[ CAS No. 18871-66-4 ] {[proInfo.proName]}

Name: 18871-66-4|1,1-Dimethoxy-N,N-dimethylethanamine|90% (contains stabilizer)
Brand: Ambeed
SKU: A986688
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Quality Control of [ 18871-66-4 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 18871-66-4 ]

CAS No. :	18871-66-4	MDL No. :	MFCD00008476
Formula :	C₆H₁₅NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FBZVZUSVGKOWHG-UHFFFAOYSA-N
M.W :	133.19	Pubchem ID :	87835
Synonyms :

Safety of [ 18871-66-4 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P210-P233-P240-P241-P242-P243-P260-P264-P270-P271-P280-P301+P312+P330-P303+P361+P353-P304+P340+P311-P305+P351+P338-P308+P311-P332+P313-P337+P313-P370+P378-P403+P233-P403+P235-P405-P501	UN#:	1993
Hazard Statements:	H225-H302-H311+H331-H315-H319-H335-H371	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 18871-66-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 18871-66-4 ]
Downstream synthetic route of [ 18871-66-4 ]

[ 18871-66-4 ] Synthesis Path-Upstream 1~11

1
[ 18871-66-4 ]
[ 769-28-8 ]
[ 64038-03-5 ]
[ 65515-39-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1556 - 1564

2
[ 769-28-8 ]
[ 18871-66-4 ]
[ 64038-03-5 ]
[ 65515-39-1 ]

Reference： [1] European Journal of Organic Chemistry, 2002, # 11, p. 1763 - 1769

3
[ 18871-66-4 ]
[ 6291-84-5 ]
[ 4271-96-9 ]

Yield	Reaction Conditions	Operation in experiment
5.33 g	at 80℃; for 1 h;	The mixture of N-methyl-1,3-diaminopropane (4.41 g, 50 mmol) and N,N-dimethylacetamide dimethyl acetal (90percent purity, 7.77 g, 52.5 mmol) was stirred at 80 °C without solvent. After 1 h, the mixture was evaporated in vacuo, and the residue was distilled under reduced pressure to give 1a (5.33 g, 95percent) as a colorless liquid; B.p. 62–64 °C/1.0 kPa. ¹H NMR (400 MHz, CDCl₃, 25 °C) δ (ppm): 1.83 (quin, J =6.0 Hz, 2H, NCH₂CH₂CH₂N), 1.96 (s, 3H, CCH₃), 2.88 (s, 3H, NCH₃), 3.13 (t, J = 6.0 Hz, 2H, NCH₂CH₂CH₂NCH₃), 3.29 (t, J = 6.0 Hz, 2H, NCH₂CH₂CH₂NCH₃). ¹³C NMR (100 MHz, CDCl₃, 25 °C) δ (ppm): 22.0 (NCH₂CH₂CH₂N), 22.7 (CCH₃), 38.7 (NCH₃), 44.2 (NCH₂CH₂CH₂NCH₃), 48.3 (NCH₂CH₂CH₂NCH₃), 155.8 (NCN).

Reference： [1] Tetrahedron Letters, 2018, vol. 59, # 18, p. 1702 - 1704

4
[ 251549-18-5 ]
[ 18871-66-4 ]

Reference： [1] Patent: EP1086950, 2001, A1,

5
[ 124-41-4 ]
[ 920-98-9 ]
[ 18871-66-4 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 19, p. 3659 - 3660

6
[ 67-56-1 ]
[ 127-19-5 ]
[ 18871-66-4 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 43, p. 7757 - 7759
[2] Journal of Chemical Research, 2011, vol. 35, # 2, p. 119 - 120

7
[ 127-19-5 ]
[ 124-41-4 ]
[ 77-78-1 ]
[ 18871-66-4 ]

Reference： [1] Chinese Chemical Letters, 2010, vol. 21, # 2, p. 163 - 166

8
[ 67-56-1 ]
[ 89865-20-3 ]
[ 18871-66-4 ]
[ 638-21-1 ]

Reference： [1] Tetrahedron Letters, 1983, vol. 24, # 19, p. 1975 - 1978

9
[ 67-56-1 ]
[ 75589-83-2 ]
[ 18871-66-4 ]
[ 89865-20-3 ]
[ 638-21-1 ]

Reference： [1] Tetrahedron Letters, 1983, vol. 24, # 19, p. 1975 - 1978

10
[ 127-19-5 ]
[ 3315-60-4 ]
[ 77-78-1 ]
[ 18871-66-4 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1986, vol. 51, # 9, p. 1964 - 1971

11
[ 18871-66-4 ]
[ 187834-88-4 ]
[ 280110-69-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: at 50℃; for 4 h; Stage #2: With toluene-4-sulfonic acid In toluene at 100℃; for 18 h;	To a solution of 1 -(tert-butoxycarbonyl)piperidine-4-carbohydrazide (967 mg, 3.97 mmol)in THF (4.3 mL) was added N,N-dimethylacetamide dimethyl acetal (872 pL, 5.96 mmol)and the reaction mixture was heated at 50°C for 4 h under nitrogen. The reaction mixture was concentrated in vacuo, the resulting residue dissolved in anhydrous toluene (4.3 mL) and para-toluene sulfonic acid (42 mg, 0.22 mmol) added. The resulting mixture was heated at 100°C overnight (18 h). The reaction mixture was concentrated in vacuo, theresulting residue partitioned between CH2CI2 (25 mL) and saturated NaHCO3 (25 mL) and the mixture stirred vigorously followed by passing through a phase-separating cartridge. The organic layer was concentrated in vacuo. The crude residue was triturated with diethyl ether followed by isohexane to afford 4-(5-methyl-[i ,3,4]oxadiazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester (924 mg, 87percent) as a pale brown solid. 1H NMR (400 MHz,CDCI3) O 4.18-4.02 (br s, 2H), 3.06-2.87 (m, 3H), 2.50 (s, 3H), 2.04-2.01 (m, 2H), 1.83-1.73 (m, 2H), 1.46 (s, 9H).

Reference： [1] Patent: WO2015/36759, 2015, A1, . Location in patent: Page/Page column 183; 184

[ 18871-66-4 ] Synthesis Path-Downstream 1~88

1
[ 3484-18-2 ]
[ 18871-66-4 ]
[ 98910-49-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1985,vol. 22,p. 341 - 343

2
[ 5334-41-8 ]
[ 18871-66-4 ]
[ 144945-01-7 ]

Reference： [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1288 - 1295

3
[ 31037-02-2 ]
[ 18871-66-4 ]
[ 116519-74-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	In methanol for 2h; Heating;

Reference： [1]Maquestiau; Vanden Eynde [Tetrahedron, 1987, vol. 43, # 18, p. 4185 - 4193]

4
[ 21230-43-3 ]
[ 18871-66-4 ]
[ 116519-75-6 ]

Reference： [1]Tetrahedron,1987,vol. 43,p. 4185 - 4193

5
[ 5423-53-0 ]
[ 18871-66-4 ]
N'-(7-chloro-1,2,4-benzotriazin-3-yl)-N,N-dimethylacetamidine [ No CAS ]

Reference： [1]Journal of Pharmaceutical Sciences,1980,vol. 69,p. 789 - 793

6
[ 18871-66-4 ]
[ 22179-72-2 ]
[ 74466-82-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	Ambient temperature;

Reference： [1]Lin, Yang-i; Lang, S. A.; Petty, Sharon R. [Journal of Organic Chemistry, 1980, vol. 45, # 19, p. 3750 - 3753]
[2]Bongartz, Jean-Pierre; Stokbroekx, Raymond; Van der Aa, Marcel; Luyckx, Marcel; Willems, Marc; Ceusters, Marc; Meerpoel, Lieven; Smets, Gerda; Jansen, Tine; Wouters, Walter; Bowden, Charlie; Valletta, Lisa; Herb, Mark; Tominovich, Rose; Tuman, Robert [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 4, p. 589 - 591]

7
[ 18871-66-4 ]
[ 119581-52-1 ]
[ 137609-32-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	at 120℃; for 2h;

Reference： [1]Haider, Norbert; Heinisch, Gottfried; Wanko, Richard [Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1441 - 1444]

8
[ 18871-66-4 ]
[ 958-09-8 ]
N-[9-((2R,4S,5R)-4-Hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-9H-purin-6-yl]-acetimidic acid methyl ester [ No CAS ]
[ 98532-92-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	In methanol at 40℃; for 18h; Yield given;
70%	In methanol at 40℃; for 18h; Yields of byproduct given;

Reference： [1]McBride, Lincoln J.; Kierzek, Ryszard; Beaucage, Serge L.; Caruthers, Marvin H. [Journal of the American Chemical Society, 1986, vol. 108, # 8, p. 2040 - 2048]
[2]McBride, Lincoln J.; Kierzek, Ryszard; Beaucage, Serge L.; Caruthers, Marvin H. [Journal of the American Chemical Society, 1986, vol. 108, # 8, p. 2040 - 2048]

9
[ 18871-66-4 ]
[ 102-93-2 ]
[ 173372-67-3 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 8428 - 8430

10
[ 631-58-3 ]
[ 18871-66-4 ]
N-[1-Dimethylamino-eth-(E)-ylidene]-thiopropionamide [ No CAS ]

Reference： [1]Tetrahedron,1996,vol. 52,p. 10095 - 10112

11
[ 13515-65-6 ]
[ 18871-66-4 ]
N-[1-Dimethylamino-eth-(E)-ylidene]-thioisobutyramide [ No CAS ]

Reference： [1]Tetrahedron,1996,vol. 52,p. 10095 - 10112

12
[ 66346-87-0 ]
[ 18871-66-4 ]
[ 68675-29-6 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 1447 - 1457

13
[ 64068-00-4 ]
[ 18871-66-4 ]
[ 68675-28-5 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 1447 - 1457

14
[ 18871-66-4 ]
[ 10299-44-2 ]
N'-[3-((2R,3R,4S,5R)-3,4-Dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-N,N-dimethyl-acetamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In methanol for 14h; Ambient temperature;

Reference： [1]Seela; Munster; Lochner; Rosemeyer [Helvetica Chimica Acta, 1998, vol. 81, # 6, p. 1139 - 1155]

15
[ 18871-66-4 ]
[ 67-64-1 ]
[ 3433-62-3 ]

