[ CAS No. 1225387-53-0 ] {[proInfo.proName]}

Name: 1225387-53-0|3H-Pyrazol-3-amine|98%
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Quality Control of [ 1225387-53-0 ]

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Product Details of [ 1225387-53-0 ]

CAS No. :	1225387-53-0	MDL No. :	MFCD31727672
Formula :	C₃H₅N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JVVRJMXHNUAPHW-UHFFFAOYSA-N
M.W :	83.09	Pubchem ID :	74561
Synonyms :

Safety of [ 1225387-53-0 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3267
Hazard Statements:	H302-H314-H317	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 1225387-53-0 ]

* 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 [ 1225387-53-0 ]
Downstream synthetic route of [ 1225387-53-0 ]

[ 1225387-53-0 ] Synthesis Path-Upstream 1~16

1
[ 1225387-53-0 ]
[ 105-53-3 ]
[ 57489-70-0 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 5, p. 204 - 208
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 10312 - 10313

2
[ 34461-00-2 ]
[ 1225387-53-0 ]
[ 63572-73-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	at 90℃;	A suspension of lH-pyrazol-5-amine (0.804 g, 9.48 mmol) and sodium nitromalonaldehyde monohydrate (1.56 g, 9.96 mmol) in acetic acid (12 mL) was heated to 9O⁰C overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting solids were collected by filtration. The solids were washed with water (3 X 20 mL) and dried in vacuo to give 5-nitro-l H-pyrazolo [3 ,4-b]pyridine (1.40 g, 84percent) as a solid.
84%	at 90℃;	A suspension of lH-pyrazol-5 -amine (0.804 g, 9.48 mmol) and sodium nitromalonaldehyde monohydrate (1.56 g, 9.96 mmol) in acetic acid (12 mL) was heated to 90°C overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting solids were collected by filtration. The solids were washed with water (3 X 20 mL) and dried in vacuo to give 5-nitro-lH-pyrazolo[3,4-b]pyridine (1.40 g, 84percent) as a solid.

Reference： [1] Patent: WO2011/25968, 2011, A1, . Location in patent: Page/Page column 49
[2] Patent: WO2009/111279, 2009, A1, . Location in patent: Page/Page column 96
[3] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1992, vol. 28, # 11, p. 1335 - 1339[4] Khimiya Geterotsiklicheskikh Soedinenii, 1992, # 11, p. 1560 - 1564
[5] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 5, p. 342 - 347

3
[ 34461-00-2 ]
[ 1225387-53-0 ]
[ 63572-73-6 ]
[ 116835-08-6 ]

Reference： [1] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 420-428

4
[ 1225387-53-0 ]
[ 87-13-8 ]
[ 43024-61-9 ]

Reference： [1] Patent: EP1918291, 2008, A1, . Location in patent: Page/Page column 22

5
[ 1225387-53-0 ]
[ 74-88-4 ]
[ 446866-62-2 ]
[ 1192-21-8 ]

Reference： [1] Patent: WO2005/30758, 2005, A1, . Location in patent: Page/Page column 60-61

6
[ 83724-91-8 ]
[ 1225387-53-0 ]
[ 274-71-5 ]

Reference： [1] Patent: US5334505, 1994, A,

7
[ 1001-26-9 ]
[ 1225387-53-0 ]
[ 29274-22-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate In N,N-dimethyl-formamide at 110℃; Inert atmosphere	The compound 5-aminopyrazole (5 g, 60 mmol)And ethyl 3-ethoxyacrylate (13 g, 90 mmol)Cesium carbonate (29 g, 90 mmol)Was mixed in 100 ml of N, N-dimethylformamide,The reaction was heated to 110 ° C overnight.Cooled to room temperature, diluted with 200 ml of water,Ether extraction (40 mL x 3), the aqueous phase was concentrated under reduced pressure,The residue was purified by silica gel column chromatography (DCM: MeOH = 10: 1)4H-pyrazolo [1,5-a] pyrimidin-5-one (8 g) in 99percent yield.

Reference： [1] Patent: CN104250252, 2017, B, . Location in patent: Paragraph 0095; 0097; 0098
[2] Journal of Organic Chemistry, 2007, vol. 72, # 3, p. 1043 - 1046

