-dioxane-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		General procedure: Et3N (4.3 mmol) and 97% EtOCOCl (4.3 mmol) in dry CHCl3(25 mL) were added to a solution of the suitable carboxylic acid 24a,24b or 25 (4.3 mmol) at 0 C. After 30 min at 0 C under stirring asolution of the suitable amine (2-phenoxyethanamine, 2-(2-methoxyphenoxy)ethanamine [37], 2-(2,6-dimethoxyphenoxy)ethanamine [38], or 1-(2-methoxyphenyl)piperazine) (4.3 mmol)in dry CHCl3 (10 mL) was added and the reaction mixture was left atroom temperature for 3 h. The solution was washed with 2 N HCl and 2 N NaOH. The organic layer was dried over Na2SO4. After evaporation of the solvent the residue was purified by column chromatography eluting with cyclohexane/EtOAc (7:3).

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 461 - 473

65
[ 1836-62-0 ]
3,3-diphenyl-1,4-dioxane-2-carboxylic acid [ No CAS ]
N-(2-(2-methoxyphenoxy)ethyl)-3,3-diphenyl-1,4-dioxane-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		General procedure: Et3N (4.3 mmol) and 97% EtOCOCl (4.3 mmol) in dry CHCl3(25 mL) were added to a solution of the suitable carboxylic acid 24a,24b or 25 (4.3 mmol) at 0 C. After 30 min at 0 C under stirring asolution of the suitable amine (2-phenoxyethanamine, 2-(2-methoxyphenoxy)ethanamine [37], 2-(2,6-dimethoxyphenoxy)ethanamine [38], or 1-(2-methoxyphenyl)piperazine) (4.3 mmol)in dry CHCl3 (10 mL) was added and the reaction mixture was left atroom temperature for 3 h. The solution was washed with 2 N HCl and 2 N NaOH. The organic layer was dried over Na2SO4. After evaporation of the solvent the residue was purified by column chromatography eluting with cyclohexane/EtOAc (7:3).

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 461 - 473

66
[ 109-09-1 ]
[ 1836-62-0 ]
N‑(2‑(2‑methoxyphenoxy)ethyl)‑N‑(pyridin‑2‑yl)pyridin‑2‑amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In methanol; at 25℃; for 72h;Inert atmosphere; Schlenk technique;	General procedure: A solution of 2-phenoxyethylamine (1.31 mL, 10 mmol) in methanol (10 mL) was added to a solution of triethylamine(Et3N) (2.76 mL, 20 mmol) in methanol (10 mL) at 0 C. A solution of 2-chloropyridine (3.80 mL, 40 mmol) in methanol(10 mL) was then added at 0 C under N2. After being stirred for 30 min, the reaction mixture was heated to 25 C and stirred for 3 days. Then, the solvent was evaporated under reduced pressure to afford a yellow solid L1 washed with methanol and dried under vacuum.

Reference： [1]Transition Metal Chemistry,2019,vol. 44,p. 681 - 688

67
[ 3678-62-4 ]
[ 1836-62-0 ]
N‑(2‑(2‑methoxyphenoxy)ethyl)‑4‑methyl‑N‑(4‑methylpyridin‑2‑yl)pyridine‑2‑amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine; In methanol; at 25℃; for 72h;Inert atmosphere; Schlenk technique;	General procedure: A solution of 2-phenoxyethylamine (1.31 mL, 10 mmol) in methanol (10 mL) was added to a solution of triethylamine(Et3N) (2.76 mL, 20 mmol) in methanol (10 mL) at 0 C. A solution of 2-chloropyridine (3.80 mL, 40 mmol) in methanol(10 mL) was then added at 0 C under N2. After being stirred for 30 min, the reaction mixture was heated to 25 C and stirred for 3 days. Then, the solvent was evaporated under reduced pressure to afford a yellow solid L1 washed with methanol and dried under vacuum.

Reference： [1]Transition Metal Chemistry,2019,vol. 44,p. 681 - 688

68
[ 1047632-41-6 ]
[ 1836-62-0 ]
3-[(9H-carbazol-4-yl)oxy]-N-[2-(2-methoxyphenoxy)ethyl]propan-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	In acetonitrile; for 5h;Inert atmosphere; Reflux;	General procedure: Corresponding 3-bromopropoxyaryl (5 mmol, 1 equiv) and amines(7.5 mmol, 1.5 equiv) was dissolved in 30 mL CH3CN. The reaction was purged with argon 3 times and stirred at reflux for 5 h, and then the mixture was cooled to room temperature and added AcOEt. Afte rwashing with brine 3 times, the organic layer was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. Purification of the crude residue by column chromatography on silica gel afforded target compounds.

Reference： [1]Bioorganic and medicinal chemistry,2020,vol. 28
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 5111 - 5131
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 5312 - 5329

69
[ 1836-62-0 ]
C₁₇H₁₇ClO₂ [ No CAS ]
2-(2,2-diphenyl-1,3-dioxolan-4-yl)-N-(2-(2-methoxyphenoxy)ethyl)ethan-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium iodide; In 2-methoxy-ethanol; for 24h;Reflux;	General procedure: To a solution of 2-phenoxy-ethylamine (5 eq.) or 2-(2-methoxyphenoxy-)ethylamine (5 eq.) in 2-methoxyethanol(25 mL per mmol of amine) the appropriate aliphatic chloride33-39 (1 eq.) and KI (cat.) was added. The mixturewas refluxed for18-48 h and concentrated. The residue was suspended in CHCl3and washed with 1M NaOH, brine, dried over anhydrous Na2SO4and concentrated. The crude was purified by flash chromatographyto give the titled compound.