Yield	Reaction Conditions	Operation in experiment
	for 18h; Heating;

Reference： [1]Kepe, Vladimir; Polanc, Slovenko; Kocevar, Marijan [Heterocycles, 1998, vol. 48, # 4, p. 671 - 678]

16
[ 818-72-4 ]
[ 18871-66-4 ]
deca-3,4-dienoic acid dimethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In toluene for 5h; Heating;
70%	With propionic acid In toluene Reflux;

Reference： [1]Trost; Pinkerton; Seidel [Journal of the American Chemical Society, 2001, vol. 123, # 50, p. 12466 - 12476]
[2]Vine, Logan E.; Schomaker, Jennifer M. [Chemistry - A European Journal, 2022, vol. 28, # 1]

17
[ 461-72-3 ]
[ 18871-66-4 ]
[ 6843-45-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	In toluene Heating;
68%	In toluene for 2h; Reflux;	10149] Preparation of 3-methylimidazolidine-2,4-dione To a solution of hydantoin (0.50 g, 5.0 mmol) in toluene(30 mE), i, i -dimethoxy-N,N-dimethylethanamine (i .3 g, i 0 mmol, 2 equiv) was added. The mixture was refluxed for 2 hours then allowed to cool down to room temperature. Direct crystallization from the toluene gives 3-methylimi- dazolidine-2,4-dione (i) as a white solid (0.39 g, 68% yield) without thrther purification. ‘H NMR (400 MHz, CD3OD):ö8.Oi (s, iH), 3.88 (s, iH), 2.8i (s, iH). ‘3C NMR (400 MHz, CD3OD): öi72.9, i58.9, 46.0, 23.2.
62%	In toluene for 3h; Heating;

50%	In toluene at 110℃; for 2h;	3 2,4-imidazolinedione (1.0 equiv) was dissolved in 40 ml of toluene,N, N-dimethylacetamide dimethyl acetal (N, N-dimethylacetamide dimethyl acetal) (3.0 equiv)The reaction solution was stirred at 110 ° C for 2 hours and then cooled to room temperature and cooled to 0 ° C for 15 minutes.Filter to get residue,The residue was washed five times with toluene and dried in vacuo to give 3-methylimidazolidine-2,4-dione (3-methyl-imidazoline-2,4-dione).Yield 50%.
	In toluene at 110℃; for 2h;	1.16 Hydantoin (19.0 g, 190 mmol, 1.0 eq) was suspended in toluene (700 ml) and N,N-dimethylacetamide dimethyl acetal (75.0 g, 563 mmol, 3.0 eq) was added. The resulting mixture was heated at 110 °C for two hours, cooled to ambient temperature and then cooled to 0° C for 15 minutes. The resulting precipitate was collected by filtration, washed with toluene (5 x 50 mL) and dried in vacuo to afford the titled compound as a pale yellow solid. NMR (400 MHz, CDC13) δ 6.09 (1 H, brs); 3.99 (1 H, s); 3.04 (1 H, s) ppm.
	In toluene for 3h; Reflux;

Reference： [1]Porter, Michael J.; White, Nicola J.; Howells, Garnet E.; Laffan, David D.P. [Tetrahedron Letters, 2004, vol. 45, # 35, p. 6541 - 6543]
[2]Current Patent Assignee: UNIVERSITY OF OTTAWA HEART INSTITUTE - US2016/324992, 2016, A1 Location in patent: Paragraph 0149
[3]Janin, Yves L.; Huel, Christiane; Flad, Genevieve; Thirot, Sylvie [European Journal of Organic Chemistry, 2002, # 11, p. 1763 - 1769]
[4]Current Patent Assignee: SICHUAN UNIVERSITY - CN106279132, 2017, A Location in patent: Paragraph 0081; 0082; 0083
[5]Current Patent Assignee: MERCK & CO INC - WO2012/151136, 2012, A1 Location in patent: Page/Page column 29
[6]Nie, Yu; Li, Jing; Yuan, Qianjia; Zhang, Wanbin [Chinese Journal of Chemistry, 2022, vol. 40, # 7, p. 819 - 824]

18
[ 769-28-8 ]
[ 18871-66-4 ]
[ 64038-03-5 ]
[ 65515-39-1 ]

Reference： [1]European Journal of Organic Chemistry,2002,p. 1763 - 1769

19
[ 7720-39-0 ]
[ 18871-66-4 ]
2-(N',N'-dimethylacetamidino)imidazole [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 4345 - 4354

20
[ 18871-66-4 ]
[ 2447-79-2 ]
N-[1-(dimethylamino)ethylidene]-2,4-dichlorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	at 120℃; for 2h;

Reference： [1]Gilligan, Paul J.; Folmer, Beverly K.; Hartz, Richard A.; Koch, Stephanie; Nanda, Kausik K.; Andreuski, Stephen; Fitzgerald, Lawrence; Miller, Keith; Marshall, William J. [Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 18, p. 4093 - 4102]

21
[ 58539-65-4 ]
[ 18871-66-4 ]
[ 35969-61-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,2006,vol. 43,p. 1311 - 1317

22
[ 700-06-1 ]
[ 18871-66-4 ]
[ 31771-46-7 ]

Reference： [1]Russian Chemical Bulletin,2007,vol. 56,p. 325 - 329

23
[ 18871-66-4 ]
[ 16588-06-0 ]
[ 476660-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N,N-dimethylacetamide dimethyl acetal; 4-chloro-3-nitrobenzamide at 100℃; Stage #2: With sodium hydroxide; hydroxylamine hydrochloride; acetic acid In 1,4-dioxane; water at 20 - 90℃;	J3 Reference Example J3 An N-(1,1-dimethoxyethyl)-N,N-dimethylamine solution of 4-chloro-3-nitrobenzamide was stirred at 100°C. After evaporation of the solvent, hydroxylamine hydrochloride, 1 M sodium hydroxide aqueous solution, 1,4-dioxane and acetic acid were added to the resulting residue and stirred at room temperature and then at 90°C. After evaporation of the solvent, the resulting residue was mixed with 1 M sodium hydroxide aqueous solution, extracted with chloroform and then purified to obtain 5-(4-chloro-3-nitrophenyl)-3-methyl-1,2,4-oxadiazole as an orange solid. F+: 240.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - EP1396490, 2004, A1 Location in patent: Page 16

24
[ 686344-58-1 ]
[ 18871-66-4 ]
[ 686344-67-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	for 4h; Heating / reflux;	N, N-DIMETHYLFORMAMIDE dimethyl acetal (16 ml, 121 MMOL) was combined with 1-benzhydryl-3-benzylaminoazetidine-3-carboxylic acid amide (1-(13A-9 b ; 3.03 g, 8.16 MMOL) and heated to reflux. After 4 hours, the suspension was cooled and extracted from saturated aqueous NaCHO3 with ethyl acetate. The combined extracts were dried (NA2SO4), and concentrated, in vacuo, to the crude solid (3.50 g). Purification of the residue on a BiotageTM Flash 40M column using 0-3% methanol in methylene chloride as eluant afforded 1-(29A-6) a as a yellowish solid (1.92 g, 62%): +ES MS (M+1) 382.3 ; H NMR (400 MHZ, CD3OD) No. 8. 66 (s, 1H), 7.59 (d, J = 7. 1 Hz, 2H), 7.49-7. 11 (m, 13H), 5.12 (s, 2H), 4.44 (s, 1H), 3.31 (d, J = 9.6 Hz, 2H), 3.20 (d, J = 9.6 Hz, 2H).

Reference： [1]Current Patent Assignee: SOLIDUS NETWORKS, INC.; PFIZER INC - WO2004/37823, 2004, A1 Location in patent: Page 84-85

25
[ 18871-66-4 ]
[ 66073-54-9 ]
[ 475155-76-1 ]

Yield	Reaction Conditions	Operation in experiment
	for 1h; Heating / reflux;	2 Reference Example 2; 3-(2-chloro-6-fluorophenyl)-5-methyl-1H-1,2,4-triazole Reference Example 2 3-(2-chloro-6-fluorophenyl)-5-methyl-1H-1,2,4-triazole The mixture of 2-chloro-6-fluorobenzamide (4.00 g, 23.0 mmol) and N,N-dimethylacetamide dimethylacetal (13 ml) was stirred under reflux with heating for 1 hour.. The residue obtained by concentration under reduced pressure was washed with petroleum ether to give yellow crystals (5.66 g).. The resulting crystals were suspended in toluene (40 ml), and hydrazine hydrate (2.23 ml, 46 mmol) was added thereto, then the solution was refluxed with heating for 4 hours.. To the reaction mixture was added ice-water (40 ml), and the precipitated crystals were collected by filtration.. The obtained crystals were recrystallized from ethyl acetate to give 3-(2-chloro-6-fluorophenyl)-5-methyl-1H-1,2,4-triazole (1.80 g, 8.51 mmol, 37%) as colorless crystals. mp: 232-233°C1H NMR (DMSO-d6) δ ppm: 2.43 (3H, s), 7.31-7.45 (3H, m), 13.90 (1H, br)19F NMR (DMSO-d6) δ ppm: -110.1 - -110. 2 (m) IR (nujol) ν cm-1: 3300, 3189, 3079, 1664,1633,1604, 1576, 1519, 1455, 1252, 902, 792 3-(2,6-dichlorophenyl)-5-methyl-1H-1,2,4-triazole (mp:221-226°C) and 3-(2,6-difluorophenyl)-5-methyl-1H-1,2,4-triazole (mp: 195-198°C) were synthesised according to the same manner.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP1386915, 2004, A1 Location in patent: Page 36-37

26
[ 18871-66-4 ]
[ 292621-45-5 ]
[ 845306-17-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N,N-dimethylacetamide dimethyl acetal; 4-bromo-2-fluorobenzamide at 120℃; for 2h; Stage #2: With sodium hydroxide; hydroxylamine hydrochloride; acetic acid In 1,4-dioxane; water at 20 - 90℃; for 3.5h; Stage #3: With sodium hydrogencarbonate In water	50 Description 50 5- (4-Bromo-2-fluorophenyl)-3-methyl-1, 2, 4-OXADIAZOLE (D50) 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ML) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (NA2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4. 72G). This material and N, N-DIMETHYLACETAMIDE dimethylacetal (17ML) were heated together at 120°C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1. 32G) in 1N NAOH SOLUTION (23. 5MI) was added, followed by dioxane (23. 5MOI) then ACOH (30MOL) The reaction mixture was stirred at rt for 30min then heated at 90°C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to-9 by addition of solid NAHC03 AND the precipitated product was collected by filtration, washed on the filter with water and dried at 40°C IN VACUO to give the title compound (D50) as a greyish-brown solid (2. 82G). LCMS electrospray (+ve) 257 and 259 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/14571, 2005, A1 Location in patent: Page/Page column 30-31