8
[ 874-14-6 ]
[ 1225387-53-0 ]
[ 29274-22-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium ethanolate In ethanol at 60℃; for 2 h;	1,3-Dimethyl uracil (3.15 g, 22.5 mmol) and sodium ethoxide (23 mL of a 21percent solution in ethanol) were added to a solution of lH-pyrazol-5 -amine (1.7 g, 20.4 mmol) in ethanol (50 mL). The resulting mixture was heated to 60 ⁰C for 2 h and was then cooled to room temperature. The pale brown solid was isolated by filtration to give pyrazolo[l,5-a]pyrimidin- 5(4H)-one (1.6 g, 58percent). Retention time (min) = 0.820, method [3], MS(ESI) 136.1 (M+Η).
12.50 g	With sodium ethanolate In ethanol at 80℃; for 5 h;	A mixture of A-5 (8.00 g, 96.28 mmol), 1,3-dimethylpyrimidine-2,4-dione (13.49 g, 96.28 mmol) and EtONa (32.76 g, 481.40 mmol) in EtOH (150 mL) was stirred at 80 °C for 5 hours. The solid was collected by filtration, washed with EtOH (50 mL), and dried in an oven to afford A-6 (12.50 g, 92.51 mmol) as a solid. 1H NMR (400MHz, DMSO-d6) δ 11 7.97 (d, 1H), 7.43 (d, 1H), 5.62 (d, 1H), 5.35 (d, 1H).

Reference： [1] Patent: WO2010/91310, 2010, A1, . Location in patent: Page/Page column 141
[2] Journal of Organic Chemistry, 2007, vol. 72, # 3, p. 1043 - 1046
[3] Patent: WO2018/98500, 2018, A1, . Location in patent: Page/Page column 84

9
[ 922-67-8 ]
[ 1225387-53-0 ]
[ 29274-22-4 ]

Reference： [1] Patent: WO2010/63487, 2010, A1, . Location in patent: Page/Page column 68

10
[ 1225387-53-0 ]
[ 934758-92-6 ]

Reference： [1] Patent: WO2015/181747, 2015, A1, . Location in patent: Page/Page column 38; 39

11
[ 1225387-53-0 ]
[ 109-64-8 ]
[ 126352-69-0 ]

Yield	Reaction Conditions	Operation in experiment
36%	With triethylamine In 1,4-dioxane at 110℃; for 5 h;	To a solution of 1 H-pyrazol-5-amine (9.8 g, 0.1 mol) and TEA (36.0 g, 0.3 mmol) m1,4-dioxane (200 mL) was added 1,3-dibromopropane (26.3 g, 0.1 mmol). After stirring at 110°C for 5 hrs, the reaction m1xture was filtered. The filtration was concentrated to dry ness. Theresidue was purified by silica gel column (DCJ\1/MeOH = 100/1) to give 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine (5.3 g, yield: 36~~) as a white solid.[001020] 1H NlVIR (300 rviHz, CDCb): 8 = 7.18 (s, 1H), 5.26 (s, 1H), 4.22-4.00 (m, 3H), 3.26-3.22 (m, 2H), 2.11-2.03 (m, 2H).

Reference： [1] Patent: WO2018/136890, 2018, A1, . Location in patent: Paragraph 001018; 001019; 001020
[2] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 3, p. 557 - 567

12
[ 123-91-1 ]
[ 1225387-53-0 ]
[ 109-64-8 ]
[ 126352-69-0 ]

Reference： [1] Patent: US5173485, 1992, A,

13
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With hydrogenchloride In ethanol; water at 0 - 20℃; for 2 h;	Will V be non-material (15 · lg, lOOmmol)And the formula II is not material (8.3g, lOOmmol)Placed in a 250 ml round bottom flask,Add 120 ml of ethanol,Cooled to 0 ° C, add 12ml concentrated hydrochloric acid, return to room temperature, stirring 2h,The reaction precipitated a pale yellow solid. After direct filtration, the cake was washed with saturated NaHC03 solution and then washed with water.After drying, 17 g of the intermediate represented by formula VI was obtained. The yield of the intermediate represented by formula VI was calculated to be 86percent.
30%	for 2 h; Reflux	The 3-aminopyrazole (2.0g, 23.9 mmol) and 20 mL of ethanol were added 100 mL three-neck flask, and stirred to dissolve, then 2-bromo-malonaldehyde (2.4 g, 16.0 mmol) was added in the flask. The system presents a reddish brown after the mixture was heated under reflux for 2 h. The reaction was cooled to room temperature and the organic solvent is evaporated to dryness. The residue was purified by column chromatography: gel (eluent petroleum ether / ethyl acetate). Pale yellow crystalline solid, yield: 30percent. ¹H NMR (CDCl₃, 400 MHz, δ ppm): 8.50 (d, J = 3.3 Hz, 1H), 7.99 (dd, J = 9.2, 1.5 Hz, 1H), 7.82 (s, 1H), 7.13 (dd, J = 9.2, 4.4 Hz, 1H). ESI-MS(m/z): 197.3 [M+H]⁺.

Reference： [1] Patent: CN105130991, 2017, B, . Location in patent: Paragraph 0037; 0041-0043
[2] Patent: WO2014/138088, 2014, A1, . Location in patent: Page/Page column 60
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 15, p. 4388 - 4392
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5830 - 5835

14
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
2.1%	at 20℃; Heating / reflux	A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1 percent; LC-MS (MH⁺): 198/200) and 6-bromopyrazolo[1 ,5-a]pyrimidine x81 (yield: 13.8 percent; LC-MS (MH⁺): 198/200).

