Name: 22013-33-8|2,3-Dihydrobenzo[b][1,4]dioxin-6-amine|96%
Brand: Ambeed
SKU: A209738
Price: 6.0 USD
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1
[ 16498-20-7 ]
[ 22013-33-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With maghemite-palladium nanocomposite; hydrogen In ethanol; ethyl acetate at 30℃; for 0.0125h;
91%	With water at 20℃; Inert atmosphere; chemoselective reaction;
87%	With hydrogen In ethanol; water at 40℃; for 2h;	2.7. Catalytic test General procedure: To evaluate the catalytic performance of Pd/ Cu-BDC MOF- Perlite, nitoarene (1 mmol) and Pd/ Cu-BDC MOF-Perlite (0.02 g) were charged in a reaction vessel containing H 2 O: EtOH (1:1) mix- ture (8 mL). Then, the reaction mixture was stirred at 40 °C and hydrogen gas with pressure of 1 bar was purged. The reaction was monitored via TLC and upon completion of the reaction, the mix- ture was cooled and Pd/ Cu-BDC MOF-Perlite was separated. The product was achieved after evaporation of the solvent and the re- covered catalyst was washed several times with EtOH and dried in oven at 80 °C overnight. The yields of the hydrogenation reactions have been estimated via GC analysis.

84%	With phenylsilane; C₇₈H₈₈Cl₂N₄Ni In tetrahydrofuran at 60℃; for 1h; Inert atmosphere; chemoselective reaction;
76.3%	With palladium on activated charcoal; hydrogen In tetrahydrofuran at 40 - 45℃; for 10h; Autoclave;	1.3 (3) 2L autoclave was charged with 102.0g (0.54mol) of Intermediate 2,3.7g palladium on carbon catalyst, 700 g of the of THF, warmed to 40 ~ 45 , maintaining the internal pressure of hydrogen charging 5 ~ 7atm 10h reaction, the reaction completion, said palladium-carbon catalyst was filtered off, the filtrate removal of THF, to give 62.2 g of red-brown oily liquid, namely intermediate 3, yield: 76.3%
32%	With nickel; hydrazine In ethanol Heating;
	With hydrogenchloride; acetone Electrolysis;
	With ethanol; palladium Hydrogenation;
	With hydrogenchloride; iron
94 %Chromat.	With formic acid; triethylamine In tetrahydrofuran at 100℃; for 15h; Inert atmosphere; Sealed tube; chemoselective reaction;
190 mg	With palladium on activated charcoal; hydrogen In methanol at 20℃;	35.3 Step 3: Synthesis of 2,3 -dihydrobenzo[b] [1 ,4]dioxin-6-amine (Compound 28) Compound 27 (200mg), methanol (2OmL), and Pd/C (100mg) catalysts were put into a 5OmL of one-necked flask, and fully stirred to dissolve. And then hydrogen gas was bubbled into the reaction mixture at room temperature and reacted overnight. After, the reaction mixture wasfiltered and the filtrate was concentrated in vacuum to afford 190mg Compound 28, which was used in the next step without further purification. MS: 152 (M+H).

Reference： [1]Rathi, Anuj K.; Gawande, Manoj B.; Ranc, Vaclav; Pechousek, Jiri; Petr, Martin; Cepe, Klara; Varma, Rajender S.; Zboril, Radek [Catalysis science and technology, 2016, vol. 6, # 1, p. 152 - 160]
[2]Dey, Raju; Mukherjee, Nirmalya; Ahammed, Sabir; Ranu, Brindaban C. [Chemical Communications, 2012, vol. 48, # 64, p. 7982 - 7984]
[3]Koohestani, Fatemeh; Sadjadi, Samahe [Journal of Molecular Structure, 2022, vol. 1250]
[4]Vijaykumar, Gonela; Mandal, Swadhin K. [Dalton Transactions, 2016, vol. 45, # 17, p. 7421 - 7426]
[5]Current Patent Assignee: VALIANT CO., LTD. - CN105859678, 2016, A Location in patent: Paragraph 0078; 0079
[6]Location in patent: scheme or table Panchenko; Fedorova; Perevalov; Jonusauskas; Fedorov [Russian Chemical Bulletin, 2009, vol. 58, # 6, p. 1233 - 1240]
[7]Heertjes; Revallier [Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 262,267] Heertjes; Dahmen [Recueil des Travaux Chimiques des Pays-Bas, 1943, vol. 62, p. 620,621]
[8]Renzi et al. [Gazzetta Chimica Italiana, 1956, vol. 86, p. 1362,1364]
[9]Heertjes; Revallier [Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 262,267] Nishino et al. [Yuki Gosei Kagaku Kyokaishi, 1959, vol. 17, p. 166,169][Chem.Abstr., 1959, p. 11280]
[10]Jagadeesh, Rajenahally V.; Banerjee, Debasis; Arockiam, Percia Beatrice; Junge, Henrik; Junge, Kathrin; Pohl, Marga-Martina; Radnik, Jörg; Brückner, Angelika; Beller, Matthias [Green Chemistry, 2015, vol. 17, # 2, p. 898 - 902]
[11]Current Patent Assignee: BETTA PHARMACEUTICALS CO LTD - WO2015/51766, 2015, A1 Location in patent: Page/Page column 55

2
[ 79-04-9 ]
[ 22013-33-8 ]
[ 42477-07-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;	General procedure D: Synthesis of acetamides 3n-w General procedure: To a solution of a substituted aniline 24n-w (1 equiv.) and triethylamine (1.2 equiv.) in CH2Cl2 at 0 C was added chloroacetyl chloride (1.2 equiv.) over 15 minutes and the reaction stirred for 1 h at 0 C, followed by 2 h at r.t.. The salt was filtered off and washed with CH2Cl2 and EtOAc. This was dissolved in 1:1 MeOH/H2O, basified with sat. NaHCO3 and extracted with CH2Cl2 followed by drying with Na2SO4. The solvent was removed in vacuo to give the acetamides 3n-w.
76.4%	Stage #1: 6-amino-3,4-benzodioxane With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: chloroacetyl chloride In acetone at 0 - 20℃; for 3h;	5.1.1 General procedures for Scheme 1 General procedure: Step 1. To the stirred solution of Aniline (1.0 equiv) in acetone was added K2CO3 (1.2 equiv.) at RT and stirred for 30min. Chloroacetyl chloride/substituted acetylchloride (1.1 equiv.) was then added at 0°C and stirred for additional 3h at room temperature. After completion of the reaction (monitored by TLC), volatiles were removed on rotary evaporator and ethyl acetate was added. Organic layer were washed with water, aq NaHCO3, brine. Organic layer was dried over sodium sulfate and evaporated on rotary evaporator and the crude residue was purified by flash chromatography to give the desired product.
70%	With triethylamine In dichloromethane at 0 - 20℃;	3 j0599J B. Preparation of Chloroacetamide Compounds General procedure: j0600J A solution of an amine (1 eq., 0.2 mM) in dichloromethane was prepared, and then cooled to 0°C. Chloroacetyl chloride (1.2 eq.) was added to the prepared solution followed by addition of triethylamine (1.2 eq.). The resulting solution was warmed to room temperatureand stirred overnight. The final solution was then washed with brine. After removing thesolvent, the crude product was purified to afford the corresponding acrylamide. In some cases, further purification may be needed, for example, recrystallization.:_ Example 3: Preparation of 2-Chloro-N-(2,3-dihydrobenzo jf3J 11 ,4J dioxin-6-yl)acetamide j0601J The procedure B of Example 2 was repeated with 1,4-benzodioxan-6-amine (1.51 g,10 mmol); product was obtained after silica gel chromatography (40% ethyl acetate inhexanes) in 70% yield as an off-white solid (1.59 g). ‘HNIVIR (400IVIHz, CDC13): 8.11 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 2.4, 8.7 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 4.25 (s, 4H), 4.17 (s, 2H). ‘3CNIVIR(100IVIHz, CDC13): 163.8, 143.7, 141.3, 130.4, 117.5, 114.0,110.2, 64.5, 64.4, 43.0. HRMS (+ESI): calculated for C,0H,,C1NO3 (M+1): 228.0422; found:228.0421.

With acetone

Reference： [1]Haverkate, Natalie A.; van Rensburg, Michelle; Kumara, Sisira; Reynisson, Jóhannes; Leung, Euphemia; Pilkington, Lisa I.; Barker, David [Bioorganic and Medicinal Chemistry, 2021, vol. 37]
[2]Gangar, Mukesh; Goyal, Sandeep; Raykar, Digambar; Khurana, Princy; Martis, Ashwita M.; Goswami, Avijit; Ghoshal, Ishani; Patel, Ketul V.; Nagare, Yadav; Raikar, Santosh; Mukherjee, Apurba; Cyriac, Rajath; Paquin, Jean-François; Kulkarni, Aditya [Bioorganic Chemistry, 2022, vol. 119]
[3]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2018/144871, 2018, A1 Location in patent: Paragraph 0599; 0600; 0601
[4]Renzi et al. [Gazzetta Chimica Italiana, 1956, vol. 86, p. 1362,1364]

3
[ 22013-33-8 ]
[ 10288-72-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydrogencarbonate; sodium nitrite; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; diethyl ether; sulfuric acid;	EXAMPLE 3 Preparation of (R,S)-1,4-Dioxan[2,3-g]-2,3-dihydro-1H-pyrrolo[2,1-b][1,3]benzoxazine-11(3aH)-one (Compound III; per generic formula: {R1 +R2 }=--O--CH2 CH2 --O--, R3 =H, n=2) STR8 The synthesis of 6-hydroxy-1,4-benzodioxan was performed by first converting 1,4-benzodioxan-6-amine (24.0 g, 0.159 mol) into the bisulfate salt in 200 mL 33% H2 SO4. A chilled suspension of the bisulfate salt was then added to a solution of NaNO2 (14 g; 0.165 mol) in 100 mL of ice water with vigorous stirring. The reaction was allowed to proceed for 20 minutes with addition of ice. The resulting solution of the diazotized amine was slowly poured into 1 L of boiling 10% H2 SO4 over a 15-minute period, then allowed to cool to 20 C. and extracted three times with 100 mL portions of CH2 Cl2. The combined organic layers were washed three times each with 1N HCl, 5% NaHCO3, and saturated NaCl solution. The solution was then dried over Na2 SO4 and the solvent was removed on a rotary evaporator. The resulting viscous oil was dissolved in 250 mL of diethyl ether, allowed to stand overnight, and filtered to remove 1 g of dark solid.

Reference： [1]European Journal of Medicinal Chemistry,1989,vol. 24,p. 619 - 622
[2]Journal of the American Oil Chemists' Society,1956,vol. 33,p. 414
[3]Journal of the Chemical Society,1957,p. 3445
[4]European Journal of Medicinal Chemistry,1990,vol. 25,p. 45 - 51
[5]Tetrahedron Letters,1988,vol. 29,p. 2665 - 2666
[6]Patent: US5736543,1998,A

4
[ 107-14-2 ]
[ 22013-33-8 ]
[ 149809-31-4 ]

Yield	Reaction Conditions	Operation in experiment
36.5%	With aluminium trichloride; boron trichloride In dichloromethane at 40℃; for 16h;
35.2%	With aluminium trichloride; boron trichloride In dichloromethane for 16h; Heating;
17%	Stage #1: 6-amino-3,4-benzodioxane With boron trichloride - methyl sulfide complex In 1,2-dichloro-ethane at 0℃; Inert atmosphere; Stage #2: chloroacetonitrile With aluminum (III) chloride In 1,2-dichloro-ethane at 0℃; Inert atmosphere; Reflux; Stage #3: With hydrogenchloride; water In 1,2-dichloro-ethane

	With gallium(III) trichloride; boron trichloride 1.) CH₂Cl₂, room temperature, overnight, 2.) CH₂Cl₂, reflux, overnight; Yield given. Multistep reaction;
	With boron trichloride In hexane; dichloromethane; water	1-(7-Amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (Formula (VII)) 1-(7-Amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (Formula (VII)) A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 1 M boron trichloride in methylene chloride (4 L, 4.00 mol). The solution is cooled to -20° C., then 1,4-benzodioxane-6-amine (500 g, 3.31 mol) available from the Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, is added as a solution in methylene chloride (250 mL) over 30 min. The temperature increases to 10° C. during the addition and is subsequently recooled back to -10° C. Chloroacetonitrile (250 mL, 3.95 mol) is added over 5 min, followed by addition of aluminum chloride (485 g, 3.64 mol). The resulting dark mixture is heated at reflux for 24 h. The reaction mixture is cooled to ambient temperature and transferred to two 20-L separatory funnels, each containing 10 L of water. After being stirred for 2.5 h, the organic layer is separated and the aqueous layer is extracted with methylene chloride (4*4 L). The combined organic layers are washed with brine (4 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant thick brown slurry is successively treated with 600 mL of methylene chloride and 2 L of hexane. The mixture is stirred at 0° C. for 30 min. The precipitate is collected by filtration on a Buchner funnel, washed with hexane (1 L) and dried in vacuo. at 30° C. yielding 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone as a yellow powder.
	With boron trichloride In hexane; dichloromethane; water	13 7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin dihydrochloride EXAMPLE 13 7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin dihydrochloride A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 1 M boron trichloride in methylene chloride (4 L, 4.00 mol). The solution is cooled to -20° C., then 1,4-benzodioxane-6-amine (500 g, 3.31 mol) available from the Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, is added as a solution in methylene chloride (250 mL) over 30 min. The temperature increases to 10° C. during the addition and is subsequently re-cooled back to -10° C. Chloroacetonitrile (250 mL, 3.95 mol) is added over 5 min, followed by addition of aluminum chloride (485 g, 3.64 mol). The resulting dark mixture is heated at reflux for 24 h. The reaction mixture is cooled to ambient temperature and transferred to two 20-L separatory funnels, each containing 10 L of water. After being stirred for 2.5 h, the organic layer is separated and the aqueous layer is extracted with methylene chloride (4*4 L). The combined organic layers are washed with brine (4 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant thick brown slurry is successively treated with 600 mL of methylene chloride and 2 L of hexane. The mixture is stirred at 0° C. for 30 min. The precipitate is collected by filtration on a Buchner funnel, washed with hexane (1 L) and dried in vacuo. at 30° C. yielding 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone as a yellow powder.
	With gallium(III) trichloride; boron trichloride In dichloromethane for 24h; Heating;

Reference： [1]Luzzio, Michael J.; Besterman, Jeffrey M.; Emerson, David L.; Evans, Michael G.; Lackey, Karen; et al. [Journal of Medicinal Chemistry, 1995, vol. 38, # 3, p. 395 - 401]
[2]Miao, Zhenyuan; Sheng, Chunquan; Zhang, Wannian; Ji, Haitao; Zhang, Jing; Shao, Luecheng; You, Liang; Zhang, Min; Yao, Jianzhong; Che, Xiaoyin [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1493 - 1510]
[3]Location in patent: experimental part Cinelli, Maris A.; Morrell, Andrew E.; Dexheimer, Thomas S.; Agama, Keli; Agrawal, Surbhi; Pommier, Yves; Cushman, Mark [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 15, p. 5535 - 5552]
[4]Fang, Francis G.; Bankston, Donald D.; Huie, Edward M.; Johnson, M. Ross; Kang, Myung-Chol; LeHoullier, Craig S.; Lewis, George C.; Lovelace, Thomas C.; Lowery, Melissa W.; McDougald, Darryl L.; Meerholz, Clive A.; Partridge, John J.; Sharp, Matthew J.; Xie, Shiping [Tetrahedron, 1997, vol. 53, # 32, p. 10953 - 10970]
[5]Current Patent Assignee: UNIVERSITY OF NORTH CAROLINA SYSTEM - US6063923, 2000, A
[6]Current Patent Assignee: UNIVERSITY OF NORTH CAROLINA SYSTEM - US5491237, 1996, A
[7]Grillet, Francois; Baumlova, Barbora; Prevost, Gregoire; Constant, Jean-Francois; Chaumeron, Sophie; Bigg, Dennis C.H.; Greene, Andrew E.; Kanazawa, Alice [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 2143 - 2146]

5
[ 62140-78-7 ]
[ 22013-33-8 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 5241 - 5250

6
[ 541-41-3 ]
[ 22013-33-8 ]
ethyl N-(2,3-dihydro-1,4-benzodioxin-6-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine In tetrahydrofuran at 20℃; for 0.5h;
95%	With triethylamine In tetrahydrofuran at 20℃; for 4h;
81%	With potassium carbonate In dichloromethane at 20℃; for 1h;

	With triethylamine In tetrahydrofuran at 20℃; for 0.5h;
	With triethylamine In tetrahydrofuran at 20℃; for 0.5h;
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h;	[mt-1 .4] Ethyl N-(2 ,3-dihydro-1 ,4-benzodioxin-6-yl)carbamate: To a solution of 2,3-dihydro-1,4-benzodioxin-6-amine (500 mg, 3.31 mmol) in DCM (10 mL) were added ethyl chloroformate (346 pL, 3.64 mmol) and DIPEA (1.2 mL, 6.62 mmol), and the mixture stirred at room temperature for 3 h.The solution was partitioned between DCM (50 mL) and 1.0 M aq. HC1 (50 mL) . The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na2504, filtered and the solvent evaporated under reduced pressure to yield the title compound as a dark oil: UPLC-MS: tR = 1.82 mm (generic method); MS (ESI) m/z calcd for CflH,4N04 (M+H): 224.1, found:224.1.