27
[ 18871-66-4 ]
[ 759427-20-8 ]
[ 845306-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N,N-dimethylacetamide dimethyl acetal; 4-bromo-3-fluorobenzamide at 120℃; for 2h; Stage #2: With sodium hydroxide; hydroxylamine hydrochloride; acetic acid In 1,4-dioxane; water at 20 - 90℃; for 3.5h; Stage #3: With sodium hydrogencarbonate In water	51 Description 51 5- (4-BROMO-3-FLUOROPHENYL)-3-METHYL-1, 2, 4-OXADIAZOLE (D51) 4-Bromo-3-fluorobenzoic acid (10. 09g) was heated at reflux in thionyl chloride (100MU) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re-evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (100MOI) and the precipitated product was collected by filtration, washed on the filter with water and dried at 40°C in vacuo to give 4-BROMO-3-FTUOROBENZAMIDE as a white solid (9.13g). This material and N, N-DIMETHYLACETAMIDE DIMETHYLACETAL (27ML) were heated together at 120°C for 2H. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried and evaporated to give the ACYLAMIDINE intermediate as a gum which solidified in vacuo, overnight (12.3 G). This intermediate was treated with a solution of hydroxylamine hydrochloride (4. 16G) in 1M aqueous NAOH (74. 2MI). dioxane (75ml) and glacial acetic acid (95ml). The reaction mixture was first stirred at rt for 30min then heated at 90°C for 3h. On cooling a first crop of crystals was filtered off and dried in vacuo at 50°C to give the title compound (D51) (5. 5G). The filtrate afforded a second crop of crystals (2. 1g). LCMS electrospray (+ve) 257 and 259 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/14571, 2005, A1 Location in patent: Page/Page column 31

28
[ 18871-66-4 ]
[ 40180-80-1 ]
[ 903522-22-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: N,N-dimethylacetamide dimethyl acetal; 3-bromo-4-methylacetophenone at 100℃; for 12h; Heating / reflux; Stage #2: With hydrazine In ethanol at 90℃; for 1h; Heating / reflux;	1 2,6-Difluoro-N-[2'-methyl-5'-(3-methyl-1H-pyrazol-5-yl)-biphenyl-4-yl]-benzamide A solution of 3'-bromo-4'-methylacetophenone (1 g, 4.69 g) in N,N-dimethylacetamide dimethyl acetal (2.5 mL) was refluxed at 100° C. for 12 hr. The solvent was removed and the residue and hydrazine monohydrate (355 mg, 7.1 mmol) was dissolved in ethanol (10 mL). The solution was refluxed at 90° C. for 1 hr before it was concentrated. Column chromatography afforded compound r in 75% overall yield.

Reference： [1]Current Patent Assignee: SYNTA PHARMACEUTICALS CORP. - US2006/173006, 2006, A1 Location in patent: Page/Page column 55

29
[ 18871-66-4 ]
[ 5471-82-9 ]
methyl 2-nitro-3-(2-oxo-n-propyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ISOPROPYLAMIDE; ethyl acetate;	10a Methyl 2-nitro-3-(2-oxo-n-propyl)benzoate A solution of <strong>[5471-82-9]methyl 3-methyl-2-nitrobenzoate</strong> (1.5 g) and N,N-dimethylacetamide dimethyl acetal (3 ml) in dimethylacetamide (5 ml) was heated at 140 C. for 3 hours. After evaporation of the solvent, the resulting brown syrup was dissolved in ethyl acetate. The solution was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale brown syrup (0.42 g, 23%). 1 H-NMR(200 MHz,CDCl3) delta: 2.26(3H,s), 3.78(2H,s), 3.90(3H,s), 7.4-7.7(2H,m), 7.91(1H,dd)

Reference： [1]Patent: US5389641,1995,A

30
[ 18871-66-4 ]
[ 292621-45-5 ]
[ 845306-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	at 120℃; for 2h;	32 5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D32); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and /V,Λ/-dimethylacetamide dimethyl acetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N NaOH solution (23.5ml) was added, followed by dioxane (23.5ml) then AcOH (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 4O0C in vacuo to give the title compound (D32) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+).
	at 120℃; for 2h;	16 Description 16; 5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D16); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with dichloromethane (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted with ethyl acetate (3x). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and Λ/,Λ/-dimethylacetamide dimethylacetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/ethyl acetate) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N sodium hydroxide solution (23.5ml) was added, followed by dioxane (23.5ml) then acetic acid (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 400C in vacuo to give the title compound (D16) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/40192, 2006, A1 Location in patent: Page/Page column 33
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/29906, 2006, A1 Location in patent: Page/Page column 18-19

31
[ 18871-66-4 ]
[ 759427-20-8 ]
[ 845306-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	at 120℃; for 2h;	31 Description 31 5-(4-Bromo-3-fluorophenyl)-3-methyl-1,2,4-oxadiazole (D31); 4-Bromo-3-fluorobenzoic acid (10.09g) was heated at reflux in thionyl chloride (100ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re-evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (100ml) and the precipitated product was collected by filtration, washed on the filter with water and dried at 400C in vacuo to give 4-bromo-3-fluorobenzamide as a white solid (9.13g). This material and Λ/,Λ/-dimethylacetamide dimethyl acetal (27ml) were heated together at 1200C for 2h. The reaction was allowed to cool to room temperature and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried and evaporated to give the acylamidine intermediate as a gum which solidified in vacuo, overnight (12.3 g). This intermediate was treated with a solution of hydroxylamine hydrochloride (4.16g) in 1M aqueous NaOH (74.2ml), dioxane (75ml) and glacial acetic acid (95ml). The reaction mixture was first stirred at room temperature for 30min then heated at 900C for 3h. On cooling a first crop of crystals was filtered off and dried in vacuo at 500C to give the title compound (D31) (5.5g). The filtrate afforded a second crop of crystals (2.1g). LCMS electrospray (+ve) 257 and 259 (MH+).
	at 120℃; for 2h;	15 Description 15; 5-(4-Bromo-3-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D15); 4-Bromo-3-fluorobenzoic acid (10.09g) was heated at reflux in thionyl chloride (100ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with dichloromethane (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (100ml) and the precipitated product was collected by filtration, washed on the filter with water and dried at 400C in vacuo to give 4-bromo-3-fluorobenzamide as a white solid (9.13g). This material and Λ/,Λ/-dimethylacetamide dimethylacetal (27ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic extract was washed with water and brine, dried and evaporated to give the acylamidine intermediate as a gum which solidified in vacuo, overnight (12.3 g). This intermediate was treated with a solution of hydroxylamine hydrochloride (4.16g) in 1 M aqueous sodium hydroxide (74.2ml), dioxane (75ml) and glacial acetic acid (95ml). The reaction mixture was first stirred at rt for 30min then heated at 9O0C for 3h. On cooling a first crop of crystals was filtered off and dried in vacuo at 500C to give the title compound (D15) (5.5g). The filtrate afforded a second crop of crystals (2.1g). LCMS electrospray (+ve) 257 and 259 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/40192, 2006, A1 Location in patent: Page/Page column 32
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/29906, 2006, A1 Location in patent: Page/Page column 18

32
[ 18871-66-4 ]
[ 4640-67-9 ]
3-Dimethylamino-2-(p-fluorobenzoyl)crotononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In chloroform; Petroleum ether; benzene;	EXAMPLE 1 3-Dimethylamino-2-(p-fluorobenzoyl)crotononitrile To a solution of 1.6 g. of p-fluorobenzoylacetonitrile [Pihl et al., Reakts. Sposobnost Org. Soedin. Tartu. Gos. Univ., 5 (1), 27, (1968)] in 30 ml. of chloroform, cooled to -10 C., is added 1.4 g. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred at -10 C. for 2 hours and the evaporated in vacuo to an oil. This oil is dissolved in 150 ml. of benzene and filtered through magnesol. The filtrate is evaporated to 50 ml. and petroleum ether is added to effect crystallization. The product is collected by filtration and then recrystallized from benzene-petroleum ether with charcoal treatment giving the desired product.
	In chloroform; benzene;	EXAMPLE 66 2-(p-Fluorobenzoyl)-3-dimethylaminocrotononitrile To a solution of 14.5 g. (0.10 m) of <strong>[4640-67-9](p-fluorobenzoyl)acetonitrile</strong> in 100 ml. of chloroform, cooled in an ice-salt bath, was added 13.3 g. (0.1 m) of N,N-dimethylacetamide dimethylacetal in 20 ml. chloroform. The reaction mixture was stirred in the ice-salt bath for 2 hours, then evaporated in vacuo to an orange oil. The oil was dissolved in 150 ml. benzene and passed through Magnesol. The filtrate was evaporated and the oil thus obtained was dissolved in 50 ml. benzene to which petroleum ether was added until the solution became cloudy. The precipitate which formed upon cooling was collected. The solid was recrystallized twice from benzene-petroleum ether, with charcoal treatment to yield 5.8 g. (27%) of light yellow crystals, m.p. 90-92 C.

Reference： [1]Patent: US4173650,1979,A
[2]Patent: US4173650,1979,A

33
[ 18871-66-4 ]
[ 4640-67-9 ]
cis-2-(p-fluorobenzoyl)-3-hydroxycrotononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; chloroform; cyclohexane;	EXAMPLE 2 Cis-2-(p-fluorobenzoyl)-3-hydroxycrotononitrile To a solution of 6.7 g. of p-fluorobenzoylacetonitrile in 100 ml. of chloroform, cooled to 0 C., is added 7 ml. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred in an ice bath for 2 hours and then at room temperature for 16 hours. The solution is evaporated in vacuo to an oil. This oil is dissolved in chloroform, filtered through magnesol and then evaporated to an oil. This oil is dissolved in 100 ml. of methanol and 20 ml of 1N hydrochloric acid is added. The reaction mixture is heated on a steam bath for 25 minutes, cooled and the precipitate is collected. The solid is recrystallized from 50 ml. of cyclohexane, giving the desired product.