Reference： [1] Patent: WO2006/128692, 2006, A2, . Location in patent: Page/Page column 86

15
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
2.1%	at 20℃; Heating / reflux	A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1 percent; LC-MS (MH⁺): 198/200) and 6-bromopyrazolo[1 ,5-a]pyrimidine x81 (yield: 13.8 percent; LC-MS (MH⁺): 198/200).

Reference： [1] Patent: WO2006/128692, 2006, A2, . Location in patent: Page/Page column 86

16
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	for 6 h; Heating; Reflux; Inert atmosphere of N₂	lH-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde(9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated <n="82"/>to reflux under N₂ for 6 hours. The reaction mixture was cooled to room temperature and concentrated to give a solid. The crude solids were suspended in MeOH (200 mL) and absorbed onto silica gel (200 g). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 5-bromo-lH- pyrazolo[3,4-b]pyridine as a solid (3.1 g, 25percent).

Reference： [1] Patent: WO2009/111279, 2009, A1, . Location in patent: Page/Page column 79-80

[ 1225387-53-0 ] Synthesis Path-Downstream 1~88

1
[ 6283-81-4 ]
[ 1225387-53-0 ]
[ 89819-56-7 ]

Reference： [1]Polish Journal of Chemistry,1982,vol. 56,p. 963 - 973

2
[ 25090-33-9 ]
[ 64-19-7 ]
[ 1225387-53-0 ]
[ 83725-01-3 ]

Reference： [1]Synthesis,1982,p. 673 - 677
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 7167 - 7176

3
[ 25090-33-9 ]
[ 1225387-53-0 ]
[ 83724-97-4 ]

Reference： [1]Synthesis,1982,p. 673 - 677

4
[ 34461-00-2 ]
[ 1225387-53-0 ]
[ 63572-73-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	In acetic acid; at 90℃;	A suspension of lH-pyrazol-5-amine (0.804 g, 9.48 mmol) and sodium nitromalonaldehyde monohydrate (1.56 g, 9.96 mmol) in acetic acid (12 mL) was heated to 9O0C overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting solids were collected by filtration. The solids were washed with water (3 X 20 mL) and dried in vacuo to give 5-nitro-l H-pyrazolo [3 ,4-b]pyridine (1.40 g, 84%) as a solid.
84%	In acetic acid; at 90℃;	A suspension of lH-pyrazol-5 -amine (0.804 g, 9.48 mmol) and sodium nitromalonaldehyde monohydrate (1.56 g, 9.96 mmol) in acetic acid (12 mL) was heated to 90C overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting solids were collected by filtration. The solids were washed with water (3 X 20 mL) and dried in vacuo to give 5-nitro-lH-pyrazolo[3,4-b]pyridine (1.40 g, 84%) as a solid.

Reference： [1]Patent: WO2011/25968,2011,A1 .Location in patent: Page/Page column 49
[2]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 96
[3]Chemistry of Heterocyclic Compounds,1992,vol. 28,p. 1335 - 1339
Khimiya Geterotsiklicheskikh Soedinenii,1992,p. 1560 - 1564
[4]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 342 - 347

5
[ 34461-00-2 ]
[ 1225387-53-0 ]
[ 63572-73-6 ]
[ 116835-08-6 ]

Reference： [1]Canadian Journal of Chemistry,1988,vol. 66,p. 420-428

6
[ 1225387-53-0 ]
[ 109-64-8 ]
[ 126352-69-0 ]

Yield	Reaction Conditions	Operation in experiment
36%	With triethylamine; In 1,4-dioxane; at 110℃; for 5h;	To a solution of 1 H-pyrazol-5-amine (9.8 g, 0.1 mol) and TEA (36.0 g, 0.3 mmol) m1,4-dioxane (200 mL) was added 1,3-dibromopropane (26.3 g, 0.1 mmol). After stirring at 110C for 5 hrs, the reaction m1xture was filtered. The filtration was concentrated to dry ness. Theresidue was purified by silica gel column (DCJ1/MeOH = 100/1) to give 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine (5.3 g, yield: 36~~) as a white solid.[001020] 1H NlVIR (300 rviHz, CDCb): 8 = 7.18 (s, 1H), 5.26 (s, 1H), 4.22-4.00 (m, 3H), 3.26-3.22 (m, 2H), 2.11-2.03 (m, 2H).

