Name: 770-17-2|2-Morpholinoacetohydrazide|95%
Brand: Ambeed
SKU: A678795
Price: 24.0 USD
Availability: InStock
Rating: 97 (26 reviews)

1
[ 3235-82-3 ]
[ 770-17-2 ]

Yield	Reaction Conditions	Operation in experiment
4.15 g	With hydrazine hydrate; In ethanol; at 120℃; for 8h;	General procedure: Ethyl bromoacetate (8.35g, 50mmol) was added dropwise to a cooled solution of 100mmol of morpholine (8.71g) or 1-methylpiperazine (10.02g) in dry benzene (20mL) and the mixture was stirred at room temperature for 3h. The white precipitate (dialkylamine hydrobromide) was then removed by filtration and the filtrate, containing the ethyl (dialkylamino)acetate, was evaporated to dryness in vacuo. To the resulting oil, dissolved in EtOH (50mL), hydrazine hydrate (2.50g, 50mmol) was added and the mixture was heated in closed vessel at 120C for 8h. After removal of solvent, the residue was treated with a little petroleum ether to give the nearly pure hydrazides as white solids.

Reference： [1]Bulletin de la Societe Chimique de France,1962,p. 250 - 254
[2]European Journal of Medicinal Chemistry,2014,vol. 86,p. 394 - 405
[3]Bioorganic Chemistry,2019,vol. 88

2
[ 30529-14-7 ]
[ 770-17-2 ]
[ 54738-57-7 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol Heating;

Reference： [1]Ross; Jamieson [Journal of Medicinal Chemistry, 1975, vol. 18, # 2, p. 158 - 161]

3
[ 1074-12-0 ]
[ 770-17-2 ]
[ 5956-95-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol

Reference： [1]Massarani; Nardi; Degen; Magistretti [Journal of medicinal chemistry, 1966, vol. 9, # 4, p. 617 - 618]

4
[ 4974-58-7 ]
[ 770-17-2 ]
[ 7037-21-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol

Reference： [1]Massarani; Nardi; Degen; Magistretti [Journal of medicinal chemistry, 1966, vol. 9, # 4, p. 617 - 618]

5
[ 70-97-3 ]
[ 770-17-2 ]
[ 7037-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol

Reference： [1]Massarani; Nardi; Degen; Magistretti [Journal of medicinal chemistry, 1966, vol. 9, # 4, p. 617 - 618]

6
[ 42069-43-2 ]
[ 770-17-2 ]
[ 6592-87-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol

Reference： [1]Massarani; Nardi; Degen; Magistretti [Journal of medicinal chemistry, 1966, vol. 9, # 4, p. 617 - 618]

7
[ 6374-92-1 ]
[ 770-17-2 ]
Morpholin-4-yl-acetic acid [5,7-dichloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidene]-hydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	In acetic acid at 60℃;

Reference： [1]Catto, A.; Cappelletti, R.; Leonardi, A.; Maggi, F.; Tajana, A.; Nardi, D. [Farmaco, Edizione Scientifica, 1983, vol. 38, # 8, p. 559 - 570]

8
[ 28284-05-1 ]
[ 770-17-2 ]
N-(2-{2-[N'-(2-Morpholin-4-yl-acetyl)-hydrazino]-2-oxo-acetyl}-phenyl)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	In 1,4-dioxane at 50℃;

Reference： [1]Catto; Cappelletti; Leonardi; et al. [Farmaco, Edizione Scientifica, 1983, vol. 38, # 1, p. 45 - 56]

9
[ 87-48-9 ]
[ 770-17-2 ]
Morpholin-4-yl-acetic acid [5-bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidene]-hydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	In acetic acid at 20 - 25℃; for 24h;

Reference： [1]Catto, A.; Cappelletti, R.; Leonardi, A.; Maggi, F.; Tajana, A.; Nardi, D. [Farmaco, Edizione Scientifica, 1983, vol. 38, # 8, p. 559 - 570]

10
[ 134-81-6 ]
[ 770-17-2 ]
3-morpholin-4-ylmethyl-5,6-diphenyl-[1,2,4]triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With ammonium acetate In acetic acid at 180℃; for 0.0833333h; microwave irradiation;

Reference： [1]Zhao, Zhijian; Leister, William H.; Strauss, Kimberly A.; Wisnoski, David D.; Lindsley, Craig W. [Tetrahedron Letters, 2003, vol. 44, # 6, p. 1123 - 1127]