Reference： [1]Patent: US4173650,1979,A

34
[ 18871-66-4 ]
[ 40018-25-5 ]
cis-2-(o-chlorobenzoyl)-3-hydroxycrotononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In chloroform	34 Cis-2-(o-chlorobenzoyl)-3-hydroxycrotononitrile A 4.4 g. portion of o-chlorobenzoylacetonitrile in 50 ml. of chloroform is reacted with 5 ml. of N,N-dimethylacetamide dimethylacetal as described in Example 2, giving the desired product.

Reference： [1]Current Patent Assignee: PFIZER INC - US4173650, 1979, A

35
[ 18871-66-4 ]
[ 128403-22-5 ]
3-dimethylamino-1-(2-nitro-4-trifluoromethylphenyl)-but-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In cyclohexane; toluene	7.a EXAMPLE 7(a) EXAMPLE 7(a) A solution of 2-nitro-4-trifluoromethylacetophenone (20.7g) and dimethylacetamide dimethyl acetal (13.2g) in toluene (100 ml) was stirred and heated at reflux overnight. Further dimethylacetamide dimethyl acetal (13.2g) was added and the mixture was stirred and heated at reflux for 1.5 hours. The mixture was cooled, washed with water, dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with a mixture of ether and cyclohexane (1:20) and filtered. The yellow solid was recrystallized from cyclohexane to give 3-dimethylamino-1-(2-nitro-4-trifluoromethylphenyl)-but-2-en-1-one (13.95g) as a yellow solid, m.p. 122°C.

Reference： [1]Current Patent Assignee: BAYER AG; SOLVAY - EP487357, 1992, A1

36
[ 18871-66-4 ]
[ 1006-34-4 ]
[ 67-56-1 ]
2-bromo-N-(1-(dimethylamino)ethylidene)-5-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	at 120℃; for 1.5h;	A mixture of 2-bromo-5-fluorobenzamide (9.57 g, 43.89 mmol) and N,N-dimethylacetamide dimethyl acetal (20 ml) was heated under argon at 120° C. for 1.5 h. The methanol formed was collected through a reflux condenser. The reaction mixture was allowed to cool and the excess N,N-dimethylacetamide dimethyl acetal was removed under reduced pressure. The residual oil was crystallized from a mixture of ether (30 ml) and hexane (50 ml) to give 9.51 g (75% yield) of the title material as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.43 (3H, s, CH3), 3.16 (3H, s, NCH3), 3.19 (3H, s, NCH3), 6.90-6.97 (1H, m, aromatic), 7.46 (1H, dd, J=3.1 Hz and J=9.1 Hz, aromatic), 7.53 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic). MS (ESI+) m/e 287 [M+H+].

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/111984, 2007, A1 Location in patent: Page/Page column 43

37
[ 18871-66-4 ]
[ 111-86-4 ]
N,N-dimethyl-N’-octylacetamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	at 60℃; for 0.166667 - 0.333333h;	1.B Example 1B. Synthesis and characterization of N'-octyl-I^N-dimethylacetamidine (1c) and N'-butyl-N,N-dimethylacetamidine (1d)N'-octyl-N.N-dimethylacetamidine (1c) was synthesized by heating an equimolar amount of n-octylamine with dimethylacetamide dimethyl acetal for 10-20 min at 60 C without solvent. Methanol, a byproduct, was removed by evaporation under high vacuum. The yield of N'-octyl-N,N-dimethylacetamidine (1c) was quantitative and was determined gravimetrically. The purity was typically 90% and was determined by 1H NMR spectroscopy. The major impurity was N-octyl-O-methylacetacetimidate as identified by 1H NMR spectroscopy. Unpurified 1c could be used as a reversibly switchable surfactant without further purification.N'-octyl-N,N-dimethylacetamidine (1c): 1H NMR (CDCI3) 0.88 (t, 3H, CH2CH;i), 1.29 (m, 10H1 C5Hj0CH3), 1.51 (quintet, 2H, NCH2CH2), 1.88 (s, 3H, CCH3), 2.87 (s, 6H, N(CH3)2), 3.18 (t, 2H1 NCH2).
97%	With dimethyl amine In tetrahydrofuran at 20℃; for 18.25h; Darkness; chemoselective reaction;
97%	With dimethyl amine In tetrahydrofuran for 18h; Darkness;

97%	In neat (no solvent) at 80℃; for 0.5h;	N,N-dimethyl-N’-octylacetamidine (1a): The mixture of octylamine (6.46 g, 50 mmol) andN,N-dimethylacetamide dimethyl acetal (90% purity, 7.77 g, 52.5 mmol) was stirred at 80 °Cwithout solvent. After 30 min, the mixture was evaporated in vacuo, and the residue wasdistilled under reduced pressure to give 1a (9.64 g, 97%) as a colorless liquid;
	at 70℃; for 1h;

Reference： [1]Current Patent Assignee: QUEEN'S UNIVERSITY AT KINGSTON - WO2007/56859, 2007, A1 Location in patent: Page/Page column 28
[2]Location in patent: experimental part Harjani, Jitendra R.; Liang, Chen; Jessop, Philip G. [Journal of Organic Chemistry, 2011, vol. 76, # 6, p. 1683 - 1691]
[3]Arthur, Troy; Harjani, Jitendra R.; Phan, Lam; Jessop, Philip G.; Hodson, Peter V. [Green Chemistry, 2012, vol. 14, # 2, p. 357 - 362]
[4]Aoyagi, Naoto; Furusho, Yoshio; Sei, Yoshihisa; Endo, Takeshi [Tetrahedron, 2013, vol. 69, # 26, p. 5476 - 5480]
[5]Location in patent: experimental part Li, Zhe-Qi; Wang, Hui-Long [Journal of Chemical Research, 2011, vol. 35, # 2, p. 119 - 120]

38
[ 18871-66-4 ]
[ 19227-14-6 ]
[ 118183-92-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	In 1,4-dioxane for 12h; Reflux;	21.2 Step 2: 4-bromo-N'-hydroxybenzimidamide (1.56 g, 7.25 mmol) and N,N-dimethylacetamide dimethyl acetal (DMA acetal, 2.9 mL, 21.8 mmol) were dissolved in dioxane (30 μL), followed by reaction under reflux for 12 hours. After completion of the reaction was confirmed by TLC, water (50 mL) and ethyl acetate (100 mL) were added to the reactants, followed by extraction. The organic layer was washed with brine and distilled under reduced pressure. The resulting solids were dried and recrystallized from hexane to afford the title compound 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (16b). Yield: 85%.MS (ESI+) m/z 239.1 (M+1)
85%	In 1,4-dioxane for 12h; Heating / reflux;	21.2 Step 2: Preparation of 3-(4-bromophenyD-5-methyl-l,,2,4-oxadiazole (16b) 4-bromo-N'-hydroxybenzimidamide (1.56 g, 7.25 mmol) and N,N-dimethylacetamide dimethyl acetal (DMA acetal, 2.9 mL, 21.8 mmol) were dissolved in dioxane (30 mL), followed by reaction under reflux for 12 hours. After completion of the reaction was confirmed by TLC, water (50 mL) and ethyl acetate (100 mL) were added to the reactants, followed by extraction. The organic layer was washed with brine and distilled under reduced pressure. The resulting solids were dried and recrystallized from hexane to afford the title compound 3-(4-bromophenyl)-5-methyl-l,2,4-oxadiazole (16b). Yield: 85%.MS(ESI+) m/z 239.1 (M+1)

Reference： [1]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD.; YUHAN CORPORATION - US2010/63041, 2010, A1 Location in patent: Page/Page column 36
[2]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD.; YUHAN CORPORATION - WO2008/108602, 2008, A1 Location in patent: Page/Page column 63; 36

39
[ 18871-66-4 ]
[ 1140496-39-4 ]
[ 62937-47-7 ]
[ 1140496-43-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: N,N-dimethylacetamide dimethyl acetal; (2R)-2-carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester at 120℃; for 2h; Stage #2: 4-chlorobenzyl-hydrazine acetate With acetic acid at 90℃; for 1.5h;	39.A Example 39; Step A; Preparation of R-benzyl 2-(2-(4-chlorobenzyl)-5-methyl-2H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate; (R)-Benzyl 2-carbamoylpyrrolidine-1-carboxylate (2.08 g, 8.4 mmol) and N,N-dimethylacetamide dimethylacetal (15 ml) were combined in a round bottom flask and then heated at 120° C. for 2 h. The reaction mixture was concentrated on a rotary evaporator and the residue obtained was dissolved in glacial HOAc (5 ml) and treated with 4-chlorobenzyl hydrazine salt (749 mg, 3.5 mmol), prepared as outlined in the procedure by R. Mornet et al., J Heterocyclic Chem. 29, 1992, 1561. The reaction mixture was heated at 90° C. for 1.5 h, cooled to rt, diluted with H2O and extracted with EtOAc. The ethyl acetate layer was washed with saturated aqueous NaHCO3 solution, H2O and brine, then dried over MgSO4. After evaporation of the solvent, the resulting residue was purified by flash column chromatography over silica gel using a gradient of 50% EtOAc-80% EtOAc in hexanes as eluent to give the desired product (2.72 g, 79% yield) as a white solid. Exact mass [MH]+ (Found: 411).