Reference： [1]Chilin, Adriana; Conconi, Maria Teresa; Marzaro, Giovanni; Guiotto, Adriano; Urbani, Luca; Tonus, Francesca; Parnigotto, Pierpaolo [Journal of Medicinal Chemistry, 2010, vol. 53, # 4, p. 1862 - 1866]
[2]Mahal, Katharina; Resch, Marcus; Ficner, Ralf; Schobert, Rainer; Biersack, Bernhard; Mueller, Thomas [ChemMedChem, 2014, vol. 9, # 4, p. 847 - 854]
[3]Mateu; Capilla; Harrak; Pujol [Tetrahedron, 2002, vol. 58, # 26, p. 5241 - 5250]
[4]Conconi, Maria Teresa; Marzaro, Giovanni; Urbani, Luca; Zanusso, Ilenia; Di Liddo, Rosa; Castagliuolo, Ignazio; Brun, Paola; Tonus, Francesca; Ferrarese, Alessandro; Guiotto, Adriano; Chilin, Adriana [European Journal of Medicinal Chemistry, 2013, vol. 67, p. 373 - 383]
[5]Marzaro, Giovanni; Castagliuolo, Ignazio; Schirato, Giulia; Palu', Giorgio; Dalla Via, Martina; Chilin, Adriana; Brun, Paola [European Journal of Medicinal Chemistry, 2016, vol. 115, p. 416 - 425]
[6]Current Patent Assignee: FONDAZIONE PER LA RICERCA SULLA FIBROSI CISTICA ON; ISTITUTO ITALIANO DI TECNOLOGIA; ISTITUTO GIANNINA GASLINI - WO2018/167695, 2018, A1 Location in patent: Page/Page column 60; 61

7
[ 108-24-7 ]
[ 22013-33-8 ]
[ 63546-19-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	at 20℃; for 3h;	6.1 Example 6: Preparation of 2-[[4-(3-methoxylpropoxy)-3-methylipyridin-2-yl]methylsulfinyl]-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazole(Compound 6) Step 1: Preparation of 6-acetylamino-2,3-dihydrobenzo[b][1,4]dioxane [Show Image] 6-amino-2,3-dihydrobenzo[b][1,4]dioxane (9 g, 60 mmol) and acetic anhydride (150 mL) were stirred at room temperature for 3 h, added to ice, extracted with dichloromethane (300 mL). The organic layer was dried, filtered, concentrated under vacuum to obtain a product (10.6 g, 91 %).
87%	at 140℃; for 8h;
	With acetic acid Inert atmosphere; Industrial scale;

With pyridine at 5 - 60℃; for 0.75h;

8 Acetanilide (2): A solution of amine 1 (1 eq) in pyridine was cooled to 5°C and acetanhydride (1.25 eq) was added dropwise with stirring. The mixture was stirred for 45 min at 60°C and poured into ice-water and stirred for 30 min at 0-10°C. The precipitate was filtered off, washed with water (100 ml) and dried.

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - EP2532665, 2012, A1 Location in patent: Page/Page column 29
[2]Mateu; Capilla; Harrak; Pujol [Tetrahedron, 2002, vol. 58, # 26, p. 5241 - 5250] Vazquez; Romero; Pujol [Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 949 - 956]
[3]Kowalczyk, Bruce A.; Robinson III, James; Gardner, John O. [Organic Process Research and Development, 2001, vol. 5, # 2, p. 116 - 121]
[4]Current Patent Assignee: GAUSE INST OF NEW ANTIBIOTICS; MEDICAL UNIVERSITY OF INNSBRUCK; UNIVERSITY OF INNSBRUCK - WO2014/207213, 2014, A1 Location in patent: Page/Page column 53

8
[ 100-52-7 ]
[ 22013-33-8 ]
N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenylmethanimine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In acetonitrile Inert atmosphere; Schlenk technique; Molecular sieve;
100%	In ethanol for 1h; Sonication;	General Procedure for the Synthesis of the Starting Imines 6 General procedure: To a solution of benzylamine (1.0 equiv) in EtOH (7.8 mL per mmol) was added the corresponding aldehyde (1.0 equiv). The reaction was sonicated for 60 min before being concentrated in vacuo. Water was added and the organics were extracted with DCM, combined, dried over MgSO4, filtered and concentrated in vacuo to afford the desired pure imine.
88%	In ethanol for 3h; Reflux;	General procedure for imine preparation General procedure: 1,4-benzodioxan-6-amine (1 mmol) was heated at reflux withthe appropriate aldehyde (1 mmol) in ethanol (5 ml) for 3 h. Thereaction mixture was cooled and then the solvent was removedunder reduced pressure. The obtaining solid product was recrystallizedin ethanol.

	With 8-aminopyrene-1,3,6-trisulfonic acid, trisodium salt In toluene at 120℃; for 24h;
	In methanol at 20℃; Inert atmosphere;
	In neat (no solvent) at 20℃; for 0.5h; Schlenk technique; Molecular sieve; Inert atmosphere;

Reference： [1]Kammer, Lisa Marie; Krumb, Matthias; Spitzbarth, Benjamin; Lipp, Benjamin; Kühlborn, Jonas; Busold, Jonas; Mulina, Olga M.; Terentev, Alexander O.; Opatz, Till [Organic Letters, 2020, vol. 22, # 9, p. 3318 - 3322]
[2]Romero, Eugénie; Oueslati, Saoussen; Benchekroun, Mohamed; D'Hollander, Agathe C.A.; Ventre, Sandrine; Vijayakumar, Kamsana; Minard, Corinne; Exilie, Cynthia; Tlili, Linda; Retailleau, Pascal; Zavala, Agustin; Elisée, Eddy; Selwa, Edithe; Nguyen, Laetitia A.; Pruvost, Alain; Naas, Thierry; Iorga, Bogdan I.; Dodd, Robert H.; Cariou, Kevin [European Journal of Medicinal Chemistry, 2021, vol. 219]
[3]Malayeri, Sina Omid; Abnous, Khalil; Arab, Atefeh; Akaberi, Maryam; Mehri, Soghra; Zarghi, Afshin; Ghodsi, Razieh [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 3, p. 1294 - 1302]
[4]Mateu; Capilla; Harrak; Pujol [Tetrahedron, 2002, vol. 58, # 26, p. 5241 - 5250]
[5]William, Ronny; Wang, Siming; Ding, Feiqing; Arviana, Elise Nerissa; Liu, Xue-Wei [Angewandte Chemie - International Edition, 2014, vol. 53, # 40, p. 10742 - 10746][Angew. Chem., 2014, vol. 126, # 40, p. 10918 - 10922,5]
[6]Bauri, Somnath; Pandey, Vipin K.; Rit, Arnab [Organic and Biomolecular Chemistry, 2020, vol. 18, # 20, p. 3853 - 3857]

9
[ 22013-33-8 ]
[ 62140-78-7 ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 5241 - 5250
[2]Patent: EP2532665,2012,A1

10
[ 13026-23-8 ]
[ 22013-33-8 ]
3-biphenyl-4-yl-<i>N</i>-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-acrylamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 71 - 90

11
[ 874143-25-6 ]
[ 22013-33-8 ]
N-(3-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylamino)pyrazin-2-yl)phenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.8%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 90℃; for 12h;	46.K In a round-bottomed flask provided with stirring and an argon atmosphere, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 6-amino-3,4-benzodioxane (45 mg, 0.29 mmol), Pd(0)2 dba3 (tris(dibenzylidene)acetone dipalladium(0)) (9 mg, 0.01 mmol), 2,2'-Bis(diphenylphosphino)-1,1'-binaphtyl (BINAP) (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol), and toluene (5 mL) were reacted at 90° C. for 12 hours. When the flask cooled down the solvent was evaporated under vacuo. The resulting solid was washed with 20 mL ethyl acetate and filtered. The volume was reduced to 1.5 mL and 0.5 mL of dichloromethane were added.
	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 4h; Heating;

Reference： [1]Current Patent Assignee: THE WELLCOME TRUST LIMITED - US2008/15191, 2008, A1 Location in patent: Page/Page column 72
[2]Niculescu-Duvaz, Ion; Roman, Esteban; Whittaker, Steven R.; Friedlos, Frank; Kirk, Ruth; Scanlon, Ian J.; Davies, Lawrence C.; Niculescu-Duvaz, Dan; Marais, Richard; Springer, Caroline J. [Journal of Medicinal Chemistry, 2006, vol. 49, # 1, p. 407 - 416]

12
[ 6280-89-3 ]
[ 22013-33-8 ]
[ 891191-80-3 ]

Reference： [1]European Journal of Medicinal Chemistry,2006,vol. 41,p. 340 - 352

13
[ 192869-80-0 ]
[ 22013-33-8 ]
[ 859825-28-8 ]

Yield	Reaction Conditions	Operation in experiment
		A. 7-Benzyl-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine The title compound was prepared using the general procedure set forth in Example 2, above, using 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.32 mL, 2.63 mmol) and <strong>[192869-80-0]7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine</strong> (0.621 g, 2.39 mmol) in acetonitile (3 mL). The title compound was obtained as a brown solid (0.756 g). MS: M+H=375.

Reference： [1]Patent: US2005/277643,2005,A1

14
[ 22013-33-8 ]
[ 171361-65-2 ]
[ 1010814-77-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	In ethanol; water;Heating / reflux;	A solution of l-oxa-spiro[2.5]octane-6-carboxylic acid ethyl ester obtained according to Tetrahedron, 1995, 51, 10259-80, (4.5 g, 24.4 mmol) and 2,3-dihydro-benzo[l,4]dioxin- 6-ylamine (3.7 g, 24.4 mmol) in EtOH/water (9:1, 100 ml) was heated at reflux overnight. The mixture was concentrated in vacuo and purified by chromatography (Hex:EA 2:1) to give the title amino alcohols (7.7 g, 94% yield) as an orange oil.1H NMR (DMSO d6) delta: 6.60-6.50 (m, IH); 6.20-6.10 (m, 2H); 5.90-5.70 (m, IH); 4.10-3.90 (m, 6H); 3.90-3.80 (m, 2H); 2.40-2.20 (m, IH); 1.80-1.40 (m, 7H), 1.40-1.20 (m, 2H); 1.10-1.00 (m, 4H).

Reference： [1]Patent: WO2008/26172,2008,A1 .Location in patent: Page/Page column 56

15
[ 233770-01-9 ]
[ 22013-33-8 ]
5-bromo-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 150℃; for 0.166667h;Microwave irradiation;	Example 9; (A) 5-BROMO-N-(2, 3-DIHYDROBENZO [B] [1, 4] DIOXIN-6-YL) PYRIDIN-3-AMINE. AMIXTURE of <strong>[233770-01-9]3-bromo-5-iodopyridine</strong> (340 mg, 1. 19 MMOL, Aldrich), 6-aminobenzodioxane (300 mg, 1. 99 mmol, Aldrich), Pd2dba3 (20 mg, 0. 022 MMOL), L, l'-bis (diphenyl- PHOSPHINO) Ferrocene (DPPF) (20 mg, 0. 036 MOL), sodium t-butoxid (140 mg, 1.44 mmol) and TOLUENE (4 ML) was heated at 150 C for 10 min in A microwave. The solvent was removed under reduced pressure and the resulting mixture was purified by silica gel chromatography (1-3% MEOH/DCM) to give 5-BROMO-N- (2, 3-dihydrobenzo [B] [1, 4] dioxin-6-yl)pyridin-3-amine as A light yellow solid [MS (ESI, pos. ion) ? M/Z : 307, 309 (M+1)].

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3497 - 3514
[2]Patent: WO2005/33105,2005,A2 .Location in patent: Page/Page column 94

16
[ 659729-09-6 ]
[ 22013-33-8 ]
C₁₉H₁₄F₃N₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3497 - 3514

17
[ 122-05-4 ]
[ 22013-33-8 ]
C₂₂H₁₈N₄O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5063 - 5067

18
[ 13799-90-1 ]
[ 22013-33-8 ]
C₂₄H₁₈Cl₂N₂O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5063 - 5067

19
[ 605-70-9 ]
[ 22013-33-8 ]
C₂₈H₂₂N₂O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5063 - 5067

20
[ 22013-33-8 ]
[ 368839-12-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-Bromosuccinimide; sulfuric acid In tetrahydrofuran at -78 - 20℃; for 1h;	4.a A solution of 2, 3-dihydro-benzo [1, 4] dioxin-6-ylamine (1 g, 6.6 mmol) in tetrahydrofuran (15 ml) was cooled to-78 deg C then treated with 1 drop of concentrated sulphuric acid followed by N-bromosuccinimide (1.2g, 6.6. mmol). The mixture was allowed to warm to room temperature over 1 hour then evaporated. The residue was dissolved in ether, washed with water then brine, dried and evaporated to afford an oil (1. 4 g, 93%). MS (+ve ion electrospray) m/z 231 (MH+).
92%	Stage #1: 6-amino-3,4-benzodioxane With N-Bromosuccinimide; sulfuric acid In tetrahydrofuran at -78℃; for 1.5h; Stage #2: With sodium carbonate In tetrahydrofuran	10d.a Preparation 10d; Preparation of 9-Chloro-10-vinyl-2,3-dihydro-[1 ,4]dioxino[2,3-f\|quinoline; a) 7-Bromo-2,3-dihydro-benzo[1 ,4]dioxin-6-ylamine; A solution of 2,3-dihydro-benzo[1 ,4]dioxin-6-ylamine (80 g, 530 mmol, 1 eq) in tetrahydrofuran (1000 mL) at -780C was treated with concentrated sulfuric acid (50 drops) then N-bromosuccinimide (94.2 g, 530 mmol, 1 eq) was added over 0.5 hour. After the addition the mixture was stirred at -780C for 1 hour then treated with solid sodium carbonate (12 g, 113 mmol, 0.21 eq). The mixture was evaporated and the residue partitioned between ether and water. The organic extract was dried, filtered and evaporated to give to oil that was chromatographed on silica gel eluting with dichloromethane to afford oil (141 g, 92%). LC/MS (ES) m/z 230 (MH+ 91%); 1 H-NMR (400 MHz1 d6- DMSO), 6.85 (1 H, s, CHCNH2 ), 6.34 (1 H1S1CHCBr), 4.79 (2H1 s, NH2), 4.16 (4H, dd, J = 16, 2 x (CH2O))

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/2490, 2004, A2 Location in patent: Page/Page column 48
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/2047, 2006, A2 Location in patent: Page/Page column 81

21
[ 1204-28-0 ]
[ 22013-33-8 ]
1,3-dioxo-1,3-dihydro-isobenzofuran-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dichloro-benzene; at 150℃; for 2h;	A mixture of trimellitic anhydride chloride (2.1 g, 9.97 mmol, Aldrich) and 1,4-benzodioxan-6-amine (1.5 g, 9.98 mmol, Aldrich) in dichlorobenzene (20 mL) was heated at 150 C. with stirring for 2 h. The reaction mixture was left to reach room temperature during which an yellow solid precipitated. The solid was filtered, washed with dichlorobenzene (20 mL) and dichloromethane (20 mL), and dried in vacuo to give the title compound as an yellow amorphous solid. MS (ESI, pos. ion) m/z: 326.5 (M+1).