11
[ 35855-10-8 ]
[ 770-17-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrazine In ethanol at 90℃; for 18h;	85.A Synthesis of 3-(6-Methoxynaphthalen-2-yl)-5-(5-Morpholin-4-Ylmethyl-1H-[1,2,4]Triazol-3-yl)-1H-Indazole (CC001) A. Morpholin-4-yl-acetic acid hydrazide A solution of methyl morpholinoacetate (2.43 g, 15.3 mmol), ethanol (20 mL) and hydrazine (0.53 mL, 16.8 mmol) was stirred at 90° C. for 18 hours. The mixture was concentrated and dried to provide the title compound (2.30 g, 95%): ES-MS (m/z) 160 [M+1]+
83.15%	With hydrazine hydrate In ethanol at 25℃; for 10h;	9.6 Synthesis step 6: Synthesis of 2-morpholinoacetyl hydrazine The compound morpholin-4-acetic acid methyl ester (27.6 g, 0.174 mol) was added to ethanol (200 mL) at 25 ° C, and hydrazine hydrate (17.4 g, 0.35 mol) was slowly added dropwise.The temperature is raised to 25 ° C. The reaction is 10. Oh, concentrated, and the remaining oil is subjected to column chromatography (eluent: CH 2 Cl 2 / MeOH (ν / ν) = 20/1)22.45 g of a white solid were obtained in a yield: 83.15%.
	With hydrazine In ethanol	A A. A. N-Amino-2-Morpholin-4-Ylacetamide To a solution of methyl 2-morpholin-4-ylacetate (1.0 g, 6.28 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.305 mL, 6.28 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a solid in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ8.11 (br s, 1H), 3.87 (br s, 2H), 3.71 (t, 4H), 3.09 (s, 6H), 2.53 (t, 4H); ES-MS (m/z) 160 [M+H]+.

	With hydrazine In ethanol	324.A A. A. N-Amino-2-morpholin-4-ylacetamide To a solution of methyl 2-morpholin-4-ylacetate (1.0 g, 6.28 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.305 mL, 6.28 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a solid in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ8.11 (br s, 1H), 3.87 (br s, 2H), 3.71 (t, 4H), 3.09 (s, 6H), 2.53 (t, 4H); ES-MS (m/z) 160 [M+H]+.
	With hydrazine hydrate In ethanol at 95℃; for 20h;	2 [00266] 2-morpholinoacetohydrazide Example 2. Synthesis of (Z)-3-(3-(3,5-bis(trifluoroniethyl)phenyl)-lH-l,2,4-triazol-l -yl)- jV-(2-morpholinoacetyl)acrylohydrazide (Compound 2). [00266] 2-morpholinoacetohydrazide. In a 25 mL, 3 -neck round-bottom flask, methyl 2- morpholinoacetate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.087 g, 1.1 eq.) was introduced dropwise at RT and the reaction mixture was refluxed at 95 °C for 20 h. The reaction mixture was concentrated under reduced pressure (40 °C, 20 mm Hg) to afford the crude 2-morpholinoacetohydrazide (0.23 g) which was used without further purification in the following step.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2005/107386, 2005, A1 Location in patent: Page/Page column 46
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN104744446, 2019, B Location in patent: Paragraph 0989; 1010-1012
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2002/103229, 2002, A1
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2004/127536, 2004, A1 Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2005/9876, 2005, A1
[5]Current Patent Assignee: BIOGEN IDEC INC. - WO2013/170068, 2013, A2 Location in patent: Paragraph 00266

12
[ 395108-15-3 ]
[ 770-17-2 ]
3-(6-methoxynaphthalen-2-yl)-5-(5-morpholin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	at 90℃; for 18h;	85.B Synthesis of 3-(6-Methoxynaphthalen-2-yl)-5-(5-Morpholin-4-Ylmethyl-1H-[1,2,4]Triazol-3-yl)-1H-Indazole (CC001) B. 3-(6-methoxynaphthalen-2-yl)-5-(5-morpholin-4-ylmethyl-1H-[1,2,4]triazol-3-yl)-1H-indazole The title compound was prepared as follows: To a flask was charged 3-(6-methoxynaphthalen-2-yl)-1H-indazole-5-carboximidic acid ethyl ester (1.0 g, 2.62 mmol) and morpholin-4-yl-acetic acid hydrazide (1.67 g, 10.5mmol). After 10 minutes, the hydrazide prepared as described in Example 422 A of International Publication No. WO 02/10137 (1.05 g, 7.31 mmol):was added and the mixture was heated at 90° C. for 18 hours. The mixture was concentrated and purified by preparatory HPLC to provide the title compound (481 mg, 42%): 1H NMR (CD3OD) δ 8.82 (s, 1H) 8.42 (s, 1H) 8.08 (d, 2H) 7.93 (t, 2H) 7.65 (br s, 1H) 7.30 (s, 1H) 7.21 (d, 1H) 4.15 (s, 3H) 3.72 (m, 6H) 2.59 (br s, 4H); ES-MS (m/z) 441 [M+1]+