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - US2009/93472, 2009, A1 Location in patent: Page/Page column 27

40
[ 18871-66-4 ]
[ 3619-17-8 ]
DMFDMA [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 50℃; for 0.5h;	8.1 Step 1 5-(3-Isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4'-methyl-biphenyl-3-carboxylic acid methyl ester The isobutyric acid hydrazide used in this example was prepared from isobutyric acid chloride and hydrazine hydrate following the procedure of Org. Synth. Vol. 81 p. 254 (2005). Isobutyric acid hydrazide (55 mg, 5.34 mmol) and 1,1-dimethoxy-ethyl)-dimethyl-amine (774 mg, 5.81 mmol) were added to 6 mL CH3CN and the mixture was heated to 50° C. and stirred for 30 minutes. 5-Amino-4'-methyl-biphenyl-3-carboxylic acid methyl ester (1.0 g, 4.15 mmol) was added, followed by 6 mL of acetic acid. The reaction mixture was heated to 120° C. and stirred for five hours, then cooled to room temperature. Solvent was removed under reduced pressure and the residue was purified via flash chromatography to give 400 mg (30%) of 5-(3-Isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4'-methyl-biphenyl-3-carboxylic acid methyl ester as a white powder.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2009/170874, 2009, A1 Location in patent: Page/Page column 70

41
[ 18871-66-4 ]
[ 2040-05-3 ]
[ 915069-77-1 ]

Yield	Reaction Conditions	Operation in experiment
		Method 6; General procedure: A mixture of the ketone (1.0 eq.) and N,N-dimethylacetamide dimethylacetal (1.0 eq.) were heated together in a microwave at 180° C. for 10 minutes. The resulting gum was re-dissolved in EtOH (0.5 M), guanidine HCl (3.0 eq.) added and the mixture was heated in the microwave at 180° C. for 30 minutes. The reaction mixture was worked up by pouring into water and extracting with CH2Cl2 (.x.2) and dried over MgSO4. The product was filtered and evaporated to dryness. Purification by column chromatography gave the product.

Reference： [1]Patent: US2009/215777,2009,A1 .Location in patent: Page/Page column 44; 47

42
[ 18871-66-4 ]
[ 3100-67-2 ]
[ 1179316-78-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 4406 - 4419

43
[ 18871-66-4 ]
[ 16332-06-2 ]
C₈H₁₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In toluene at 120℃; for 6h;

Reference： [1]Location in patent: scheme or table Barber, Christopher G.; Blakemore, David C.; Chiva, Jean-Yves; Eastwood, Rachel L.; Middleton, Donald S.; Paradowski, Kerry A. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1499 - 1503]

44
[ 18871-66-4 ]
[ 199328-10-4 ]
[ 1205679-40-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 20℃; for 1h;	EXAMPLE 1; 3-{l-[4-(2-Amino-phenylcarbamoyl)-phenylamino]-ethylidene}-2-oxo-2,3- dihydro-lH-indole-5-carboxylic acid methyl ester; Preparation of Intermediate (hereinafter "Int") Ib:; To a suspension of Int-la (1.05 g, 5.5 mmol) in dimethylformamide (DMF) (7.5 mL) was added N,N- dimethylacetamide-dimethyl acetal (1.2 mL, 7.14 mmol). The reaction mixture was stirred at room temperature for 1 hour and diluted with Et2theta (7.5 mL). The resulting solid was filtered, washed with ether, and dried to give Int-lb. MS found for C14H16N2O3 (m/z): 261.1 [M++.].

Reference： [1]Patent: WO2010/9166,2010,A1 .Location in patent: Page/Page column 52-53

45
[ 18871-66-4 ]
[ 5333-27-7 ]
[ 1232892-80-6 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 4; 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine; The synthetic procedure used in this preparation is outlined in Scheme D. Step 1; 5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole; A solution of <strong>[5333-27-7]1-(4-methyl-3-nitro-phenyl)-ethanone</strong> and (1,1-dimethoxy-ethyl)-dimethyl-amine in DMF was heated at 90 C. for 3 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the residue was dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixture was cooled to 0 oC, and hydrazine hydrate (5 ml) at 0 C. was added. The mixture was stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue was purified by ?flash chromatography? (0 to 30% EtOAc in hexanes) to give 8.5 g of 5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a yellowish solid, which was recrystallized from EtOAc to give 8.2 g of yellow powder.
		Step 1 5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazoleA solution of <strong>[5333-27-7]1-(4-methyl-3-nitro-phenyl)-ethanone</strong> and (1,1-dimethoxy-ethyl)-dimethyl-amine in DMF was heated at 90 C. for 3 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the residue was dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixture was cooled to 0 C., and hydrazine hydrate (5 ml) at 0 C. was added. The mixture was stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue was purified by ?flash chromatography? (0 to 30% EtOAc in hexanes) to give 8.5 g of 5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a yellowish solid, which was recrystallyzed from EtOAc to give 8.2 g of yellow powder.

Reference： [1]Patent: US2010/160384,2010,A1 .Location in patent: Page/Page column 58
[2]Patent: US2011/71143,2011,A1 .Location in patent: Page/Page column 39

46
[ 18871-66-4 ]
[ 185622-63-3 ]
[ 1147756-64-6 ]

Reference： [1]Heterocycles,2009,vol. 77,p. 855 - 863

47
[ 18871-66-4 ]
[ 66335-38-4 ]
[ 1226642-71-2 ]

Reference： [1]Chinese Chemical Letters,2010,vol. 21,p. 163 - 166

48
[ 15018-66-3 ]
[ 18871-66-4 ]
[ 457072-59-2 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2010,vol. 58,p. 369 - 374

49
[ 18871-66-4 ]
[ 5333-27-7 ]
C₁₂H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 90℃; for 3h;	A solution of <strong>[5333-27-7]1-(4-methyl-3-nitro-phenyl)-ethanone</strong> and (1,1-dimethoxy-ethyl)-dimethyl-amine in DMF was heated at 90 C. for 3 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the residue was dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixture was cooled to 0 C., and hydrazine hydrate (5 ml) at 0 C. was added. The mixture was stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue was purified by "flash chromatography" (0 to 30% EtOAc in hexanes) to give 8.5 g of 5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a yellowish solid, which was recrystallized from EtOAc to give 8.2 g of yellow powder.

Reference： [1]Patent: US2011/28502,2011,A1 .Location in patent: Page/Page column 46-47

50
[ 18871-66-4 ]
[ 31576-51-9 ]
[ 1268135-99-4 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 1683 - 1691

51
[ 18871-66-4 ]
[ 26961-27-3 ]
[ 90402-35-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 80℃; for 0.1h; Microwave irradiation;	4.2. General procedures for the syntheses of formimidamide and acetimidamide derivatives General procedure: Benzonitriles were suspended in 2.5 equiv of N,N-dimethylformamide dimethylacetal or N,N-dimethylacetamide dimethylacetal and were irradiated at 1200 W under microwaves. The resulting mixture was cooled to room temperature and refrigerated overnight. The precipitate formed was filtered, washed with diethyl ether and dried. Purification by column chromatography over silica gel using CH2Cl2/PE (5:5, v/v) as the eluent gave the desired compound.

Reference： [1]Location in patent: experimental part Loidreau, Yvonnick; Besson, Thierry [Tetrahedron, 2011, vol. 67, # 26, p. 4852 - 4857]

52
[ 18871-66-4 ]
[ 1885-32-1 ]
2,3,8-trimethylquinazolin-4-one [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 6089 - 6099

53
[ 18871-66-4 ]
[ 313279-12-8 ]
2,3-dimethyl-8-nitroquinazolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In N,N-dimethyl-formamide at 150℃; for 120h;

Reference： [1]Location in patent: experimental part Nathubhai, Amit; Patterson, Richard; Woodman, Timothy J.; Sharp, Harriet E. C.; Chui, Miranda T. Y.; Chung, Hugo H. K.; Lau, Stephanie W. S.; Zheng, Jun; Lloyd, Matthew D.; Thompson, Andrew S.; Threadgill, Michael D. [Organic and Biomolecular Chemistry, 2011, vol. 9, # 17, p. 6089 - 6099]

54
[ 18871-66-4 ]
[ 21575-13-3 ]
[ 1352198-45-8 ]

Yield	Reaction Conditions	Operation in experiment
72%	In toluene for 3h; Reflux;

Reference： [1]Location in patent: experimental part Okuda, Kensuke; Muroyama, Hideki; Hirota, Takashi [Journal of Heterocyclic Chemistry, 2011, vol. 48, # 6, p. 1407 - 1413]

55
[ 18871-66-4 ]
[ 19808-35-6 ]
[ 1352198-37-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,2011,vol. 48,p. 1407 - 1413

56
[ 18871-66-4 ]
[ 625446-22-2 ]
[ 1372148-66-7 ]

Reference： [1]Synlett,2012,p. 448 - 452

57
[ 18871-66-4 ]
[ 625446-22-2 ]
[ 1315179-91-9 ]

Yield	Reaction Conditions	Operation in experiment
	for 3.25h;Reflux;	Reference Example 1 A solution of 12.3 g of <strong>[625446-22-2]4-bromo-2-fluoroacetophenone</strong> in 25.0 g of DMADA was heated under reflux for 3 hours and 15 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; hexane : ethyl acetate = 6:1 ? 1:1], and suspended in diisopropyl ether, and the solid was filtered to obtain 7.96 g of (E)-1-(4-bromo-2-fluorophenyl)-3-dimethylamino-2-buten-1-one as a yellow white solid. 1H-NMR (CDCl3) delta:2.66 (s, 3H), 3.07 (s, 6H), 5.51 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 10.0, 1.8 Hz, 1H), 7.31 (ddd, J = 8.2, 1.8, 0.5 Hz, 1H), 7.62 (dd, J 8.2, 8.2 H2, 1H).

Reference： [1]Patent: EP2527343,2012,A1 .Location in patent: Page/Page column 15

58
[ 18871-66-4 ]
[ 412018-50-9 ]
[ 1315179-94-2 ]

Yield	Reaction Conditions	Operation in experiment
	for 2h;Reflux;	Reference Example 3 A solution of 8.00 g of <strong>[412018-50-9]3-acetyl-2, 6-dichloropyridine</strong> in 12 mL of DMADA was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; hexane : ethyl acetate = 3:1 ? 1:3], and suspended in a mixed solvent of ethyl acetate and diisopropyl ether, and the solid was filtered to obtain 3.91 g of (E)-1-(2, 6-dichloropyridin-3-yl)-3-dimethylamino-2-buten-1-one as a yellow solid. 1H-NMR (CDCl3) delta:2.67 (s, 3H), 3.08 (brs, 6H), 5.25 (s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.74 (d, J =8.1 Hz, 1H).

