Name: 3535-37-3|3,4-Dimethoxybenzoyl chloride|98%
Brand: Ambeed
SKU: A914059
Rating: 97 (32 reviews)

1
[ 934-90-7 ]
[ 3535-37-3 ]
[ 101867-39-4 ]

Reference： [1]Chemicke Zvesti,1957,vol. 11,p. 351,353
Chem.Abstr.,1958,p. 387

2
[ 93-07-2 ]
[ 3535-37-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine; thionyl chloride In benzene	2 Preparation of 6-[N-(3',4'-dihydroxybenzoyl)-amino]caproic acid EXAMPLE 2 Preparation of 6-[N-(3',4'-dihydroxybenzoyl)-amino]caproic acid In a 2-neck 100 ml-round bottom flask, 10.0 g (54.9 m mol) of veratric acid was dissolved in 50 ml of benzene, and after adding 2 to 3 drops of pyridine to the solution, 13 g (109 m mol) of thionyl chloride was dropped into the solution while stirring the solution at room temperature within 3 min. Then the content was heated to 70° to 80° C. on a water bath, and maintained at the temperature for 2 hours under a reflux condenser and agitation. Then, the solvent and excess thionyl chloride were evaporated off under a reduced pressure to obtain 11.0 g of veratroyl chloride as colourless powder in a yield of 100%.
100%	With thionyl chloride In dichloromethane at 40℃; for 4h;	1.1 1) Synthesis of intermediate 1: 0.98 g of 3,4-dimethoxybenzoic acid (5.4 mmol) was dissolved in 40 mL of dichloromethane,Followed by addition of 0.78 mL of SOCl2 (10.8 mmol) at 40 ° C under reflux for 4 h.Evaporated solvent,A white solid,That is, intermediate 1,Yield 100%.
100%	With thionyl chloride at 20℃; for 5h;

100%	Stage #1: Veratric acid With N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.0833333h; Stage #2: With oxalyl dichloride In dichloromethane at 20℃; for 12h;
99%	With thionyl chloride; urea In toluene at 100℃; for 3h;
98%	With oxalyl dichloride In N,N-dimethyl-formamide; benzene for 2h; Ambient temperature;
98%	With thionyl chloride In toluene at 40 - 55℃; for 2.5h;	3 Toluene (312 ml) is charged in a IL 4neck RBF fitted with magnetic stirrer thermowel, water condenser and calcium chloride guard tube. 3, 4-dimethoxy benzoic acid (78 gms ; 0.4286 moles) is charged followed by N,N-dimethylformamide (3 ml) . The reaction mass is heated with stirring to 40°C. Thionyl chloride, 38 ml (61.18gms, 05143 moles) is added at 4O0C over a period of 30 minutes. The reaction mixture is heated to 50-55°C and stir for 2 hours. The reaction is monitored by TLC. After the reaction is complete, the solvent is distilled off completely. The product is directly taken for next stage considering the yield as 98 %.
98%	With thionyl chloride In toluene at 40 - 55℃; for 2.5h;	3 Preparation of 3,4-Dimethoxy Benzoyl Chloride Example-3 Preparation of 3,4-Dimethoxy Benzoyl Chloride Toluene (312 ml) is charged in a 1 L 4 neck RBF fitted with magnetic stirrer thermowel, water condenser and calcium chloride guard tube. 3,4-dimethoxy benzoic acid (78 gms; 0.4286 moles) is charged followed by N,N-dimethylformamide (3 ml). The reaction mass is heated with stirring to 40° C. Thionyl chloride, 38 ml (61.18 gms, 05143 moles) is added at 40° C. over a period of 30 minutes. The reaction mixture is heated to 50-55° C. and stir for 2 hours. The reaction is monitored by TLC. After the reaction is complete, the solvent is distilled off completely. The product is directly taken for next stage considering the yield as 98%.
98.5%	With thionyl chloride Reflux;
83.6%	With thionyl chloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 8h;	1; 2 Example 2: Preparation of 3,4-dimethoxybenzoyl chloride: Add 1821 mg of 3,4-dimethoxybenzoic acid to the reactor.Add 40 ml of tetrahydrofuran,Stirring,0.5 ml of N,N-dimethylformamide was added at room temperature.Then stir at room temperature for 0.5 hours.Add 3 grams of thionyl chloride,The reaction was then stirred at room temperature for 8 hours.After the reaction is completed,After the post-treatment and purification process,The compound 3,4-dimethoxybenzoyl chloride is obtained,The yield was 83.6%.
	With thionyl chloride
	With carbon disulfide; phosphorus(V) chloride
	With carbon disulfide; phosphorus(V) chloride
	With phosphorus(V) chloride
	With phosphorus(V) chloride
	With phosphorus(V) chloride In Carbon tetrachloride
	With oxalyl dichloride In N,N-dimethyl-formamide
	With thionyl chloride In benzene for 1.5h; Heating;
	With thionyl chloride for 3h; Heating;
	With thionyl chloride In benzene at 45 - 50℃; for 0.5h;
	With thionyl chloride at 80℃; for 2.5h; Yield given;
	With thionyl chloride for 1h; Heating;
	With thionyl chloride In benzene
	With thionyl chloride In benzene for 2.5h; Heating;
	With thionyl chloride In dichloromethane for 1h; Heating;
	With thionyl chloride In benzene for 2h; Heating;
	With thionyl chloride for 0.5h; Heating;
	With thionyl chloride for 0.5h; Heating;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 2h; Heating; Yield given;
	With thionyl chloride for 1h; Heating;
	With thionyl chloride In chloroform Heating;
	With thionyl chloride Heating;
	With thionyl chloride for 2h; Heating;
	With thionyl chloride Ambient temperature;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 3h; Ambient temperature;
	With thionyl chloride for 2h; Heating;
	With phosphorus(V) chloride In dichloromethane
	With thionyl chloride; N,N-dimethyl-formamide
	With thionyl chloride for 2h; Ambient temperature;
	With oxalyl dichloride In dichloromethane at 0 - 20℃; for 1h;
	With pyridine; thionyl chloride In benzene for 0.5h; Heating;
	With thionyl chloride for 12h; Heating;
	With thionyl chloride In benzene for 24h; Heating;
	With thionyl chloride for 6h; Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h;
	With thionyl chloride In dichloromethane for 4h; Heating;
5.78 g	With thionyl chloride for 2.5h; Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 4h; cooling;
	With thionyl chloride at 90℃; for 4h;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 2h;
	With thionyl chloride at 80℃; for 1h;
	With thionyl chloride In 1,4-dioxane for 3h; Heating;
	With thionyl chloride In toluene at 70℃; for 2h;
	In thionyl chloride; Petroleum ether	2 PREPARATION 2: PREPARATION 2: 3,4-DIMETHOXYBENZOYL CHLORIDE 20 g (0.1 mole) of 3,4-dimethoxybenzoic acid are suspended in 170 ml of thionyl chloride and refluxed for 2 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes immediately after the addition of petroleum ether. The crystals are spun and washed with petroleum ether. Melting point: 70° C.
	With thionyl chloride	24.iii EXAMPLE 24 (iii) 2.9 g of 3,4-dimethoxybenzoic acid and 4 ml of thionyl chloride were heated for 4 hours at reflux and concentrated under reduced pressure to obtain 3,4-dimethoxybenzoyl chloride.
	With thionyl chloride
	With thionyl chloride for 2h; Reflux;
	With thionyl chloride In dichloromethane at 22℃;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
	With thionyl chloride In toluene for 2h; Heating / reflux;	4 10.1 kg of veratric acid and 27.0 kg of toluene are charged into a reactor, the mixture is heated under reflux (105-1 15°C) and 7.4 kg of thionyl chloride are added dropwise. The mixture is kept under reflux for at least 2 hours, and is EPO distilled under vacuum, to obtain an oily residue which 10.1 kg of toluene are added to. The solution is then brought to 20-50°C, and the aforesaid reaction mixture is added dropwise to a stainless steel reactor, which 13.5 kg of 4-(2- dimethylaminoethoxy)-benzylamine dihydrochloride, 81 kg of toluene, 11.5 kg of triethylamine, were previously charged into, at a temperature ranging from 75 to 80°C.After adding the reaction mixture dropwise, the reaction mixture thus obtained is stirred at 75-80°C for at least two hours. Upon completion of the reaction, 40.5 kg of deionized water are added, 1 1.5 kg of 30% ammonia are added dropwise and the reaction mixture is taken to 55-60°C until complete solution. The aqueous phase is separated and removed. 27.0 kg of deionized water are added and the mixture is cooled to 40-45 °C until obtaining a good degree of precipitation. The mixture is then centrifuged, the precipitate is washed with 10.1 kg of deionized water and the same quantity of toluene. A sample of product is taken and the loss of weight determined; this analysis shows that the wet product contains 16 kg of dry itopride.Reaction yield compared to 4-(2-dimethylaminoethoxy) benzylamine dihydrochloride: 88.3%.
	With thionyl chloride for 4h; Reflux;
	With thionyl chloride at 80℃; for 2h;
	With thionyl chloride In toluene Reflux;
	With thionyl chloride for 2h; Reflux;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 3h; Cooling with ice;
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1.5h; Inert atmosphere;
	With oxalyl dichloride
	With thionyl chloride at 80℃; for 2h;
	With thionyl chloride for 2h; Reflux;	7.3.4. General procedure C (acid chloride synthesis) General procedure: The benzoic acid was mixed with SOCl2. The mixture was heated at reflux for 2 h. The solvent was evaporated in vacuo. The solid was dissolved in DCE (20 mL) and the mixture was concentrated in vacuo. This afforded the acid chloride, which was immediately used in the crude form.
	With thionyl chloride for 2h; Reflux;
	With thionyl chloride In N,N-dimethyl-formamide; toluene at 20℃; Inert atmosphere;	4.2. General procedure for the preparation of a solution of acid chlorides in CH₂Cl₂ General procedure: To a solution of carboxylic acids (1.7 mmol) in dry DMF (100 μL) and dry toluene (15 mL) under nitrogen atmosphere, freshly distillated thionyl chloride (3.4 mmol) was added and the solution was stirred at room temperature overnight. The solvent and thionyl chloride were removed under vacuum. The acid chloride was dissolved with dichloromethane (15 mL) under nitrogen atmosphere and directly used for the synthesis of the boronic acid.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane	1 ,4-dimethoxybenzoic acid (1) (l.OOg , 5.5 mmol) was slurried in 5 mL of DCM . Oxalyl chloride (0.9 mL, 10.5 mmol) was then added, and five drops of DMF were added to initiate the reaction. The mixture was stirred overnight during which time it became a yellow solution. The solution was concentrated and dried in vacuo to remove the solvent and oxalyl chloride. The resultant solid was redissolved in 7 mL of DCM, cooled to -78 °C, and 1.5 mL of pyridine was added. Then, 0.696 g of 2-bromo-4,5-dimethoxy aniline (3 mmol) was added in 5 mL of DCM. A solid formed causing stirring to be difficult, and therefore, an additional 6 mL portion of DCM was added. The mixture was warmed to 23 °C, and after the reaction was complete, quenched with 20 mL of water. The layers were separated, the organic was washed with 20 mL of brine, dried with Na2S04, and concentrated. The crude product was purified by columnchromatography and then PTLC (0.5% MeOH in DCM as eluent) to give 1.05 g (88% yield) of benzamide (2) as an off-white solid. 1H NMR (200 MHz, CDC13) δ 8.25 (bs, 2H, overlapping peak), 7.57 (d, / = 2 Hz, 1H), 7.48 (dd, / = 2 Hz, 8.4 Hz, 1H), 7.06 (s, 1H), 6.98 (d, / = 8.4 Hz, 1H), 4.09-3.99 (3 overlapping singlets, 9H), 3.90 (s, 3H).
	With thionyl chloride In N,N-dimethyl-formamide at 70℃; for 4h;
	With thionyl chloride for 3h; Reflux; Inert atmosphere;	N-(5-Hydroxypentyl)-3,4-dimethoxybenzamide (5c): A mixture of 3,4-dimethoxylbenzoic acid (600 mg) in thionyl chloride (5.6 mL) was refluxed under nitrogen for 3 h. The excess thionyl chloride was removed under reduced pressure and the resulting residue was dried under vacuum to get a solid, which was added 9 mL of dry dichloromethane (9 mL) to make a solution of 3,4-dimethoxybenzoic chloride in dichloromethane with a concentration of ~0.36 M. To a mixture of 5-amino-1-pentanol (113 mg, 1.10 mmoL) and triethylamine (0.31 mL, 2.2 mmol) in 2 mL dichloromethane, was added the solution of 3,4-dimethoxybenzoic chloride in dichloromethane (0.36 M, 3 mL). The resulting mixture was stirred at room temperature for 1 h. Aqueous workup and purification by column chromatography on silica gel provided the desired product (265 mg, 90%) as a white solid.
	With oxalyl dichloride; N,N-dimethyl-formamide at 20℃; for 1h;
	With thionyl chloride for 2h; Reflux;
	With thionyl chloride for 3h; Reflux;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 5h; Inert atmosphere;
	With thionyl chloride at 60 - 80℃;
	With thionyl chloride at 75℃; for 6h; Inert atmosphere;	General procedure for the preparation of 3m-3p General procedure: The mixture of suitable substituted benzoic acid (5a-5d, 0.01 mol) and thionyl chloride (5 ml) was stirred at 75 °C for 6 h under nitrogen. After removal of excess thionyl chloride in vacuo, 4-methoxy-2-nitroaniline (1b, 0.01 mol) and anhydrous Na2CO3 (0.1 mol) were added to the reaction mixture dissolved in anhydrous acetone (50 ml). After stirring at 54 °C for 1 h, the solvent was removed under vacuum and the residue was poured into ice water with stirring. The precipitated solid was fitered, washed with ice water and dried to obtain the corresponding N-phenylbenzamide derivatives (7a-7d). To a solution of N-phenylbenzamide derivatives (7a-7d, 0.01 mol) in anhydrous acetic acid (50 ml) was added iron powder (0.03 mol), and then the mixture was refluxed at 100 °C. After completion of the reaction as indicated by TLC, the solvent was evaporated under reduced pressure and the residue was extracted with CH2Cl2 (3 × 20 mL). The combined organic fractions were washed with saturated NaHCO3, brine, dried (Na2SO4), and evaporated in vacuo. The residue was chromatographed on silica gel using petroleum ether/EtOAc (10:1-4:1).
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane	4.2.28 General benzanilide synthesis, Method A General procedure: The benzoyl chloride was prepared by stirring benzoic acid (1.0 mmol) with SOCl2 (0.363 mL, 5.0 mmol) and DMF (1 drop) in CH2Cl2 (5 ml) for overnight and evaporating the volatile materials under reduced pressure. To the solution of benzoyl chloride in CH2Cl2 (5mL) were added an aniline (1.0 mmol) and DIEA (0.871 mL, 5.0 mmol), and the reaction was stirred until no starting material by TLC (1-24 h) at room temperature. After dilution with CH2Cl2 (30mL), the organic layer was washed with brine (40 mL), dried with anhydrous MgSO4, and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography to obtain a benzanilide.
	With phosphorus(V) chloride
	With thionyl chloride; N,N-dimethyl-formamide at 60℃; for 3h;
	With thionyl chloride In dichloromethane at 20℃; for 18h; Inert atmosphere;	(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-(3,4-dimethoxyphenyl)-methanone (5a) (CAS no: 328023-12-7)⁴ To 3,4-dimethoxybenzoic acid (364mg, 2.0mmol) in 3ml of CH2Cl2 was added SOCl2 (218μl, 3.0mmol) dropwise over 5 min under nitrogen atmosphere. The mixture was stirred at room temperature for 18 h. Excess SOCl2 and CH2Cl2 were removed in vacuo to afford crude (9a). (9a) was not purified but was used immediately for the subsequent step.
	With thionyl chloride Reflux;	3.2. Synthesis of ethyl 4-(3-benzoylthioureido) benzoates (1a-j) General procedure: Variously substituted benzoic acids (0.02 mol) were treatedwith 2 mL (1.3 eq) of thionylchloride through a dropping funneland the reaction mixture was heated under reflux for 2-3 h yieldscorresponding acid chlorides. To a stirred solution of potassiumthiocyanate (1.2 g, 0.02 mol) in 10 mL dry acetone, placed in roundbottom flask fitted with a reflux condenser. (1.5 mL, 0.02 mol) offreshly prepared acid chlorides was added drop wise. After the initialreaction had subsided a solution of ethyl 4-animobenzoate(0.02 mol) in acetone (20 mL) was added slowly with constantstirring followed by reflux for 1-2 h. The mixture was poured intocrushed ice when the ethyl 4-(3-benzoylthioureido) benzoates(1a-j) precipitated as solid. The solid product was filtered, thendried and recrystallized from suitable solvent.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 2h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; Schlenk technique;
	With thionyl chloride In toluene at 100℃; for 6h;
	With thionyl chloride for 2h; Reflux;	29 General procedure for antagonists synthesis (1, 4a-n) General procedure: A mixture of commercial carboxylic acid in freshly distilled thionyl chloride is warmed into reflux for 2 h, then cooled to room temperature and evaporated under vacuum to dryness to afford quantitatively corresponding acid chlorides (3). This crude material might be used without further purification. A mixture of these acid chloride (1.0 equiv) and ammonium thiocyanate (1.0 equiv) is heated in refluxing dry acetone for 1h. Then, the mixture is cooled to room temperature, and a solution of benzimidazole in dry acetone is carefully added. The mixture is warmed again for 1 h, then cooled to 0 °C, and hydrolyzed with ice. The precipitate is washed with cold water and crude material is crystallized into ethanol.
	With thionyl chloride; N,N-dimethyl-formamide at 80 - 90℃; for 2h; Reflux;	General procedure: A solution of 4-methoxybenzoic acid 1a (1.0 g) and DMF (catalytic amount) in thionyl chloride (5 mL) was stirred at 80-90°C for 2 h. After reclaimed the thionyl chloride under reduced pressure, 4-methoxybenzoyl chloride 2a was yielded. 4-methoxybenzoyl chloride 2a was dissolved in dried CH2Cl2 and reacted with excess furan (5mL) catalyzed by AlCl3. The reaction mixture was stirred at 0°C for 2 h and then warmed to room temperature and stirred for additional 12 h. After the reaction was completed, the reaction was quenched by carefully pouring the mixture into iced water (100 mL) and the resultant compound was collected by filtration. Then, the filtrate was extracted with CH2Cl2 (320mL), and dried with anhydrous Na2SO4. The solvent was removed under reduced pressure to yield brown solid. The brown solid was purified by silica gel column chromatography (Petroleum ether/EtOAc 80:20, v/v) to give compound 3a as light yellow solid. 10% (eq) BBr3 (5 mL) was added to a solution of compound 3a in CH2Cl2 (20 mL). The reaction mixture was stirred at -78°C for 30 min and then warmed to room temperature and stirred for additional 3.5 h. After the reaction was completed, it was quenched by carefully pouring the mixture into iced water (100 mL), extraction of the aqueous layer three times with EtOAc, washing with 5% NaHSO3 (40 mL) and water (100 mL), and drying with anhydrous Na2SO4. The solvent was removed under reduced pressure to yield a light red solid 4a (0.643 g, 58% yield).
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0℃; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0℃; Inert atmosphere;
	With thionyl chloride for 0.5h; Inert atmosphere; Reflux;
	With thionyl chloride Reflux;
	With thionyl chloride Reflux;
	With oxalyl dichloride In N,N-dimethyl-formamide at 20℃; for 1h;
	With thionyl chloride; N,N-dimethyl-formamide for 3.5h; Reflux; Schlenk technique;	51 4.2.51 3,4-Dimethoxy-N-(4-phenylpiperazin-1-yl)benzamide (10) A 25 mL Schlenk tube was charged with 100 mg (549 μmol, 1.00 equiv) 3,4-dimethoxybenzoic acid, 218 mg (140 μL, 1.83 mmol, 3.33 equiv) thionylchloride and one catalytic drop of anhydrous DMF. The light yellow suspension was heated under reflux for 3.5 h. The excess thionylchloride was removed under high vacuum over a cooling trap to obtain a light yellow solid (acid chloride). A 25 mL one-neck round bottom flask was charged with 117 mg (659 μmol, 1.20 equiv) 4-phenylpiperazin-1-amine and 2.0 mL 10% aqueous NaOH (2.0 mL). The solution was cooled to 0 °C and a solution of the acid chloride in 1 mL absolute DCM was added. The mixture was stirred at rt for 30 min, during which a colorless solid precipitated. The solid was collected by filtration, washed with DCM and dried under vacuum. Final purification by recrystallization from EtOH (25 mL) yielded the pure product.