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2005/107386, 2005, A1 Location in patent: Page/Page column 46

13
1-(pyridin-2-yl)piperidine-4-carbonyl chloride [ No CAS ]
[ 770-17-2 ]
3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid N'-(2-morpholin-4-yl-acetyl)-hydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine In dichloromethane at 20℃; for 18h;	3 The acid of Preparation 2 (0.5 g, 2.4 mmol) was suspended in dichloromethane (20 mL) containing N, N-dimethylformamide (2 drops) and oxalyl chloride (1.27 mL, 14 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred for 2 hours at room temperature and then was evaporated under reduced pressure. The yellow solid was suspended in dichloromethane (5 mL) and N-methylmorpholine (0.32 mL, 2.9 mmol) added cautiously. Morpholin-4-yl-acetic acid hydrazide (462 mg, 2.9 mmol) (see reference Bull. Soc. Chim. Fr. 1962,250) was added, and the mixture was then stirred at room temperature for 18 hours. The reaction was diluted into dichloromethane (100 mL) and washed with aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was triturated with ethyl acetate, to give the title compound as a solid (306 mg) 1H NMR (400MHz, CDCI3) : No. 1. 94 (m, 4H), 2.60 (s, 5H), 2.79 (s, 2H), 2. 99 (m, 2H), 3.72 (m, 4H), 4.33 (d, 2H), 6.63 (m, 1H), 6.73 (d, 1H), 7.51 (m, 1H), 8.14 (m, 1H), 8.82 (s, 1H), 9.22 (broad s, 1 H); LRMS m/z ES+ 348 [M+H] +

Reference： [1]Current Patent Assignee: PFIZER INC - WO2005/79808, 2005, A1 Location in patent: Page/Page column 36-37

14
[ 1103774-11-3 ]
[ 770-17-2 ]
[ 1103774-43-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With acetic acid In tetrahydrofuran; ethanol at 20℃; for 24h;

Reference： [1]Location in patent: experimental part Diaz, Philippe; Phatak, Sharangdhar S.; Xu, Jijun; Astruc-Diaz, Fanny; Cavasotto, Claudio N.; Naguib, Mohamed [Journal of Medicinal Chemistry, 2009, vol. 52, # 2, p. 433 - 444]

15
[ 1062197-39-0 ]
[ 770-17-2 ]
[ 1062197-50-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	In 1-methyl-pyrrolidin-2-one at 160℃; for 3h;	134A Example 134A; 7-(2,4-Dichlorophenyl)-2-(morpholin-4-ylmethyl)[1,2,4]triazolo[1,5-c]pyrimidin-5-ol 1.33 g (4.7 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 740 mg (4.7 mmol) of 2-morpholin-4-ylacetohydrazide are dissolved in NMP (6 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 3 h. The reaction mixture is cooled to RT and ethyl acetate (100 ml) and water (50 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase dichloromethane/methanol 100:1 to 50:1). 1.25 g (70% of theory) of the product are obtained.LCMS (method 8): Rt=0.68 min. (m/z=380 (M+H)+)1H-NMR (400 MHz, DMSO-d6): d=12.37 (br s, 1H), 7.85 (d, 1H), 7.64 (m, 2H), 6.85 (s, 1H), 4.44 (br s, 2H), 3.71 (s, 2H), 3.59 (m, 4H), 3.40 (s, 2H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/113441, 2010, A1 Location in patent: Page/Page column 55-56

16
[ 1062197-41-4 ]
[ 770-17-2 ]
[ 1062197-51-6 ]