Reference： [1]Patent: US2005/165046,2005,A1 .Location in patent: Page/Page column 13

22
[ 3282-30-2 ]
[ 22013-33-8 ]
[ 301307-05-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 15 - 45℃; for 3h;	1 Step 1 - N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2,2-dimethyl-propanamide To a solution of 2,3-dihydro-1,4-benzodioxan-6-amine (20.0 g, 132 mmol, CAS 22013-33-8) and diisopropylethylamine (20.5 g, 158 mmol) in acetonitrile (100 mL) was added 2,2-dimethylpropanoyl chloride (17.5 g, 145 mmol) and the reaction mixture was stirred at 15 °C for 0.5 hrs. Then the reaction mixture was stirred at 45 °C for 2.5 hrs. On completion, the reaction mixture was concentrated in vacuo and the residue was diluted with 500 mL of DCM. The organic layer was separated and washed with 1N HCl solution until the pH=6. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with MTBE (500 mL) to give the title compound (30.0 g, 96% yield) as a white solid.1H NMR (400MHz, CDCl3) δ = 7.20 (br. s., 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 2.4, 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.29 - 4.21 (m, 4H), 1.31 (s, 9H).
	With triethylamine In diethyl ether at 12 - 16℃; for 0.166667h;	140.a To a solution OF 22. 5 g (149 MMOL) 2,3-dihydro-benzo [1,4] dioxin-6-ylamine and 25 mi (179 MMOL) triethylamine in 1 I diethyl ether is added at 12°C within 10 minutes 20 ml (164 MMOL) pivaloyl chloride dissolved in 250 ml diethyl ether. The temperature is kept between 12-16°C. The reaction mixture is stirred at room temperature for 1 hour. Then it is washed with 2 x with 300 ml water, 2 x with 150 ml 1 N HCI and 2 x with brine, dried with NA2SO4 and partially evaporated to A volume of 80 ml. This leads to a suspension. Hexane is added and the solid is filtered to give N- (2, 3-Dihydro-benzo [1,4] DIOXIN-6-YL)-2, 2-dimethyl-propionamide
	With N-ethyl-N,N-diisopropylamine In acetonitrile

With triethylamine In dichloromethane at 0 - 20℃; for 10h; Inert atmosphere;

Reference： [1]Current Patent Assignee: RAZE THERAPEUTICS - WO2018/106636, 2018, A1 Location in patent: Paragraph 00270
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2005/26158, 2005, A1 Location in patent: Page/Page column 34
[3]Rakitina, Tatiana V.; Zeifman, Alexey A.; Titov, Ilya Yu.; Svitanko, Igor V.; Lipkin, Aleksey V.; Stroylov, Viktor S.; Stroganov, Oleg V.; Novikov, Fedor N.; Chilov, Ghermes G. [Mendeleev Communications, 2012, vol. 22, # 6, p. 287 - 289]
[4]Shi, Yang; Liu, Jiahui; Yang, Yudong; You, Jingsong [Chemical Communications, 2019, vol. 55, # 38, p. 5475 - 5478]

23
[ 100-52-7 ]
[ 22013-33-8 ]
N-(2,3-dihydro-1,4-benzodioxin-6-yl)benzylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium tris(acetoxy)borohydride In dichloromethane; acetic acid at 20℃; for 2h;	73.73a To a solution of benzaldehyde (1.00 mL, 9.90 mmol) and 3, 4-ethylenedioxy aniline (1.50 g, 9.90 mmol) in CH2Cl2 (25.0 mL) was added sodium triacetoxyborohydride (2.30 g, 10.9 mmol) and glacial acetic acid (0.50 mL, 9.90 mmol). The mixture was stirred 2 h at ambient temperature, quenched with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over MgSU4, filtered, and concentrated in vacuo to afford the title compound as a dark oil (2.40 g, 99%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.30 - 7.35 (m, 2 H), 7.23 - 7.30 (m, 2 H), 7.15 - 7.23 (m, 1 H), 6.58 (d, J=8.6 Hz, 1 H), 6.19 (d, J=2.5 Hz, 1 H), 6.16 (q, J=2.6 Hz, 1 H), 4.19 (s, 2 H), 4.10 - 4.14 (m, 2 H), 4.05 - 4.09 (m, 2 H). MS(ES+) m/e 242 [M+H]+.
	Multi-step reaction with 2 steps 1: neat (no solvent) / 0.5 h / 20 °C / Schlenk technique; Molecular sieve; Inert atmosphere 2: 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane / neat (no solvent) / 24 h / 20 °C / Schlenk technique; Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/38571, 2007, A2 Location in patent: Page/Page column 65
[2]Bauri, Somnath; Pandey, Vipin K.; Rit, Arnab [Organic and Biomolecular Chemistry, 2020, vol. 18, # 20, p. 3853 - 3857]

24
[ 501-53-1 ]
[ 22013-33-8 ]
[ 950824-97-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydrogencarbonate In water; acetone at 0 - 20℃; for 2h;	39.39.i Example 39 : 4-hydr oxy-4- [2-(6-methoxy- [1,5] naphthyridin-4-yl)-ethyl] - cyclohexanecarboxylic acid (2,3-dihydro-benzo[l,4]dioxin-6-yl)-methyl-amide:39.i. (2, 3-dihydro-benzo [ 1 , 4] dioxin-6-yl)-carbamic acid benzyl ester.A mixture of 2,3-dihydro-benzo[l,4]dioxin-6-ylamine (1.51 g, 10 mmol) and NaHCO3 (1.68 g, 20 mmol) in acetone/water (1 :1, 4O mL) was cooled to 00C and benzyl chloroformate (1.05 eq) was added dropwise. The mixture was stirred at 00C for Ih and at rt for Ih. Acetone was evaporated in vacuo and the mixture partitioned between ether and water. The org. phase was washed with brine, dried over MgSO4 and concentrated to give the benzyl-protected aniline as a colourless solid (2.8 g, 98% yield).1H NMR (DMSO d6) δ: 9.51 (s, 1 H), 7.36 (m, 5 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.85 (dd, J = 8.8, 2.3 Hz, 1 H), 6.72 (m, 1 H), 5.09 (s, 2 H), 4.16 (m, 4 H).
98%	With sodium hydrogencarbonate In water; acetone at 0 - 20℃; for 2h;	39.i 39.i. A mixture of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (1.51 g, 10 mmol) and NaHCO3 (1.68 g, 20 mmol) in acetone/water (1:1, 40 mL) was cooled to 0° C. and benzyl chloroformate (1.05 eq) was added dropwise. The mixture was stirred at 0° C. for 1 h and at rt for 1 h. Acetone was evaporated in vacuo and the mixture partitioned between ether and water. The org. phase was washed with brine, dried over MgSO4 and concentrated to give the benzyl-protected aniline as a colourless solid (2.8 g, 98% yield). 1H NMR (DMSO d6) δ: 9.51 (s, 1H), 7.36 (m, 5H), 7.02 (d, J=2.1 Hz, 1H), 6.85 (dd, J=8.8, 2.3 Hz, 1H), 6.72 (m, 1H), 5.09 (s, 2H), 4.16 (m, 4H).
	With sodium hydrogencarbonate In water; acetone	1.1.iii; C Procedure C: Cbz-Protection of AminesA mixture of amine (1 mmol), sat. aq. NaHCO3 (2 mL) and acetone (2 mL) is treated drop wise with benzyl chloroformate (1.05 eq). After CO2 evolution ceased, the mixture is partitioned between EA and sat. aq. NaHCO3, the org. layer dried over MgSO4 and concentrated under reduced pressure.; 1.iii) (R)-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-oneA solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to procedure C in THF (60 mL) was cooled to -78° C. before the drop wise addition of n-BuLi (5.1 mL of a 2.5 M solution in hex, 1.2 eq). The mixture was stirred at -78° C. for 1 h and then warmed to -15° C. At this temperature (R)-glycidyl butyrate (1.98 g, 1.2 eq) was added drop wise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40° C. until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated. CC (hex/EA 2:1 to 1:1) gave the desired intermediate as beige solid (1.09 g, 41%).1H NMR (DMSO d6) δ: 7.13 (d, J=2.5 Hz, 1H), 6.96 (dd, J=2.5, 8.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 5.16 (t, J=5.8, 1H), 4.70-4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.10-3.90 (m, 1H), 4.80-4.70 (m, 1H), 4.70-4.60 (m, 1H), 4.60-4.50 (m, 1H).

	With sodium hydrogencarbonate In water; acetone	1.iii 1 Hi) (K)-3-(2, 3-Dihydro-benzo[l, 4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one A solution of (2,3-dihydro-benzo[l,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to procedure C in THF (60 mL) was cooled to -78°C before the drop wise addition of n-BuLi (5.1 mL of a 2.5 M solution in hex, 1.2 eq). The mixture was stirred at -78°C for 1 h and then warmed to -15°C. At this temperature (7^-glycidyl butyrate (1.98 g, 1.2 eq) was added drop wise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 400C until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated. CC (hex/EA 2:1 to 1 :1) gave the desired intermediate as beige solid (1.09 g, 41%). 1H NMR (DMSO d6) δ: 7.13 (d, J=2.5 Hz, IH), 6.96 (dd, J=2.5, 8.9 Hz, IH), 6.86 (d, J=8.9 Hz, IH), 5.16 (t, J=5.8, IH), 4.70-4.50 (m, IH), 4.30-4.10 (m, 4H), 4.10-3.90 (m, IH), 4.80-4.70 (m, IH), 4.70-4.60 (m, IH), 4.60-4.50(m, IH).; Procedure C: Cbz-protection of aminesA mixture of amine (1 mmol), sat. aq. NaHCO3 (2 mL) and acetone (2 mL) is treated drop wise with benzyl chloroformate (1.05 eq). After CO2 evolution ceased, the mixture is partitioned between EA and sat. aq. NaHCO3, the org. layer dried over MgSO4 and concentrated under reduced pressure.
	With sodium hydrogencarbonate In water; acetone	C; 1.i Method C: Cbz-protection of anilines:; A mixture of aniline (1 mmol), sat. aq. NaHCO3 (2 mL) and acetone (2 mL) is treated dropwise with Cbz-Cl (1 05 eq). After CO2 evolvement ceased, the mixture is partitioned between EA and aq. bicarbonate, the organic layer dried over MgSO4 and concentrated.; Example 1 : (E)- [fS)-3-(2,3-dihydro-benzo [ 1 ,4] dioxin-6-yl)-2-oxo-oxazolidin- 5-ylmethyl]-3-(6-methoxy-[l,5]naphthyridin-4-yl)-acrylamide:; Li. (R)-3-(2 ,3-dihydro-benzo [ 1,4] dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one:; A solution of (2,3-dihydro-benzo[l,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to method C) in THF (60 rnL) was cooled to -78°C before the dropwise addition of n-BuLi (5.1 mL of a 2.5M solution in hexanes, 1.2 eq.). The mixture was stirred at -78°C for 1 h and then warmed to -15°C. At this temperature (R)- glycidyl butyrate (1.98 g, 1.2 eq.) was added dropwise. The mixture was stirred at rt overnight. CS2CO3 (tip of a spatula) was added and the mixture heated at 400C until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated.Chromatography on SiO2 (Hex/EA 2:1, 1 :1) gave the desired intermediate as a beige solid(1.09 g, 41% yield).1H NMR (DMSO d6) δ: 7.13 (d, J = 2.5 Hz, IH), 6.96 (dd, J = 2.5, 8.9 Hz, IH), 6.86 (d, J = 8.9 Hz, IH), 5.16 (t, J = 5.8 Hz, IH), 4.70-4.50 (m, IH), 4.30-4.10 (m, 4H),4.10-3.90 (m, IH), 4.80-4.70 (m, IH), 4.70-4.60 (m, IH), 4.60-4.50 (m, IH).
	With sodium carbonate In tetrahydrofuran; water at 0 - 20℃; for 1h;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/107965, 2007, A1 Location in patent: Page/Page column 111
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2009/105232, 2009, A1 Location in patent: Page/Page column 43
[3]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - US2011/39823, 2011, A1 Location in patent: Page/Page column 34; 35
[4]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - WO2008/126034, 2008, A2 Location in patent: Page/Page column 89-90
[5]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2008/126024, 2008, A2 Location in patent: Page/Page column 130; 133
[6]Mudithanapelli, Chandrashekar; Dhorma, Lama Prema; Kim, Mi-Hyun [Organic Letters, 2019]

25
trans-4-[2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexanecarboxylic acid [ No CAS ]
[ 22013-33-8 ]
trans-4-[(rac)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexanecarboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 5h;	34.34.iv 34.iv. trans-4-[(rac)-2-hydroxy-2-(6-methoxy-[l,5]naphthyridin-4-yl)-ethyl]- cyclohexanecarboxylic acid (2, 3-dihydro-benzo[l, 4] ' dioxin-6-yl)- amide : To a solution of intermediate 34.iii.(51 mg, 0.155 mmol) and 1 ,4-benzodioxan-6-amine (28 mg, 1.2 eq) in DMF (2 mL) were added DIPEA (0.077 mL, 3 eq), HOBt (21 mg, 1 eq) and EDCI (36 mg, 1.2 eq) at rt. After stirring for 5 h at rt the mixture was poured into EA and brine and the phases were separated. The aq. layer was 3 times extracted with EA and the org. layer was washed several times with a NaCl solution, dried over MgSO4 and concentrated under reduced pressure. Purification by preparative HPLC (Waters, NarrowD) and lyophilisation afforded the title compound as a colourless solid (37 mg, 51% yield).1H NMR (DMSO d6) δ: 9.61 (s, IH), 8.77 (d, J = 4.5 Hz, IH), 8.26 (d, J = 9.0 Hz, IH), 7.77 (d, J = 4.5 Hz, IH), 7.24 (m, 2H), 6.98 (dd, J = 8.8, 1.8 Hz, IH), 6.75 (d, J = 8.5 Hz, IH), 5.70 (d, J = 9.0 Hz, IH), 5.37 (br. s, IH), 4.20 (d, J = 4.8 Hz, 4H), 4.02 (s, 3H), 2.22 (m, 2H), 1.75 (m, 5H), 1.44 (m, 3H), 1.03 (m, 2H). MS (ESI, m/z): 464.3 [M+H+].
51%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 5h;	34.iv 34.iv. To a solution of intermediate 34.iii. (51 mg, 0.155 mmol) and 1,4-benzodioxan-6-amine (28 mg, 1.2 eq) in DMF (2 mL) were added DIPEA (0.077 mL, 3 eq), HOBt (21 mg, 1 eq) and EDCI (36 mg, 1.2 eq) at rt. After stirring for 5 h at rt the mixture was poured into EA and brine and the phases were separated. The aq. layer was 3 times extracted with EA and the org. layer was washed several times with a NaCl solution, dried over MgSO4 and concentrated under reduced pressure. Purification by preparative HPLC (Waters, NarrowD) and lyophilisation afforded the title compound as a colourless solid (37 mg, 51% yield). 1H NMR (DMSO d6) δ: 9.61 (s, 1H), 8.77 (d, J=4.5 Hz, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.77 (d, J=4.5 Hz, 1H), 7.24 (m, 2H), 6.98 (dd, J=8.8, 1.8 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.70 (d, J=9.0 Hz, 1H), 5.37 (br. s, 1H), 4.20 (d, J=4.8 Hz, 4H), 4.02 (s, 3H), 2.22 (m, 2H), 1.75 (m, 5H), 1.44 (m, 3H), 1.03 (m, 2H). MS (ESI, m/z): 464.3 [M+H+].