Reference： [1]Patent: WO2018/136890,2018,A1 .Location in patent: Paragraph 001018; 001019; 001020
[2]Bioorganic and Medicinal Chemistry,1997,vol. 5,p. 557 - 567

7
[ 1225387-53-0 ]
[ 29176-21-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 3⁽⁵⁾-aminopyrazole With hydrogenchloride; sodium nitrite In water at -2 - 0℃; for 0.25h; Stage #2: With sodium azide In water at 0 - 20℃; for 12h;	3-Azidopyrazole (3). A solution of NaNO2 (1.8 g, 26 mmol) in H2O (25 ml) was added dropwise with vigorous stirring to a cooled (-2°C) solution of 3-aminopyrazole (4) (2.0 g, 24 mmol) in a mixture of concentrated HCl (7 ml) and H2O (10 ml); during the addition the temperature in the mixture was not allowed to rise above 0°C. The mixture was stirred for additional 15 min, then a solution of NaN3 (1.95 g, 30 mmol) in H2O (10 ml) was slowly (over ~40 min) added dropwise at the same temperature. After warming of the reaction mixture ceased, the cooling bath was removed, and the reaction mixture was allowed to warm up to room temperature overnight. NaHCO3 (4.0 g, 48 mmol) was added, and the suspension was extracted with CH2Cl2 (5×50 ml). The combined organics were dried over MgSO4, solvent was removed under reduced pressure, and the residue was recrystallized from hexane. Yield 2.38 g (87%), white cotton-like substance, mp 61-63°C, Rf 0.5 (CHCl3-MeCN,5:1). IR spectrum, ν, cm-1: 3180, 3060, 2982, 2933, 2846, 2126, 1542, 1473, 1365, 1310, 1225, 1186, 1047, 994, 925, 798, 753,601, 531. 1H and 13C spectra match literature data.10 Compound 3 is soluble in all common solvents from H2O to hexane.
77.2%	With hydrogenchloride; sodium azide; sodium nitrite In water at 0 - 20℃; for 20h;
	With hydrogenchloride; sodium azide; sodium nitrite 2.) 30 min; Yield given. Multistep reaction;

Reference： [1]Gladyshkin, Aleksei G.; Sheremetev, Aleksei B. [Chemistry of Heterocyclic Compounds, 2019, vol. 55, # 8, p. 779 - 782][Khim. Geterotsikl. Soedin., 2019, vol. 55, # 8, p. 779 - 782,4]
[2]Chen, Xiuxian; Jin, Qingqing; Wu, Lizhu; Tung, ChenHo; Tang, Xinjing [Angewandte Chemie - International Edition, 2014, vol. 53, # 46, p. 12542 - 12547][Angew. Chem., 2014, vol. 126, # 46, p. 12750 - 12755,6]
[3]Clarke, David; Mares, Richard W.; McNab, Hamish [Journal of the Chemical Society. Perkin transactions I, 1997, # 12, p. 1799 - 1804]

8
[ 75824-03-2 ]
[ 1225387-53-0 ]
6-methylsulfanyl-4<i>H</i>-1,4,5,7,8,9a-hexaaza-cyclopenta[<i>b</i>]naphthalen-9-one [ No CAS ]

Reference： [1]Synlett,2006,p. 472 - 474

9
[ 874-14-6 ]
[ 1225387-53-0 ]
[ 29274-22-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium ethanolate; In ethanol; at 60℃; for 2h;	1,3-Dimethyl uracil (3.15 g, 22.5 mmol) and sodium ethoxide (23 mL of a 21% solution in ethanol) were added to a solution of lH-pyrazol-5 -amine (1.7 g, 20.4 mmol) in ethanol (50 mL). The resulting mixture was heated to 60 0C for 2 h and was then cooled to room temperature. The pale brown solid was isolated by filtration to give pyrazolo[l,5-a]pyrimidin- 5(4H)-one (1.6 g, 58%). Retention time (min) = 0.820, method [3], MS(ESI) 136.1 (M+Eta).
12.50 g	With sodium ethanolate; In ethanol; at 80℃; for 5h;	A mixture of A-5 (8.00 g, 96.28 mmol), 1,3-dimethylpyrimidine-2,4-dione (13.49 g, 96.28 mmol) and EtONa (32.76 g, 481.40 mmol) in EtOH (150 mL) was stirred at 80 C for 5 hours. The solid was collected by filtration, washed with EtOH (50 mL), and dried in an oven to afford A-6 (12.50 g, 92.51 mmol) as a solid. 1H NMR (400MHz, DMSO-d6) delta 11 7.97 (d, 1H), 7.43 (d, 1H), 5.62 (d, 1H), 5.35 (d, 1H).