Reference： [1]Patent: EP2527343,2012,A1 .Location in patent: Page/Page column 16

59
[ 18871-66-4 ]
[ 25594-62-1 ]
[ 1425037-54-2 ]

Yield	Reaction Conditions	Operation in experiment
1.49 g	at 100℃; for 3h;	Scheme A14 l-(quinoxalin-2-yl)ethanone (1.13 g, 6.56 mmol) and N,N-dimethylacetamide dimethylacetal (1.173 ml, 7.22 mmol) were combined and heated to 100 C for 3h. The mixture was cooled to r.t. 1H NMR indicated that the material was sufficiently pure to carry onto the next step without further purification (1.49g, 94% yield). 3-(dimethylamino)-l-(quinoxalin-2-yl)but- 2-en-l-one (791 mg, 3.28 mmol) and methylhydrazine (0.174 ml, 3.28 mmol) were combined in acetic acid (6 ml) and stirred at 55 C until the reaction was judged to be complete by LCMS. The acetic acid was removed and the material was taken up in DCM and washed with saturated NaHC03 solution. The organic extracts were dried over Na2S04, filtered, and concentrated. 1H NMR (500 MHz, CDC13) delta 9.14 (1H, s), 8.13-8.1 1 (2H, m), 7.83-7.77 (2H, m), 6.72 (1H, s), 4.37 (3H, s), 2.39 (3H, s). MS m/z = 225.3.

Reference： [1]Patent: WO2013/28382,2013,A1 .Location in patent: Page/Page column 46

60
[ 18871-66-4 ]
[ 746630-34-2 ]
[ 1523249-71-9 ]

Yield	Reaction Conditions	Operation in experiment
4.78 g	In toluene; for 16h;Reflux;	A mixture of l-(4-bromo-2,6-difluorophenyl)ethanone (prepared according to the method described in PCT Patent Publication WO 2004/72070; 4.56 g, 19.4 mmol) and N,N-dimethylacetamide dimethyl acetal (6.94 g, 58.2 mmol) in toluene (45 mL) was refluxed for 16 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to yield the title compound (4.78 g). in NMR delta 7.79 (br s, 1H), 7.11 (m, 2H), 5.31 (br s, 1H), 3.12 (br s, 3H), 2.89 (s, 3H).

Reference： [1]Patent: WO2014/4064,2014,A1 .Location in patent: Page/Page column 37; 38

61
[ 18871-66-4 ]
[ 944401-56-3 ]
[ 1536390-46-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	In methanol; at 80℃; for 8h;	2-Amino-5-bromo-4-(trifluoromethyl)pyridine (5 g, 20.75 mmol) was suspended in methanol (50 mL) and N,N-dimethylacetamide dimethyl acetal (9.15 mL, 62.6 mmol) was added. The mixture was heated to reflux at 80C for 8 h. The mixture was concentrated under vacuum and diluted with ethyl acetate (150 mL), then washed with saturated aqueous sodium bicarbonate solution (50 mL), followed by water (3 x 50 mL) and brine (50 mL). The organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound (6.45 g, 96%) as a dark red oil. 5H (500 MHz, CDCI3) 8.49 (s, 1H), 7.14-6.93 (m, 1H), 3.10 (s, 6H), 2.07 (s, 3H). Method C HPLC-MS: MH+ mlz 310/312, RT 1.23 minutes (96%)

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 117

62
[ 98198-48-2 ]
[ 18871-66-4 ]
[ 1536390-60-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	In methanol; at 80℃; for 16h;	2-Amino-5-bromo-4-methylpyridine (5 g, 26.7 mmol) was dissolved in methanol (50 mL) and N,N-dimethylacetamide dimethyl acetal (12 mL, 82.1 mmol) was added. The mixture was heated at 80C for 16 h. Methanol was removed under vacuum and the residue was dissolved in ethyl acetate (100 mL), then washed with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title compound (6.2 g, 90%) as a brown oil. deltaEta (500 MHz, CDCls) 8.32 (s, 1H), 6.66 (s, 1H), 3.07 (s, 6H), 2.32 (s, 3H), 2.00 (s, 3H). Method B HPLC-MS: MH+ mlz 256/258, RT 0.92 minutes (97%).

Reference： [1]Patent: WO2014/9295,2014,A1 .Location in patent: Page/Page column 118; 119

63
[ 18871-66-4 ]
[ 232597-42-1 ]
[ 1573060-70-4 ]

Yield	Reaction Conditions	Operation in experiment
	for 20h; Reflux;	1. General Procedure for the Synthesis of 3-(Dimethylamino)-1-arylprop-2-en-1-ones 1a-l General procedure: A solution of substituted acetophenone (2 nmol) in N,N-dimethylformamide dimethyl acetal or N,N-dimethylacetamide dimethyl acetal (10 mL) was refluxed for 20 h during which time some methanol was formed and removed through a reflux condenser. After cooling, the precipitate was collected by suction to give compounds 1.

Reference： [1]Dou, Guolan; Xu, Pan; Li, Qiang; Xi, Yukun; Huang, Zhibin; Shi, Daqing [Molecules, 2013, vol. 18, # 11, p. 13645 - 13653]

64
[ 18871-66-4 ]
[ 10297-73-1 ]
(E)-3-(dimethylamino)-1-(4-(methylsulfonyl)phenyl)but-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	In toluene for 3h; Reflux;	(E)-3-(Dimethylamino)-1-(4-(methylsulfonyl)phenyl)but-2-en-1-one (2d) 1-(4-(Methylsulfonyl)phenyl)ethanone (1d) (1.98 g, 10 mmol) was dissolved in dry PhMe (20mL) and DMADMA (2.19 mL, 15 mmol) was added to reaction mixture. Reaction mixture wasrefluxed for 3 h. Upon cooling the product precipitated from reaction mixture and was filtered of.Recrystallization from EtOAc. Yield: 1.69 g (63 %), yellow solid, mp 168.1-170.0 °C. 1H NMR(CDCl3, 300 MHz): δ 2.67 (3H, s, CH3); 3.12 (3H, s, CH3); 3.11 (6H, s, NMe2); 5.60 (1H, s,CH); 7.92-8.00 (4H, m, Ph). 13C NMR (CDCl3, 75.5 MHz): δ 16.7, 40.4, 44.5, 92.3, 127.2,128.1, 141.3, 148.2, 165.4, 185.8. (C13H17NO3S calculated: C, 58.40; H, 6.41; N, 5.24. found C,58.41; H, 6.58; N, 5.20); EI-HRMS: m/z = 268.1003 (MH+); C13H18NO3S calculated: m/z =268.1007 (MH+); νmax (KBr) 3011, 2997, 2917, 1608, 1538, 1477, 1434, 1385, 1353, 1306, 1290,1223, 1179, 1153, 1082, 1026, 973, 918, 863, 851 cm-1.

Reference： [1]Bezensek, Jure; Groselj, Uros; Stare, Katarina; Svete, Jurij; Stanovnik, Branko [ARKIVOC, 2014, vol. 2014, # 2, p. 294 - 307]

65
[ 18871-66-4 ]
[ 1801-10-1 ]
N2,N2,N4,N4-tetramethyl-6-(3-(trifluoromethyl)phenyl)-2,4-diamine [ No CAS ]

Reference： [1]Australian Journal of Chemistry,2015,vol. 68,p. 184 - 195

66
[ 18871-66-4 ]
[ 187834-88-4 ]
[ 280110-69-2 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a solution of 1 -(tert-butoxycarbonyl)piperidine-4-carbohydrazide (967 mg, 3.97 mmol)in THF (4.3 mL) was added N,N-dimethylacetamide dimethyl acetal (872 pL, 5.96 mmol)and the reaction mixture was heated at 50C for 4 h under nitrogen. The reaction mixture was concentrated in vacuo, the resulting residue dissolved in anhydrous toluene (4.3 mL) and para-toluene sulfonic acid (42 mg, 0.22 mmol) added. The resulting mixture was heated at 100C overnight (18 h). The reaction mixture was concentrated in vacuo, theresulting residue partitioned between CH2CI2 (25 mL) and saturated NaHCO3 (25 mL) and the mixture stirred vigorously followed by passing through a phase-separating cartridge. The organic layer was concentrated in vacuo. The crude residue was triturated with diethyl ether followed by isohexane to afford 4-(5-methyl-[i ,3,4]oxadiazol-2-yl)-piperidine- 1-carboxylic acid tert-butyl ester (924 mg, 87%) as a pale brown solid. 1H NMR (400 MHz,CDCI3) O 4.18-4.02 (br s, 2H), 3.06-2.87 (m, 3H), 2.50 (s, 3H), 2.04-2.01 (m, 2H), 1.83-1.73 (m, 2H), 1.46 (s, 9H).

Reference： [1]Patent: WO2015/36759,2015,A1 .Location in patent: Page/Page column 183; 184

67
[ 18871-66-4 ]
[ 69249-22-5 ]
N'-(6-bromo-1,2,4-triazin-3-yl)-N,N-dimethylacetamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	In toluene; at 20℃; for 2h;	To a stuffed solution of Intermediate] (1.4 g, 8.04 mmol) in toluene (20 mL) was added N,N-dimethylacetamide dimethyl acetal (1 .07g, 8.04 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentratedin vacuo, then the crude residue was washed with saturated aqueous NaOH solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (1% methanol in dichloromethane) to give the title compound (640 mg, 33%) as a brown gum. 0H (400 MHz, DMSO-d6) 8.64 (s, 1H), 3.10(d, 6H, J 13.2 Hz), 2.11 (s, 3H). LCMS (ES+) 246 (M+H), RT 1.57 minutes.

Reference： [1]Patent: WO2015/86503,2015,A1 .Location in patent: Page/Page column 83

68
[ 88497-27-2 ]
[ 18871-66-4 ]
N'-(6-bromopyridazin-3-yl)-N,N-dimethylacetamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In N,N-dimethyl-formamide; at 120℃; for 18h;Sealed tube;	INTERMEDIATE 2 Nf-(6-Bromopyridazin-3-yl)-N,N-dimethylacetamidine To a solution of <strong>[88497-27-2]6-bromopyridazin-3-amine</strong> (2 g, 1.14 mmol) in DMF (10 mL) was added N,N-dimethylacetamide dimethyl acetal (1.52 g, 1.14 mmol). The reaction mixture was heated in a sealed tube at 120C for 18 h, then concentrated in vacuo. The residue was diluted with DCM (20 mL) and washed with aqueous sodium bicarbonate solution (10 mL). The aqueous layer was back-extracted with DCM (2 x 20 mL), then the combined organic layers were dried over anhydrous sodium sulphate, filtered, concentrated in vacuo and washed with Et20 (2 x 20 mL), to afford the title compound (2.6 g, 96%) as a brown solid. deltaEta (400 MHz, CDC13) 7.39 (d, IH, / 8.8 Hz), 6.83 (d, IH, 78.8 Hz), 3.11 (s, 6H), 2.12 (s, 3H). LCMS (ES+) 245 (M+H)+, RT 1.83 minutes.