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[56]Current Patent Assignee: ADIR - US5332735, 1994, A
[57]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US4239903, 1980, A
[58]Location in patent: experimental part Narasimhan, Balasubramanian; Ohlan, Sucheta; Ohlan, Ruchita; Judge, Vikramjeet; Narang, Rakesh [European Journal of Medicinal Chemistry, 2009, vol. 44, # 2, p. 689 - 700]
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[61]Location in patent: scheme or table Uto, Yoshikazu; Ogata, Tsuneaki; Harada, Jun; Kiyotsuka, Yohei; Ueno, Yuko; Miyazawa, Yuriko; Kurata, Hitoshi; Deguchi, Tsuneo; Watanabe, Nobuaki; Takagi, Toshiyuki; Wakimoto, Satoko; Okuyama, Ryo; Abe, Manabu; Kurikawa, Nobuya; Kawamura, Sayako; Yamato, Michiko; Osumi, Jun [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4151 - 4158]
[62]Current Patent Assignee: ERREGIERRE SPA. - WO2006/51079, 2006, A1 Location in patent: Page/Page column 6-7
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[65]Location in patent: scheme or table Czaplewski, Lloyd G.; Collins, Ian; Boyd, E. Andrew; Brown, David; East, Stephen P.; Gardiner, Mihaly; Fletcher, Rowena; Haydon, David J.; Henstock, Vincent; Ingram, Peter; Jones, Clare; Noula, Caterina; Kennison, Leanne; Rockley, Chris; Rose, Valerie; Thomaides-Brears, Helena B.; Ure, Rebecca; Whittaker, Mark; Stokes, Neil R. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 2, p. 524 - 527]
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[74]Current Patent Assignee: PROTAMED, INC. - WO2012/118935, 2012, A1 Location in patent: Page/Page column 31-32
[75]Kümmerle, Arthur E.; Schmitt, Martine; Cardozo, Suzana V. S.; Lugnier, Claire; Villa, Pascal; Lopes, Alexandra B.; Romeiro, Nelilma C.; Justiniano, Hélène; Martins, Marco A.; Fraga, Carlos A. M.; Bourguignon, Jean-Jacques; Barreiro, Eliezer J. [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7525 - 7545]
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[81]Gao, Xi-Ai; Wang, Xian-Xue; Yan, Hao; Li, Jian; Yan, Ru-Long; Huang, Guo-Sheng [Journal of the Indian Chemical Society, 2013, vol. 90, # 3, p. 381 - 385]
[82]Zhou, Binhua; Li, Baojian; Yi, Wei; Bu, Xianzhang; Ma, Lin [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3759 - 3763]
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3
[ 134-20-3 ]
[ 3535-37-3 ]
[ 67836-52-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine In dichloromethane at 20℃; for 0.5h;	1 Methyl 2-aminobenzoate (compound A) (2.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (2.0 ml) and 3,4-dimethoxybenzoyl chloride (compound B) (3.14 g) were added to the solution at room temperature, and the mixture was stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated to give methyl 2-[(3,4-dimethoxybenzoyl)amino]benzoate as a useful intermediate (4.17 g, yield 100%).
	With triethylamine In benzene for 3h; Ambient temperature;

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1614676, 2006, A1 Location in patent: Page/Page column 43
[2]Stephen; Wadge [Journal of the Chemical Society, 1956, p. 4420]
[3]Kirino; Yamamoto; Kato [Agricultural and Biological Chemistry, 1980, vol. 44, # 9, p. 2149 - 2153]

4
[ 6315-89-5 ]
[ 3535-37-3 ]
[ 59699-54-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine In dichloromethane
88%	With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere;	2. General procedure 1: preparation of 3,4-dimethoxyanilides 1 General procedure: To a solution of 3,4-dimethoxyaniline (0.77 g, 5.0 mmol) in CH2Cl2 (8.0 mL) was added pyridine (4.0 mL, 50 mmol) and benzoyl chloride (0.70 g, 5.0 mmol) in CH2Cl2 (2.0 mL) at 0 °C, and stirred at room temperature under argon. The reaction was monitored by TLC. The resulting mixture was quenched with 1M HCl, extracted with CH2Cl2 (3 x 20 mL). The combined organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The crude compounds were purified with silica gel column chromatography (EtOAc : hexane = 1 : 2) and recrystallized from EtOAc/hexane to get the target anilide 1a (0.62 g, 48%).
	With diethyl ether; potassium carbonate

With triethylamine In dichloromethane

Reference： [1]Moreno; Tellitu; Etayo; SanMartín; Domínguez [Tetrahedron, 2001, vol. 57, # 25, p. 5403 - 5411]
[2]Fujimoto, Shigenobu; Matsumoto, Kenji; Iwata, Takayuki; Shindo, Mitsuru [Tetrahedron Letters, 2017, vol. 58, # 10, p. 973 - 976]
[3]Easson; Pyman [Journal of the Chemical Society, 1931, p. 2991,2994]
[4]Gita, Haruhisa; Sobe, Yoshiaki; Akaku, Haruo; Ekine, Rena; Oto, Yuso; Isawa, Satoru; Hayashi, Hideya [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 549 - 551]

5
[ 3535-37-3 ]
[ 71-43-2 ]
[ 10425-11-3 ]

Reference： [1]Journal of the American Chemical Society,1949,vol. 71,p. 3663

6
[ 3535-37-3 ]
[ 4402-32-8 ]
[ 101450-70-8 ]

Reference： [1]Dubravkova et al. [Chemicke Zvesti, 1957, vol. 11, p. 351,353][Chem.Abstr., 1958, p. 387]

7
[ 3535-37-3 ]
[ 1521-41-1 ]

Reference： [1]Monatshefte fur Chemie,1901,vol. 22,p. 418
Monatshefte fuer Chemie,1906,vol. 27,p. 43
[2]Organic Letters,2005,vol. 7,p. 4777 - 4779
[3]Acta Chimica Academiae Scientiarum Hungaricae,1980,vol. 103,p. 259 - 270
[4]European Journal of Medicinal Chemistry,2009,vol. 44,p. 689 - 700
[5]Journal of Medicinal Chemistry,2009,vol. 52,p. 3366 - 3376
[6]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 524 - 527

8
[ 3535-37-3 ]
[ 120-29-6 ]
[ 500-56-1 ]

Yield	Reaction Conditions	Operation in experiment
66%	With dmap; triethylamine In dichloromethane at 20℃; for 12h; Inert atmosphere;	8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxybenzoate (3) To a solution of commercial endo-tropine (1 g, 7.08 mmol, 1 equiv) in anhyd DCM were added 2,3-dimethoxybenzoyl chloride (1.562 g, 7.78 mmol, 1.1 equiv), NEt3 (2.961 mL, 21.2 mmol, 3 equiv), and 4-dimethylaminopyridine (0.951 g, 7.78 mmol, 1.1 equiv) under argon atmosphere. The reaction mixture was stirred at rt overnight before being cooled at 0 °C and quenched with sat. aq NH4Cl. The aqueous layer was extracted with DCM (3 ×). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel yielded the desired product (4.53 mmol) as a white solid; yield: 64 % (4.53 mmol); mp 223-224 °C; Rf = 0.58 (85:15 DCM/MeOH). IR (neat): 2939, 2361, 1703, 1600, 1514, 1467, 1449, 1417, 1345, 1272, 1220, 1175, 1133, 1025, 877, 764, 632 cm-1.1H NMR (300 MHz, CDCl3): = 7.56 (dd, J1 = 8.4 Hz, J2 = 1.9 Hz, 1 H,H6′), 7.51 (d, J = 1.9 Hz, 1 H, H2′), 6.90 (d, J = 8.4 Hz, 1 H, H5′), 5.37 (m, 1H, H3), 3.94 (s, 3 H, H7′), 3.92 (s, 3 H, H8′), 3.78 (br s, 2 H, H1,5), 2.77 (s, 3H, H9), 2.55-2.25 (m, 6 H, H2,4,6,7), 2.20-2.05 (m, 2 H, H6,7). 13C NMR (75 MHz, CDCl3): = 165.19 (C8), 153.53 (C4′), 149.06 (C3′),123.14 (C6′), 122.38 (C1′), 112.10 (C2′), 110.53 (C5′), 65.19 (C3), 61.91(C1,5), 56.22 (C7′), 56.15 (C8′), 40.21 (C9), 34.49 (C2,4), 24.95 (C6,7). MS: m/z = 306.1705 ([M + H]+).
	With toluene

Reference： [1]Alami, Mouad; Ghermani, Noureddine; Hassine, Manel; Jannet, Hichem Ben; Messaoudi, Samir [Synthesis, 2020, vol. 52, # 3, p. 450 - 458]
[2]Orechoff; Konowalowa [Chemische Berichte, 1934, vol. 67, p. 1153,1156] Orechoff; Konowalowa [Zhurnal Obshchei Khimii, 1937, vol. 7, p. 646,651][Chemisches Zentralblatt, 1937, vol. 108, # II, p. 77]

9
[ 13330-96-6 ]
[ 3535-37-3 ]
[ 36686-11-0 ]

Reference： [1]Pharmaceutical Chemistry Journal,1972,vol. 6,p. 14 - 17
Khimiko-Farmatsevticheskii Zhurnal,1972,vol. 6,p. 15 - 18

10
[ 141-97-9 ]
[ 3535-37-3 ]
[ 4687-37-0 ]