Reference： [1]Patent: WO2010/91310,2010,A1 .Location in patent: Page/Page column 141
[2]Journal of Organic Chemistry,2007,vol. 72,p. 1043 - 1046
[3]Patent: WO2018/98500,2018,A1 .Location in patent: Page/Page column 84

10
[ 1001-26-9 ]
[ 1225387-53-0 ]
[ 29274-22-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate; In N,N-dimethyl-formamide; at 110℃;Inert atmosphere;	The compound 5-aminopyrazole (5 g, 60 mmol)And ethyl 3-ethoxyacrylate (13 g, 90 mmol)Cesium carbonate (29 g, 90 mmol)Was mixed in 100 ml of N, N-dimethylformamide,The reaction was heated to 110 ° C overnight.Cooled to room temperature, diluted with 200 ml of water,Ether extraction (40 mL x 3), the aqueous phase was concentrated under reduced pressure,The residue was purified by silica gel column chromatography (DCM: MeOH = 10: 1)4H-pyrazolo [1,5-a] pyrimidin-5-one (8 g) in 99percent yield.

Reference： [1]Patent: CN104250252,2017,B .Location in patent: Paragraph 0095; 0097; 0098
[2]Journal of Organic Chemistry,2007,vol. 72,p. 1043 - 1046

11
[ 1001-26-9 ]
[ 1225387-53-0 ]
ethyl 3-[5-amino-3-(3-bromophenyl)-1H-pyrazol-1-yl]-3-ethoxypropanoate [ No CAS ]
2-(3-bromophenyl)-7-ethoxy-6,7-dihydropyrazolo[1,5-a]pyrimidin-5(4H)-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 1043 - 1046

12
[ 1225387-53-0 ]
[ 87-13-8 ]
[ 29274-18-8 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 1043 - 1046
[2]ChemMedChem,2014,vol. 9,p. 2516 - 2527

13
[ 83724-91-8 ]
[ 1225387-53-0 ]
[ 274-71-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydrogencarbonate; In sodium hydroxide; concentrated acetic acid; diethyl ether; ethanol; water;	pyrazolo[1,5-a]pyrimidine General Procedure The 5-amino-1H-pyrazol (2) (0,06 mol) and 2-allyl-3-ethoxy-acrolin) (1) (0,06 mol) in concentrated acetic acid (70 ml) are refluxed for 3 hours. After cooling the mixture is treated as follows: Variant A: The reaction solution is concentrated until dryness under reduced pressure, the residue is dried in a dessicator over solid sodium hydroxide and crystallized in methanol. Variant B: After concentrating and drying of the reaction product, it is distilled in a vacuum over sodium hydroxide. Variant C: After concentrating and drying of the reaction product it is sublimed in high vacuum over sodium hydroxide. Variant D: The product crystallizes. It is filtered, dried and purified by soxhlet-extraction with methanol. 3.2 g. 2,6-Dimethyl-3-nitropyrazolo[1,5-a]pyrimidine (see Synthesis, communications page 673/1982) are dissolved in 320 ml. ethanol and mixed with 320 ml. 5% sodium bicarbonate solution in water. To this mixture are added portionwise, while stirring and cooling, 14.2 g. sodium dithionite until the thin layer chromatogram indicates the absence of starting material. The reaction mixture is concentrated somewhat and extracted three times with ethyl acetate. The organic phase is dried and evaporated. The residue is dissolved in a little ethanol and mixed with an equimolar amount of hydrogen chloride in diethyl ether. The precipitated crystals are filtered off with suction. There are obtained 2.9 g. (80% of theory) of the title compound (12.7.1); m.p. 224 C. (decomp.). TLC (silica gel, chloroform/methanol/methyl ethyl ketone/glacial acetic acid/water 75:35:25:5:8 v/v/v/v/v): Rf =0.73.

Reference： [1]Patent: US5334505,1994,A

14
[ 123-91-1 ]
[ 1225387-53-0 ]
[ 109-64-8 ]
[ 126352-69-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;	Preparation 13 5-Aminopyrazole (10 g) and 1,3-dibromopropane (13.4 ml) were added to 1,4-dioxane (20 ml) under stirring at ambient temperature. Triethylamine (40.1 ml) was added thereto. The mixture was refluxed under stirring for 4 hours. The reaction mixture was cooled to 0-5 C. in an ice-bath and stirred for 30 minutes. An insoluble material was filtered off, and the filtrate was evaporated under reduced pressure to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.1 g). IR (Nujol): 3220, 1570, 1460 cm-1.

Reference： [1]Patent: US5173485,1992,A

15
[ 65973-52-6 ]
[ 1225387-53-0 ]
[ 66492-33-9 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid;	EXAMPLE 1 6-Chloropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one 205 g. of 4,6-dichloropyridine-3-carboxylic acid, methyl ester and 166 g. of 5-aminopyrazole are refluxed together in 300 ml. of acetic acid for 10 hours with stirring. The crystalline 6-chloropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is filtered off, washed with water and recrystallized from dimethylformamide, yield: 185 g. (84percent); m.p. > 300°.