Reference： [1]Patent: WO2015/86501,2015,A1 .Location in patent: Page/Page column 88

69
[ 18871-66-4 ]
[ 13166-10-4 ]
(E)-2-(4-(dimethylamino)pent-3-en-2-ylidene)malononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With acetic anhydride In toluene at 20℃; Inert atmosphere;

Reference： [1]Longstreet, Ashley R.; Rivalti, Daniel; McQuade, D. Tyler [Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8583 - 8596]

70
[ 10432-44-7 ]
[ 18871-66-4 ]
(E)-2-(3-(dimethylamino)-1-(thiophen-2-yl)but-2-en-1-ylidene)malononitrile [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 8583 - 8596

71
[ 18871-66-4 ]
[ 769-28-8 ]
[ 64038-03-5 ]
[ 65515-39-1 ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1556 - 1564

72
[ 609-38-1 ]
[ 18871-66-4 ]
(E)-N-(1-(dimethylamino)ethylidene)furan-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	In toluene for 2h; Reflux;	General procedure for the preparation of (E)-N-(1-(dimethylamino)ethylidene)-carboxamides General procedure: The starting amides (30.0 mmol) were suspended in toluene (40 mL) and 1.5 equivalents of N,N-dimethylacetamide dimethylacetal (45.0 mmol) were added. The reaction mixture was refluxed for 2-10 h. The reaction mixture was then cooled. Generally, the corresponding products deposited upon cooling and were thus collected via vacuum filtration and washed with diethyl ether to remove any impurities. In other cases, the volatile components were removed under reduced pressure and the products were obtained and purified with column chromatography, using various mixtures of ethyl acetate/petroleum ether as the eluent.

Reference： [1]Prek, Benjamin; Bezenšek, Jure; Počkaj, Marta; Stanovnik, Branko [Tetrahedron, 2017, vol. 73, # 4, p. 338 - 350]

73
[ 18871-66-4 ]
[ 1801-10-1 ]
N-(1-(dimethylamino)ethylidene)-3-(trifluoromethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	In toluene;Reflux;	General procedure: The starting amides (30.0 mmol) were suspended in toluene (40 mL) and 1.5 equivalents of N,N-dimethylacetamide dimethylacetal (45.0 mmol) were added. The reaction mixture was refluxed for 2-10 h. The reaction mixture was then cooled. Generally, the corresponding products deposited upon cooling and were thus collected via vacuum filtration and washed with diethyl ether to remove any impurities. In other cases, the volatile components were removed under reduced pressure and the products were obtained and purified with column chromatography, using various mixtures of ethyl acetate/petroleum ether as the eluent.

Reference： [1]Tetrahedron,2017,vol. 73,p. 338 - 350

74
[ 1072-97-5 ]
[ 18871-66-4 ]
[ 17570-98-8 ]
(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(2-pyridyl) methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%		To a suspension of 5-bromopyridin-2-amine (357.0 mg, 2.06 mmol) in MeOH (7 mL) was added Ν,Ν-dimethylacetamide dimethyl acetal (305.36 mg, 2.06 mmol) and the reaction mixture was heated to 80C for 18 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with EtOAc (10 mL) and then washed with saturated NaHCO3 (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The material was dissolved in toluene (7 mL) and <strong>[17570-98-8]2-bromo-1-(2-pyridyl)ethanone hydrobromide</strong> (644.1 mg, 2.06 mmol) was added followed with DIPEA (0.36 mL, 2.06 mmol) and the reaction mixture was heated in a sealed tube at 140C for 30 min. The mixture was cooled to rt, diluted with EtOAc (10 mL) and washed with water (2 x 30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The material was triturated with Et2O and hexane to afford the title compound (113.0 mg, 17%) as a solid. 1H NMR (500 MHz, CDCl3) δ 9.85-9.73 (m, 1H), 8.83 (dd, J=4.3, 1.6 Hz, 2H), 7.61 (dt, J=20.0, 5.6 Hz, 2H), 7.47 (dd, J=4.3, 1.6 Hz, 2H), 2.14 (s, 3H). MS (ESI) [M+H]+ 316.1/318.1;

Reference： [1]Patent: WO2017/66876,2017,A1 .Location in patent: Page/Page column 112; 113

75
[ 1072-97-5 ]
[ 18871-66-4 ]
[ 5349-17-7 ]
(6-bromo-2-methyl-imidazo[1,2-a]pyridin-3-yl)-(4-pyridyl) methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%		To a suspension of 5-bromopyridin-2-amine (357 mg, 2.06 mmol) in MeOH (7 mL) was added Nu,Nu-dimethylacetamide dimethyl acetal (305.4 mg, 2.06 mmol) and the reaction mixture was heated to 80C for 18 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted in EtOAc (10 ml) and the organic layer was washed with saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was diluted in toluene (7 mL) and 2-bromo-1-(4-pyridyl)ethanone hydrobromide (644.1 mg, 2.06 mmol) was added followed by DIPEA (0.36 mL, 2.06 mmol) and the reaction mixture was heated in a sealed tube at 140C for 30 min. The mixture was cooled to rt, diluted with EtOAc (10 mL) and the organic layer was washed with water (2 x 30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The material was triturated with Et2O and hexane to afford the title compound (113.0 mg, 17%) as a solid. 1H NMR (500 MHz, CDCl3) delta 9.85-9.73 (m, 1H), 8.83 (dd, J=4.3, 1.6 Hz, 2H), 7.61 (dt, J=20.0, 5.6 Hz, 2H), 7.47 (dd, J=4.3, 1.6 Hz, 2H), 2.14 (s, 3H). MS (ESI) [M+H]+ 316.1/318.1;

Reference： [1]Patent: WO2017/66876,2017,A1 .Location in patent: Page/Page column 115; 116

76
[ 18871-66-4 ]
[ 2338-75-2 ]
[ 1221133-66-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: N,N-dimethylacetamide dimethyl acetal; 4-(Trifluoromethyl)phenylacetonitrile In dichloromethane at 100℃; for 24h; Sealed tube; Inert atmosphere; Microwave irradiation; Stage #2: With hydrazine hydrochloride In ethanol; water at 80℃; for 12h;

Reference： [1]Qu, Chunrong; Ding, Mingmin; Zhu, Yingmin; Lu, Yungang; Du, Juan; Miller, Melissa; Tian, Jinbin; Zhu, Jinmei; Xu, Jian; Wen, Meng; Er-Bu; Wang, Jule; Xiao, Yuling; Wu, Meng; McManus, Owen B.; Li, Min; Wu, Jilin; Luo, Huai-Rong; Cao, Zhengyu; Shen, Bing; Wang, Hongbo; Zhu, Michael X.; Hong, Xuechuan [Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4680 - 4692]

77
[ 60-35-5 ]
[ 18871-66-4 ]
[ 108290-86-4 ]
ethyl 2,4-dimethylpyrrolo[1,2-a][1,3,5]triazine-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		[00179] A suspension of acetamide (590 mg, 10 mmol) and 1,1-dimethoxy-N,N- dimethylethan-1-amine (1.33 g, 10 mmol) in toluene (20 mL) was heated to reflux for 2 h followed by the addition of a solution of <strong>[108290-86-4]ethyl 2-amino-1H-pyrrole-3-carboxylate</strong> (1.54 g, 10 mmol) in acetic acid (2 mL). The reaction mixture was stirred at reflux for 4 h, then cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE/EA; 1/2) to give ethyl 2,4-dimethylpyrrolo[1,2-a][1,3,5]triazine-8-carboxylate (780 mg, 36%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) delta 7.54 (d, J = 3.5 Hz, 1H), 7.26 (d, J = 3.5 Hz, 1H), 4.26 (d, J = 7.0 Hz, 2H), 2.76 (s, 3H), 2.55 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). LC- MS m/z: 220.0 [M+H]+. LC-MS Purity (214 nm): 96%; tR = 1.43 min.

Reference： [1]Patent: WO2017/192929,2017,A1 .Location in patent: Paragraph 00179

78
[ 18871-66-4 ]
[ 2016-42-4 ]
methyl N-tetradecylethanimidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.5%	In methanol at 40 - 50℃; for 0.3055h;	2 Example 2 This example provides a methyl N-tetradecanoyl acetimidate synthesized by the following steps:Weighed 2.32g of tetradecyl amine to a four-necked flask equipped with a condenser, a vacuum apparatus and a thermometer, was added 35mL ofMethanol, heated in a constant temperature oil bath until the tetradecylamine is completely dissolved;When the temperature rose to 40 ° C, 1.89g of N, N-dimethylacetamide dimethyl acetal was slowly added dropwise to the solution and reacted for 18h at 0.1MPa;Spotting the plate with thin layer chromatography (VCHCl3: CH3OH = 3: 1), no material point appears, indicating that fourteen amine completely turns;Reduced to 0.05MPa, the reaction was continued at 50 20min, to obtain a pale yellow liquid product,That is, methyl N-tetradecylethanimidate. The yield of methyl N-tetradecylethanimidate in this Example was 72.5%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PETROLEUM CORPORATION - CN107473984, 2017, A Location in patent: Paragraph 0036-0040; 0045-0050

79
[ 18871-66-4 ]
[ 143-27-1 ]
methyl N-hexadecyl acetimidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.8%	In methanol at 35 - 40℃; for 15h;	2 This example provides a methyl N-hexadecyl acetimidate synthesized by the following steps Weigh 2.54g of hexadecylamine to a four-necked flask equipped with a condenser, a vacuum apparatus and a thermometer, add 60mL ofMethanol, heated in a constant temperature oil bath until hexadecylamine is completely dissolved;When the temperature rose to 35 ° C, 1.95 g of N, N-dimethylacetamide dimethyl acetal was slowly added dropwise to the solution,0.1MPa reaction 10h;Specimens were spotted with thin layer chromatography (VCHCl3: CH3OH = 3: 1), and no material point appeared, which showed the complete conversion of hexadecylamine.Decompression to 0.05MPa, the reaction was continued at 40 5h, to obtain a pale yellow liquid product,That is, N-hexadecyl ethanimidate,The yield of methyl N-hexadecyl ethanimidate in this example was 71.8%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PETROLEUM CORPORATION - CN107473985, 2017, A Location in patent: Paragraph 0037-0040; 0045-0050