Yield	Reaction Conditions	Operation in experiment
448 g	With potassium hydroxide; In water; at 0 - 25℃; for 4h;pH 10 - 11;	260 grams of ethyl acetoacetate was added to 880 grams of purified water.Cooled to 0 to 5 C;84 ml of a 30% strength potassium hydroxide solution was added to the solution.Adjust the pH of the solution to 10~11,Then, a residual potassium hydroxide solution having a mass concentration of 30% and all 3,4-dimethoxybenzoyl chloride are simultaneously added dropwise.Keep the reaction temperature not exceeding 10 C,After the addition is completed, the temperature is raised to 25 C.Insulation reaction for 4 hours,Quenching the reaction by adding ammonium chloride,Continue to stir for 20 hours.Finally add the remaining purified water,Stir,Rest,Layered,The lower layer was collected and dried over anhydrous sodium sulfate.448 g of an oily liquid ethyl 3,4-dimethoxybenzoylacetate;

Reference： [1]Journal of Agricultural and Food Chemistry,2005,vol. 53,p. 9566 - 9570
[2]Pharmaceutical Chemistry Journal,1988,vol. 22,p. 26 - 30
Khimiko-Farmatsevticheskii Zhurnal,1988,vol. 22,p. 35 - 39
[3]Patent: CN109369592,2019,A .Location in patent: Paragraph 0037; 0046; 0055; 0064; 0073; 0082; 0091; 0100

11
[ 1990-24-5 ]
[ 3535-37-3 ]
[ 86253-61-4 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1983,p. 475 - 482

12
[ 2295-58-1 ]
[ 3535-37-3 ]
[ 22395-16-0 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1992,vol. 31,p. 391 - 395
[2]Phytochemistry,1983,vol. 22,p. 243 - 246

13
[ 20059-73-8 ]
[ 3535-37-3 ]
[ 122898-67-3 ]

Yield	Reaction Conditions	Operation in experiment
89.3%	With N-ethyl-N,N-diisopropylamine; In toluene; at 70℃; for 2h;Cooling with ice;	60g (0.309mol) dissolved in 300ml of oil IX of toluene, was added 44.6g (0.346mol) of diisopropylethylamine under ice-bath solution containing 52g (0.309mol)Of a toluene solution of 3,4-dimethoxybenzoyl chloride, the dropwise addition was heated to 70 , the reaction was continued for 2 hours. After completion of the reaction was added 500ml of water, washed once, and then adjusted to pH 3 aqueous hydrochloric acid, aqueous layer , extracted twice with toluene, basified aqueous layer was then adjusted to a pH of 9-10 to give 90.0 g of white solid itopride, yield 89.3%;
		1) Preparation of 3,4-dimethoxybenzoic acid solution (solution A) 10 mmol of 3,4-dimethoxybenzoic acid was dissolved in 50 ml of CH 2 Cl 2 and stored at -10 C.2) Preparation of Oxalyl Chloride Solution (Solution B) 12 mmol of oxalyl chloride was dissolved in 50 ml of CH2Cl2 and stored at -10 C.3) Preparation of ADPA solution (C solution) After dissolving 10 mmol of ADPA in 100 ml of CH2Cl2, 20 mmol of triethylamine was added and the mixture was stored at -10 C.4) Preparation of itopride The solution A and the solution B were respectively pumped and mixed at a T-junction maintained at -10 C, and then passed through a microchip at 30 C. The solution C was pumped into the reaction mixture of A and B, mixed at the T junction maintained at -10 C, and then passed through a microchip at 100 C.5) Reaction termination and separation The reaction was terminated by addition of 30% aqueous ammonia, and extracted three times with CH2Cl2 to collect an organic layer. The organic layer is washed once with brine, dehydrated with MgSO4 and filtered. The final filtrate was distilled under reduced pressure to remove the organic solvent to obtain itopride.

Reference： [1]Patent: CN105985257,2016,A .Location in patent: Paragraph 0007; 0014
[2]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 202 - 211
[3]Patent: KR101819771,2018,B1 .Location in patent: Paragraph 0023; 0058-0067

14
[ 63-64-9 ]
[ 3535-37-3 ]
[ 59699-59-1 ]

Reference： [1]Journal of the American Chemical Society,1980,vol. 102,p. 6513 - 6519

15
[ 13375-29-6 ]
[ 3535-37-3 ]
[ 94621-56-4 ]

Reference： [1]Helvetica Chimica Acta,1963,vol. 46,p. 1059 - 1060

16
[ 141-78-6 ]
[ 3535-37-3 ]
[ 4687-37-0 ]

Reference： [1]Tetrahedron Asymmetry,1996,vol. 7,p. 1077 - 1088
[2]European Journal of Organic Chemistry,2011,p. 6314 - 6319

17
[ 617-89-0 ]
[ 3535-37-3 ]
N-(furan-2-ylmethyl)-3,4-dimethoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With Amberlite IRA-68 In ethyl acetate Ambient temperature;
50%	With triethylamine In dichloromethane at 20℃; Cooling with ice;	15 Example 15 Take a 100ml single bottle,Add 10ml of anhydrous methylene chloride,0.31 g of triethylamine and 0.1 g of 2-furanamine were stirred and dissolved.A solution of 0.31 g of 3,4-dimethoxybenzoyl chloride dissolved in dichloromethane was added dropwise on an ice bath.Stir overnight at room temperature. After the reaction was completed, quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated.Column chromatography gave the target compound 3o 0.13 g (50%).
50%	With triethylamine In dichloromethane at 0 - 20℃;	General Procedure for Synthesis of Compounds (3a-3q) General procedure: To a mixture of Methyl 2-aminothiophene-3-carboxylate (0.1 g, 636.18 umol, 1.0 eq.) and triethylamine (0.19 g, 1.91 mmol, 3.0 eq.) in anhydrous dichloromethane (10 mL), 3,4,5-Trimethoxybenzoyl chloride 2a (0.22 g, 954.28 umol,1.5 eq.) in dichloromethane was slowly added at 0 °C. After stirring at r.t overnight, the reaction mixture was diluted with water (3×10 mL), and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to afford compound 3a.

Reference： [1]Gayo, Leah M.; Suto, Mark J. [Tetrahedron Letters, 1997, vol. 38, # 4, p. 513 - 516]
[2]Current Patent Assignee: SHANGHAI INSTITUE OF TECHNOLOGY - CN107721975, 2018, A Location in patent: Paragraph 0063; 0064; 0065
[3]Yang, Yan; Yao, Zhiyi [Letters in drug design and discovery, 2018, vol. 15, # 12, p. 1319 - 1328]

18
[ 3535-37-3 ]
[ 71-43-2 ]
[ 4038-14-6 ]

Reference： [1]Journal of medicinal chemistry,1997,vol. 40,p. 2140 - 2147

19
[ 5004-88-6 ]
[ 3535-37-3 ]
2-(3,4-Dimethoxy-benzoylamino)-4,5-dimethoxy-benzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 549 - 551

20
[ 5020-41-7 ]
[ 3535-37-3 ]
3,4-dimethoxybenzoic acid 2-(3-methoxyphenyl)ethyl ester [ No CAS ]

Reference： [1]Synthesis,2003,p. 1693 - 1698
[2]Organic Process Research and Development,2007,vol. 11,p. 1015 - 1024

21
[ 5396-18-9 ]
[ 3535-37-3 ]
[ 460744-74-5 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 6466 - 6475
[2]RSC Advances,2016,vol. 6,p. 64544 - 64556

22
[ 14080-51-4 ]
[ 3535-37-3 ]
2-(3,4-dimethoxy-benzoylamino)-thiophene-3-carboxylic acid amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3282 - 3286

23
[ 77651-38-8 ]
[ 3535-37-3 ]
2-(3,4-dimethoxybenzamido)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3282 - 3286

24
[ 3535-37-3 ]
[ 212512-28-2 ]
[ 1026457-04-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With pyridine for 18h; Heating;
67%	With dmap; N-ethyl-N,N-diisopropylamine at 80℃; Sealed tube;	4.12.2. N-(3,5-dimethoxy-2-(2-methoxyacetyl)phenyl)-3,4-dimethoxybenzamide (33) N,N-Diisopropylethylamine (1.00 mL, 5.93 mmol) and 4-dimethylaminopyridine (0.044 g, 0.36 mmol) were added to a solutionof 31 (0.40 g, 1.80 mmol) and 3,4-dimethoxybenzoyl chloride(0.38 g,1.90 mmol) in DCM (4 mL). The reaction mixturewas stirredovernight at 80 C in a sealed tube. The reaction was quenched by addition of water and extracted with DCM (3 20 mL). The combinedorganic layers were dried over MgSO4 and evaporated todryness under reduced pressure. The residue was crystallized fromethanol to obtain the amide 33 (0.50 g, 67%).

Reference： [1]Sui, Zhihua; Nguyen, Van N.; Altom, Jason; Fernandez, Jeffrey; Hilliard, Jamese J.; Bernstein, Jeffrey I.; Barrett, John F.; Ohemeng, Kwasi A [European Journal of Medicinal Chemistry, 1999, vol. 34, # 5, p. 381 - 387]
[2]Albiñana, Carlos Berenguer; Brynda, Jiří; Fanfrlík, Jindřich; Flieger, Miroslav; Hodek, Jan; Karlukova, Elena; Kožíšek, Milan; Konvalinka, Jan; Machara, Aleš; Majer, Pavel; Radilová, Kateřina; Weber, Jan; Zima, Václav [European Journal of Medicinal Chemistry, 2020, vol. 208]

25
[ 3535-37-3 ]
[ 256642-33-8 ]
N-(2-acetyl-3,5-dimethoxyphenyl)-3,4-dimethoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; N-ethyl-N,N-diisopropylamine In toluene at 80℃; Sealed tube;	4.12.1. N-(2-Acetyl-3,5-dimethoxyphenyl)-3,4-dimethoxybenzamide (32) N,N-Diisopropylethylamine (1.00 mL, 5.93 mmol) and 4-dimethylaminopyridine (0.024 g, 0.19 mmol) were added to a solutionof 30 (0.38 g, 1.97 mmol) and 3,4-dimethoxybenzoyl chloride(0.44 g, 2.17 mmol) in toluene (3 mL). The reaction mixture wasstirred overnight at 80 C in a sealed tube. The reaction wasquenched by addition of water and extracted with DCM(3 20 mL). The combined organic layers were dried over MgSO4and evaporated to dryness under reduced pressure. The residuewas crystallized from ethanol to obtain the amide 32 (0.70 g, 95%).
	With pyridine Heating;

Reference： [1]Albiñana, Carlos Berenguer; Brynda, Jiří; Fanfrlík, Jindřich; Flieger, Miroslav; Hodek, Jan; Karlukova, Elena; Kožíšek, Milan; Konvalinka, Jan; Machara, Aleš; Majer, Pavel; Radilová, Kateřina; Weber, Jan; Zima, Václav [European Journal of Medicinal Chemistry, 2020, vol. 208]
[2]Sui, Zhihua; Nguyen, Van N.; Altom, Jason; Fernandez, Jeffrey; Hilliard, Jamese J.; Bernstein, Jeffrey I.; Barrett, John F.; Ohemeng, Kwasi A [European Journal of Medicinal Chemistry, 1999, vol. 34, # 5, p. 381 - 387]

26
[ 2328-12-3 ]
[ 3535-37-3 ]
(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-(3,4-dimethoxyphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydroxide In dichloromethane; water at 20℃; for 3h;	(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-(3,4-dimethoxyphenyl)-methanone (5a) (CAS no: 328023-12-7)⁴ NaOH (140mg, 3.5mmol) was dissolved in 10 ml of distilled water and added to a suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (266mg, 1.16mmol) in 5ml of CH2Cl2. To this mixture was added crude (9a), pre-dissolved in 5ml of CH2Cl2, in a dropwise manner and stirred vigorously at room temperature for 3h. The reaction mixture was extracted with CH2Cl2 and the organic layer washed with saturated NaHCO3 solution and dried over anhydrous Na2SO4. Purification by flashcolumn chromatography (2:1 EtOAc/Hexanes) afforded (5a) as a cream solid, 60%. 1H NMR (400 Mhz, CDCl3): 6.972-6.991 (m, 2H), 6.824 (d, J = 8.01 Hz, 1H), 6.574 (s, 1H), 6.498 (s, 1H), 4.597-4.675 (m, 2H), 3.856 (s, 3H), 3.831 (s, 3H), 3.796 (s,3H), 3.771 (s, 3H), 2.770-2.799 (m, 2H), 1.600-1.630 (m, 2H). 13C NMR (100 Mhz, CDCl3): δ149.494, 147.994, 146.895, 127.792, 127.149, 123.823, 123.809, 119.124, 110.556, 109.951, 109.584, 108.114, 67.158, 55.031, 55.001, 54.984, 37.736, 27.917, 21.966. ESI-MS: m/z 357.9 [M+1]+. HPLC purity: system A: 95.97% (254nm), 95.95% (280nm); system B: 98.97% (254nm), 99.31% (280nm).
	With triethylamine In dichloromethane for 4h; Heating;

Reference： [1]Ho, Sherman Si Han; Go, Mei Lin [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 22, p. 6127 - 6133]
[2]Raghuraman, Arjun; Riaz, Muhammad; Hindle, Michael; Desai, Umesh R. [Tetrahedron Letters, 2007, vol. 48, # 38, p. 6754 - 6758]

27
[ 3535-37-3 ]
sodium-compound of (+-)-3-acetyl-5-<4-ethoxy-3-methoxy-benzyl>-dihydro-furan-2-one [ No CAS ]
[ 4687-37-0 ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1665 - 1673

28
[ 3535-37-3 ]
sodium-compound of (+-)-3-acetyl-5-<4-ethoxy-3-methoxy-benzyl>-dihydro-furan-2-one [ No CAS ]
[ 478-01-3 ]

Reference： [1]Heterocycles,2003,vol. 60,p. 2775 - 2784

29
[ 3535-37-3 ]
sodium compound of benzoylacetic acid ethyl ester [ No CAS ]
[ 4687-37-0 ]

Reference： [1]Journal of Chemical Research - Part S,1998,p. 136 - 137

30
[ 3535-37-3 ]
[ 4687-37-0 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1982,p. 2477 - 2486
[2]Journal of the Chemical Society. Perkin transactions I,1982,p. 183 - 190
[3]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1980,vol. 19,p. 748 - 749

31
[ 3535-37-3 ]
[ 17290-70-9 ]

Reference： [1]Journal of the Indian Chemical Society,1988,vol. 65,p. 107 - 109

32
[ 3535-37-3 ]
[ 478-01-3 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1940,vol. 60,p. 614; engl. Ref. S. 246
Chem.Abstr.,1941,p. 7964
[2]Chemical Communications,2011,vol. 47,p. 2868 - 2870
[3]Organic Process Research and Development,2019,vol. 23,p. 595 - 602

33
[ 3535-37-3 ]
[ 2174-59-6 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1940,vol. 60,p. 614; engl. Ref. S. 246
Chem.Abstr.,1941,p. 7964
[2]Chemical Communications,2011,vol. 47,p. 2868 - 2870
[3]Organic Process Research and Development,2019,vol. 23,p. 595 - 602

34
[ 754214-56-7 ]
[ 3535-37-3 ]
(3,4-dimethoxy-phenyl)-(1H-pyrrolo[2,3-b]pyridine-5-yl)-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.6%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 20 - 100℃; for 40h;	To the crude pinacol ester 44 (310 mg, 1.27 mmol) in dry toluene (25 mL) was sequentially added cesium carbonate (2.07 g, 6.35 mmol), tetrakis (TRIPHENYLPHOSPHINE) palladium (0) (73 mg, 0.06 mmol) and 3,4- dimethoxybenzoyl chloride (510 mg, 2.54 mmol). The mixture was heated at 100 C in the dark. After 28 h a further portion of tetrakis (triphenylphosphine) palladium (0) (90 mg, 0. 08 mmol) was added. Following another 22 h the mixture was allowed to cool to ambient temperature and diluted with EtOAc and water and partitioned. The organic layer was washed with saturated sodium hydrogen carbonate, saturated brine, dried (MgSO4), filtered and concentrated. The crude residue was purified by preparative LCMS (column LUNA 10 U C18 (2) OOG-4253-VO 250x50 MM) using water-acetonitrile (0. 1% ACOH) as eluent (in gradient; flow 80 mL/min) to afford ketone 45 [12.6 mg, 3.6% (2 steps) ] as a white solid. 1H NMR (400 MHz ; CDC13) S 3.99 (s, 3H), 4.00 (s, 3H), 6.54 (dd, J= 2.0 and 3.5 Hz, 1H), 6. 98 (d, J= 8. 5 HZ, 1H), 7. 38 (dd, J= 2.5 and 3. 5 Hz, 1H), 7.71 (d, J= 2.0 Hz, 1H), 7. 81 (dd, J= 0.7 and 2.5 Hz, 1H), 7.93 (dd, I= 2.0 and 8. 5 HZ, 1H), 8. 22 (d, J= 2.5 Hz, 1H) and 8. 90 (brs, NH).