Yield	Reaction Conditions	Operation in experiment
26%	In 1-methyl-pyrrolidin-2-one at 190℃; for 4h;	135A Example 135A; 2-(Morpholin-4-ylmethyl)-7-[4-(trifluoromethyl)phenyl][1,2,4]-triazolo[1,5-c]pyrimidin-5-ol 2.4 g (8.4 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.34 g (8.4 mmol) of 2-morpholin-4-ylacetohydrazide are dissolved in NMP (12 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 190° C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is washed with saturated sodium bicarbonate solution, separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1, then with dichloromethane/methanol 100:1). 850 mg (26% of theory) of the product are obtained.LCMS (method 8): Rt=0.74 min. (m/z=380 (M+H)+)1H-NMR (400 MHz, DMSO-d6): d=12.36 (br s, 1H), 8.05 (d, 2H), 7.92 (d, 2H), 7.18 (s, 1H), 4.45 (m, 2H), 3.70 (s, 2H), 3.60 (m, 4H), 3.29 (s, 2H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/113441, 2010, A1 Location in patent: Page/Page column 56

17
[ 1266237-97-1 ]
[ 770-17-2 ]
[ 1266237-19-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	In methanol at 45℃; for 3h;	36 Example 36 (£)-N'-(1-(3-(Difluoro(quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethylidene)-2-morpholinoacetohydrazide1-(3-(difluoro(quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (25 mg, 0.074 mmol) and 2-morpholinoacetohydrazide (12 mg, 0.075 mmol) were dissolved in MeOH and the pH of the reaction solution was adjusted to 5. The solution was then stirred at 450C for 3 hours. Solvent was evaporated and the crude product was purified on HPLC (neutralized to free base) to give the title compound as a white solid (18 mg, 50%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.02(s, 1 H), 8.55(d, 1 H), 8.43(d, 2H), 8.17 (d, 1 H), 8.01 (m, 2H), 7.65(d, 1 H), 3.59(m, 4H), 2.13(m, 4H). LCMS (method B): [MH]+ = 481.1 , tR = 1.66 min.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2011/18454, 2011, A1 Location in patent: Page/Page column 90

18
[ 532-55-8 ]
[ 770-17-2 ]
[ 1276375-46-2 ]

Yield	Reaction Conditions	Operation in experiment
0.74 g	In Isopropyl acetate at 60℃; for 3h;
1.91 g	In isopropyl alcohol at 60℃; for 3h;

Reference： [1]Amerkhanova; Nurkenov; Fazylov; Shlyapov; Uali; Satpaeva [Russian Journal of General Chemistry, 2012, vol. 82, # 11, p. 1815 - 1818][Zh. Obshch. Khim.]
[2]Nurkenov; Fazylov; Satpaeva, Zh. B.; Kulakov; Turdybekov; Turdybekov; Talipov; Ibragimov [Russian Journal of General Chemistry, 2013, vol. 83, # 3, p. 520 - 525][Zh. Obshch. Khim., 2013, vol. 83, # 3, p. 467 - 472,6]

19
[ 333-20-0 ]
[ 770-17-2 ]
[ 528597-48-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	With hydrogenchloride In water at 95℃; for 4h;

Reference： [1]Nurkenov; Fazylov; Satpaeva, Zh. B.; Kulakov; Turdybekov; Turdybekov; Talipov; Ibragimov [Russian Journal of General Chemistry, 2013, vol. 83, # 3, p. 520 - 525][Zh. Obshch. Khim., 2013, vol. 83, # 3, p. 467 - 472,6]

20
[ 75-15-0 ]
[ 770-17-2 ]
[ 155219-13-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium hydroxide In ethanol Cooling;

Reference： [1]Nurkenov; Fazylov; Satpaeva, Zh. B.; Kulakov; Turdybekov; Turdybekov; Talipov; Ibragimov [Russian Journal of General Chemistry, 2013, vol. 83, # 3, p. 520 - 525][Zh. Obshch. Khim., 2013, vol. 83, # 3, p. 467 - 472,6]

21
[ 1388842-44-1 ]
[ 770-17-2 ]
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-(2-morpholinoacetyl)acrylohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.1 g	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at -60℃; for 1h;	2 100267] (Z)-3-(3-(3, 5-bis(trifluoromethyl)phenyl)-lH-l, 2, 4-triazol-l-yl)-N'-(2- morpholinoacetyl)acrylohydrazide (Compound 2). 100267] (Z)-3-(3-(3, 5-bis(trifluoromethyl)phenyl)-lH-l, 2, 4-triazol-l-yl)-N'-(2- morpholinoacetyl)acrylohydrazide (Compound 2). In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1 .0 eq.) was dissolved in CH2C12: EtOAc (20 mL, 2: 1 ) and cooled to -60 °C where 2- morpholinoacetohydrazide (0.23 g, 1.0 eq.) was introduced dropwise. T3P (50%> in EtOAc) (1.27 mL, 1.5 eq.) was added dropwise followed by DIPEA (0.96 mL, 2 eq.) and the reaction mixture was stirred for 1 h at -60 °C. The reaction mixture was concentrated under reduced pressure (25 °C, 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3 %> methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l ,2,4-triazol-l -yl)-N'- (2-morpholinoacetyl)acrylohydrazide (0.1 g, yield: 14%).