80
[ 18871-66-4 ]
[ 124-30-1 ]
methyl N-octadecylethanimidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.3%	In methanol at 50 - 70℃; for 3.2h; Green chemistry;	1 This embodiment provides a methyl ester of N-octadecylethyl acetimidate, which is synthesized by the following steps [0037] Weigh 2.78 g of octadecylamine into a four-neck flask equipped with a condenser tube, a vacuum device, and a thermometer and add 55 mL of it.Methanol, in a constant temperature oil bath, heated to octadecylamine completely dissolved;[0038] When the temperature rises to 70[deg.] C., 1.72 g of N,N-dimethylacetamide dimethyl acetal is slowly added dropwise to the solution.O.IMPa reaction 2.8h;[0039] Thin-layer chromatography (VCHC13: CH3QH = 3:1) was used for spot climbing, no raw material spots appeared, indicating complete conversion of octadecylamine;[0040] The pressure was reduced to 0.07 MPa, and the reaction was continued at 50 °C for 30 min to obtain a pale yellow liquid product. S was N-octadecylThe yield of methyl acetimidate and methyl N-octadecylethyliminoacetate was 71.3%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PETROLEUM CORPORATION - CN107686455, 2018, A Location in patent: Paragraph 0035-0050

81
[ 18871-66-4 ]
[ 6291-84-5 ]
[ 4271-96-9 ]

Yield	Reaction Conditions	Operation in experiment
5.33 g	In neat (no solvent); at 80℃; for 1.0h;	The mixture of N-methyl-1,3-diaminopropane (4.41 g, 50 mmol) and N,N-dimethylacetamide dimethyl acetal (90% purity, 7.77 g, 52.5 mmol) was stirred at 80 C without solvent. After 1 h, the mixture was evaporated in vacuo, and the residue was distilled under reduced pressure to give 1a (5.33 g, 95%) as a colorless liquid; B.p. 62-64 C/1.0 kPa. 1H NMR (400 MHz, CDCl3, 25 C) delta (ppm): 1.83 (quin, J =6.0 Hz, 2H, NCH2CH2CH2N), 1.96 (s, 3H, CCH3), 2.88 (s, 3H, NCH3), 3.13 (t, J = 6.0 Hz, 2H, NCH2CH2CH2NCH3), 3.29 (t, J = 6.0 Hz, 2H, NCH2CH2CH2NCH3). 13C NMR (100 MHz, CDCl3, 25 C) delta (ppm): 22.0 (NCH2CH2CH2N), 22.7 (CCH3), 38.7 (NCH3), 44.2 (NCH2CH2CH2NCH3), 48.3 (NCH2CH2CH2NCH3), 155.8 (NCN).

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 1702 - 1704

82
[ 18871-66-4 ]
[ 1735-88-2 ]
C₁₃H₁₄FN₃O [ No CAS ]

Reference： [1]Archiv der Pharmazie,2018,vol. 351

83
[ 6271-78-9 ]
[ 18871-66-4 ]
2-chloro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; acetic acid; at 120℃; for 3h;	A mixture of <strong>[6271-78-9]2-chloropyridine-5-carboxamide</strong> (4.20 g) and dimethylacetamide dimethyl acetal (10.0 g) was stirred with heating at 120C for 3 h The reaction mixture was concentrated under reduced pressure and a mixed solution of hydroxylamine hydrochloride (2.24 g), 1.0 mol/L aqueous sodium hydroxide solution (33.0 mL) and acetic acid (30.0 mL) was added. 1,4-Dioxane (30.0 mL) was further added, and the reaction mixture was stirred with heating at 80C for 3 h After cooling to room temperature, water was added, and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform/methanol=100/0 - 95/5) to give the title compound (3.66 g). MS(ESI)m/z; 196,198[M+H]+

Reference： [1]Patent: EP3372601,2018,A1 .Location in patent: Paragraph 0727; 0728

84
[ 18871-66-4 ]
[ 2338-75-2 ]
C₁₂H₁₁F₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N,N-dimethylacetamide dimethyl acetal; 4-(Trifluoromethyl)phenylacetonitrile at 100℃; for 2h; Microwave irradiation; Stage #2: With hydrazine hydro-chloride In ethanol; water at 80℃;	5.d Step d: Synthesis of intermediate 5: Add 8.88 g (48 mmol) of 4-trifluorophenylacetonitrile to a 10 mL microwave tube, N,N-dimethylacetamide dimethyl acetal 5.32 g (40 mmol) was added. Microwave reaction was carried out at 100 °C for 2 h. Take hydrazine hydrochloride 4.11g (60mmol) was added to a 25mL round bottom flask, followed by EtOH 8mL, H2O 5mL was added, wherein the microwave reaction solution was added. The mixture was reflux at 80 °C overnight, the reaction was cooled to room temperature after completion of the reaction solution, ΕΑ (20mLx 3) was basified and extracted with saturated NaHCO3, and the combined EA phases were washed with saturated brine, dried over anhydrous MgSO4, filtered and rotary evaporation, and EA with PE to give a pale yellow solid was recrystallized. Yield of two steps is 87.75%.

Reference： [1]Current Patent Assignee: KUNMING XIANGHAO SCIENCE AND TECHNOLOGY - CN103694242, 2016, B Location in patent: Paragraph 0089; 0093

85
[ 18871-66-4 ]
[ 129322-83-4 ]
[ 1246078-79-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 120℃; for 0.333333h;Microwave irradiation;	(a) l-(2,4,5-trifluorophenyl)ethanone (348 mg, 2 mmol) was dissolved in DMADA (800 mu), the mixture was microwave irradiated at 120 C for 20 min. The reaction mixture was concentrated in vacuum and hexane was added. The solid was filtered and washed with hexane to give 3-(dimethylamino)-l-(2,4,5-trifluorophenyl)prop-2-en-l-one 458 mg as a yellow solid, yield: 100%. LC/MS: (ESI) [M+H]+= 230.3

Reference： [1]Patent: WO2018/237349,2018,A1 .Location in patent: Paragraph 0337; 0338

86
[ 2941-62-0 ]
[ 18871-66-4 ]
(4aR,6R,8R,8aR)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carbohydrazide [ No CAS ]
2-methyl-6-(3-methyl-5-((4aR,6R,8R,8aR)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: N,N-dimethylacetamide dimethyl acetal; (4aR,6R,8R,8aR)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carbohydrazide In acetonitrile at 50℃; for 0.5h; Stage #2: 6-amino-2-methylbenzothiazole With acetic acid In acetonitrile at 120℃; for 16h;	280.2 Step 2: Synthesis of 2-methyl-6-(3-methyl-5-((4aR,6R,8R,8aR)-2-phenyl-8-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)-4H- 1,2,4-triazol-4-yl)benzo[d]thiazole: To a solution of (4aR,6R,8R,8aR)-2-phenyl-8-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6- carbohydrazide (50 mg, 0.105 mmol) in acetonitrile (10 mL) was added N,N- dimethylacetamide dimethyl acetal (14.01 mg, 0.105 mmol) and the mixture was heated at 50 °C for 30 min. 2-Methylbenzo[d]thiazol-6-amine (17.27 mg, 0.105 mmol) in acetonitrile (10.00 mL) was then added at 50 °C followed by acetic acid (1 mL, 17.47 mmol) and the reaction mixture was slowly warmed to 120 °C and stirred for 16 h. The reaction mixture was concentrated and the residue was purified via silica gel (0407) chromatography (0-4% MeOH in DCM) to give 2-methyl-6-(3-methyl-5- ((4aR,6R,8R,8aR)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole (50 mg, 74%) as an off-white solid. LC-MS, [M+H]+ = 646.2, (Method C : tR = 2.99).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2019/67702, 2019, A1 Location in patent: Page/Page column 296-297

87
[ 18871-66-4 ]
[ 1068-57-1 ]
[ 145901-11-7 ]
6-(3,5-dimethyl-1,2,4-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of lH-pyrrolo[2,3-b]pyridin-6-amine (2 g, 15.02 mmol, 1 eq), l, l-dimethoxy-N,N- dimethyl-ethanamine (18.22 g, 136.80 mmol, 20.00 mL, 9.11 eq) was stirred at 130 C for 1 h. The mixture was cooled to 0 C, cone. HC1 (4 mL) was added dropwise, followed by acetohydrazide (6.68 g, 90.12 mmol, 6 eq) and the resulting mixture was stirred at 0 C for 30 min. Then, the temperature was raised to 130 C and the solution was stirred for another 2 h. The resulting solution was concentrated. The residue was purified by column chromatography (SiCK DCM/MeOH = 70/1 to 7/1) to afford the title compound (10.5 g, crude, HC1) as a yellow oil. (Note: The reaction was combined with another reaction in 200 mg scale for work up)

Reference： [1]Patent: WO2019/143719,2019,A1 .Location in patent: Paragraph 225

88
[ 18871-66-4 ]
[ 1513849-41-6 ]
methyl 4-[(E)-1-(dimethylamino)ethylidenecarbamoyl]-2-methoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	at 90℃; for 0.5h;	Intermediate 58: methyl 4-[(E)-l-(dimethylamino)ethylidenecarbamoyl]-2-methoxy- benzoate 542 mg (2.59 mmol) of methyl 4-carbamoyl-2-methoxy-benzoate (Intermediate 57) were suspended in 2 mL of l,l-dimethoxy-N,N-dimethyl-ethanamine (13 mmol, 5 eq.) and the mixture was stirred at 90 °C. After 30 min. the reaction is complete and the volatiles were removed under high vacuum to have a brown oil which used for the next step without further purification (612 mg, 85 %). HPLC-MS: tr = 1.90 min. (92 %). LRMS (m/z): 279 (M+l)

Reference： [1]Current Patent Assignee: ALMIRALL SA - WO2021/204626, 2021, A1 Location in patent: Page/Page column 73

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[ 18871-66-4 ]

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[ 18871-66-4 ] Synthesis Path-Upstream 1~11

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