Reference： [1]Patent: WO2004/78757,2004,A2 .Location in patent: Page 77

35
[ 139756-02-8 ]
[ 3535-37-3 ]
[ 851133-91-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine In dichloromethane at 0 - 25℃; for 12.5h;	20 Preparation 20: 4-(3, 4-Dimethoxyphenylcarboxamido)-1-methyl-3-propyl-lH-5-pyrazolecarboxamide A mixture of 4-amino-l-methyl-3-propyl-lH-5-pyrazolecarboxmide (19.57g, 107.5 mmol) and triethylamine (54.4g, 134.38 mmol) in dichloromethane (300 mL) were taken in a 1 liter 3 neck round bottom flask fitted with a nitrogen balloon, pressure equalizing addition funnel and a septum. To the mixture was added a solution of 3, 4-dimethoxy-1- benzenecarbonylchloride (21. 5g, 107. 5mmol) in dichloromethane (lOOmL) at 0 °C through a pressure equalizing addition funnel over a period of 0.5 h under nitrogen atmosphere. The reaction temperature was raised to 25 °C after addition and the contents were stirred for another 12 h. Dichloromethane was removed from the reaction mixture under reduced pressure and the solid obtained was washed with cold water (2 x 150 mL), filtered and dried under vacuum to get the title compound 33g, (89 %) as a white solid.

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2005/40163, 2005, A1 Location in patent: Page/Page column 67-68

36
[ 4651-81-4 ]
[ 3535-37-3 ]
[ 773071-56-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine In dichloromethane at 0 - 20℃; for 12h;	N Methyl 2-aminothiophene-3-carboxylate (compound A) (160 mg) was dissolved in anhydrous methylene chloride (5 ml). Pyridine (120 mg: dissolved in 2 ml of anhydrous methylene chloride) and 3,4-dimethoxybenzoyl chloride (compound B) (300 mg) were added to the solution at 0°C, and the mixture was stirred at room temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 2-(3,4-dimethoxy-benzoylamino)-thiophene-3-carboxylic acid methyl ester (320 mg, yield 100%).
15%	With triethylamine In dichloromethane at 20℃; Cooling with ice;	14 Example 14 Take a 100ml single bottle,Add 10ml of anhydrous methylene chloride,0.19 g of triethylamine and 0.1 g of methyl 2-aminothiophene-3-carboxylate,Stir to dissolveA solution of 0.19 g of 3,4-dimethoxybenzoyl chloride dissolved in dichloromethane was added dropwise on an ice bath.Stir at room temperature overnight. After the reaction is complete, add water to quench.Dichloromethane extraction, drying over anhydrous sodium sulfate, and concentration.Column chromatography gave target compound 3n 0.03 g (15%).
15%	With triethylamine In dichloromethane at 0 - 20℃;	General Procedure for Synthesis of Compounds (3a-3q) General procedure: To a mixture of Methyl 2-aminothiophene-3-carboxylate (0.1 g, 636.18 umol, 1.0 eq.) and triethylamine (0.19 g, 1.91 mmol, 3.0 eq.) in anhydrous dichloromethane (10 mL), 3,4,5-Trimethoxybenzoyl chloride 2a (0.22 g, 954.28 umol,1.5 eq.) in dichloromethane was slowly added at 0 °C. After stirring at r.t overnight, the reaction mixture was diluted with water (3×10 mL), and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to afford compound 3a.

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1614676, 2006, A1 Location in patent: Page/Page column 183
[2]Current Patent Assignee: SHANGHAI INSTITUE OF TECHNOLOGY - CN107721975, 2018, A Location in patent: Paragraph 0060; 0061; 0062
[3]Yang, Yan; Yao, Zhiyi [Letters in drug design and discovery, 2018, vol. 15, # 12, p. 1319 - 1328]

37
[ 3535-37-3 ]
[ 56973-26-3 ]
5-carbamoyl-1H-imidazole-4-yl 3',4'-dimethoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 Following a procedure similar to that of Example 1 but using 0.636 g of 4-carbamoylimidazolium-5-olate and 1.30 g of 3,4-dimethoxybenzoyl chloride there was obtained 1.353 g of 5-carbamoyl-1H-imidazole-4-yl 3',4'-dimethoxybenzoate. m.p.: 209.5 C. (dec.) Crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 216.5 C.

Reference： [1]Patent: US4410696,1983,A

38
[ 444287-40-5 ]
[ 3535-37-3 ]
[ 927671-94-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	5.138 5.138 N-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YL-METHYL]-3,4-DIMETHOXY-BENZAMIDE To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,4-dimethyoxybenzoyl chloride (0.6 g, 2.8 mmol). The mixture was stirred at room temperature overnight followed by the addition of MeOH (1 mL). The reaction mixture was then washed with water (40 mL), 1N HCl (2×40 mL), and brine (40 mL), dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl-methyl]-3,4-dimethoxy-benzamide as a white solid (0.8 g, 79%): mp, 198-200° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.2 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.51-2.59 (m, 2H), 2.64 (m, 1H), 3.81 (s, 6H), 4.94 (d, J=5.9 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.51-7.58 (m, 2H), 7.83-7.70 (m, 3H), 9.02 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.22, 48.86, 55.53, 55.60, 110.67, 110.92, 120.56, 121.80, 126.10, 127.05, 131.50, 133.06, 134.77, 139.66, 148.28, 151.44, 166.09, 166.96, 167.57, 169.83, 172.74. Anal Calcd for C23H21N3O7+0.2H2O: C, 60.71; H, 4.74; N, 9.23. Found: C, 60.39; H, 4.51; N, 8.99.

Reference： [1]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); BRISTOL-MYERS SQUIBB CO; SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2007/49618, 2007, A1 Location in patent: Page/Page column 123

39
[ 696-60-6 ]
[ 3535-37-3 ]
[ 943518-63-6 ]

Yield	Reaction Conditions	Operation in experiment
95 - 97%	With triethylamine; In dichloromethane; at 15 - 20℃; for 1 - 1.5h;	Dichloromethane (750 ml) is charged into a IL 4neck RBF equipped with mechanical stirrer, thermowel, addition funnel and calcium chloride guard tube, p- hydroxybenzylamine (50 gms ; 0.4065 moles) is charged, followed by triethyl amine (56.6 ml ; 0.4065 moles) . The flask is cooled to 150C. 3,4-dimethoxybenzoyl chloride (81.5 gms.;0.4065 moles) dissolved in 100 ml of dichloromethane is added over a period of 30-45 minutes, maintaining the temperature of the reaction between 15-200C. The reaction mixture is stirred for 30-45 minutes at 15-200C. The progress of the reaction is monitored on HPLC and the reaction is continued till the starting material is <2% . Dichloromethane is distilled off under vacuum (at 40-450C). The residue is triturated with 500 ml of water and stirred for 2 hours.The solid is filtered and washed with 3xl00ml of water. The material is dried in oven at 70-750C for 10-15 hours till moisture content is <3%.Product weight 110-112 gms. Purity by HPLC 94-96 % Yield 95-97 %
95 - 97%	With triethylamine; In dichloromethane; at 15 - 20℃; for 1 - 1.5h;	Example-4 Preparation of N-(4-Hydroxy Benzyl)-3,4-Dimethoxy Benzamide Dichloromethane (750 ml) is charged into a 1 L 4 neck RBF equipped with mechanical stirrer, thermowel, addition funnel and calcium chloride guard tube, p-hydroxybenzylamine (50 gms; 0.4065 moles) is charged, followed by triethyl amine (56.6 ml; 0.4065 moles). The flask is cooled to 15 C. 3,4-dimethoxybenzoyl chloride (81.5 gms; 0.4065 moles) dissolved in 100 ml of dichloromethane is added over a period of 30-45 minutes, maintaining the temperature of the reaction between 15-20 C. The reaction mixture is stirred for 30-45 minutes at 15-20 C. The progress of the reaction is monitored on HPLC and the reaction is continued till the starting material is <2%. Dichloromethane is distilled off under vacuum (at 40-45 C.). The residue is triturated with 500 ml of water and stirred for 2 hours. The solid is filtered and washed with 3*100 ml of water. The material is dried in oven at 70-75 C. for 10-15 hours till moisture content is <3%. Product weight: 110-112 gms. Purity by HPLC: 94-96% Yield: 95-97%
95%	With pyridine; In dichloromethane; at 20℃; for 2h;Reflux;	p-Hydroxybenzylamine 200 g and 3,4-dimethoxybenzoyl chloride 326 g were placed in a dry reaction flask containing 1000 ml of dichloromethane.Stir 129 g of pyridine carefully at room temperature and heat at reflux for 2 h. The reaction is complete and the solvent is distilled off.The residue was washed with water and dried to give the product as a yellow solid, weight 448 g, purity 98%. Yield 95%.

Reference： [1]Patent: WO2007/74386,2007,A2 .Location in patent: Page/Page column 9
[2]Patent: US2009/177008,2009,A1 .Location in patent: Page/Page column 3
[3]Patent: CN107892657,2018,A .Location in patent: Paragraph 0020-0021

40
[ 115279-57-7 ]
[ 3535-37-3 ]
[ 1067189-44-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In dichloromethane; at 20℃; for 16h;	3,4-Dimethoxy-benzoyl chloride (2.77 g; 13.8 mmol) was added portionwise to a solution of <strong>[115279-57-7]2-(4-amino-phenyl)-2-methyl-propionitrile</strong> (1.85 g; 11.5 mmol), prepared as in l(B), in triethylamine (3.20 mL; 23.0 mmol) and dry DCM (30 mL). The reaction was stirred at room temperature for 16 hours and then diluted with DCM, washed sequentially with 2M K2CO3, IN HCl and brine. The organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography [SiO2, Petroleum ether/EtOAc (95/5 to 8/2)] to afford the title compound as a white powder (2.68 g; 72% yield). 1H NMR (300 MHz, CDC13) delta(ppm): 7.78 (br. s., 1 H), 7.62-7.73 (m, 2 H), 7.51 (d, 1 H), 7.46-7.51 (m, 2 H), 7.40 (dd, 1 H), 6.93 (d, 1 H), 3.98 (s, 3 H), 3.96 (s, 3 H), 1.74 (s, 6 H)LCMS (RT): 2.10 min (Method B); MS (ES+) gave m/z: 325.19 (MH+). MP: 139-141 C.

Reference： [1]Patent: WO2008/117175,2008,A2 .Location in patent: Page/Page column 98

41
[ 394-33-2 ]
[ 3535-37-3 ]
[ 1049032-96-3 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5135 - 5139

42
[ 1003-99-2 ]
[ 3535-37-3 ]
[ 1049032-70-3 ]

Yield	Reaction Conditions	Operation in experiment
59%	With dmap; triethylamine In dichloromethane at 20℃; for 18h;
	With triethylamine In dichloromethane at 20℃; for 3h;

Reference： [1]Aiello, Stefania; Wells, Geoffrey; Stone, Erica L.; Kadri, Hachemi; Bazzi, Rana; Bell, David R.; Stevens, Malcolm F. G.; Matthews, Charles S.; Bradshaw, Tracey D.; Westwell, Andrew D. [Journal of Medicinal Chemistry, 2008, vol. 51, # 16, p. 5135 - 5139]
[2]Wang, Hao; Wu, Qi; Zhang, Jian-Dong; Li, Hai-Yan; Li, Hong-Xi [Organic Letters, 2021, vol. 23, # 6, p. 2078 - 2083]

43
[ 95-53-4 ]
[ 3535-37-3 ]
[ 1522-70-9 ]

Yield	Reaction Conditions	Operation in experiment
73.9%	Stage #1: <i>o</i>-toluidine With potassium 2-methylbutan-2-olate In toluene at 90℃; for 0.5h; Stage #2: for 0.5h; Reflux; Stage #3: 3,4-dimethoxybenzoic acid chloride Further stages;	3,4-dimethoxy-N-(o-tolyl)benzamide: A solution of commercially available potassium 2-methylbutan-2-olate (12.78 ml, 21.73 mmol, 1.09 equiv) in toluene (1.7M) via syringe was added to a 90 °C solution of o-toluidine (2.36 g, 22.0 mmol, 1.10 equiv)in toluene (20 ml). The reaction mixture was refluxed for 30 min, then a solution of 3,4-dimethoxybenzoyl chloride (4.00 g, 20.0 mmol, 1.00 equiv) in toluene (20 ml) was added dropwise via syringe to the refluxing solution. The mixture was refluxed for an additional hour followed by a second addition of potassium 2-methylbutan-2-olate (12.78 ml, 21.73 mmol, 1.09equiv) in toluene (1.7 M). The mixture was refluxed for 4 h. The reaction was cooled to room temperature overnight. The resulting mixture was heated to 80 °C followed by sequential addition of water (200 mL) and concentrated HCL (14 mL). The bottom aqueous layer was removed. The organic layer contained a suspended solid. The organic layer was filtered to afford 3,4-dimethoxy-N-o-tolylbenzamide (CBU-91, 2.46 g, 14.74 mmol, 73.9% yield) as agray solid.1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H, J = 8.3Hz), 7.63 (s, 1H), 7.54 (d, 1H, J = 2.0Hz),7.41 (dd, 1H, J = 8.3, 2.1Hz), 7.23-7.29 (m, 1H), 7.10-7.15 (m, 1H), 6.93 (d, 1H J = 8.4Hz),3.97 (s, 3H), 3.96 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 152.5, 149.3,137.6, 134.8, 131.2, 127.7, 127.6, 126.9, 126.8, 121.9, 111.9, 111.9, 56.6, 56.5, 18.9; HRMS (ESI)m/z 272.1380 (272.1281 calc for C16 H18 O3 N1, MH).
	In diethyl ether