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/107965, 2007, A1 Location in patent: Page/Page column 108-109
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2009/105232, 2009, A1 Location in patent: Page/Page column 42

26
trans-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexanecarboxylic acid [ No CAS ]
[ 22013-33-8 ]
trans-4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexanecarboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	1.1.iii 1 iii. trans-4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexanecarboxylic acid (2, 3-dihydro-benzo [ 1 , 4] dioxin-6-yl)-amide :A solution of TPPA (50% in EA, 2.16 mL) was added dropwise to a stirred solution of intermediate l.ii (0.988 g, 3.62 mmol), 2,3-dihydro-benzo[l,4]dioxin-6-ylamine (0.555 g, 1 eq.) and DIPEA (1.89 mL, 3 eq.) in DCM (20 mL) at rt. The mixture was stirred at rt for2 h, diluted with DCM (20 mL) and washed with M HCl (20 mL) and water (40 mL), dried over MgSO4 and concentrated. Chromatography over SiO2 (Hex/EA 2:1) gave the product (1.14 g, 77% yield) as a beige solid.1H NMR (CDCl3) δ: 7.22 (d, J =2.4 Hz, IH); 6.96 (br, s, IH); 6.85 (dd, J = 2.4, 8.7 Hz, IH); 6.73 (d, J =8.7 Hz, IH); 4.19 (s, 4H); 3.38 (d, J =6.3 Hz, 2H); 2.10 (m, IH); 1.95 (m, 2H); 1.85 (m, 2H); 1.6-1.4 (m, 4H); 1.0-0.8 (m, 4H); 0.84 (s, 9H); 0.02 (s, 6H). MS (ESI, m/z): 406.0 [M+H+].
77%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 20℃; for 2h;	1.iii 1.iii. A solution of TPPA (50% in EA, 2.16 mL) was added dropwise to a stirred solution of intermediate 1.ii (0.988 g, 3.62 mmol), 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (0.555 g, 1 eq.) and DIPEA (1.89 mL, 3 eq.) in DCM (20 mL) at rt. The mixture was stirred at rt for 2 h, diluted with DCM (20 mL) and washed with 1M HCl (20 mL) and water (40 mL), dried over MgSO4 and concentrated. Chromatography over SiO2 (Hex/EA 2:1) gave the product (1.14 g, 77% yield) as a beige solid. 1H NMR (CDCl3) δ: 7.22 (d, J=2.4 Hz, 1H); 6.96 (br, s, 1H); 6.85 (dd, J=2.4, 8.7 Hz, 1H); 6.73 (d, J=8.7 Hz, 1H); 4.19 (s, 4H); 3.38 (d, J=6.3 Hz, 2H); 2.10 (m, 1H); 1.95 (m, 2H); 1.85 (m, 2H); 1.6-1.4 (m, 4H); 1.0-0.8 (m, 4H); 0.84 (s, 9H); 0.02 (s, 6H). MS (ESI, m/z): 406.0 [M+H+].

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/107965, 2007, A1 Location in patent: Page/Page column 76
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2009/105232, 2009, A1 Location in patent: Page/Page column 30

27
[ 1034925-97-7 ]
[ 22013-33-8 ]
[ 1034925-30-8 ]

Yield	Reaction Conditions	Operation in experiment
74%	With caesium carbonate In toluene for 12h; Heating / reflux;	1.47.b A mixture of compound (a) (100 mg), Pd(OAc)2 (6.3 mg), BINAP (17 mg),cesium carbonate (110 mg) and 2,3-Dihydro-benzo[l,4]dioxin-6-ylamine (84 mg) in 15 ml toluene was reflaxed for 12 hours. The reaction mixture was eluted through a silica bed with Toluene and then with PE: EtOAc (1:1). The toluene fraction was discarded and the solvent of the PE:EtOAc fraction was removed under reduced pressure. The crude product was purified by Combiflash (linear gradient PE - THF). Yield 87 mg, 74 %.1H NMR (300 MHz, CDC13, rt) δ 0.08 (m, 2H5 CH2), 0.48 (m, 2H, CH2), 0.87 (m, IH, CH), 2.799 (d, 2H, J= 5.1 Hz, CH2), 4.285 (s, 4H, 2xArOCH2), 4.62 (s, broad, IH, NH), 6.71 (m, broad, 2H, ArH), 6.882 (d, IH, J= 8.7 Hz, ArH), 6.979 (m, broad, IH, ArH), 7.190 (d, IH, J= 2.1 Hz, ArH) and 7.968 (d, IH, J= 8.7 Hz, ArH).MS: m/z 429.0 (M+)

Reference： [1]Current Patent Assignee: PHARMOS CORPORATION - WO2008/75353, 2008, A1 Location in patent: Page/Page column 67

28
[ 308831-98-3 ]
[ 22013-33-8 ]
5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-3-(3,4-ethylenedioxyphenyl)-6-[4-(3-methoxyureido)phenyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 6-amino-3,4-benzodioxane With dimethylaluminum chloride In hexane; dichloromethane at 15 - 25℃; for 1h; Cooling with ice; Stage #2: ethyl 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylate In hexane; dichloromethane at 15 - 25℃; for 24h;	8 Example 8 5-(N-Benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-3-(3,4-ethylenedioxyphenyl)-6-[4-(3-methoxyureido)phenyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione To a solution of 3,4-ethylenedioxyaniline (3.90 g, 25.8 mmol) in dichloromethane (100 ml) was added a solution of 1.01M dimethylaluminum chloride in hexane (25.5 ml, 25.8 mmol) under ice-cooling.. The mixture was allowed to warm to room temperature with stirring for 1 hour.. To this solution was added a solution of the compound obtained in Reference Example 14 (3.44 g, 5.16 mmol) in dichloromethane (60 ml), and the mixture was stirred at room temperature for 1 day.. This reaction mixture was partitioned between chloroform and saturated aqueous sodium chloride solution and the aqueous layer was extracted with chloroform.. The organic layers were combined, washed with aqueous sodium chloride solution and dried (MgSO4) and the solvent was distilled off under reduced pressure.. The residue was chromatographed on silica gel to give the title compound as white amorphous powder (3.2 g, 85%). mp: 185-187° C. 1H-NMR (300 MHz, CDCl3) δ: 2.05 (3H, s), 3.57 (2H, s), 3.83 (3H, s), 3.90 (2H, s), 4.29 (4H, s), 5.35 (2H, s), 6.75-7.01 (5H, m), 7.12-7.33 (7H, m), 7.55 (2H, d, J=8.0 Hz), 7.63 (1H, s), 7.72 (2H, d, J=8.0 Hz). IR (KBr): 1717, 1702, 1686, 1657, 1636, 1626, 1560, 1543, 1522, 1510, 1475 cm-1.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US6340686, 2002, B1 Location in patent: Page column 42

29
[ 85070-67-3 ]
[ 22013-33-8 ]
[ 1061518-30-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4393 - 4396

30
2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile [ No CAS ]
[ 22013-33-8 ]
[ 1201195-69-8 ]

Yield	Reaction Conditions	Operation in experiment
24%	With ammonium formate In methanol at 80℃; for 2h;	55.a.1 A solution of 5 mmol (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (prepared as per example 47, step 1) and 1.1 eq. 2,3-Dihydro-benzo[1,4]dioxin-6-ylamine in MeOH (20 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (200 mg) and stirred at 80° C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (24%) as a light yellow oil. MS m/e: 325.0 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2009/312314, 2009, A1 Location in patent: Page/Page column 45

31
[ 1620-75-3 ]
[ 22013-33-8 ]
[ 944882-89-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4868 - 4872

32
[ 22013-33-8 ]
[ 57744-67-9 ]

Yield	Reaction Conditions	Operation in experiment
94.22%	Stage #1: 6-amino-3,4-benzodioxane With hydrogenchloride; sodium nitrite In water at -5 - 0℃; for 0.5h; Inert atmosphere; Stage #2: With potassium iodide In water at 0 - 5℃; Inert atmosphere;	4.2 2.4.2. 6-Iodo-1,4-benzodioxane (2) A mechanically stirred mixture of 6-amino-1,4-benzodioxane (5.29 g, 35 mmol) and 36 % HCl (50 mL) was cooled to -5 °C. A solution of NaNO2 (2.90 g, 42 mmol) in 20 mL H2O was cooled to 0 °C and slowly added while maintaining the temperature at -5 °C. The final solution was stirred at 0 °C for 30 min. A solution of KI (11.62 g, 70 mmol) in 30 mL H2O was added dropwise keeping the temperature between 0 and 5 °C. The resulting mixture was stirred overnight and extracted twice with diethyl ether. The organic layer was consecutively washed with a concentrated NaHSO3 solution, 5 % NaOH and water and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using silica gel and dichloromethane-hexane (3:2; v/v) as the eluent to give 2, a pale yellow oil phase (8.64 g, 94.22%). 1H NMR (500 MHz, d6-DMSO, ppm): δ 7.18 (s, 1H), 7.13 (d, J = 8.45 Hz, 1H), 6.68 (d, J = 8.45 Hz, 1H), 4.22 (s, -OCH2CH2O-, 4H).
86%	Stage #1: 6-amino-3,4-benzodioxane With hydrogenchloride; sodium nitrite In water at 0℃; for 0.416667h; Stage #2: With urea In water for 0.25h; Stage #3: With potassium iodide In dichloromethane; water at 20℃;	6-Iodo-2,3-dihydrobenzo[b][l,4]dioxine (S9-2).; 2,3-dihydrobenzo[b][l,4]dioxin-6-amine (S9-1; 5 g, 33 mmol) was dissolved in 10% HCl solution and cooled to 0°C. Then, 30 mL of a cold aqueous solution of NaN02 (4.6 g, 66 mmol) was added over a period of 15 min and the reaction mixture was stirred at 0°C for an additional 10 min, followed by the addition of urea (1.6 g, 27 mmol). After 15 min, 40 mL of a suspension of KI (16.5 g, 100 mmol) in water/CH2Cl2 (1:1) was added. The reaction mixture was stirred overnight at roomtemperature then extracted with CH2C12, dried over MgS0 . And condensed under reduced pressure and the residue was purified by flash chromatography (hexane:EtOAc, 100:0 to 90:10) to afford S9-2 (7.4 g, 86%) as a colorless oil. 1H NMR (500 MHz, CDC13) δ 7.28 δ (s, 1H), 7.13 (d, J= 8.5 Hz, 1H), 6.63 (d, J= 8.5 Hz, 1H), 4.27-4.24 (m, 4H).

Reference： [1]Kim, Se Hun; Choi, Jun; Sakong, Chun; Namgoong, Jin Woong; Lee, Woosung; Kim, Dong Hoe; Kim, Boeun; Ko, Min Jae; Kim, Jae Pil [Dyes and Pigments, 2015, vol. 113, p. 390 - 401]
[2]Current Patent Assignee: MEMORIAL SLOAN-KETTERING CANCER CENTER - WO2011/44394, 2011, A1 Location in patent: Page/Page column 110

33
[ 55686-94-7 ]
[ 22013-33-8 ]
[ 1261078-72-1 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 4508 - 4522

34
[ 13246-46-3 ]
[ 22013-33-8 ]
[ 1344729-71-0 ]

Yield	Reaction Conditions	Operation in experiment
90.5%	In ethanol; for 3h;Reflux;	General procedure: The appropriate amine (10 mmol) was heated at reflux with the appropriate aldehyde (10 mmol) in ethanol (50 mL) for 3 h. The reaction mixture was cooled and then the solvent evaporated in vacuo. The resulting solid product was recrystallised from ethanol.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 6055 - 6068

35
[ 37470-83-0 ]
[ 22013-33-8 ]
[ 1344729-70-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	In ethanol; for 3h;Reflux;	General procedure: The appropriate amine (10 mmol) was heated at reflux with the appropriate aldehyde (10 mmol) in ethanol (50 mL) for 3 h. The reaction mixture was cooled and then the solvent evaporated in vacuo. The resulting solid product was recrystallised from ethanol.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 6055 - 6068

36
[ 252921-13-4 ]
[ 22013-33-8 ]
[ 1239165-09-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With caesium carbonate In toluene at 80℃; for 2h;	9.2 (2) Production of methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)aminonicotinate 10.6 g (37 mmol) of methyl 2-(trifluoromethylsulfonyloxy)nicotinate and 6.2 g (41 mmol) of 3,4-ethylenedioxybenzylamine were dissolved in toluene (100 mL), and 17.0 g (52 mmol) of cesium carbonate, 1.0 g (1.1 mmol) of tris(dibenzylideneacetone)dipalladium(0), and 1.3 g (5.2 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added thereto. The resulting mixture was heated and stirred for 2 hours at 80° C. The solvent was distilled off from the reaction mixture, water and ethyl acetate were added to the residue, and the resulting mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic phase was washed with an aqueous solution of citric acid and water in this order, and then was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:9 to 1:2), and thus 9.86 g of the title compound was obtained as an orange-colored viscous product (yield: 93%). 1H-NMR data (CDCl3/TMS δ (ppm)): 3.91 (3H, s), 4.24 (4H, br), 6.64-6.66 (1H, m), 6.83 (1H, d), 6.97 (1H, dd), 7.37 (1H, d), 8.19 (1H, dd), 8.33 (1H, dd), 9.92 (1H, br)

Reference： [1]Current Patent Assignee: KUMIAI CHEMICAL INDUSTRY CO LTD - US2011/287937, 2011, A1 Location in patent: Page/Page column 74

37
[ 27320-81-6 ]
[ 22013-33-8 ]
[ 1383579-72-3 ]

Yield	Reaction Conditions	Operation in experiment
58.8%	With pyridine In dichloromethane at 0 - 20℃; for 2h;	2 Synthesis of compound 29a:; To a solution of amine 29 (0.07 gm, 0.463 mmol) in DCM, sulfonyl chloride 28 (0.14 gm, 0.35 mmoles) was added followed by pyridine (10 mI7 gm starting material) at 0°C and the reaction mixture was allowed to stir at room temperature for 2 hrs. After completion, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with 6N HC1 and dried over Na2S04 and concentrated under reduced pressure to obtain product 29a (0.10 gm, 58.8% yield).JH NMR (500 MHz, DMSO-d6) δ 3.21 (s, 3H), 4.19 (s, 4H), 4.78 (s, 2H), 6.58 (d, IH), 6.6 (s, IH), 6.71 (d, IH), 7.15 (d, IH), 7.34 (d, IH), 7.29 (s, IH), 9.83 (s, 1H).MS: 375 (M-l peak).
58.8%	With pyridine In dichloromethane at 0 - 20℃; for 2h;	2 Synthesis of Compound 29a To a solution of amine 29 (0.07 gm, 0.463 mmol) in DCM, sulfonyl chloride 28 (0.14 gm, 0.35 mmoles) was added followed by pyridine (10 mL/gm starting material) at 0° C. and the reaction mixture was allowed to stir at room temperature for 2 hrs. After completion, the reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with 6N HCl and dried over Na2SO4 and concentrated under reduced pressure to obtain product 29a (0.10 gm, 58.8% yield). (0867) 1H NMR (500 MHz, DMSO-d6) δ 3.21 (s, 3H), 4.19 (s, 4H), 4.78 (s, 2H), 6.58 (d, 1H), 6.6 (s, 1H), 6.71 (d, 1H), 7.15 (d, 1H), 7.34 (d, 1H), 7.29 (s, 1H), 9.83 (s, 1H). MS: 375 (M-1 peak).