Reference： [1]Patent: US4075210,1978,A

16
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
13.8%; 2.1%	In ethanol; at 20℃;Heating / reflux;	A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1 %; LC-MS (MH+): 198/200) and 6-bromopyrazolo[1 ,5-a]pyrimidine x81 (yield: 13.8 %; LC-MS (MH+): 198/200).

Reference： [1]Patent: WO2006/128692,2006,A2 .Location in patent: Page/Page column 86

17
[ 1225387-53-0 ]
[ 109-94-4 ]
[ 29274-23-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: ethyl acetate; formic acid ethyl ester With sodium In toluene at 20 - 40℃; for 16h; Stage #2: 3⁽⁵⁾-aminopyrazole In ethanol; toluene for 4h; Heating / reflux; Stage #3: With hydrogenchloride In water	Sodium (30 wt. % dispersion in toluene, Acros 24326) (250 mL, 2.9 mol), toluene (1 L) and ethyl acetate (290 mL, 3 mol) were added to a 5 L three necked, round-bottomed flask. Ethyl formate (30 mL, 0.37 mmol) was added to the reaction mixture and the contents heated to 35-40 0C using a hot air gun. After initiation (2-16 h), ethyl formate (206 mL, 2.55 mol) was added dropwise to the suspension, taking care to ensure that the reaction temperature did not rise above 35 0C. After stirring for 16 h at room temperature, a solution of 3-aminopyrazole (122 g, 1.47 mol) in ethanol (1 L) was added to the brown mixture and was refluxed for 4 h. The viscous, yellow suspension was allowed to cool and was concentrated in vacuo, the residue was dissolved in hot water (500 mL) and the contents acidified by the addition of cone. HCI (140 mL). The precipitate was collected by filtration and dried to yield the desired product, 7-hydroxypyrazolo[1,5-a]pyrimidine, as a white solid (152 g, 77 %). 1H NMR (250 MHz, DMSO) δ 12.37 (brs, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1 H), 5.66 (d, J = 7.3 Hz, 1 H); 13C NMR (62.9 MHz, DMSO) δ 156.6, 142.6, 141.7, 139.4, 95.2, 88.9; MS (APCI) 136 [M+H]+.

Reference： [1]Current Patent Assignee: EIRX THERAPEUTICS PLC - WO2007/17678, 2007, A1 Location in patent: Page/Page column 43

18
[ 24424-99-5 ]
[ 1225387-53-0 ]
[ 952674-76-9 ]

Yield	Reaction Conditions	Operation in experiment
		Treatment of commercially available aminopyrazole 1 with di-tert-butyl-dicarbonate affords compound 2. Oxidation of 2 with dibenzoyl peroxide and KOH (U.S. Pat. No. 4,945,166) produces 1-hydroxypyrazole 3. Reaction of 3 with methyl iodide and N,N-diisopropylethylamine gives 1-methoxypyrazole 4 (J. Org. Chem. 1995, 60, 4995). Nitrosation of 4 with isoamyl nitrite produces the nitroso compound 5. Hydrogenation of 5 with Pd/C under hydrogen gives compound 6. Deprotection of 6 with 2N-HCl in 1,4-dioxane results in the formation of 2-Methoxy-2H-pyrazole-3,4-diamine 7.

Reference： [1]Patent: US2007/50922,2007,A1 .Location in patent: Page/Page column 7-8

19
[ 1225387-53-0 ]
[ 87-13-8 ]
[ 43024-61-9 ]

Yield	Reaction Conditions	Operation in experiment
		Stage 1.1: 7-Hydroxy-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl; Literature reference: Yasuo Makisumi; Chem.Pharm.Bull. 1962; Vol. 10; p. 620-626. 2H-Pyrazol-3-ylamine (5.10 g; 60.1 mMol) is dissolved in EtOH (120 ml) and treated with a solution of 2-Ethoxymethylene-malonic acid diethyl ester (13.4 g; 60 mMol) in EtOH (120 mL) at RT. The yellowish solution is stirred at reflux for 19 h followed by addition of acetic acid (60 mL). Stirring at reflux is continued for another 57 h. After cooling the white suspension to RT, the crystalline product is filtered off and dried at 60C to obtain the title compound 1.1 as white crystals (1.81 g); mp. 81-81C; MS(ESI+):m/z= 254.1 (M+H)+; HPLC: tRet = 4.71 minutes (System 1). Additional amounts of the title compound can be obtained by concentration of the mother liquor followed by refluxing in acetic acid (150 mL) for 4 h and isolation as described above.