Reference： [1]Ahmad, Faiyaz; Bahde, Robert J.; Chung, Jay H.; Huang, Tianjiao; Kim, Jeonghan; Kim, Myung K.; Park, Sung-Jun; Philp, Andrew; Trenkle, William C. [PLoS ONE, 2021, vol. 16, # 6 June]
[2]Location in patent: experimental part Narasimhan, Balasubramanian; Ohlan, Sucheta; Ohlan, Ruchita; Judge, Vikramjeet; Narang, Rakesh [European Journal of Medicinal Chemistry, 2009, vol. 44, # 2, p. 689 - 700]

44
[ 90-24-4 ]
[ 3535-37-3 ]
[ 71847-56-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With pyridine at 100℃; for 0.166667h;	15 Example 15 synthesis of 2-acetyl-3,5-dimethoxyphenyl 3,4-dimethoxybenzoate (12) 3,4-dimethoxybenzoyl chloride (10.55 g, 52.72 mmol, 1.2 eq) was added to a suspension of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone (8.62 g, 43.93 mmol, 1eq) in pyridine (120 mL). The reaction mixture was then stirred at 100°C for 10 mins. After cooling, to this suspension was added ethanol (100 mL) then water (100 mL). This solution was placed at 0°C and following scratching with a glass rod to afford white tiny crystals. The precipitate was filtered, washed with ethanol/water (1/1) (30 mL), dried to give 11.57 g (73%) of a white solid. Molecular Weight: 360.36 (C19H20O7). 1H-NMR δ (CDCl3, 300 MHz) ppm (J in Hz): 2.47 (s, 3H, CH3CO), 3.82 (s, 3H, MeO), 3.85 (s, 3H, MeO), 3.94 (s, 3H, MeO), 3.95 (s, 3H, MeO), 6.37 (d, 1H, J=2.2, H-3'), 6.39 (d, 1H, J=2.2, H-5'), 6.92 (d, 1H, J=8.5, H-5'), 7.61 (d, 1H, J=2.0, H-2'), 7.79 (dd, 1H, J=2.0, J=8.5, H-6').
60%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In pyridine at 50 - 75℃; for 1.25h;	4.1.2.1. 2-Acetyl-3, 5-dimethoxyphenyl 3, 4-dimethoxy benzoate (7) 4.1.2.1. 2-Acetyl-3, 5-dimethoxyphenyl 3, 4-dimethoxy benzoate (7). 1-(2-Hydroxy-4, 6-dimethoxyphenyl)ethanone (5) (1 g,5.09 mmol) was dissolved in pyridine (20 mL) and heated to 50°C. DBU (1% v/v of pyridine) was added and the mixture was stirred at 50°C for 30 min. 3,4-Dimethoxy benzoyl chloride (6) (1.53 g,7.63 mmol, 1.5 eq.) was added slowly over 15 min, the mixture was heated to 75°C and stirred for 1 h. The reaction was cooled to room temperature, acidified to pH 5 with 2 M HCl and extracted with EtOAc (2 x 20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the desired product. The pure compound was obtained as a white solid after purification by column chromatography [Hexane: CHCl3:EtOAc (3:6:1 v/v/v)]. Yield: 60%
	With pyridine at 110℃;	3.1.1. General Procedure for the Synthesis of Flavones General procedure: A mixture of the corresponding 2'-hydroxyacetophenone (1 equiv) and benzoyl chloride (1.1 equiv) in pyridine (10 mL/mmol of acetophenone) was heated at 110 °C for 2-3 h. The mixture was then poured into ice and HCl and extracted with ethyl acetate. The extract was washed with water and aqueous sodium carbonate and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to yield the crude phenolic ester. Powdered KOH (4-5 g) was added to a solution ofthe ester in pyridine (10-15 mL) and the mixture was stirred vigorously at 60 °C for 4 h. The mixture was then poured into ice and HCl, extracted with ethyl acetate and dried over sodium sulphate to give the 1,3-diketone in 60%-80% yield. To a yellow suspension of the 1,3-diketone (2 mmol) in glacial acetic acid (7 mL), concentrated sulfuric acid (a few drops) was added and refluxed overnight. The resulting mixture was cooled and water added until no further white precipitate was formed. The crude solid was filtered, purified using column chromatography and crystallised from methanol to give the flavone in 35%-55% yield.

With pyridine at 75℃; for 1h;

Reference： [1]Current Patent Assignee: AXOGLIA THERAPEUTICS - EP2112145, 2009, A1 Location in patent: Page/Page column 15
[2]Ravishankar, Divyashree; Watson, Kimberly A.; Boateng, Samuel Y.; Green, Rebecca J.; Greco, Francesca; Osborn, Helen M.I. [European Journal of Medicinal Chemistry, 2015, vol. 97, p. 259 - 274]
[3]Swaminathan, Meyyammai; Chee, Chin Fei; Chin, Sek Peng; Buckle, Michael J. C.; Rahman, Noorsaadah Abd.; Doughty, Stephen W.; Chung, Lip Yong [Molecules, 2014, vol. 19, # 7, p. 8933 - 8948]
[4]Ravishankar, Divyashree; Watson, Kimberly A.; Greco, Francesca; Osborn, Helen M. I. [RSC Advances, 2016, vol. 6, # 69, p. 64544 - 64556]

45
[ 95331-56-9 ]
[ 3535-37-3 ]
[ 314044-24-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2350 - 2353

46
[ 1004546-45-5 ]
[ 3535-37-3 ]
[ 1050676-94-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine; 3,4-dimethoxybenzoic acid chloride In dichloromethane at 20℃; for 2.33333h; Inert atmosphere; Stage #2: With sodium hydroxide In dichloromethane; water for 1h; Inert atmosphere;	AA-13 Example AA-13; 2',3',4',9'-Tetrahydro-N,N-dimethyl-4-butyl-2'-(3,4-dimethoxybenzylcarbonyl)-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) (less polar diastereoisomer)3,4-Dimethoxyphenylacetyl chloride (380 mg, 1.77 mmol) was dissolved in abs. dichloromethane (5 ml), under argon, and the free base of the less polar spiroamine AA-9 (200 mg, 0.59 mmol), dissolved in dichloromethane (15 ml), was added, at room temperature, in the course of 50 min. A precipitate immediately formed. Stirring was carried out for a further 1.5 h at room temperature. For working up, water (10 ml) and 1N sodium hydroxide solution (5 ml) were added to the mixture, and stirring was carried out for 1 h. The phases were separated. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were washed with water (20 ml), dried and concentrated. A beige-colored oil (357 mg) was thereby obtained and was separated by chromatography [silica gel 60 (40 g); ethyl acetate (250 ml), ethyl acetate/methanol (8:1, 200 ml)]. The amide was isolated in the form of a colorless solid in a yield of 75% (230 mg) with a melting point of 135-140° C.

Reference： [1]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - US2010/48554, 2010, A1 Location in patent: Page/Page column 22

47
[ 17430-98-7 ]
[ 3535-37-3 ]
[ 1094325-17-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran at 20℃; for 4h;	3 Synthesis Example 3 To 5 ml of THF were added 0.30 g of 3,4-dimethoxybenzoyl chloride, 0.21 g of (1S)-1-cyclohexylethylamine and 0.23 g of triethylamine, followed by stirring at room temperature for 4 hours. To the reaction mixture, ethyl acetate was added and insolubles were filtered off through Celite. The filtrate was concentrated under reduced pressure. The residue was washed with MTBE,and N-((1S)-1-cyclohexylethyl)-3,4-dimethoxybenzamide was obtained (hereinafter, referred to as the present compound 3).Present compound 3 [Show Image] 1H-NMR (CDCl3) δ: 0.99-1.49 (8H, m), 1.54-1.87 (6H, m), 3.92 (3H, s), 3.94 (3H, s), 4.01-4.13 (1H, m), 5.82-5.90 (1H, m), 6.85 (1H, d, J = 8.4 Hz), 7.23 (1H, dd,J=8.4, 2.0 Hz), 7.44 (1H, d, J = 2.0 Hz).

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP2179651, 2010, A1 Location in patent: Page/Page column 36

48
[ 918414-58-1 ]
[ 13338-49-3 ]
[ 3535-37-3 ]
N-[(E)-3-(2,4-difluoro-phenyl)-2-methyl-allyl]-N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3,4-dimethoxy-benzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 6; N-[(E)-3-(2,4-Difluoro-rhohenyl)-2-methyl-allyl]-N-(4,5-dihydro-lH-imidazol-2-ylmethyl)- 3,4-dimethoxy-benzamide hydrochloride , (19); 19[0124] The 2-Chloromethyl-4,5-dihydro-lH-imidazole hydrochloride 53 mg (0.34 mmol), was heated to 7O0C with (E)-3-(2,4-Difluoro-phenyl)-2-methyl-allylamine (0.34 mmol) in 1 mL ethanol for 3 days. The solvent was evaporated and the residue dissolved/suspended in 3 mL DCM followed by the addition of 61 mg (0.31 mmol of 3,4-dimethoxybenzoyl chloride EPO <DP n="40"/>and 91 muL (0.65 mmol) of triethylamine. After 1 hour the solvent was evaporated and the product was purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min. Fractions containing pure product were evaporated with 1 mL IM HCl aq. to yield 42 mg of the hydrochloride salt as pale yellow solid. LC-MSD, m/z for C23H25F2N3O3 [M+H]+: 430.2; 1H NMR (400 MHz, CDC13/HC1): delta 1.7 (s, 3 H), 3.85 (s, 3 H), 3.9 (s, 3 H)5 3.95 (s, 3 H), 4.3 (s, 2 H), 4.7 (s, 2 H), 6.3 (s, IH), 6.4 (bs, 2 H), 6.7-6.9 (m, 3 H), 7.1-7.3 (m, 3 H), 10.2 (bs, 2 H).

Reference： [1]Patent: WO2007/2842,2007,A2 .Location in patent: Page/Page column 38-39

49
[ 2033-24-1 ]
[ 64-17-5 ]
[ 3535-37-3 ]
[ 4687-37-0 ]

Yield	Reaction Conditions	Operation in experiment
90%		[Reference Example 1] Ethyl 3-(3,4-dimethoxyphenyl)-3-oxopropionate To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (14.4 g 10 mmol) in dichloromethane (30 mL), pyridine (0.81 mL, 10 mmol) was added at 0C or less, and this was stirred at -5C for 0.5 hours. Subsequently, 3,4-dimethoxybenzoylchloride (2.00 g 10 mmol) was added at 0C or less, stirred at -5C for 0.5 hours, 0C for 0.5 hours, and 25C for 0.5 hours, and then 1 M hydrochloric acid (30 mL) was added while cooling on ice. This was then extracted with dichloromethane. After drying over magnesium sulfate, dichloromethane was distilled off, this was redissolved in ethanol (30 mL), refluxed for 1.5 hours, stirred at room temperature for 10 hours. It was then stirred at 60C for 14 hours, ethanol was distilled off, and this was purified by silica gel column chromatography (elude: hexane: tetrahydrofuran = 3:1) which resulted in a colorless oily material (2.27 g, 90% yield).

Reference： [1]Patent: EP1900728,2008,A1 .Location in patent: Page/Page column 164-165

50
[ 19840-99-4 ]
[ 3535-37-3 ]
[ 1161124-44-2 ]

Reference： [1]Medicinal Chemistry Research,2010,vol. 19,p. 193 - 209
[2]Chemical Biology and Drug Design,2012,vol. 80,p. 291 - 299

51
[ 137686-07-8 ]
[ 3535-37-3 ]
[ 1255203-05-4 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 5274 - 5277
[2]Chemistry - A European Journal,2012,vol. 18,p. 7219 - 7223

52
[ 41994-51-8 ]
[ 3535-37-3 ]
[ 1262971-68-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid ; hydrochloride With sodium hydroxide In acetone at 20℃; Stage #2: 3,4-dimethoxybenzoic acid chloride With sodium hydroxide In acetone at 20℃; Stage #3: With hydrogenchloride In water	4.3. 2-Propionyl-1,2,3,4-tetrahydroisoquiniline-3-carboxylic acid (18b) General procedure: To a suspension of 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid hydrochloride (17, 10 g, 46.8 mmol) in acetone (60 mL) was added 2 N NaOH (40 mL) solution at room temperature. The clear solution obtained then added dropwise into a solution of propionyl chloride (5.2 g, 57 mmol) in acetone (20 mL) at room temperature, simultaneously 2 N NaOH was added dropwise and pH maintained above 10. The reaction mixture was stirred at room temperature for 2 h, the solvent was evaporated under reduce pressure. The solution was acidified to pH 5-6 with 3 N HCl. The white solid separated, filtered it and dried to give 18b 9 g, yield 87%.