Reference： [1]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - WO2012/88314, 2012, A1 Location in patent: Page/Page column 58-59; 61
[2]Current Patent Assignee: AGIOS PHARMACEUTICALS INC - US9181231, 2015, B2 Location in patent: Page/Page column 80; 82

38
[ 615-13-4 ]
[ 22013-33-8 ]
[ 1153745-37-9 ]

Yield	Reaction Conditions	Operation in experiment
96.5%		A. N-2,3-Dihydro-benzo[1,4]dioxin-6-yl-N-indan-2-ylamine (compound 57) To a stirred solution of <strong>[615-13-4]2-indanone</strong> (2 g, 15.1 mmol) in DCE (50 mL) were added 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (2.28 g, 15.1 mmol), Na(OAc)3BH (4.81 g, 22.6 mmol), AcOH (1.8 mL) successively at 0 C. and the mixture was stirred overnight at rt. The reaction mixture was dissolved in ethyl acetate and was washed with 1N NaOH, water and brine. The solution was dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash chromatography eluting with 9-10% ethyl acetate-hexane to get compound 57. Yield: 3.9 g (96.5%); 1H-NMR (400 MHz, DMSO-d6): delta 7.21-7.11 (m, 4H), 6.60-6.56 (m, 1H), 6.14-6.11 (m, 2H), 5.41 (d, J=7 Hz, 1H), 4.16-4.02 (m, 6H), 3.32-3.21 (m, 2H), 2.77-2.71 (m, 2H);LCMS [M+H]=268.2, RT=3.54 minutes, (Program P1, Column Y).
96.5%	With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 0 - 20℃;	A. N-2,3-Dihydro-benzo[l,4]dioxin-6-yl-N-indan-2-ylamine (compound 57) To a stirred solution of <strong>[615-13-4]2-indanone</strong> (2 g, 15.1 mmol) in DCE (50 mL) were added 2,3-dihydro-benzo[l,4]dioxin-6-ylamine (2.28 g, 15.1 mmol), Na(OAc)3BH (4.81 g, 22.6 mmol), AcOH (1.8 mL) successively at 0C and the mixture was stirred overnight at rt. The reaction mixture was dissolved in ethyl acetate and was washed with IN NaOH, water and brine. The solution was dried over Na2S04, filtered and concentrated. The crude material was purified by Combiflash chromatography eluting with 9-10% ethyl acetate-hexane to get compound 57. Yield: 3.9 g (96.5%); 1H-NMR (400 MHz, DMSO-<): delta 7.21-7.11 (m, 4 H), 6.60-6.56 (m, 1 H), 6.14- 6.11 (m, 2 H), 5.41 (d, J = 7 Hz, 1 H), 4.16-4.02 (m, 6 H), 3.32-3.21 (m, 2 H), 2.77-2.71 (m, 2 H); LCMS [M+H] = 268.2, RT = 3.54 minutes, (Program PI, Column Y).

Reference： [1]Patent: US2012/214809,2012,A1 .Location in patent: Page/Page column 78-79
[2]Patent: WO2014/28675,2014,A1 .Location in patent: Page/Page column 138-139

39
2,5-dioxopyrrolidin-1-yl 2-(diisopropoxyphosphoryl)acetate [ No CAS ]
[ 123-46-6 ]
[ 22013-33-8 ]
[ 6066-82-6 ]
[ 1426294-37-2 ]
C₁₃H₂₉N₃O₅P⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]ACS Combinatorial Science,2013,vol. 15,p. 208 - 215

40
[ 1426294-34-9 ]
[ 123-46-6 ]
[ 22013-33-8 ]
[ 6066-82-6 ]
[ 1426294-45-2 ]
C₁₄H₃₁N₃O₅P⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Reference： [1]ACS Combinatorial Science,2013,vol. 15,p. 208 - 215

41
[ 22013-33-8 ]
[ 121-60-8 ]
[ 462619-75-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 6-amino-3,4-benzodioxane With sodium carbonate In water at 20℃; for 0.5h; Stage #2: p-acetylaminobenzenesulfonyl chloride In water at 20℃;	N-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-4-acetamidobenzenesulfonamide (III). N-(2,3-Dihydrobenzo[1,4]-dioxin-6-amine (1mL; 0.002 mol; I) was suspended in 25 mL distilled water and 10% aqueous Na2CO3 was added to maintain the pH at 9-10 and reaction mixture were stirred for half an hour. Then 4a-cetamidobenzenesulfonylchloride (0.47 g; 0.002 mol; II) was added in the mixture along at gradual stirring and was further stirred for several hours till completion of the reaction, which was monitored byTLC till single spot. The product was precipitated at pH 2 using conc. HCl and filtered out, washed with distilled water, and air dried to afford N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-acetamidobenzenesulfonamide (III) as light brown powder. Yield 78%; mp 264°C; molecular formula: C16H16O5N2S; molecular weight: 348 g mol-1; IR: 3248 (N-H stretching), 3046 (C-H stretching of aromatic ring), 2978 (-CH2 stretching), 1714 (C=O stretching), 1635 (C=C stretching of aromatic ring), 1385 (-SO2 stretching), 1152 (C-O-C stretching of ether); 1H NMR: 10.27 (s, 1H, -NHSO2), 9.80 (s, 1H, -NHCO), 7.68 (d, J = 8.8 Hz, 2H, H-2' & H-6'), 7.61 (d, J = 8.8 Hz, 2H, H-3' & H-5'), 6.67 (d, J = 8.4 Hz, 1H, H-8), 6.54 (d, J = 2.4 Hz, 1H, H-5), 6.49 (dd, J = 2.4, 8.4 Hz, 1H, H-7), 4.14 (s, 4H, CH2-2 & CH2-3), 2.05 (s, 3H, -COCH3).
	With sodium carbonate In water at 20℃;

Reference： [1]Abbasi; Tariq; Aziz-Ur-Rehman; Siddiqui; Ahmad; Malik; Shah [Russian Journal of Bioorganic Chemistry, 2016, vol. 42, # 2, p. 198 - 209][Bioorg. Khim.]
[2]Irshad, Misbah; Abbasi, Muhammad Athar; Rehman, Aziz-Ur; Siddiqui, Sabahat Zahra; Ashraf, Muhammad; Ejaz, Syeda Abida; Lodhi, Muhammad Arif; Jamal, Syed Babar [Journal of the Chemical Society of Pakistan, 2014, vol. 36, # 4, p. 660 - 673]

42
[ 105-36-2 ]
[ 22013-33-8 ]
diethyl-2,2’-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)azanediyl)diacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 18h;	B.i Step (i): Diethyl 2 ,2’-((2, 3-di hydrobenzo[b][1 ,4]dioxin-6-yl)azanediyl)diacetate (4) Ethyl 2-bromoacetate (1.54 ml, 13.89 mmcl) was added dropwiseto a stirred solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (3) (0.81 mL, 6.62 mmol) and DIPEA (2.89 mL, 16.54 mmol)in MeCN (7 mL). The reaction mixture was stirred at 6000 for 18 h and then partitioned between2 M HCI(aq.) (20 mL), and EtOAc (20 mL), the aqueous phase was extracted with EtOAc (20 mL)and the combined organics were washed successively with 2M HCI(aq.) (2 x 20 mL), water (2 x20 mL), and brine (20 mL), dried (Mg504), filtered and solvents removed in vacuo to give diethyl2,2’-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)azanediyl)diacetate (4) (2.3 g, 97%) as a brown oil:mlz 324 (M+H) (ES).

Reference： [1]Current Patent Assignee: UNIVERSITY OF LEICESTER - WO2014/195718, 2014, A1 Location in patent: Page/Page column 27; 28

43
[ 22118-09-8 ]
[ 22013-33-8 ]
[ 1219012-44-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In dichloromethane at 0 - 20℃; Inert atmosphere;
71%	With potassium carbonate In dichloromethane at 0℃; for 0.333333h; Inert atmosphere;	N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-bromoacetamide A flame-dried 100-mL round bottomed flask equipped with a stirbar under an argon atmosphere was charged with freshly purified 3,4-(ethylenedioxy)aniline (3.02 g, 20 mmol) and dry dichloromethane (45 mL, 0.43 M). Vacuum oven-dried potassium carbonate (3.87 g, 28 mmol, 1.40 equiv) was then added, and the reaction was cooled to 0° C. Then, bromoacetyl chloride (2.17 mL, 26 mmol, 1.30 equiv) was added via syringe and the reaction was stirred at 0° C. for 20 min and then allowed to warm to room temperature. Saturated aqueous sodium bicarbonate was added (50 mL) and the mixture was extracted with dichloromethane (3*75 mL). The combined organic layers were washed with brine (150 mL), and dried over anhydrous sodium sulfate. The solution was concentrated via rotary evaporation to afford N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-bromoacetamide as a purple-gray solid (3.88 g, 14.2 mmol, 71% yield). 1H NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.15 (d, J=2.5 Hz, 1H), 6.90 (dd, J=8.7, 2.5 Hz, 1H), 6.83 (d, J=8.7, 1H), 4.25 (s, 4H), 4.02 (s, 2H).
71%	With potassium carbonate In dichloromethane at 0℃; for 0.333333h; Inert atmosphere;	N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-bromoacetamide A flame-dried 100-mL round bottomed flask equipped with a stirbar under an argon atmosphere was charged with freshly purified 3,4-(ethylenedioxy)aniline (3.02 g, 20 mmol) and dry dichloromethane (45 mL, 0.43 M). Vacuum oven-dried potassium carbonate (3.87 g, 28 mmol, 1.40 equiv) was then added, and the reaction was cooled to 0° C. Then, bromoacetyl chloride (2.17 mL, 26 mmol, 1.30 equiv) was added via syringe and the reaction was stirred at 0° C. for 20 min and then allowed to warm to room temperature. Saturated aqueous sodium bicarbonate was added (50 mL) and the mixture was extracted with dichloromethane (3*75 mL). The combined organic layers were washed with brine (150 mL), and dried over anhydrous sodium sulfate. The solution was concentrated via rotary evaporation to afford N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-bromoacetamide as a purple-gray solid (3.88 g, 14.2 mmol, 71% yield). 1H NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.15 (d, J=2.5 Hz, 1H), 6.90 (dd, J=8.7, 2.5 Hz, 1H), 6.83 (d, J=8.7, 1H), 4.25 (s, 4H), 4.02 (s, 2H).

49%

With potassium carbonate In dichloromethane for 24h; Inert atmosphere; Reflux;

1 2-bromo-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide In a flame dried 100 mL flask equipped with a stir bar, 2,3-dihydro-1,4-benzodioxin-6-amine (2.27 g, 15.0 mmol, 1.84 mL) and potassium carbonate (2.49 g, 18.0 mmol) were suspended in DCM (50.0 mL). Bromoacetyl chloride (2.60 g, 16.5 mmol, 1.37 mL) was added slowly, and the flask was flushed with Ar, and fitted with a reflux condenser and Ar balloon. The reaction mixture was heated and stirred at reflux for 24 h. After cooling to RT, the mixture was slowly poured into 100 mL of ice water. The aqueous solution was extracted with DCM (2*100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to furnish 2-bromo-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide (2.00 g, 7.33 mmol, 48.9% yield) as a solid. Crude solid was sufficiently pure by NMR and used in subsequent step without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.21 (d, J=2.5 Hz, 1H), 6.95 (dd, J=8.7, 2.5 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 4.27-4.13 (overlap, 4H), 3.98 (s, 2H). 13C NMR: (125 MHz, DMSO-d6) δ 164.28, 142.96, 139.72, 132.24, 116.91, 112.43, 108.31, 64.18, 63.93, 30.43. ESI-MS: [M+H]+ calculated for C10H10BrNO3 273.982; found 274.058. UV: λ (max) 262.2 nm.

Reference： [1]Sun, Zhuming; Khan, Jihan; Makowska-Grzyska, Magdalena; Zhang, Minjia; Cho, Joon Hyung; Suebsuwong, Chalada; Vo, Pascal; Gollapalli, Deviprasad R.; Kim, Youngchang; Joachimiak, Andrzej; Hedstrom, Lizbeth; Cuny, Gregory D. [Journal of Medicinal Chemistry, 2014, vol. 57, # 24, p. 10544 - 10550]
[2]Current Patent Assignee: BOSTON UNIVERSITY - US2022/62272, 2022, A1 Location in patent: Paragraph 0276; 0277
[3]Current Patent Assignee: BOSTON UNIVERSITY - US2022/62272, 2022, A1 Location in patent: Paragraph 0276; 0277
[4]Current Patent Assignee: BOSTON UNIVERSITY - US2020/39996, 2020, A1 Location in patent: Paragraph 0407; 0415-0417

44
[ 75-03-6 ]
[ 22013-33-8 ]
N-ethyl-2,3-dihydro-1,4-benzodioxin-6-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 6-amino-3,4-benzodioxane With trifluoroacetic anhydride In dichloromethane at 20℃; for 0.583333h; Cooling with ice; Stage #2: With lithium hydride In N,N-dimethyl-formamide for 0.25h; Cooling with ice; Inert atmosphere; Stage #3: ethyl iodide In N,N-dimethyl-formamide at 20℃;	29 5.1.29 N-Ethyl-2,3-dihydro-1,4-benzodioxin-6-amine A stirred solution of 2,3-dihydro-1,4-benzodioxin-6-amine (3.01 g, 19.9 mmol) in CH2Cl2 (20 ml) was cooled in an ice-water bath and treated dropwise with trifluoroacetic anhydride (4.10 ml, 29.4 mmol) over a period of 5 min. After stirring for 30 min at room temperature, the reaction mixture was concentrated to dryness, and ethyl acetate was added to the residue. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product obtained was dissolved in DMF (35 ml) and cooled in an ice-water bath. To the solution was added lithium hydride (190 mg, 23.9 mmol), and the mixture was stirred for 15 min under an argon atmosphere. To this was added ethyl iodide (1.93 ml, 23.9 mmol), and the resulting mixture was stirred overnight at room temperature. After concentration, the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product obtained was dissolved in MeOH (50 ml) and treated with 28% NH3 (30 ml), and the mixture was heated to reflux for 4 h. After concentration, the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed (hexane/ethyl acetate 6:1-5:1) to give the title compound (3.33 g, 93%): 1H NMR (500 MHz, CDCl3) δ 6.68 (d, J = 8.6 Hz, 1H), 6.07-6.18 (m, 2H), 4.08-4.25 (m, 4H), 3.10-3.33 (br, 1H), 2.98-3.10 (m, 2H), 1.13-1.24 (m, 3H); MS (EI) m/z 179 (M+).

Reference： [1]Inami, Hiroshi; Shishikura, Jun-Ichi; Yasunaga, Tomoyuki; Ohno, Kazushige; Yamashita, Hiroshi; Kato, Kota; Sakamoto, Shuichi [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1788 - 1799]

45
4-((1-carboxypentyl)oxy)-5-(cyclopentylethynyl)-2-hydroxybenzoic acid [ No CAS ]
[ 22013-33-8 ]
5-(cyclopentylethynyl)-4-((1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-1-oxohexan-2-yl)oxy)-2-hydroxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.2%	Stage #1: 4-((1-carboxypentyl)oxy)-5-(cyclopentylethynyl)-2-hydroxybenzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: 6-amino-3,4-benzodioxane With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	2 4.5. General procedure for the preparation of compounds 6-13 General procedure: For resynthesis of hits in large scale, the 4-carboxymethoxy in4-(carboxymethoxy)-2-hydroxybenzoic acid (0.1 mmol, 1.0 equiv)was activated by 1-O-benzotriazole-N,N,N0 ,N0-tetramethyluroniumhexafluoro-phosphate (HBTU) (0.1 mmol, 1.0 equiv) in DMF for5 min, then 1-hydroxybenzotriazole (HOBt) (0.1 mmol, 1.0 equiv)and N,N-diisopropylethylamine (0.4 mmol, 4.0 equiv) and amine(0.12 mmol, 1.2 equiv) was added. After stirring at room temperaturefor 2 h, the reaction liquids were directly sent to HPLC purification.Protocol for the Prep-HPLC purification method: reversephase HPLC was carried out on Sunfire Prep C18 OBD column(30 150 mm, 5 lm). Solvent A: water with 0.1% trifluoroaceticacid: Solvent B: Methanol with 0.1% trifluoroacetic acid.Gradient: After 5 min at the initial condition of 90% A and 10% B,solvent B was increased to 100% within 45 min, then maintainedat 100% B for 10 min. Flow rate was 50 mL/min, UV detector at 254 nm.