Reference： [1]Patent: EP1918291,2008,A1 .Location in patent: Page/Page column 22

20
[ 898-22-6 ]
[ 1225387-53-0 ]
[ 916212-87-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	In N,N-dimethyl-formamide; at 100℃;	Step A. Under an argon atmosphere a solution of commercially available [l,3,5]triazine-2,4,6-tricarboxylic acid triethyl ester (818 mg) and 3-aminopyrazole (460 mg) in dry DMF (8 mL) was heated to 1000C overnight and then concentrated. The remaining residue was dissolved in CHCl3, washed with 10% aqueous citric acid and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2ZMeOH) to afford the title compound as a colorless solid (409 mg, 56%). [MH]+ = 265.

Reference： [1]Patent: WO2008/63671,2008,A2 .Location in patent: Page/Page column 149

21
[ 25007-54-9 ]
[ 1225387-53-0 ]
[ 1030018-65-5 ]

Yield	Reaction Conditions	Operation in experiment
32%	In methanol; for 16h;Heating / reflux;	Step A. <strong>[25007-54-9]Dimethyl 2-oxosuccinate</strong> (6.05 g, 37.8 mmol) and lH-pyrazol-3 -amine (3.14 g, 37.8 mmol) was heated to reflux in methanol (55 mL) for 16 h. After cooling down, the solid was collected by filtration and washed with methanol to afford methyl 7-hydroxypyrazolo[l,5-a]pyrimidine-5-carboxylate (2.32 g, 32%) as yellow solid. [MH]+ = 194.0.

Reference： [1]Patent: WO2008/63671,2008,A2 .Location in patent: Page/Page column 157

22
[ 1225387-53-0 ]
[ 20577-61-1 ]
[ 916211-75-1 ]
[ 916211-74-0 ]

Yield	Reaction Conditions	Operation in experiment
6%; 72%	In methanol; for 5h;Heating / reflux;	Preparative Example 13. To a solution of commercially available lH-pyrazol-5 -amine (86.4 g) in MeOH (1.80 L) was added commercially available methyl acetopyruvate (50.0 g). The mixture was heated to reflux for 5 h and then cooled to room temperature overnight. The precipitated yellow needles were collected by filtration and the supernatant was concentrated at 4O0C under reduced pressure to ~2/i volume until more precipitate began to form. The mixture was cooled to room temperature and the precipitate was collected by filtration. This concentration/ precipitation/filtration procedure was repeated to give 3 batches. This material was combined and recrystallized from MeOH to give the major isomer, methyl 7- methyl-pyrazolo[l,5-a]pyrimidine-5-carboxylate (81.7 g, 72%). [MH]+ = 192.The remaining supernatants were combined, concentrated and purified by chromatography (silica, cyclohexane/EtOAc) to afford the minor isomer, methyl 5-methyl-pyrazolo[l,5-a]pyrimidine-7-carboxylate (6.8 g, 6%). [MH]+ = 192.

Reference： [1]Patent: WO2008/63671,2008,A2 .Location in patent: Page/Page column 131

23
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 705263-10-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With hydrogenchloride; In ethanol; water; at 0 - 20℃; for 2.0h;	Will V be non-material (15 · lg, lOOmmol)And the formula II is not material (8.3g, lOOmmol)Placed in a 250 ml round bottom flask,Add 120 ml of ethanol,Cooled to 0 C, add 12ml concentrated hydrochloric acid, return to room temperature, stirring 2h,The reaction precipitated a pale yellow solid. After direct filtration, the cake was washed with saturated NaHC03 solution and then washed with water.After drying, 17 g of the intermediate represented by formula VI was obtained. The yield of the intermediate represented by formula VI was calculated to be 86%.
30%	In ethanol; for 2.0h;Reflux;	The 3-aminopyrazole (2.0g, 23.9 mmol) and 20 mL of ethanol were added 100 mL three-neck flask, and stirred to dissolve, then 2-bromo-malonaldehyde (2.4 g, 16.0 mmol) was added in the flask. The system presents a reddish brown after the mixture was heated under reflux for 2 h. The reaction was cooled to room temperature and the organic solvent is evaporated to dryness. The residue was purified by column chromatography: gel (eluent petroleum ether / ethyl acetate). Pale yellow crystalline solid, yield: 30%. 1H NMR (CDCl3, 400 MHz, delta ppm): 8.50 (d, J = 3.3 Hz, 1H), 7.99 (dd, J = 9.2, 1.5 Hz, 1H), 7.82 (s, 1H), 7.13 (dd, J = 9.2, 4.4 Hz, 1H). ESI-MS(m/z): 197.3 [M+H]+.