Reference： [1]Location in patent: experimental part Chaniyara, Ravi; Kapuriya, Naval; Dong, Huajin; Lee, Pei-Chih; Suman, Sharda; Marvania, Bhavin; Chou, Ting-Chao; Lee, Te-Chang; Kakadiya, Rajesh; Shah, Anamik; Su, Tsann-Long [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 275 - 286]

53
[ 593-56-6 ]
[ 3535-37-3 ]
[ 25563-13-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In water; ethyl acetate at 0 - 20℃;
	With potassium carbonate In water; ethyl acetate at 0 - 20℃;
	Stage #1: N-methoxylamine hydrochloride With potassium carbonate In water; ethyl acetate Stage #2: 3,4-dimethoxybenzoic acid chloride In water; ethyl acetate at 0 - 20℃; for 5h;

	With potassium carbonate In water; ethyl acetate at 0 - 20℃; Inert atmosphere;
	With potassium carbonate In water; ethyl acetate at 0 - 20℃; for 1h; Inert atmosphere;
	With potassium carbonate In water; ethyl acetate at 0℃; for 4h; Inert atmosphere;
	With potassium carbonate In water; ethyl acetate at 0 - 20℃;
	With potassium carbonate In water; ethyl acetate at 0 - 20℃; Inert atmosphere;
	With potassium carbonate In water; ethyl acetate at 0 - 20℃; for 4h;

Reference： [1]Wrigglesworth, Joe W.; Cox, Brian; Lloyd-Jones, Guy C.; Booker-Milburn, Kevin I. [Organic Letters, 2011, vol. 13, # 19, p. 5326 - 5329]
[2]Wang, Guan-Wu; Yuan, Ting-Ting; Li, Dan-Dan [Angewandte Chemie - International Edition, 2011, vol. 50, # 6, p. 1380 - 1383]
[3]Li, Dan-Dan; Yuan, Ting-Ting; Wang, Guan-Wu [Chemical Communications, 2011, vol. 47, # 48, p. 12789 - 12791]
[4]Wu, Jia-Qiang; Qiu, Zhi-Ping; Zhang, Shang-Shi; Liu, Jing-Gong; Lao, Ye-Xing; Gu, Lian-Quan; Huang, Zhi-Shu; Li, Juan; Wang, Honggen [Chemical Communications, 2015, vol. 51, # 1, p. 77 - 80]
[5]Zhang, Shang-Shi; Wu, Jia-Qiang; Lao, Ye-Xing; Liu, Xu-Ge; Liu, Yao; Lv, Wen-Xin; Tan, Dong-Hang; Zeng, Yao-Fu; Wang, Honggen [Organic Letters, 2014, vol. 16, # 24, p. 6412 - 6415]
[6]Chen, Zenghua; Hu, Le'an; Zeng, Fanyun; Zhu, Ranran; Zheng, Shasha; Yu, Qingzhen; Huang, Jianhui [Chemical Communications, 2017, vol. 53, # 30, p. 4258 - 4261]
[7]Sharma, Nidhi; Saha, Rajib; Parveen, Naziya; Sekar, Govindasamy [Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1947 - 1958]
[8]Mayakrishnan, Sivakalai; Tamizmani, Masilamani; Maheswari, Naryanan Uma [Chemical Communications, 2020, vol. 56, # 98, p. 15462 - 15465]
[9]Wang, Huihong; Cao, Fei; Gao, Weiwei; Wang, Xiaodong; Yang, Yuhang; Shi, Tao; Wang, Zhen [Organic Letters, 2021, vol. 23, # 3, p. 863 - 868]

54
[ 3731-51-9 ]
[ 3535-37-3 ]
[ 86425-45-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In tetrahydrofuran at 0 - 20℃; for 3h;	4.1.1. General procedure for the synthesis of N1-(2-pyridylmethyl)-substituted benzamides (3a-h) General procedure: To a stirred solution of 2-pyridylmethanamine (1) (1 mmol) in dry THF was added triethylamine (1.1 mmol) followed by substituted benzoylchlorides (2a-h) at 0 °C. The reaction mixture was stirred for 3 h and the reaction was monitored by TLC. After completion of reaction, THF was removed under vacuum to get the crude products. This was further purified by column chromatography (EtOAc-Hexane) to get the pure compounds (3a-h).
78%	With triethylamine In tetrahydrofuran at 0 - 20℃; for 3h;	General procedure for the synthesis of N1-(2-pyridylmethyl)substituted benzamides (8a-e) Method A General procedure: To a stirred solution of 2-pyridylmethanamine 6 (1 mmol) in dry THF was added triethylamine(3.0 mmol) followed by substituted benzoylchlorides (7a-e, 1.1 mmol)at 0 °C. The reaction mixture was stirred for 3 h and the reaction was monitored by TLC. After the completion of the reaction, THF was removed under vacuum to get the crude products. This was further purified by column chromatography (EtOAc-Hexane) to obtain the purecompounds (8a-e).

Reference： [1]Location in patent: experimental part Kamal, Ahmed; Ramakrishna; Raju; Rao, A.V. Subba; Viswanath; Nayak, V. Lakshma; Ramakrishna, Sistla [European Journal of Medicinal Chemistry, 2011, vol. 46, # 6, p. 2427 - 2435]
[2]Sunkari, Satish; Bonam, Srinivasa Reddy; Rao, A.V. Subba; Riyaz, Sd; Lakshma Nayak; Kumar, Halmuthur Mahabalarao Sampath; Kamal, Ahmed; Nagendra Babu, Bathini [Bioorganic Chemistry, 2019, vol. 87, p. 484 - 494]

55
[ 1342891-17-1 ]
[ 3535-37-3 ]
[ 1342891-18-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 20℃;
98%	With triethylamine In dichloromethane at 20℃;	9 To a solution of 25a (60 mg, 0.226 mmol) in DCM (3 mL) was added triethylamine (0.06 mL, 0.452 mmol) and 3,4-dimethoxybenzoyl chloride (54 mg, 0.271 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was washed with dH20 (x2) and sat. NaHCC (x 2), dried over MgS04 and concentrated in vacuo. Purification by column: silica gel: 3: 1 DCM EtOAc gave a quantitative yield of a light yellow oil. 1H NMR (CDC13): δ 7.26 - 7.17 (m, 3H), 7.17 - 7.08 (m, 3H), 7.06 - 6.97 (m, 2H), 6.95 (t, J = 5.0 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.53 - 6.40 (m, 1H), 5.92 - 5.79 (m, 1H), 5.16 (s, 2H), 3.83 (s, 3H), 3.66 (s, 3H), 1.46 ppm (s, 6H). 13C NMR (CDC13): δ 169.9, 150.3, 149.0, 148.6, 147.9, 144.7, 140.6, 135.1, 129.0, 127.8, 127.2, 126.3, 124.0, 123.6, 123.0, 122.3, 112.6, 109.9, 77.4, 77.0, 77.0, 76.7, 55.8, 55.7, 55.6, 28.2 ppm. HRMS (ESI) m/z calcd for C26H27N204 [(M + H)+] 431.1971, found: 431.1951.

Reference： [1]Location in patent: experimental part Mooring, Suazette Reid; Jin, Hui; Devi, Narra S.; Jabbar, Adnan A.; Kaluz, Stefan; Liu, Yuan; Van Meir, Erwin G.; Wang, Binghe [Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8471 - 8489]
[2]Current Patent Assignee: EMORY UNIVERSITY; UNIVERSITY SYSTEM OF GEORGIA - WO2011/133659, 2011, A2 Location in patent: Page/Page column 63-64; 93

56
[ 1021926-19-1 ]
[ 3535-37-3 ]
[ 1357168-44-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In 1,4-dioxane at 20℃; Inert atmosphere;	4.1.1. General procedure for the preparation of the substituted benzamide 1-39 General procedure: K2CO3 (5 mmol, 5eq) and substituted acyl chloride (1.2 mmol, 1.2 eq) were successively added to a solution of the aniline e (1.0 mmol, 1.0 eq) in 3 mL dry 1, 4 -dioxane and the mixture was stirred at room temperature overnight. 10 mL H2O and 3 mL saturated aqueous Na2CO3 was added to the mixture and it was stirred at room temperature overnight. The precipitated solid was collected by filtration and purified by silica gel column chromatography.

Reference： [1]Location in patent: experimental part Zhong, Bo; Cai, Xiaohan; Chennamaneni, Snigdha; Yi, Xin; Liu, Lili; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin [European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 432 - 444]

57
[ 6320-40-7 ]
[ 3535-37-3 ]
[ 1335150-57-6 ]

Yield	Reaction Conditions	Operation in experiment
		E^m )je 4; Step 1; Magnesium turnings (3.9 g) and TMF (50 ml) were placed in a dry flask equipped with a dropping funnel, which contained THF {800ml) solution of 2,4)6-tribromotoluene (53 g). One tent of the solution in the dropping funnel was added to the flask. After a few minutes, solvent in the reaction flask started to boil, An ice bath was applied. The remaining solution in the dropping funnel was added drop wise at 0C over a half hour interval. The resulting mixture was stirred at room temperature for one hour. The temperature was cooled to 0C and b.s[2-(N,N~dimethyiamino)ethyl]e.ther (28.4 g) was added and stirred for one hour. 3,4- Dimethoxybenzoyl chloride (35.5 g) was added in one portion. The resulting mixture was stirred for 18 h at room temperature. Water {500 mL) was added to the mixture. 12N HCI was used to adjust the pH to 2. DC was added to the mixture (500 ml). The resulting organic layer was collected, washed with water, saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated. Yellow oil (65 g) was obtained. The oil was used directly in the next step.

Reference： [1]Patent: WO2012/82506,2012,A1 .Location in patent: Page/Page column 43-44

58
[ 6320-40-7 ]
[ 3535-37-3 ]
C₂₁H₂₀Br₂O₆ [ No CAS ]

Reference： [1]Patent: WO2012/82506,2012,A1

59
[ 1375800-71-7 ]
[ 3535-37-3 ]
[ 1375800-58-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;	7.3.6. General procedure E (acid chloride coupling) General procedure: The amine was mixed with Et3N in anhydrous DCM. A solution of the acid chloride in DCM was added dropwise at room temperature. The mixture was stirred for 2-4 h at room temperature and then basified with 2 M aq. K2CO3 to pH > 11. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with H2O (1x), dried over Na2SO4, filtered and concentrated in vacuo. This afforded the crude product.

Reference： [1]Wijtmans, Maikel; Maussang, David; Sirci, Francesco; Scholten, Danny J.; Canals, Meritxell; Mujić-Delić, Azra; Chong, Milagros; Chatalic, Kristell L.S.; Custers, Hans; Janssen, Elwin; De Graaf, Chris; Smit, Martine J.; De Esch, Iwan J.P.; Leurs, Rob [European Journal of Medicinal Chemistry, 2012, vol. 51, p. 184 - 192]

60
[ 168828-90-8 ]
[ 3535-37-3 ]
[ 1390617-32-9 ]

Reference： [1]Asian Journal of Chemistry,2012,vol. 24,p. 3479 - 3482

61
[ 13676-47-6 ]
[ 3535-37-3 ]
[ 1308881-13-1 ]

Reference： [1]Chemical Biology and Drug Design,2012,vol. 79,p. 1018 - 1024

62
[ 2508-29-4 ]
[ 3535-37-3 ]
[ 1421021-94-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine In dichloromethane at 20℃; for 1h;	N-(5-Hydroxypentyl)-3,4-dimethoxybenzamide (5c): General procedure: A mixture of 3,4-dimethoxylbenzoic acid (600 mg) in thionyl chloride (5.6 mL) was refluxed under nitrogen for 3 h. The excess thionyl chloride was removed under reduced pressure and the resulting residue was dried under vacuum to get a solid, which was added 9 mL of dry dichloromethane (9 mL) to make a solution of 3,4-dimethoxybenzoic chloride in dichloromethane with a concentration of ~0.36 M. To a mixture of 5-amino-1-pentanol (113 mg, 1.10 mmoL) and triethylamine (0.31 mL, 2.2 mmol) in 2 mL dichloromethane, was added the solution of 3,4-dimethoxybenzoic chloride in dichloromethane (0.36 M, 3 mL). The resulting mixture was stirred at room temperature for 1 h. Aqueous workup and purification by column chromatography on silica gel provided the desired product (265 mg, 90%) as a white solid. 1H NMR (300 MHz, CDCl3): ä 7.36 (s, 1 H); 7.29 (d, J = 8.3 Hz, 1 H); 7.00 (m, 1 H); 6.74 (d, J= 8.3Hz, 1 H); 3.80 (s, 3 H); 3.78 (s, 3 H); 3.52 (t, J = 6.2 Hz, 2 H); 3.30 (m, 2 H); 3.15 (s, 1 H); 1.50 (m, 4 H); 1.34 (m, 2H). 13C NMR (75 MHz, CDCl3): ä 167.3, 151.3, 148.5, 127.0, 119.6, 110.3, 110.1, 62.0, 55.7(2), 39.8, 31.9, 29.1, 23.0.

Reference： [1]Hu, Yueqing; Zhang, Jun; Chandrashankra, Oormila; Ip, Fanny C.F.; Ip, Nancy Y. [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 3, p. 676 - 683]

63
[ 1418025-85-0 ]
[ 3535-37-3 ]
[ 1418024-09-5 ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: 3-aminomethyl-7-chloro-1-phenyl-1H-quinolin-4-one; 3,4-dimethoxybenzoic acid chloride In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h; Inert atmosphere;	II.I-57 Example 1-57 N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,4-dimethoxy-benzamide Example 1-57 N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,4-dimethoxy-benzamide In a 200 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(lH)- one (intermediate D) (25 mg, 0.088 mmol) and 3,4-dimefhoxybenzoyl chloride (17.6 mg, 0.088 mmol) were combined with methylene chloride (3 mL) to give a yellow suspension. The reaction mixture was cooled to 0 °C. After 15 min. stirring at reduced temperature, NN-diisopropylethylamine (56.7 mg, 76.6 μί, 0.439 mmol) was added. The reaction mixture quickly became a yellow solution, then was stirred at 0 °C for 1 hr. After this time, LC/MS indicated that the reaction was complete. The reaction mixture was warmed to room temperature, then stirred overnight. In the morning, the reaction mixture was concentrated over silica gel. Flash chromatography (25 gram Analogix column, 20% ethyl acetate-hexanes ramped to 100% ethyl acetate) was used to purify the product. N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,4-dimethoxy-benzamide (26 mg, 59%) was obtained as a white solid. MS calcd. for C25H21CIN2O4 [(M+H)+] 448.9, obsd. 449.1.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/7676, 2013, A1 Location in patent: Page/Page column 169; 170

64
[ 1293990-73-4 ]
[ 3535-37-3 ]
[ 1427180-88-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium carbonate In water; ethyl acetate at 0℃; for 2h;
80%	With sodium carbonate In water; ethyl acetate at 0 - 20℃; for 5h;	4.7 4.2.2. Procedure 2 General procedure: To a solution of benzoic acid (1.0 equiv) in dry CH2Cl2 (3 mL per mmol of acid) was added SOCl2 (5.0 equiv) at room temperature followed by the addition of a catalytic amount of DMF (4 drops per 10 mmol of acid). The mixture was refluxed for 8 h. After cooling, solvent and excess reagent were removed in vacuo to afford the crude acid chloride, which was used in the next step without further purification. O-Pivaloylhydroxylamine triflate19 (1.2 equiv) was added to a biphasic mixture of Na2CO3 (2.0 equiv) in EtOAc/H2O (9 mL per mmol of acid chloride, 2:1). To the cooled mixture containing the pivaloylhydroxylamine at 0 °C was added crude acid chloride (1.0 equiv) in EtOAc (1 mL per mmol of acid chloride) dropwise. The reaction mixture was allowed to reach room temperature within 5 h. The layers were separated and the aqueous layer was extracted with EtOAc (210 mL (per mmol of acid chloride)). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide the crude product which was purified by flash chromatography to afford pure O-pivaloyl hydroxamic acid.