Reference： [1]He, Yantao; Guo, Xing; Yu, Zhi-Hong; Wu, Li; Gunawan, Andrea M.; Zhang, Yan; Dixon, Jack E.; Zhang, Zhong-Yin [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 12, p. 2798 - 2809]

46
1-[3-cyano-6-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid [ No CAS ]
[ 22013-33-8 ]
1-(3-cyano-6-(trifluoromethyl)pyridin-2-yl)-N-(3,4-ethylenedioxyphenyl)piperidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 1-[3-cyano-6-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: 6-amino-3,4-benzodioxane In dichloromethane at 20℃; for 24h;	1 4.1.4. General procedure for the preparation of 1-heteroarylpiperidinecarboxamides 4-23, 27-32 General procedure: To a stirred solution of 3, or 24-26 (0.50 mmol) in DCM (5 mL) were added HOBt (102 mg, 0.60 mmol) and EDC (116 mg,0.60 mmol). The mixture was stirred for 30 min at room temperature. Then a substituted aryl, benzyl, or phenethylamine(0.60 mmol) was added, and the mixture was stirred 24 h at room temperature. After evaporation of the solvent, the residue was taken up with brine and extracted with AcOEt. The organic phase was washed with 0.5 N hydrochloric acid, saturated NaHCO3, and brine, dried (Na2SO4), and evaporated under vacuum. The residue was crystallized with i-Pr2O/MeOH to give piperidinecarboxamide s4-23, 27-32 in 46-92% yields.

Reference： [1]Congiu, Cenzo; Onnis, Valentina; Balboni, Gianfranco; Schiano-Moriello, Aniello; Di Marzo, Vincenzo; De Petrocellis, Luciano [European Journal of Medicinal Chemistry, 2015, vol. 100, p. 129 - 138]

47
[ 22013-33-8 ]
[ 53484-16-5 ]
C₁₆H₁₅N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere;	A mixture of Pd2(dba)3 (0.01 mmol) and Xantphos (0.01 mmol) in 1,4-dioxane (1 mL) was sonicated and added under nitrogen to a mixture of <strong>[53484-16-5]6-bromo-1-methyl-benzimidazole</strong> (0.45 mmol), 2,3-dihydro-1,4-benzodioxin-6-amine (0.58 mmol) and Cs2CO3 (0.62 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 110° C. for 12 h. The mixture was diluted (DCM), washed (H2O), dried (phase separator and concentrated. The residue was purified by prep HPLC to yield the desired product (Compound B). [0542] MW: 281.3. MS Ms?d: 282.1. [0543] NMR: 1H NMR (400 MHz, DMSO-d6): delta=7.94 (1H, s), 7.80 (1H, br s), 7.45 (1H, d), 7.05 (1H, d), 6.86 (1H, dd), 6.73 (1H, dd), 6.61-6.57 (2H, m), 4.22-4.16 (4H, m), 3.71 (3H, s).
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere; Sonication;	3.2. Compound B j00316j A mixture of Pd2(dba)3 (0.01 mmol) and Xantphos (0.01 mmol) in 1,4-dioxane (1 mL) was sonicated and added under nitrogen to a mixture of 6-bromo- 1 -methyl-benzimidazole (0.45 mmol), 2,3-dihydro-1,4-benzodioxin-6-amine (0.58 mmol) and Cs2CO3 (0.62 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 110°C for 12 h. The mixture was diluted (DCM), washed (H20), dried (phase separator and concentrated. The residue was purified by prep HPLC to yield the desired product (Compound B).j00317j MW: 281.3. MS Ms?d: 282.1.j00318j NMR: 1H NMR (400 MHz, DMSO-d6): = 7.94 (1 H, s), 7.80 (1 H, br s), 7.45 (1 H, d), 7.05 (1 H, d), 6.86 (1 H, dd), 6.73 (1 H, dd), 6.61-6.57 (2 H, m), 4.22-4.16 (4 H, m), 3.71 (3 H, s).
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere; Microwave irradiation;	A mixture of Pd2(dba)3 (0.01 mmol) and Xantphos (0.01 mmol) in 1 ,4-dioxane (1 mE) was sonicated and added undernitrogen to a mixture of <strong>[53484-16-5]6-bromo-1-methyl-benzimidazole</strong> (0.45 mmol), 2,3-dihydro-1 ,4-benzodioxin-6-amine (0.58 mmol) and Cs2CO3 (0.62 mmol) in 1,4-dioxane (2 mE). The mixture was stirred at 1100 C. for 12 h. The mixture was diluted (DCM), washed (H20), dried (phase separator andconcentrated. The residue was purified by prep HPEC toyield the desired product (Compound B).

Reference： [1]Patent: US2015/203455,2015,A1 .Location in patent: Paragraph 0540-0543
[2]Patent: WO2015/110378,2015,A1 .Location in patent: Paragraph 00316; 00317; 00318
[3]Patent: US9440929,2016,B2 .Location in patent: Page/Page column 124

48
[ 22013-33-8 ]
[ 2043-61-0 ]
[ 1043893-79-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With oxygen In acetonitrile at 60℃; for 24h; Green chemistry;	General procedure: To a mixture of p-methoxyaniline (1a, 0.5 mmol) and cyclohexanecarboxaldehyde(2e, 0.6 mmol), and CH3CN (1.5 mL) in a 25ml round-bottomed flask at 60°C underair, the reaction vessel was allowed to stir at 60 °C for 24 h. After reaction, theresulting mixture was isolated by column chromatography on silica gel withEtOAc/petroleum (1:2) to obtain the products(3a) as brown solid. The compounds(3b-3n) were obtained by the same method.

Reference： [1]Qin, Yuancheng; Cheng, Yuanyuan; Luo, Xubiao; Li, Mingjun; Xie, Yu; Gao, Yunhua [Synlett, 2015, vol. 26, # 13, p. 1900 - 1904]

49
[ 1780-40-1 ]
[ 22013-33-8 ]
N₄-(3,4-ethylenedioxyphenyl)-2,5,6-trichloro-4-pyrimidineamine [ No CAS ]
N₂,N₄-bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine [ No CAS ]
N₄,N₆-bis(3,4-ethylenedioxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 80℃; for 72h;	A mixture of 3,4-ethylenedioxyaniline (0.775 g, 5 mmol) and <strong>[1780-40-1]2,4,5,6-<strong>[1780-40-1]tetrachloropyrimidine</strong></strong> (0.434 g, 2 mmol) in the presence of DIPEA (1.043 mL, 6 mmol) in EtOAc (10 mL) was heated at 80 C. for 3 days. The reaction was diluted with water (50 mL), acidified (2N HCl) and extracted with EtOAc (3×50 mL). The residue obtained after removal of solvent was chromatographed using 5-30% EtOAc/hexanes to obtain three products viz. N4-(3,4-Ethylenedioxyphenyl)-2,5,6-trichloro-4-pyrimidineamine (R926466): 1H NMR (CDCl3): delta 7.18 (d, 1H, J=2.7 Hz), 6.92 (dd, 1H, J=2.1 and 8.7 Hz), 6.87 (d, 1H, J=9 Hz); LCMS: ret. time: 33.53 min.; purity: 100%; MS (m/e): 292 (MH+); N2,N4-Bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine (R926467): 1H NMR (CDCl3): delta 7.11 (d, 1H, J=2.4 Hz), 7.06 (d, 1H, J=2.1 Hz), 7.04 (s, 1H0, 6.94 (m, 2H), 6.84 (d, 1H, J=8.1 Hz), 6.76 (bd, 2H, J=8.7 Hz), 4.27 (bs, 4H), 4.24 (bs, 1H); LCMS: ret. time: 26.54 min.; purity: 87%; MS (m/e): 364 (MH+); and N4,N6-Bis(3,4-ethylenedioxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine (R926468): 1H NMR (CDCl3): delta 7.07 (t, 1H, J=2.4 Hz), 6.99 (s, 2H), 6.83 (dd, 2H, J=2.4 and 8.7 Hz), 6.75 (dd, 2H, J=1.8 and 9 Hz), 4.19 (bs, 4H); LCMS: ret. time: 34.70 min.; purity: 99%; MS (m/e): 365 (MH+).

Reference： [1]Patent: US2015/266828,2015,A1 .Location in patent: Paragraph 1697

50
[ 22013-33-8 ]
[ 2243-83-6 ]
N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-naphthamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydrogencarbonate In dichloromethane at 0℃; for 5h;	N-(2,3-Dihydro-Benzo[1,4]Dioxin-6-yl) 2-Naphthamide (SPA099;C₁₉H₁₅O₃N). To a solution of 2,3-dihydro-benzo[1,4]dioxin-6-amine (349mg,2.31 mmol) and NaHCO3 (222 mg, 2.64 mmol) in 10 ml ofCH2Cl2 wasadded 2-naphthoyl chloride (400 mg, 2.10 mmol) at 0°C slowly, and thereaction mixture was stirred for 5 hours at 0°C. The reaction mixturewas diluted with 1N HCl solution and extracted with EtOAc. The organic layer was washed with 1 N NaOH solution and brine and thendried over MgSO4. The solvent was removed in vacuo, and the residue was triturated with Et2O to give 580 mg (90%) of SPA099 as a white solid: 1H NMR (500 MHz, CDCl3): d 8.30 (s, 1H), 8.06 (bs, 1H),7.83∼7.85 (m, 4H), 7.49∼7.56 (m, 2H), 7.31 (d, J 5 1.9 Hz, 1H), 7.06(dd, J51.9, 8.6 Hz, 1H), 6.82 (d, J58.6 Hz, 1H), 4.23 (s, 4H); 13CNMR(125 MHz, CDCl3)): d 165.66, 143.60,140.70, 134.81, 132.63, 132.23,131.70, 128.97, 128.68, 127.80, 127.47, 126.89, 123.58, 117.30, 114.01,110.23, 64.46, 64.33.

Reference： [1]Sim, Woo-Cheol; Kim, Dong Gwang; Lee, Kyeong Jin; Choi, You-Jin; Choi, Yeon Jae; Shin, Kye Jung; Jun, Dae Won; Park, So-Jung; Park, Hyun-Ju; Kim, Jiwon; Oh, Won Keun; Lee, Byung-Hoon [Journal of Pharmacology and Experimental Therapeutics, 2015, vol. 355, # 3, p. 362 - 369]

51
C₁₂H₁₅BrO₂ [ No CAS ]
[ 22013-33-8 ]
C₂₀H₂₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.5%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In toluene at 105 - 110℃; for 9h; Inert atmosphere;	5.5 (5) three 1L flask was added 30g (0.11mol) of Intermediate 11 (prepared by Example 5), 16.7g (0.11mol) of Intermediate 3,21.2g (0.22mol) of sodium tert-butoxide and 400g of toluene, nitrogen was added 2.0g (2.2 × 10-3mol) Pd2 (dba) 3,1.3g (4.4 × 10-3mol) (t-Bu) 3PH · BF4, was heated to 105 ~ 110 refluxed 9h. The reaction was completed, the reaction mixture was filtered and the filtrate was washed with 400g of water, dried over anhydrous sodium sulfate, silica gel through the column, from toluene to give a tan solid. The above tan solid was recrystallized from toluene to give 27.2 g of white solid, yield: 72.5%.

Reference： [1]Current Patent Assignee: VALIANT CO., LTD. - CN105859678, 2016, A Location in patent: Paragraph 0150; 0151

52
C₁₀H₁₁BrO₂ [ No CAS ]
[ 22013-33-8 ]
C₁₈H₁₉NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.3%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In toluene at 105 - 110℃; for 9h; Inert atmosphere;	5.6 (6) 1L three flask was added 30g (0.12mol) of Intermediate 13 (prepared by Example 5), 18.6g (0.12mol) of Intermediate 3,23.7g (0.25mol) of sodium tert-butoxide and 400g of toluene, nitrogen was added 2.25g (2.5 × 10-3mol) Pd2 (dba) 3,1.45g (5.0 × 10-3mol) (t-Bu) 3PH · BF4, was heated to 105 ~ 110 refluxed 9h. Completion of the reaction, the reaction solution was filtered, and the filtrate washed with 400g of water, dried over anhydrous sodium sulfate, and columned on silica gel, removal of toluene to give a brown oily liquid. The above tan solid from ethanol, ethyl acetate (mass ratio of 5: 1) and recrystallized to give a white solid 31.3g, yield: 81.3%.

Reference： [1]Current Patent Assignee: VALIANT CO., LTD. - CN105859678, 2016, A Location in patent: Paragraph 0152; 0153

53
[ 52287-51-1 ]
[ 22013-33-8 ]
bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.6%	With potassium tert-butylate; palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 105 - 110℃; for 6.5h;Inert atmosphere;	(5) 1L three flask was added 82.4g (0.38mol) of Intermediate 1,48.6g (0.32mol) of intermediate 3 (prepared in Example 1 through the embodiment), 59.1g (0.53mol) of potassium tert-butoxide, 500g of toluene, a nitrogen gas protection was added 0.7g (3.0 × 10-3mol) of palladium acetate, 1.7g (6.0 × 10-3) (t-Bu) 3PH · BF4, was heated to 105 ~ 110 6.5h under reflux the reaction, the reaction was completed, the reaction solution was filtered, The filtrate was washed with 300g of water, dried over anhydrous sodium sulfate, and columned on silica gel, removal of toluene to give a tan powder. The above tan powdery solid by toluene, n-hexane (mass ratio 1: 1) and recrystallized to give 41.7g light yellow powdered solid, yield: 45.6%.

Reference： [1]Patent: CN105859678,2016,A .Location in patent: Paragraph 0082; 0083

54
C₁₂H₁₅BrO₂ [ No CAS ]
[ 22013-33-8 ]
C₂₀H₂₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.5%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In toluene at 105 - 110℃; for 10h; Inert atmosphere;	1.7 (7) 1L three flask was added 40g (0.148mol) Intermediate 6,22.3g (0.148mol) was added 2.6g of Intermediate 3,28.5g under (0.296mol) of sodium t-butoxide, 400g toluene, nitrogen (2.8 × 10-3mol) Pd2 (dba) 3,1.7g (5.9 × 10-3mol) (t-Bu) 3PH · BF4, heated to 105 ~ 110 reflux 10h, the reaction was completed, the reaction solution was filtered, and the filtrate washed with water 400g , dried over anhydrous sodium sulfate, silica gel and columned off toluene was reddish-brown solid. The above-described red-brown solid with hexane-ethyl acetate (mass ratio 2: 1) and recrystallized to give a white solid 40.1g, yield: 79.5%.