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2013/170068, 2013, A2 Location in patent: Paragraph 00267

22
[ 75-15-0 ]
[ 770-17-2 ]
[ 89723-68-2 ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium hydroxide In water for 0.333333h; Microwave irradiation;

Reference： [1]Fazylov; Nurkenov; Kenzhetaeva; Satpaeva, Zh. B.; Karipova, G. Zh. [Russian Journal of General Chemistry, 2013, vol. 83, # 9, p. 1794 - 1795][Zh. Obshch. Khim., 2013, vol. 83, # 9, p. 1579 - 1580,2]

23
[ 770-17-2 ]
N,N-diethyl-5-(isopropylamino-9-(4-morpholinylmethyl))[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diphenyl ether-biphenyl eutectic / 1.5 h / 160 °C 2: ethanol / 16 h / 140 °C

Reference： [1]Di Braccio, Mario; Grossi, Giancarlo; Alfei, Silvana; Ballabeni, Vigilio; Tognolini, Massimiliano; Flammini, Lisa; Giorgio, Carmine; Bertoni, Simona; Barocelli, Elisabetta [European Journal of Medicinal Chemistry, 2014, vol. 86, p. 394 - 405]

24
[ 770-17-2 ]
N,N-diethyl-5-(4-methyl-1-piperazinyl)-9-(4-morpholinylmethyl)[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diphenyl ether-biphenyl eutectic / 1.5 h / 160 °C 2: dimethyl sulfoxide / 2 h / 130 °C

Reference： [1]Di Braccio, Mario; Grossi, Giancarlo; Alfei, Silvana; Ballabeni, Vigilio; Tognolini, Massimiliano; Flammini, Lisa; Giorgio, Carmine; Bertoni, Simona; Barocelli, Elisabetta [European Journal of Medicinal Chemistry, 2014, vol. 86, p. 394 - 405]

25
[ 126567-71-3 ]
[ 770-17-2 ]
5-chloro-N,N-diethyl-9-(4-morpholinylmethyl)[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With diphenyl ether-biphenyl eutectic at 160℃; for 1.5h;	5.1.8 General procedure for the synthesis of 9-[(dialkylamino)methyl]-5-chloro-N,N-diethyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 11a,b General procedure: The mixture of 2,4-dichloro-N,N-diethyl-1,8-naphthyridine-3-carboxamide 10[9] (2.98g, 10.0mmol) and 4-morpholinylacetic acid hydrazide 9a (2.39g, 15.0mmol) or 4-methyl-1-piperazinylacetic acid hydrazide 9b (2.58g, 15.0mmol) and Dowtherm A (10mL) was stirred at 160°C for 1.5h. After cooling, 10% aqueous Na2CO3 (50mL) and CH2Cl2 (50mL) were added and the mixture was further stirred at room temperature for 30min. After discarding some insoluble impurities by filtration, the mixture was transferred in a separatory funnel, then the organic layer was collected and the aqueous one was exhaustively extracted with CH2Cl2. The combined extracts were dried (anhydrous Na2SO4) then evaporated to dryness at reduced pressure, and the residue was chromatographed on a silica gel column eluting first with CH2Cl2 to remove Dowtherm A. Then the column was eluted with EtOAc to remove small amounts of starting compound 10 and some impurities; the subsequent elution with the mixture EtOAc-acetone-MeOH (9:9:2) gave oily residues from which, after treatment with a small amount of diisopropyl ether, pure compounds 11a,b separated out as pale pink crystalline solids, which then were crystallized from an appropriate solvent or solvent mixture.