Reference： [1]Presset, Marc; Oehlrich, Daniel; Rombouts, Frederik; Molander, Gary A. [Organic Letters, 2013, vol. 15, # 7, p. 1528 - 1531]
[2]Mishra, Vivek Kumar; Ravikumar, Ponneri C.; Maier, Martin E. [Tetrahedron, 2016, vol. 72, # 41, p. 6499 - 6509]

65
[ 292057-70-6 ]
[ 3535-37-3 ]
[ 1428559-03-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; triethylamine In dichloromethane at 20℃; for 16h;	17 Preparation of 2’-(((5-(3”, 4”- Dimethoxybenzoyl) -5H- [1,2,4] triazino [5,6-b] indol -3-yl) thio) methyl) benzonitrile To a stirred suspension of 2'(((5H-[l,2,4]triazino[5,6-b]indol-3-yl) thio) methyl) benzonitrile (100 mg, 0.32 mmol), DMAP (0.8 mg, 0.06 mmol) and Et3N (86 μΐ,, 0.63 mmol) in CH2C12 (5 mL) at rt was added 3,4-dimethoxybenzoyl chloride (95 mg, 0.48 mmol). The resulting mixture was stirred at rt for 16h. CH2C12 (30 mL) was added to the suspension and washed with water (30 mL). The organic layer was washed with brine (30 mL), dried over MgS04, filtered and concentrated in vacuo. The resulting solid was washed with methanol to yield a white solid (87 mg, 56 %). δΗ (500 MHz, DMSO-d6, 363 K) 3.73 (3 H, s), 3.80 (3 H, s), 4.25 (2 H, s), 7.09 (1 H, d, / = 8.5 Hz), 7.35 (1 H, d, / = 7.9 Hz), 7.44-7.48 (1 H, m), 7.55 (1 H, d, / = 1.9 Hz), 7.58-7.61 (1 H, m), 7.63-7.67 (2 H, m), 7.80 - 7.85 (2 H, m), 8.14 (1 H, d, / = 8.5 Hz), 8.43 (1 H, d, / = 7.9 Hz). 5c (125 MHz, DMSO-d6) 32.1, 55.8, 55.9, 110.8, 111.7, 113.4, 115.9, 117.2, 119.5, 121.4, 125.1, 125.3, 125.5, 128.3, 130.2, 131.5, 133.2, 133.2, 139.7, 140.5, 142.2, 147.3, 148.4, 153.8, 166.3, 166.8. mp 234-235°C
56%	With dmap; triethylamine In dichloromethane at 20℃; for 16h;	3.69 4.3.69 2′-(((5-(3″,4″-Dimethoxybenzoyl)-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)methyl)benzonitrile (79) To a stirred suspension of 2'(((5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)methyl)benzonitrile 7 (100 mg, 0.32 mmol), DMAP (0.8 mg, 0.06 mmol) and Et3N (86 μL, 0.63 mmol) in CH2Cl2 (5 mL) at rt was added 3,4-dimethoxybenzoyl chloride (95 mg, 0.48 mmol). The resulting mixture was stirred at rt for 16 h. CH2Cl2 (30 mL) was added to the suspension and washed with water (30 mL). The organic layer was washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was washed with methanol and dried to yield the title compound (79) as a white solid (87 mg, 56%); mp (Gallenkamp) 234-235 °C; νmax (solid) 3115, 2932, 2229, 1697, 1514, 1378; HPLC (Method 2) >99%, tR = 11.81 min; δH (500 MHz, DMSO-d6, 363 K) 3.73 (3H, s, O-CH3), 3.80 (3H, s, O-CH3), 4.25 (2H, s, S-CH2), 7.09 (1H, d, J = 8.5 Hz, C(5")H), 7.35 (1H, d, J = 7.9 Hz, C(3')H), 7.46 (1H, app td, J = 7.6, 1.3 Hz, C(5')H), 7.55 (1H, d, J = 1.9 Hz, C(2")H), 7.59 (1H, td, J = 7.6, 1.3 Hz, C(4')H), 7.63-7.67 (2H, m, C(8)H and C(6")H), 7.80-7.85 (2H, m, C(7)H and C(6)'), 8.14 (1H, d, J = 8.5 Hz, C(6)H), 8.43 (1H, d, J = 7.9 Hz, C(9)H); δC (125 MHz, DMSO-d6) 32.1, 55.8, 55.9, 110.8, 111.7, 113.4, 115.9, 117.2, 119.5, 121.4, 125.1, 125.3, 125.5, 128.3, 130.2, 131.5, 133.2, 133.2, 139.7, 140.5, 142.2, 147.3, 148.4, 153.8, 166.3, 166.8; m/z (ESI+) ([M+Na]+, 100%); HRMS (ESI+) C26H19N5NaO3S ([M+Na]+) requires 504.1110; found 504.1107.
56%	With dmap; triethylamine In dichloromethane at 20℃; for 16h;	17 Preparation of 2'-((5-(3",4"-Dimethoxybenzoyl)-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)methyl)benzonitrile Example 17 Preparation of 2'-((5-(3",4"-Dimethoxybenzoyl)-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)methyl)benzonitrile To a stirred suspension of 2'(((5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)methyl)benzonitrile (100 mg, 0.32 mmol), DMAP (0.8 mg, 0.06 mmol) and Et3N (86 μL, 0.63 mmol) in CH2Cl2 (5 mL) at rt was added 3,4-dimethoxybenzoyl chloride (95 mg, 0.48 mmol). The resulting mixture was stirred at rt for 16 h. CH2Cl2 (30 mL) was added to the suspension and washed with water (30 mL). The organic layer was washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was washed with methanol to yield a white solid (87 mg, 56%). δH (500 MHz, DMSO-d6, 363 K) 3.73 (3H, s), 3.80 (3H, s), 4.25 (2H, s), 7.09 (1H, d, J=8.5 Hz), 7.35 (1H, d, J=7.9 Hz), 7.44-7.48 (1H, m), 7.55 (1H, d, J=1.9 Hz), 7.58-7.61 (1H, m), 7.63-7.67 (2H, m), 7.80-7.85 (2H, m), 8.14 (1H, d, J=8.5 Hz), 8.43 (1H, d, J=7.9 Hz) δC (125 MHz, DMSO-d6) δ2.1, 55.8, 55.9, 110.8, 111.7, 113.4, 115.9, 117.2, 119.5, 121.4, 125.1, 125.3, 125.5, 128.3, 130.2, 131.5, 133.2, 133.2, 139.7, 140.5, 142.2, 147.3, 148.4, 153.8, 166.3, 166.8 mp 234-235° C.

Reference： [1]Current Patent Assignee: UNIVERSITY OF OXFORD; Oxford University Innovation (in: Oxford University) - WO2013/41859, 2013, A1 Location in patent: Paragraph 00232-00235
[2]Gianella-Borradori, Matteo; Christou, Ivy; Bataille, Carole J.R.; Cross, Rebecca L.; Wynne, Graham M.; Greaves, David R.; Russell, Angela J. [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 1, p. 241 - 263]
[3]Current Patent Assignee: UNIVERSITY OF OXFORD; Oxford University Innovation (in: Oxford University) - US2014/378451, 2014, A1 Location in patent: Paragraph 0438-0442

66
[ 26687-82-1 ]
[ 3535-37-3 ]
[ 1358907-96-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; at 0℃; for 1h;	General procedure: To a stirred solution of <strong>[26687-82-1]arctigenin</strong> 1 (180 mg, 0.4 mmol) and TEA (0.11 mL, 0.8 mmol) in 3 mL CH2Cl2 was added R1COCl (0.6 mmol) at 0 C slowly. Then the mixture was stirred at 0 C for 1 h. Aftercompletion of the reaction, water (20 mL) was added, and the solutionwas extracted with CH2Cl2 (3 20 mL). The combined organicextracts were washed with brine, dried, filtered, and concentratedunder reduced pressure. The crude product was purified by chromatographyon silica gel from (EtOAc/PE = 1/2) to afford the pureproduct 3a-r.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3882 - 3893

67
[ 1460737-83-0 ]
[ 3535-37-3 ]
[ 1460737-90-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In ethanol; dichloromethane at 20℃; Inert atmosphere;	General procedure for the synthesis of 1-cyclopropyl-6-fluoro-4-oxo-7-(4-[4-(substituted benzoyl orbenzenesulfonyl) piperazino]carbopiperazino)-1,4-dihydro-3-quinolinecarboxylic acids 5a-m General procedure: To a solution of amine 4 (0.67 g, 1.5 mmol) in DCM/EtOH (150 mL, 4:1) was added triethylamine (0.4 mL, 3.0 mmol) and the appropriate aroyl or benzenesulfonyl halide (1.2 mmol). The mixture was stirred at room temperature under argon for several hours depending on the completion of the reaction,which was checked by tlc. After evaporation of solvent under vacuum, the residue was purified by silica gel chromatography and recrystallized from an appropriate solvent to give the title products.

Reference： [1]Chen, Po-Ting; Lin, Wen-Po; Lee, An-Rong; Hu, Ming-Kuan [Molecules, 2013, vol. 18, # 7, p. 7557 - 7569]

68
[ 91-59-8 ]
[ 3535-37-3 ]
[ 331270-79-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	4.2.28 General benzanilide synthesis, Method A General procedure: The benzoyl chloride was prepared by stirring benzoic acid (1.0 mmol) with SOCl2 (0.363 mL, 5.0 mmol) and DMF (1 drop) in CH2Cl2 (5 ml) for overnight and evaporating the volatile materials under reduced pressure. To the solution of benzoyl chloride in CH2Cl2 (5mL) were added an aniline (1.0 mmol) and DIEA (0.871 mL, 5.0 mmol), and the reaction was stirred until no starting material by TLC (1-24 h) at room temperature. After dilution with CH2Cl2 (30mL), the organic layer was washed with brine (40 mL), dried with anhydrous MgSO4, and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography to obtain a benzanilide.

Reference： [1]St. John, Sarah E.; Jensen, Katherine C.; Kang, Soosung; Chen, Yafang; Calamini, Barbara; Mesecar, Andrew D.; Lipton, Mark A. [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 19, p. 6022 - 6037]

69
[ 919278-39-0 ]
[ 3535-37-3 ]
[ 1363775-28-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;	To pyrazole (3 mmol, 1.0 equiv) and Et3N (4.5 mmol, 1.5 equiv) dissolved in dichloromethane (15 mL) was added acyl chloride (3.15 mmol, 1.05 equiv) in an ice-waterbath. After the completion of addition, the resultant reaction mixture was warmed to room temperature and kept for 2hrs. On the completion of the reaction, the solvent of the reaction mixture was removed under reduced pressure. The residue was poured into water (50 mL) andthe desired product was obtained.

Reference： [1]ARKIVOC,2014,vol. 2014,p. 72 - 93

70
[ 4943-86-6 ]
[ 3535-37-3 ]
N-(2-(4-chlorophenylcarbamoyl)phenyl)-3,4-dimethoxybenzamide [ No CAS ]

Reference： [1]ChemMedChem,2015,vol. 10,p. 742 - 751

71
[ 1131-62-0 ]
[ 3535-37-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: 1-(3,4-dimethoxyphenyl)ethanone With pyridine; disulfur dichloride In chlorobenzene at 20℃; for 2h; Stage #2: With sulfuryl dichloride In chlorobenzene at 20 - 132℃; for 15.5h;	21 Example 21: 3,4-Dimethoxybenzoyl chloride To a mixture of 3',4'-dimethoxyacetophenone (0.180 mg, 1.0 mmol), pyridine (0.012 ml, 0.15 mmol), and chlorobenzene (0.35 ml) was added S2CI2 (0.16 ml, 2.0 mmol) while stirring at room temperature. After 2 h S02C12 (0.121 ml, 1.5 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was then stirred at 132 °C for 15 h. The mixture was diluted with CDCI3 (2 ml), an internal standard was added (1BU3PO4, 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that 3,4-dimethoxybenzoyl chloride had been formed in 77% yield. 1H NMR (PhCl, CDCI3, 400 MHz) delta = 7.75 (d, J = 8 Hz, 1H), 7.45 (s, 1H), 6.82 (d, J = 8 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H).
47%	Stage #1: 1-(3,4-dimethoxyphenyl)ethanone With pyridine; sulfur monochloride In chlorobenzene at 20℃; Stage #2: With thionyl chloride In chlorobenzene at 20 - 132℃;
79 %Spectr.	With pyridine; disulfur dichloride at 70 - 136℃; for 22h;	16 Example 16: 3,4-Dimethoxybenzoyl chloride A mixture of 3,4-dimethoxyacetophenone (0.182 g, 1.00 mmol), sulfur monochloride (0.320ml, 4.0 mmol), and pyridine (0.008 ml, 0.10 mmol) was stirred at 70 °C for 4 h, and then at136 °C for 18 h. To the mixture was added iBu3PO4 (0.0552 ml, 0.20 mmol) and CDC13, andanalysis by 1H NMR indicated that 3,4-dimethoxybenzoyl chloride had been formed in 79% yield.1H NMR (CDC13, 400 MHz) delta 7.83 (dd, J = 8 Hz, 1 Hz, 1H), 7.53 (d, J = 1 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H)13C NMR (CDC13, 100 MHz) delta 167.2, 155.2, 149.0, 127.2, 125.5, 112.8, 110.4, 56.3, 56.1

Reference： [1]Current Patent Assignee: LONZA GROUP AG - WO2017/5606, 2017, A1 Location in patent: Page/Page column 38
[2]Zaragoza, Florencio [Journal of Organic Chemistry, 2015, vol. 80, # 20, p. 10370 - 10374]
[3]Current Patent Assignee: LONZA GROUP AG - WO2016/202757, 2016, A1 Location in patent: Page/Page column 34

72
[ 96-47-9 ]
[ 3535-37-3 ]
4-chloropentyl-3,4-dimethoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With iron In 1,2-dichloro-ethane at 70℃; Schlenk technique; Inert atmosphere; regioselective reaction;	General Procedure for the Synthesis of esters/chloroesters 3. General procedure: To a stirring mixture of acyclic/cyclic ether (1, 1.1 mmol) and acid chloride (2, 1.0 mmol) indichloroethane (10 mL) was added iron powder (0.31 g, 0.2 mmol) and stirred at 45-84 oCdepending on the reactants used. The reaction was monitored by TLC (5% EtOAc:hexane) andwas complete in 3-8 h, after which the contents were filtered to separate iron. Volatiles in thefiltrate were removed under reduced pressure in rotary evaporator and the crude was directly subjected to silica gel chromatography using 5% EtOAc in hexane to give the correspondingesters/chloro-esters (3) in good to excellent yields.