Reference： [1]Current Patent Assignee: VALIANT CO., LTD. - CN105859678, 2016, A Location in patent: Paragraph 0086; 0087

55
[ 22013-33-8 ]
[ 100-51-6 ]
N-(2,3-dihydro-1,4-benzodioxin-6-yl)benzylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With [(η5-pentamethylcyclopentadienyl)Ir^IIIbis-(κC-1,3-dimethylimidazol-2-ylidene)Cl]BF₄; potassium <i>tert</i>-butylate In toluene at 80℃; for 12h;	4.2. General method for the N-alkylation of amines with alcohols General procedure: To a 15 mL reaction tube in a glovebox, was added complex Ir3(0.5 mol%), KOtBu (75 mol%), the alcohol (0.5 mmol) and the amine(0.5 mmol) at room temperature. Then the tube was closed andremoved from the glovebox. The reaction mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixturewas diluted with ethyl acetate, filtered and dried under vacuum.The product was purified by column chromatography oversilica-gel (300-400 mesh) with an appropriate mixture of petroleum ether and ethyl acetate (80:1).
87%	With 1,10-Phenanthroline; tungsten hexacarbonyl; potassium <i>tert</i>-butylate In 1,4-dioxane at 130℃; for 24h;
86%	With 1,10-Phenanthroline; potassium <i>tert</i>-butylate; nickel dibromide In toluene at 130℃; for 48h; chemoselective reaction;

86%	With potassium <i>tert</i>-butylate In toluene at 140℃; for 24h;
85%	With potassium <i>tert</i>-butylate; C₃₈H₃₇ClN₂PRu⁽¹⁺⁾*C₃₂H₁₂BF₂₄^(1-) In neat (no solvent) at 70℃; for 12h; Sealed tube; Inert atmosphere; Schlenk technique; Green chemistry;
80%	With C₃₄H₃₈Cl₄N₆Ni₂; potassium 2-methylbutan-2-olate In toluene at 140℃; for 12h; Inert atmosphere;	2. General procedure for Ni-catalyzed N-alkylation of aromatic amines with alcohols General procedure: To a Young tube, was charged with Ni4 (39 mg, 0.05 mmol), t-AmOK (191 mg, 1.5 mmol) and toluene (4 mL). Stirred the mixture for 2-3 minutes. Then, aromatic amine (1.0 mmol) and alcohol (2.0 mmol) were added. After stirring the resultant mixture at 140 oC for 12 h, the reaction temperature was allowed to cool to room temperature. Solvent was removed in vacuo and the desired product was isolated by column chromatography.
65%	With potassium <i>tert</i>-butylate; C₁₇H₁₉N₅; molybdenum hexacarbonyl In toluene at 120℃; for 24h;	Synthetic Procedures for the Synthesis of Amines: General procedure: A mixture ofaryl amines (0.5 mmol), benzyl alcohol (0.6 mmol), Mo(CO)6 (0.02mmol, 4 mol%), L1 (0.02 mmol, 4 mol%), and KOtBu (0.75 mmol) intoluene (2.0 mL) were allowed to react at 120 C for 24 h under a airatmosphere. The solvent was concentrated under vacuum, and theamines were isolated by flash chromatography.
55%	With potassium <i>tert</i>-butylate In octane at 140℃; for 24h; Inert atmosphere; Sealed tube;
45%	With dimanganese decacarbonyl; potassium <i>tert</i>-butylate In toluene at 20℃; for 48h; Inert atmosphere; Sealed tube;

Reference： [1]Feng, Xinshu; Huang, Ming [Polyhedron, 2021, vol. 205]
[2]Lan, Xiao-Bing; Ye, Zongren; Yang, Chenhui; Li, Weikang; Liu, Jiahao; Huang, Ming; Liu, Yan; Ke, Zhuofeng [ChemSusChem, 2021, vol. 14, # 3, p. 860 - 865]
[3]Vellakkaran, Mari; Singh, Khushboo; Banerjee, Debasis [ACS Catalysis, 2017, vol. 7, # 12, p. 8152 - 8158]
[4]Beller, Matthias; Gawande, Manoj B.; Jagadeesh, Rajenahally V.; Kadam, Ravishankar G.; Li, Xinmin; Ma, Zhuang; Petr, Martin; Zbořil, Radek; Zhou, Bei [Chemical Science, 2022, vol. 13, # 1, p. 111 - 117]
[5]Huang, Ming; Li, Yinwu; Lan, Xiao-Bing; Liu, Jiahao; Zhao, Cunyuan; Liu, Yan; Ke, Zhuofeng [Organic and Biomolecular Chemistry, 2021, vol. 19, # 15, p. 3451 - 3461]
[6]Jiang, Yong; Hu, Miao; Sun, Nan; Hu, Baoxiang; Shen, Zhenlu; Hu, Xinquan; Jin, Liqun [Tetrahedron Letters, 2020, vol. 61, # 51]
[7]Wu, Di; Bu, Qingqing; Guo, Cheng; Dai, Bin; Liu, Ning [Molecular catalysis, 2021, vol. 503]
[8]Subaramanian, Murugan; Ramar, Palmurukan M.; Sivakumar, Ganesan; Kadam, Ravishankar G.; Petr, Martin; Zboril, Radek; Gawande, Manoj B.; Balaraman, Ekambaram [ChemCatChem, 2021, vol. 13, # 20, p. 4334 - 4341]
[9]Huang, Ming; Li, Yukui; Li, Yinwu; Liu, Jiahao; Shu, Siwei; Liu, Yan; Ke, Zhuofeng [Chemical Communications, 2019, vol. 55, # 44, p. 6213 - 6216]

56
[ 92795-47-6 ]
[ 22013-33-8 ]
N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	Stage #1: 2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #2: 6-amino-3,4-benzodioxane In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	5.5 General procedure for the synthesis of substituted 2-oxo-N,4-diphenyl-1,2-dihydroquinoline-3-carboxamide (5a-5m) General procedure: The 2-oxo-4-phenyl-1,2-dihydroquinoline-3-carboxylic acid (0.00066mol), was dissolve in 8mL of dry DMF, to this mixture add HOBt (0.00083mol), and DIC (0.00083mol) were added and stirred at room temperature under nitrogen atmospheric condition. The progress of the reaction was monitored with TLC, stirring was stopped when TLC showed disappearance of acid spot. The resulting mixture was slowly added to a solution of amines (0.00066mol) in dry DMF (2mL), while the temperature was maintained at 0-5°C. Then the reaction mixture was left for stirring at room temperature, till the disappearance of activated ester spot in TLC. After completion of the reaction, the reaction mixture was partitioned with EtOAc and small amount of water. The EtOAc layer was passed over anhydrous sodium sulfate to remove residual water, and then dried under vacuum to give crude product. The crude product was adsorbed and loaded on alumina (70-230) mesh column. The column was eluted with 5-50% methanol in chloroform to give desired compound in yield ranging from 65 to 91%.

Reference： [1]Kumar, Gautam; Sathe, Asawari; Krishna, Vagolu Siva; Sriram, Dharmarajan; Jachak, Sanjay M. [European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1 - 13]

57
[ 848398-41-4 ]
[ 22013-33-8 ]
C₁₄H₁₂ClN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃;	General procedure: A solution of <strong>[848398-41-4]2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (4, 1.89g, 10mmol) in DMSO (10mL) was added commercially available 3,4-dimethoxyaniline (1.53g, 10mmol) and DIPEA (2.58g, 20mmol). The solution was heated to 60C and stirred overnight. Then the solution was poured into water and extracted with EtOAc, the organic layer was washed by brine, dried with anhydrous Na2SO4, and filtered and concentrated under reduced pressure. The crude product was further purified by flash chromatography on silica gel (EtOAc/hexane=1:1) to afford 8 compound 5 (2.00g, yield 65%) as an off-white solid. 1H NMR (400MHz, CDCl3) delta: 6.90-6.81 (m, 3H), 4.88 (s, 2H), 4.42 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4375 - 4381

58
[ 22013-33-8 ]
[ 171361-65-2 ]
trans-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Patent: WO2008/26172,2008,A1

59
[ 50672-84-9 ]
[ 134-81-6 ]
[ 22013-33-8 ]
N-(4-(1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-diphenyl-1H-imidazol-2-yl)naphthalen-4-yl)phenyl)-N-phenylbenzenamine [ No CAS ]

Reference： [1]RSC Advances,2019,vol. 9,p. 6658 - 6680

60
[ 50672-84-9 ]
[ 134-81-6 ]
[ 22013-33-8 ]
2-(1-bromonaphthalen-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-diphenyl-1H-imidazole [ No CAS ]

Reference： [1]RSC Advances,2019,vol. 9,p. 6658 - 6680

61
[ 50672-84-9 ]
[ 84-11-7 ]
[ 22013-33-8 ]
2-(1-bromonaphthalen-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-phenanthro[9,10-d]imidazole [ No CAS ]

Reference： [1]RSC Advances,2019,vol. 9,p. 6658 - 6680

62
[ 104-15-4 ]
[ 22013-33-8 ]
2,3-dihydrobenzo[b][1,4]dioxine-6-diazonium 4-methylbenzenesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: toluene-4-sulfonic acid; 6-amino-3,4-benzodioxane With acetic acid In tetrahydrofuran for 0.0833333h; Cooling with ice; Stage #2: With tert.-butylnitrite In tetrahydrofuran at 0 - 20℃; for 1.16667h;	Diazonium Tosylates 4a-k; General Procedure General procedure: To a stirred ice-cooled solution/suspension of the corresponding aniline(15.0 mmol) in THF (5 mL), a solution of p-toluenesulfonic acidmonohydrate (3.043 mg, 16.0 mmol) in glacial acetic acid (15 mL) wasadded. The resulting suspension was stirred for 5 min and t-BuONO(2.44 mL, 22.5 mmol) was added in one portion. The mixture wasstirred at 0 °C for 20 min, then the ice bath was removed and stirringwas continued for 50 min at ambient temperature. The resulting solutionwas poured into Et2O (150 mL) and the mixture was stirred for 30min. The precipitate was collected by filtration, washed with Et2O(2 × 50 mL) and dried under reduced pressure at 30 °C. The obtainedarenediazonium tosylates were used without any further purification.
	Stage #1: toluene-4-sulfonic acid; 6-amino-3,4-benzodioxane With acetic acid In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: With tert.-butylnitrite In tetrahydrofuran at 0 - 20℃; for 1.16667h;	3-Arylglutaconic acids 1a - p General procedure: To a stirred ice-cooled solution or suspension of the respective aniline (15.0 mmol) in THF (5 mL) was added a solution of p-TsOH·H2O (3.04 g, 16.0 mmol) in glacial AcOH (15 mL). The resulting suspension was stirred for 5 min whereupon t-BuONO (2.44 mL, 22.5 mmol) was added in one portion. The mixture was stirred at 0 °C for 20 min, the ice bath was removed, and the stirring was continued for 50 min at r.t. The resulting solution was poured into Et2O (150 mL) and the mixture was stirred for 30 min. The precipitate of 9 (crystalline in all cases ex- cept for 9d) was separated, washed with Et2O, and dried in vacuo.

Reference： [1]Chuprun, Sergey; Dar'In, Dmitry; Kantin, Grigory; Krasavin, Mikhail [Synthesis, 2019, vol. 51, # 21, p. 3998 - 4005]
[2]Dar'In, Dmitry; Kantin, Grigory; Bakulina, Olga; Žalubovskis, Raivis; Krasavin, Mikhail [Synthesis, 2019, vol. 51, # 10, p. 2230 - 2236]

63
[ 77112-53-9 ]
[ 22013-33-8 ]
N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)imidazo[1,2-a]pyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With 1-methyl-1H-imidazole; 2-chloro-1-methyl-pyridinium iodide; In N,N-dimethyl-formamide; at 80℃; for 0.25h;Inert atmosphere; Microwave irradiation; Sealed tube; Green chemistry;	General procedure: Imidazo[1,2-a]pyrazine-2-carboxylic acid (5) (1.0 equiv.) Mukaiyama?s reagent and 2-chloro-1-methylpyridinium iodide (1.2 equiv.) were suspended in DMF (5.0 mL) under nitrogen atmosphere. Into the reaction mixture, aliphatic/aromatic amines (6a-l) (1.0 equiv.) and 1-methylimidazole (2.0 equiv.) were added. A homogeneous solution was formed after a gentle stirring. The reaction mixture was sealed in a microwave glass reactor and then irradiated by microwave oven at a constant temperature of 80 C with continuous stirring (1 min ramp, 15 min reaction time). After the reaction was completed, the solvent was removed through a rotary evaporator and the resulting residue was extracted by a biphasic system of 45 mL diethyl ether and 45 mL water. After the layer separation, the ether layer was dried by anhydrous sodium sulphate, followed by an evaporation of ether to get compounds 7a-l (Scheme-I).

Reference： [1]Asian Journal of Chemistry,2020,vol. 32,p. 84 - 90

64
[ 762-04-9 ]
[ 22013-33-8 ]
[ 21487-45-6 ]
[(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-(1,3-diphenyl-1Hpyrazol-4-yl)methyl]phosphonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With Porcine Pancreas Lipase In neat (no solvent) at 45℃; Enzymatic reaction;	4.2. General procedure for the synthesis of N-aryl substituted α-aminophosphonate bearing pyrazole moiety General procedure: In a round bottom flask, PPL (20 mg) was added to a mixture of 1Hpyrazole-4-carbaldehyde derivative (1 mmol), substituted amine(1 mmol) and diethyl phosphite (1.2 mmol). The reaction mixture wasthen stirred at 45 °C under solvent-free condition and the progress ofthe reaction was monitored by TLC. After completion of the reaction,enzyme was removed by filtration and the filterate was extracted withdichloromethane. Organic layer was washed with excess of brine anddried over anhydrous Na2SO4. Solvent was concentrated under reducedpressure and the crude product thus obtained was purified by crystallizationusing ethyl acetate: n-hexane (1:4) to give white solid.

Reference： [1]Dhavan, Pratik; Jadhav, B. L.; Pavale, Ganesh; Ramana, M. M. V.; Shaikh, Sarfaraz [Bioorganic Chemistry, 2020, vol. 96]

65
[ 762-04-9 ]
[ 22013-33-8 ]
[ 36663-00-0 ]
diethyl ((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)methyl)phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With Porcine Pancreas Lipase In neat (no solvent) at 45℃; Enzymatic reaction;	4.2. General procedure for the synthesis of N-aryl substituted α-aminophosphonate bearing pyrazole moiety General procedure: In a round bottom flask, PPL (20 mg) was added to a mixture of 1Hpyrazole-4-carbaldehyde derivative (1 mmol), substituted amine(1 mmol) and diethyl phosphite (1.2 mmol). The reaction mixture wasthen stirred at 45 °C under solvent-free condition and the progress ofthe reaction was monitored by TLC. After completion of the reaction,enzyme was removed by filtration and the filterate was extracted withdichloromethane. Organic layer was washed with excess of brine anddried over anhydrous Na2SO4. Solvent was concentrated under reducedpressure and the crude product thus obtained was purified by crystallizationusing ethyl acetate: n-hexane (1:4) to give white solid.

Reference： [1]Dhavan, Pratik; Jadhav, B. L.; Pavale, Ganesh; Ramana, M. M. V.; Shaikh, Sarfaraz [Bioorganic Chemistry, 2020, vol. 96]

66
[ 59923-03-4 ]
[ 22013-33-8 ]
(E)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-ethoxyphenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;	1 (E)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-ethoxyphenyl)acrylamide (E)-3-(2-ethoxyphenyl)prop-2-enoic acid (577 mg, 3.00 mmol) was weighed into a flame-dried 250 mL round bottom flask and placed under an atmosphere of nitrogen. Anhydrous DCM (7.50 mL) was added, and the flask was cooled to 0° C. 3,4-(ethylenedioxy)aniline (453 mg, 3.00 mmol, 369 uL) was added in one portion, followed by EDCHCl (575 mg, 3.00 mmol). The reaction was warmed to ambient temperature and stirred for 1 h. Upon completion, the reaction mixture was diluted with 300 mL ethyl acetate and 100 mL of 1M HCl. The biphasic solution was filtered to remove insoluble material, and the layers were separated. The organic layer washed with an additional portion of 1M HCl (100 mL), saturated aqueous sodium bicarbonate (1100 mL), and brine (1*100 mL). The organic layer was then dried over sodium sulfate, filtered, and condensed in vacuo to give (E)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(2-ethoxyphenyl)prop-2-enamide (0.918 g, 2.82 mmol, 94.0% yield) as a yellow solid, and used without further purification. 1H NMR: (400 MHz, Chloroform-d) δ 8.01 (d, J=15.5 Hz, 1H), 7.49 (d, J=7.0 Hz, 1H), 7.37-7.27 (overlap, 3H), 7.02 (d, J=7.2 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.63 (d, J=15.5 Hz, 1H), 4.29-4.20 (overlap, 4H), 4.10 (q, J=6.5 Hz, 2H), 1.47 (t, J=6.5 Hz, 3H). ESI-MS: [M+H]+ calculated for C19H19NO4 326.131; found 326.459. UV: λ (max) 254.2 nm.