Reference： [1]Di Braccio, Mario; Grossi, Giancarlo; Alfei, Silvana; Ballabeni, Vigilio; Tognolini, Massimiliano; Flammini, Lisa; Giorgio, Carmine; Bertoni, Simona; Barocelli, Elisabetta [European Journal of Medicinal Chemistry, 2014, vol. 86, p. 394 - 405]

26
ethyl 3-bromo-1H-indazole-5-carbimidate [ No CAS ]
[ 770-17-2 ]
4-(3-(3-bromo-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)methylmorpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine In methanol at 90℃; for 16h; Sealed tube;	18 4-(3-(3-Bromo-1H-indazol-5-yl)-1H-1,2,4-triazol-5-yl)methyl)morpholine. To a stirred solution of ethyl 3-bromo-1H-indazole-5-carbimidate (0.5 g, 1.86 mmol) and 2-morpholinoacetohydrazide (0.29 g, 1.86 mmol; see International Patent Application Publication No. WO 02/10137, 2002) in methanol (5 mL) were added triethylamine (0.56 g, 5.59 mmol). The reaction was heated at 90 °C for 16 h in a sealed tube. Completion of the reaction was confirmed by LCMS. The reaction mixture worked-up and the product isolated and purified via standard methods to afford 4-(3-(3-bromo-1H-indazol-5-yl)-1H-1,2,4-triazol-5- yl)methyl)morpholine (0.34 g, 50%) as white solid.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/89977, 2016, A1 Location in patent: Paragraph 00181

27
[ 1609082-37-2 ]
[ 770-17-2 ]
8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-N'-(morpholin-4-ylacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 2-(4-morpholinyl)acetylhydrazine In N,N-dimethyl-formamide at 20℃;	76 Example 76 8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-N'-(morpholin-4-ylacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide Example 76 8-[(2,6-Difluorobenzyl)oxy]-2,6-dimethyl-N'-(morpholin-4-ylacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide 101 mg (0.27 mmol) of HATU and 0.13 ml (0.72 mmol) of N,N-diisopropylethylamine were added to 80 mg (0.24 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid from Example 16A in 0.71 ml of DMF. The reaction mixture was stirred at RT for 10 min, 46 mg (0.29 mmol) of (morpholin-4-yl)acetohydrazide were added and the mixture was stirred at RT overnight. TFA and methanol were added and the reaction solution was purified by preparative HPLC (RP18 column, mobile phase: methanol/water gradient with addition of 0.1% TFA). The product fractions were concentrated and taken up in dichloromethane, 1 ml of saturated aqueous sodium bicarbonate solution was added and the mixture was stirred for one hour. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 90 mg of the target compound (79% of theory). LC-MS (Method 23): Rt=0.77 min MS (ESpos): m/z=474 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): δ=2.32 (s, 3H), 2.53 (s, 3H), 2.54 (s, 4H), 3.09 (s, 2H), 3.64 (t, 4H), 5.30 (s, 2H), 6.96 (s, 1H), 7.20-7.28 (m, 2H), 7.55-7.63 (m, 1H), 8.36 (s, 1H), 9.74 (s, 1H), 9.81 (s, 1H).

Reference： [1]Current Patent Assignee: BAYER AG - US2017/57954, 2017, A1 Location in patent: Paragraph 0832; 0833; 0834; 0835; 0836

28
(E)-N'-(1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-N,N-dimethylformimidamide [ No CAS ]
[ 770-17-2 ]
1-(4-methoxyphenyl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-3-[3-(morpholin-4-yl)methyl-4H-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.2%	With acetic acid at 80℃; for 2h;	1 5.3.4. General procedure for preparation of triazole compounds (15a-15f) General procedure: A mixture of different substituted hydrazides (0.36 mmol),HOAc (1 mL) and intermediate 14 (0.15 g, 0.30 mmol) was stirredat 80 C for 2 h. After being cooled to rt., the reaction mixturewas poured into ice-water (10 mL). The precipitate was filteredand purified by silica gel column chromatography (eluent, CH2Cl2/MeOH = 30:1-20:1) to afford target products 15a-15f.

Reference： [1]Sun, Xiaoqing; Hong, Zexin; Liu, Moyi; Guo, Su; Yang, Di; Wang, Yong; Lan, Tian; Gao, Linyu; Qi, Hongxia; Gong, Ping; Liu, Yajing [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 10, p. 2800 - 2810]

29
[ 770-17-2 ]
C₁₉H₂₄N₈OS₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium hydroxide / water; ethanol / 13 h / Reflux 2: triethylamine / ethanol / 6 h 3: trifluoroacetic acid / ethanol / 9 h / Reflux 4: hydrazine hydrate / ethanol / 10 h / Reflux 5: 2 h / 125 °C