Reference： [1]Bodduri, V.D. Vijaykumar; Choi, Kyung-Min; Vaidya, Raghavender Rao; Patil, Kalpesh; Chirumarry, Sridhar; Jang, Kiwan; Yoon, Yong-Jin; Falck, John R.; Shin, Dong-Soo [Tetrahedron Letters, 2015, vol. 56, # 51, p. 7089 - 7093]

73
[ 99-92-3 ]
[ 3535-37-3 ]
N-(4-acetylphenyl)-3,4-dimethoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;	General Procedure General procedure: The acid chlorides 25 (1 mmol) were suspended in dry THF (5 mL) under argon, 4`-aminoacetophenone (135 mg, 1 mmol) and K2CO3 (68 mg, 0.5 mmol) were added and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure. Aqueous HCl (0.5 M, 15 mL) was added, and the solution was extracted with ethyl acetate (30 mL). The crude residue obtained after evaporation of solvent was purified by silica gel flash chromatography using hexane-ethyl acetate (1:1) or by crystallization from 70% methanol to afford the desired product.
	With triethylamine In tetrahydrofuran at 80℃;

Reference： [1]Eissa, Ibrahim H.; Mohammad, Haroon; Qassem, Omar A.; Younis, Waleed; Abdelghany, Tamer M.; Elshafeey, Ahmed; Abd Rabo Moustafa, Mahmoud M.; Seleem, Mohamed N.; Mayhoub, Abdelrahman S. [European Journal of Medicinal Chemistry, 2017, vol. 130, p. 73 - 85]
[2]Chen, Shaobin; Huang, Jianan; Huang, Qinghui; Li, Yuanzhi; Luo, Yingqi; Wang, Chengxu; Wu, Wenhao; Yu, Lihong; Zha, Dailong; Zhang, Chao; Zhang, Jianye; Zhou, Wenmin [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 47]

74
[ 3535-37-3 ]
[ 13063-04-2 ]

Reference： [1]Patent: CN104356139,2017,B

75
[ 3366-95-8 ]
[ 3535-37-3 ]
1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl 3,4-dimethoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		General procedure: In a round bottom flask (fitted with dropping funnel, condenser,and a glass u-tube connected to a flask containing NaOH toneutralize the HCl) containing <strong>[3366-95-8]Secnidazole</strong> (2 g, 10.8 mmol) weadded toluene (20 mL), and pyridine (2 mL). The flask was heatedwith stirring for 30 min at 70 C. Later 4-methylbenzoylchloride(CAS: 212-864-8, Aldrich, 2 g, 12.9 mmol) was slowly added(through dropping funnel) to the flask and stirring continued at70 C for 4.5 h. The reaction mixture was allowed to cool andtreated with saturated aqueous NaHCO3 solution and water. Theorganic layer was separated (separatory funnel) and solvent wasremoved (rotary/vacuum) to obtain the product. This was recrystallizedfrom chloroform/toluene to obtain pure white crystals in77% yield.

Reference： [1]Journal of Molecular Structure,2017,vol. 1149,p. 792 - 802

76
[ 16502-01-5 ]
[ 3535-37-3 ]
[ 66168-36-3 ]

Yield	Reaction Conditions	Operation in experiment
91.1%	With N-ethyl-N,N-diisopropylamine In chloroform at 0 - 20℃; for 2h; Inert atmosphere;	(3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(3-(trifluoromethyl) phenyl) methanone (6a) General procedure: Under an inert argon atmosphere and at 0 °C, 3-(trifluoromethyl)benzoyl chloride (0.21 ml, 1.44 mmol) isadded dropwise to a mixture of compound 5 (0.2 g, 1.16mmol) and N,N-diisopropylethylamine (DIPEA) (0.3 ml,1.72 mmol) in chloroform (6 ml). After stirring at roomtemperature for 2 h, the reaction mixture was extractedusing chloroform (1 × 30 ml), saturated solution of ammoniumchloride (1 × 30 ml), and brine (1 × 30 ml). Theorganic phase was dried over Na2SO4, concentrated invacou, and purified by flash column chromatography onsilica gel by eluting with a mixture of DCM/methanol(98:2) to give the desired products (6a) as golden yellowsolid. Yield: 75%.

Reference： [1]Abdelwaly, Ahmad; Salama, Ismail; Gomaa, Mohamed S.; Helal, Mohamed A. [Medicinal Chemistry Research, 2017, vol. 26, # 12, p. 3173 - 3187]

77
[ 76629-10-2 ]
[ 76-05-1 ]
[ 3535-37-3 ]
7-chloro-1-(3,4-dimethoxybenzoyl)-2,3-dihydro-1,8-naphthyridin-4(1H)-one trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28 mg		C) 7-Chloro-1-(3,4-dimethoxybenzoyl)-2,3-dihydro-1,8-naphthyridin-4(1H)-one trifluoroacetic acid salt To a solution of <strong>[76629-10-2]7-chloro-2,3-dihydro-1,8-naphthyridin-4(1H)-one</strong> (0.6 g) in THF (30 mL), a 1 M solution of lithium bis(trimethylsilyl)amide in hexane (3.3 mL) was added at-75C to -70C. The reaction mixture was stirred at the same temperature as above for 30 minutes, and then, a solution of 3,4-dimethoxybenzoyl chloride (0.8 g) in THF (5 mL) was added thereto over 30 minutes. The temperature of the reaction mixture was raised to room temperature, and the reaction mixture was poured to water, followed by extraction with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by reverse-phase HPLC to obtain the title compound (28 mg). MS: [M+H]+ 346.9.

Reference： [1]Patent: EP3287441,2018,A1 .Location in patent: Paragraph 0469

78
[ 31891-06-2 ]
[ 3535-37-3 ]
C₁₆H₁₇NO₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With triethylamine; In dichloromethane; at 20℃;Cooling with ice;	Take a 100ml single bottle,Add 10ml of anhydrous methylene chloride,0.17 g of triethylamine and 0.1 g of <strong>[31891-06-2]2-aminothiophene-3-carboxylic acid ethyl ester</strong> were stirred to dissolve,A solution of 0.17 g of 3,4-dimethoxybenzoyl chloride dissolved in dichloromethane was added dropwise in an ice bath and stirred overnight at room temperature.After the reaction was completed, quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated.Column chromatography gave the target compound 3p 0.07 g (36%).

Reference： [1]Patent: CN107721975,2018,A .Location in patent: Paragraph 0066; 0067; 0068

79
[ 56621-48-8 ]
[ 3535-37-3 ]
(3,4-dimethoxyphenyl)(4-(4-hydroxyphenyl)piperazin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With triethylamine; In dichloromethane; at 20℃;Cooling with ice;	Take a 100ml single bottle,Add 10ml of anhydrous methylene chloride,0.17 g of triethylamine and 0.1 g of p-hydroxyphenylpiperazine were stirred to dissolve,A solution of 0.17 g of 3,4-dimethoxybenzoyl chloride dissolved in dichloromethane was added dropwise on an ice bath.Stir at room temperature overnight. After the reaction is completed, quench with water and extract with dichloromethane.Dry over anhydrous sodium sulfate and concentrate.Column chromatography gave the target compound 3t 0.04 g (20%).
20%	With triethylamine; In dichloromethane; at 0 - 20℃;	General procedure: To a mixture of Methyl 2-aminothiophene-3-carboxylate (0.1 g, 636.18 umol, 1.0 eq.) and triethylamine (0.19 g, 1.91 mmol, 3.0 eq.) in anhydrous dichloromethane (10 mL), 3,4,5-Trimethoxybenzoyl chloride 2a (0.22 g, 954.28 umol,1.5 eq.) in dichloromethane was slowly added at 0 C. After stirring at r.t overnight, the reaction mixture was diluted with water (3×10 mL), and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water and brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to afford compound 3a.

Reference： [1]Patent: CN107721975,2018,A .Location in patent: Paragraph 0078; 0079; 0080
[2]Letters in drug design and discovery,2018,vol. 15,p. 1319 - 1328

80
[ 304858-65-9 ]
[ 3535-37-3 ]
N-(5-bromo-2-(1H-tetrazol-5-yl)phenyl)-3,4-dimethoxybenzamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 422 - 427

81
[ 304858-65-9 ]
[ 3535-37-3 ]
C₁₆H₁₃BrN₂O₃ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 422 - 427

82
[ 3535-37-3 ]
[ 13052-92-1 ]
ethyl 2-(3,4-dimethoxyphenyl)benzo[d]oxazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With trichlorophosphate; In 1,4-dioxane; at 20 - 90℃; for 15h;Inert atmosphere;	General procedure: To a stirred solution of 10 (0.55 mmol) in anhydrous 1,4-dioxane (3 mL) was added substituted benzoyl chloride (1.1 mmol, 2.0 equiv.) in anhydrous 1,4-dioxane (2 mL) at room temperature under nitrogen atmosphere. The reaction mixture was then warmed to 90C and stirred for 3 h. At this stage, POCl3 (0.16 mL, 1.65 mmol, 3.0 equivalents) was added dropwise and stirring was continued further 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, solvent and the excess POCl3 was removed under reduced pressure. EtOAc (25 mL) and H2O (10 mL) were added to the crude compound and two layers were separated. Aqueous layer was extracted with EtOAc(2 × 20 mL). The combined organic layer was washed with H2O (2 × 15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (EtOAc:hexane = 1:5-1:2) to afford the pure product.

Reference： [1]Bulletin of the Korean Chemical Society,2018,vol. 39,p. 743 - 749

83
[ 34761-09-6 ]
[ 3535-37-3 ]
ethyl 3-[(3,4-dimethoxybenzoyl)amino]-1-benzothiophene-2-carboxylate [ No CAS ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2019,vol. 34,p. 55 - 74

84
6-amino-1-((6-chloropyridin-3-yl)methyl)-8-nitro-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one [ No CAS ]
[ 3535-37-3 ]
N-(1-((6-chloropyridin-3-yl)methyl)-8-nitro-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridin-6-yl)-3,4-dimethoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.8%	With triethylamine In dichloromethane at 0 - 20℃;	The synthesis of the target compound 5a-s, 6a-e General procedure: General procedure for preparation of 5a-s, 6a-e: To a solution of 4 (0.15 g, 0.47 mmol.) and Et3N (0.08 mL, 0.58 mmol) in DCM (10 mL) at 0 °C, acyl chloride 7 (0.56 mmol) was added dropwise. The reaction was gradually warmed to room temperature, the termination of the reaction was measured by TLC, then quenched with water and extracted into DCM (3×10 mL). The organic phase was washed saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude residue was purified by silica flash column chromatography afforded compound 5a-s, 6a-e.

Reference： [1]Zhang, Letian; Liu, Kun; Shao, Xusheng; Li, Zhong; Xu, Xiaoyong [Chinese Chemical Letters, 2019, vol. 30, # 2, p. 340 - 344]

85
C₂₅H₂₁BrOP⁽¹⁺⁾*Br^(1-) [ No CAS ]
[ 3535-37-3 ]
7-bromine-2-(3,4-dimethoxyphenyl) benzofuran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine In toluene at 110℃; for 2h;	2.1.2. General procedure for the preparation of 2-phenylbenzofuran (1-4). General procedure: A mixture of 2-hydroxybenzyltriphenylphosphonium bromide(0.50 g, 1.11 mmol) and benzoyl chloride (0.12 mL, 1.11 mmol) in amixed solvent (toluene 20 mL and Et3N 0.5 mL) was stirred under refluxfor 2 h. The precipitate was removed by filtration. The filtrate wasconcentrated, and the residue was purified by silica gel chromatography(hexane/EtOAc 9:1) to give the desired compounds 1-4.
	With triethylamine In toluene at 110℃; for 2h;

Reference： [1]Fais, Antonella; Kumar, Amit; Medda, Rosaria; Pintus, Francesca; Delogu, Francesco; Matos, Maria J.; Era, Benedetta; Delogu, Giovanna L. [Bioorganic Chemistry, 2019, vol. 84, p. 302 - 308]
[2]Delogu, Giovanna Lucia; Era, Benedetta; Floris, Sonia; Medda, Rosaria; Sogos, Valeria; Pintus, Francesca; Gatto, Gianluca; Kumar, Amit; Westermark, Gunilla Torstensdotter; Fais, Antonella [International Journal of Biological Macromolecules, 2021, vol. 169, p. 428 - 435]

86
[ 2783-17-7 ]
[ 3535-37-3 ]
C₃₀H₄₄N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;	General procedure: To a solution of 1,12-<strong>[2783-17-7]diaminododecane</strong> (26 mmol, 1 eq) in 80 ml of anhydrous methylene chloride under nitrogenatmosphere are added simultaneously via syringes, triethylamine (130 mmol, 5 eq) andbenzoyl chloride (78.3 mmol, 3 eq) dissolved in 50 mL of anhydrous methylene chloride.After 2 hours at room temperature, filtration of the white solide and washed with water anddiethyl ether gave the desired dibenzamide 3a-g.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2203 - 2207

87
methyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate [ No CAS ]
[ 3535-37-3 ]
methyl 2-(6-(3,4-dimethoxybenzamido)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In tetrahydrofuran at 20℃; for 12h;	General procedure for synthesis of methyl 2-(6-benzamido-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (5) General procedure: The methyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate 4 (1 mmol, 0.2 g) and triethylamine (1.3 mmol, 0.1 g) was dissolved in tetrahydrofuran (50 mL). After the mixture was cooled to 0 oC, the substituted benzoyl chloride (1.1 mmol, 0.2 g) was added to the mixture dropwise. The reaction mixture temperature was naturally increased to room temperature, and this mixture was stirred for an additional 12 h (monitored by TLC). After the reaction, the result mixture was poured into ice water and extracted with EtOAc (3×20 mL), the combined organic phases were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel using petroleum ether (PE)/EtOAc (3:1) to afford compound 5.

Reference： [1]Han, Zhongfei; Qi, Gang; Zhu, Junkai; Zhang, Yundong; Xu, Yin; Yan, Kang; Zhu, Changjin; Hao, Xin [Bioorganic Chemistry, 2020, vol. 105]

88
[ 2894-45-3 ]
[ 3535-37-3 ]
N-(2-(2-chlorobenzoyl)phenyl)-3,4-dimethoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With pyridine In dichloromethane at 20℃; for 4h;	N-(2-(2-Bromobenzoyl)phenyl)benzamide (4a) General procedure: A solution of 3b (0.83 g, 3 mmol) andpyridine (1 mL) in dichloromethane (20 mL) was cooled to 0 °C. Benzoyl chloride (0.46 mL,4 mmol) was added dropwise. The solution was then allowed to warm to room temperatureand stirred for 4 h. After quenching with aqueous HCl (0.5 M, 20 mL), it was extracted withdichloromethane (3 × 20 mL) and washed with brine (3 × 20 mL). The combined organiclayers were dried over Na2SO4 and concentrated under reduced pressure. The crude productwas purified by column chromatography (10% ethyl acetate/cyclohexane) to yield 4a as whitecrystals (0.69 g, 61%).

Reference： [1]Waltemate, Jana; Ivanov, Igor; Ghasemi, Jahan B.; Aghaee, Elham; Daniliuc, Constantin Gabriel; Müller, Klaus; Prinz, Helge [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 32]

Type	HazMat fee for 500 gram (Estimated)
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Inaccessible (Haz class 6.1), Domestic	USD 80+
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CAS No. :	3535-37-3	MDL No. :	MFCD00000674
Formula :	C₉H₉ClO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VIOBGCWEHLRBEP-UHFFFAOYSA-N
M.W :	200.62	Pubchem ID :	77070
Synonyms :

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3261
Hazard Statements:	H314	Packing Group:	Ⅱ
GHS Pictogram:

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[ CAS No. 3535-37-3 ] {[proInfo.proName]}

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[ 3535-37-3 ] Synthesis Path-Upstream 1~7

[ 3535-37-3 ] Synthesis Path-Downstream 1~88

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[ 3535-37-3 ]

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