Reference： [1]Current Patent Assignee: BOSTON UNIVERSITY - US2020/39996, 2020, A1 Location in patent: Paragraph 0407-0410

67
[ 955369-56-9 ]
[ 22013-33-8 ]
2-allyl-6-((2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino)-1-(6-( 2-hydroxypropane-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83 mg		To a toluene solution containing the compound Int-1 (100 mg) was added m-CPBA (97 mg), followed by stirring at room temperature for 20 minutes. DIEA (108 mg) and compound A03 (51 mg) were added to the solution, followed by stirring at room temperature overnight. Ethyl acetate (50 mL) was added, and the organic phase was washed three times with a saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo from the filtrate. Petroleum ether / ethyl acetate (3 mL, 2 : 1), a white solid was precipitated, filtered, and the solid was dried to obtain the target product HY-B003 (83 mg).

Reference： [1]Patent: CN110872296,2020,A .Location in patent: Paragraph 0156-0158

68
[ 42276-46-0 ]
[ 22013-33-8 ]
N-(4-bromophenyl)-2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine In N,N-dimethyl-formamide at 80℃; for 4.5h; Microwave irradiation;	N-(4-Bromophenyl)-2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)propanamide (1) A mixture of 2-bromo-N-(4-bromophenyl)propanamide 43(40.0 mg, 0.130 mmol), 2,3-dihydrobenzo[b][1,4]dioxin-6-amine(18.0 μL, 0.143 mmol) and triethylamine (36.0 μL, 0.261 mmol) in DMF (0.7 mL)was heated to 80 oC under microwave irradiation for 4.5 hours.Direct purification of the reaction mixture by MDAP (high pH, Method C)afforded the title compound 1 (30.7mg, 0.081 mmol, 63 % yield) as a light brown gum. 1H NMR (400 MHz,MeOD-d4): δ 1.49 (d, J = 7.1 Hz, 3H), 3.84 (q, J = 7.1 Hz, 1H), 4.11-4.14 (m, 2H),4.16-4.18 (m, 2H), 6.19-6.22 (m, 2H), 6.63-6.66 (m, 1H), 7.42-7.45 (m, 2H),7.48-7.53 (m, 2H). Exchangeable protonsnot observed. 13C NMR (100 MHz, MeOD-d4): δ 19.3, 56.9, 65.4, 65.9, 103.6, 108.4, 117.8, 118.5, 123.1 (2C), 132.8 (2C), 137.8,138.6, 143.3, 145.4, 176.4. νmax (neat): 3318, 2872, 1668, 1626,1589, 1504, 1394, 1320, 1280, 1240, 1208, 1175, 1067, 1008, 920, 884, 823, 743cm-1. HR-MS (ESI): C17H18BrN2O3[M+H+] requires 377.0495, found 377.0513.

Reference： [1]Burley, Glenn A.; Cacho, Monica; Torres, Pedro; Vela-Gonzalez del Peral, Laura; Whitehurst, Benjamin C.; Young, Robert J. [Bioorganic and medicinal chemistry letters, 2020]

69
[ 2322-46-5 ]
[ 22013-33-8 ]
N-(4-bromophenyl)-2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-methylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium hydride In tetrahydrofuran at 20℃;	N-(4-Bromophenyl)-2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-methylpropanamide(7) To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (49.5 mg, 0.328mmol) in THF (2 mL) was added NaH (14.2 mg, 0.355 mmol, 60% wt/wt). Thismixture was stirred for 10 minutes, after which time 2-bromo-N-(4-bromophenyl)-2-methylpropanamide S1 (88.0 mg, 0.273 mmol) in THF (2 mL)was added. The mixture was stirred overnight at room temperature. Water (10 mL)was added and the mixture was extracted with EtOAc (3 x 10 mL). The combinedorganics were washed with brine, dried over MgSO4, and concentrated.The residue was dissolved in MeOH (1 mL) and purified by MDAP (high pH, MethodD) to afford the title compound 7(60.4 mg, 0.154 mmol, 57 % yield) as a light brown solid. 1H NMR (400 MHz,DMSO-d6): δ 1.40 (s, 6H),4.07-4.09 (m, 2H), 4.12-4.14 (m, 2H), 5.45 (s, 1H), 6.05-6.09 (m, 2H), 6.59 (d,J = 8.5 Hz, 1H), 7.44-7.47 (m, 2H),7.62-7.66 (m, 2H), 9.85 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 25.2 (2C), 57.8, 63.6, 64.2, 103.5, 108.5, 114.8,116.9, 121.7 (2C), 131.3 (2C), 135.4, 138.4, 140.6, 143.3, 175.2. νmax(neat): 3296, 2978, 2927, 2875, 1671, 1591, 1503, 1392, 1312, 1282, 1240, 1207,1171, 1068, 1005, 913, 882, 804, 710 cm-1. HR-MS (ESI): C18H20BrN2O3[M+H+] requires 391.0652, found 391.0653.

Reference： [1]Burley, Glenn A.; Cacho, Monica; Torres, Pedro; Vela-Gonzalez del Peral, Laura; Whitehurst, Benjamin C.; Young, Robert J. [Bioorganic and medicinal chemistry letters, 2020]

70
[ 50-00-0 ]
[ 22013-33-8 ]
[ 90609-94-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: formaldehyd; 6-amino-3,4-benzodioxane With sodium methylate In methanol at 20℃; for 20h; Stage #2: With sodium tetrahydroborate In methanol at 40℃; for 3h;	N-Methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (S2) To a solution of sodium methoxide (268 mg, 4.96mmol)in MeOH (3 mL),paraformaldehyde (298 mg, 9.92 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (150 mg, 0.992 mmol) were added. Thismixture was stirred at room temperature for 20 hours. Sodium borohydride (113mg, 2.98 mmol)was then added in portions, and the mixture was stirred for a further 3 hoursat 40 oC. After this time the mixture was filtered and the organicswere removed under reduced pressure. The residue was dissolved in DCM, washedwith water and brine then dried over a hydrophobic frit. The organics wereremoved, under reduced pressure to afford the title compound S2 (153 mg, 0.926 mmol, 93 % yield) as a light brown oilthat was used without further purification. 1H NMR (400 MHz,DMSO-d6): δ 2.58 (d, J = 5.4 Hz, 3H), 4.09-4.11 (m, 2H),4.15-4.17 (m, 2H), 5.16 (q, J = 5.4Hz, 1H), 6.02 (d, J = 2.7 Hz, 1H),6.05 (dd, J = 2.7, 8.6 Hz, 1H), 6.59(d, J = 8.6 Hz, 1H). LCMS (high pH):tR = 0.77 min, [M+H+] 166; (area% total: 97).

Reference： [1]Burley, Glenn A.; Cacho, Monica; Torres, Pedro; Vela-Gonzalez del Peral, Laura; Whitehurst, Benjamin C.; Young, Robert J. [Bioorganic and medicinal chemistry letters, 2020]

71
[ 22013-33-8 ]
[ 98-74-8 ]
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-nitrobenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 6-amino-3,4-benzodioxane With sodium carbonate In water for 0.5h; Stage #2: 4-Nitrobenzenesulfonyl chloride In water at 25℃; for 4h;	N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-nitrobenzenesulfonamide(III) 1,4-Benzodioxane-6-amine(I) (2 mL; 0.02 mol) was suspended in 50 mL distilled water, followed by the addition of 10 mL 10% aqueousNa2CO3 in the reaction mixture and stirred for 0.5 h,after which 4-nitrobenzenesulfonyl chloride (II) (3.61 g;0.016 mol) was added slowly to the reaction contents. The reaction solution was further stirred for 4 h at room temperature and was monitored with TLC untilsingle spot, which indicated the reaction completion.The solid product was collected by filtration, washed with distilled water, and dried to achieve pure N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-nitrobenzenesulfonamide(III) as greenish amorphous powder in 95%yield, mp 122°C, molecular formula C14H12N2O6S,molecular weight 336 g mol-1. IR: 3254 (N-Hstretching), 3048 (C-H stretching of aromatic ring),1644 (C=C stretching of aromatic ring), 1386 (-SO2stretching), 1332 (-NO2 stretching), 1158 (C-O-Cstretching of ether). 1H NMR (CDCl3, 500 MHz):8.30 (br.d, J = 8.7 Hz, 2H, H-3' and H-5'), 7.93 (br.d,J = 8.7 Hz, 2H, H-2' and H-6'), 6.75 (d, J = 8.5 Hz,1H, H-8), 6.65 (d, J = 2.3 Hz, 1H, H-5), 6.52 (dd, J =2.3, 8.5 Hz, 1H, H-7), 4.24 (br.s, 4H, CH2-2 andCH2-3).

Reference： [1]Aziz-ur-Rehman; Irshad, M.; Muhammad, A. Abbasi; Shah, Syed A. Ali; Shahid, M.; Siddiqui, Sabahat Z. [Russian Journal of Bioorganic Chemistry, 2020, vol. 46, # 2, p. 223 - 234][Bioorg. Khim.]

72
2-(1-(2,2-bis(diethoxyphosphoryl)ethyl)-1H-indol-3-yl)-1-oxoacetic acid [ No CAS ]
[ 22013-33-8 ]
tetraethyl-2-(3-(2-(6-(benzo-1,4-dioxane)amino)-2-oxoacetyl)-1H-indol-1-yl)ethane-1,1-diyldiphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 6.25h;	General procedure for the preparaqtion of indolylglyoxylamides 4a-e. General procedure: DMAP (1 mmol) and the corresponding amine (1 mmol) were added to a solution of acids 3a or 3b (1 mmol) in 20 mL of CH2Cl2. Then DIC (1.2 mmol) was added after 15 min. The mixture was stirred for 6 h at 20 °C , then a solution of 1 g of NH4Cl in 20 mL of water was added. The organic layer was separated, washed with 10 mL of water and dried with Na2SO4. After distillation of the solvent in vacuo, the residue was purified chromatographically on silica gel, using a mixture of acetone-hexane (50:50) as an eluent.

Reference： [1]Brel, Valery K.; Artyushin, Oleg I.; Chuprov-Netochin, Roman N.; Leonov, Sergey V.; Semenova, Marina N.; Semenov, Victor V. [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 23]

73
2-(1-(2,2-bis(diethoxyphosphoryl)ethyl)-6-fluoro-1H-indol-3-yl)-2-oxoacetic acid [ No CAS ]
[ 22013-33-8 ]
tetraethyl-2-(6-fluoro-3-(2-(6-(benzo-1,4-dioxane)amino)-2-oxoacetyl)-1H-indol-1-yl)ethane-1,1-diyldiphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 6.25h;	General procedure for the preparaqtion of indolylglyoxylamides 4a-e. General procedure: DMAP (1 mmol) and the corresponding amine (1 mmol) were added to a solution of acids 3a or 3b (1 mmol) in 20 mL of CH2Cl2. Then DIC (1.2 mmol) was added after 15 min. The mixture was stirred for 6 h at 20 °C , then a solution of 1 g of NH4Cl in 20 mL of water was added. The organic layer was separated, washed with 10 mL of water and dried with Na2SO4. After distillation of the solvent in vacuo, the residue was purified chromatographically on silica gel, using a mixture of acetone-hexane (50:50) as an eluent.

Reference： [1]Brel, Valery K.; Artyushin, Oleg I.; Chuprov-Netochin, Roman N.; Leonov, Sergey V.; Semenova, Marina N.; Semenov, Victor V. [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 23]

74
2-(4-((6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid [ No CAS ]
[ 22013-33-8 ]
N-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-2-(4-((6-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃;	General procedure A: Synthesis of compounds 1, 3, 4a-j, and 16. General procedure: Acids such as 7, 11, 14, or 15 (0.14mmol), amine (0.16mmol), HATU (0.16mmol), and Et3N (0.28mmol) were dissolved in anhydrous DMF (1mL). The reaction mixture was stirred at ambient temperature overnight. The completion of the reaction was monitored by LC-MS analysis. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine twice, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography to get the title compound.

Reference： [1]Yan, Wei; Zhang, Lingtian; Lv, Fengping; Moccia, Marialuisa; Carlomagno, Francesca; Landry, Christophe; Santoro, Massimo; Gosselet, Fabien; Frett, Brendan; Li, Hong-yu [European Journal of Medicinal Chemistry, 2021, vol. 216]

75
[ 22013-33-8 ]
[ 2038-44-0 ]
N1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N2-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)-N1’,N2’-dihydroxyoxalamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With triethylamine In ethanol at -10 - 20℃;	2.2.1. Nucleophilic reaction between dichloroglyoxime and substituted aryl amines General procedure: General procedure. Primary aryl amine (2.2 equiv.) in 3 mL ethanol was added into two necked RB flask that contained a solution of dichloro- glyoxime (0.393 g, 2.5 mmol) in 3 mL ethanol (-10 °C). After tri- ethylamine was added, the reaction was allowed to proceed with continued stirring of the solution at room temperature by the time TLC showed the absence of the starting materials (3-4 hours). The resultant solid was gathered by vacuum filtration to give the prod- ucts ( 3a-m ).

Reference： [1]Bayrak, Nilüfer; Mataracı-Kara, Emel; Ozbek-Celik, Berna; Tuyun, Amaç Fatih; Yıldırım, Hatice; Yıldız, Mahmut [Journal of Molecular Structure, 2021, vol. 1242]

76
[ 1514-82-5 ]
[ 201230-82-2 ]
[ 22013-33-8 ]
C₁₂H₁₀F₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With palladium diacetate; ruphos In toluene at 100℃; for 12h;

Reference： [1]Beller, Matthias; Hao, Meng; Huang, Wei-Heng; Li, Yang; Neumann, Helfried; Sun, Ning; Zhang, Cai-Lin [Chemical Science, 2021, vol. 12, # 31, p. 10467 - 10473]

77
[ 762-04-9 ]
[ 591-31-1 ]
[ 22013-33-8 ]
diethyl (((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)(3-methoxyphenyl)methyl)phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With nano ferrite supported glutathione In neat (no solvent) at 20℃; for 0.5h; Microwave irradiation;	General procedure for the synthesis of (((2,3-dihydrobenzo[b][1,4]dioxin-6yl)amino)(-substituted phenyl)methyl) phosphonates (4a-k) General procedure: The reaction mixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (2 mmol), 3-methoxybenzaldehyde(2 mmol), diethylphosphite (2 mmol) and nano-FGT (10 mol%) werestirred in 50mL conical flask under 400W microwave irradiation. The progress of thereaction was monitored by TLC analysis by using ethyl acetate: hexane (7:3) as eluent.After the completion of reaction, the resulting reaction mixture was treated with DCMand filtered to separate the catalyst for reuse. After separation of the catalyst, the filtratewas washed with 20mL of DCM and dried in the oven. The filtrate was quenched with10mL of water and evaporated by using rotary evaporator. Later the residue obtainedwas purified by recrystallization from ethanol to obtain the desire products (4a-k).Spectral data for the compound 4aDiethyl(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)(3-methoxyphenyl)methylphosphonate (4a)Yield 93% (Pale Yellow solid); m.p.: 159-162 C. 1H NMR (400 MHz,) d 7.22 (dd,J14.0, 6.0 Hz, 1H, Ar-H), 7.06-6.95 (m, 2H, Ar-H), 6.78 (d, J8.0 Hz, 1H, Ar-H),6.61 (d, J8.4 Hz, 1H Ar-H,), 6.12 (d, J10.3 Hz, 2H, Ar-H), 4.62-4.51 (d, 2H,P-CH), 4.13-4.10 (dd, J16.5, 9.2 Hz, 6H, O-CH2), 4.09 (d, 8 Hz, 1H, NH) 4.1-3.89(m, 4H, O-CH2), 1.29-1.09 (m, 6H, O-CH2-CH3).13C NMR (101 MHz,) d 159.87,143.96, 141.27, 137.73, 136.38, 129.62, 120.32, 117.64, 113.48, 107.75, 102.80, 77.44,77.12, 76.80, 64.71, 64.18, 63.35, 57.62, 56.12, 55.29, 16.41. 31P NMR (180 MHz): d24.06 ppm. FTIR (cm1): max 3296 (-NH), 1232 (PO), 1016 (P-O-C), 785 (P-C).HRMS (ESI) m/z calcd. for C20H26NO6P [MH] 407.1498, found 407.1498.