Reference： [1]Patent: CN105130991,2017,B .Location in patent: Paragraph 0037; 0041-0043
[2]Patent: WO2014/138088,2014,A1 .Location in patent: Page/Page column 60
[3]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4388 - 4392
[4]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5830 - 5835

24
[ 65192-28-1 ]
[ 1225387-53-0 ]
[ 1062368-61-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrogenchloride In ethanol; water at 0 - 20℃; for 2h;	2 The synthesis of the intermediates of formula III-1 is as follows Substituting substance of formula I (10 g, 56 mmol)And substance II of formula II (4.7 g, 56 mmol)Placed in a 250 ml round bottom flask,Add 80 ml of ethanol,Cooled to 0 ° C, 8 ml of concentrated hydrochloric acid was added,Back to room temperature, stirring 2h,The reaction precipitated a pale yellow solid. After direct filtration, the cake was washed with saturated NaHC03 solution and then washed with water. Dried to give a pale yellow solid product, 10.3 g. The pale yellow product was the intermediate of formula III-1 and it was calculated that the yield of the intermediate of formula III-1 was 82%.
	In ethanol; acetic acid at 80℃; for 7h;

Reference： [1]Current Patent Assignee: CHENGDU ZEPLETECH - CN105130991, 2017, B Location in patent: Paragraph 0049-0053
[2]Cuny, Gregory D.; Yu, Paul B.; Laha, Joydev K.; Xing, Xuechao; Liu, Ji-Feng; Lai, Carol S.; Deng, Donna Y.; Sachidanandan, Chetana; Bloch, Kenneth D.; Peterson, Randall T. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 15, p. 4388 - 4392]

25
[ 157327-41-8 ]
[ 1225387-53-0 ]
[ 1029721-17-2 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 120℃;	1. 7-[2-(4-CYCLOBUTYLPIPERAZIN- l-YL)-2-OXOETHYL]-5,6,7,8- TETRAHYDRO PYRAZOLO[1,5-A]PYRIDO[4,3-D]PYRIMIDINE (SCHEME 2); Compound 1; <n="54"/>Step 1. tert-Butyl 7,8-dihydropyrazolo[l,5-a]pyrido[3,4-d]pyrimidine-6(5H)- carboxylate; To a solution of 3-dimethylaminomethylene-4-oxo-piperidine-l-carboxylic acid tert-butyl ester (775 mg, 3.05 mmol) in anhydrous DMF (10 mL) is added 5- aminopyrazole (253 mg, 3.05 mmol). The mixture is heated at 120 0C overnight. The mixture is cooled to RT and partitioned between Et2O (100 mL) and H2O (100 mL), followed by extraction with Et2O (2 x 100 mL). The organic extracts are combined, washed with water (100 mL) and brine (100 mL), dried and evaporated to give the crude product. MS (+VE) m/z 275.21 (M+ +1 ).

Reference： [1]Patent: WO2009/3003,2008,A2 .Location in patent: Page/Page column 52-53

26
[ 2318-25-4 ]
[ 1225387-53-0 ]
5-Amino-pyrazolo<1,5-a>pyrimidin-7(4H)-on [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: ethyl 3-ethoxy-3-iminopropanoate hydrochloride With sodium hydrogencarbonate In ethyl acetate Cooling with ice; Stage #2: 3⁽⁵⁾-aminopyrazole In ethanol at 80 - 85℃; Inert atmosphere;	1.A Example 1: Preparation of Intermediates IE, 1J, IO and IS[0348] Step A: Commercially available HCI salt of ethyl 3-ethoxy-3-iminopropionate 1A (25 g, 1.0 equivalent) was neutralized by adding it portion wise to a mixture of ice, saturated NaHC03 and EtOAc with vigorous stirring for 5-10 minutes. The bi-layer was separated and the aqueous layer was extracted with EtOAc. Combined organic layers were washed with brine, dried over MgS04, filtered and dried in vacuo. The colorless oil was dissolved in EtOH (1.0 M) and the solution was added to an ethanolic solution (0.5 M) of lH-pyrazol-5-amine (IB) (1.0 equivalent) , 3-methyl-lH-pyrazol-5-amine (1G) (1.0 equivalent), 3-ethyl-lH-pyrazol-5-amine (1L) (1.0 equivalent) or 3 -cyclopropyl- lH-pyrazol-5 -amine (IP) (1.0 equivalent). The mixture was heated to 80-85 °C under nitrogen for 15-24 h. The mixture was then filtered warm on a fritted funnel under nitrogen. The collected precipitate was washed once with cold EtOH and then Et20 under nitrogen. The product 1C (87%), 1H (72%), 1M (74%) or 1Q (88%), respectively, was dried under vacuum and then used without further purification.[0349] 1C: 1H NMR (400 MHz, DMSO-d6) δ ppm 4.73 (s, 1 H) 5.91 (d, J=1.77 Hz, 1 H) 6.54 (s, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 11.42 (br. s., 1 H).[0350] 1H: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3 H) 4.70 (s, 1 H) 5.75 (s, 1 H) 6.54 (s, 2 H) 11.39 (br. s., 1 H); ESI-MS: m/z 164.9 (M+H)+.[0351] 1M: 1H NMR (400 MHz, DMSO- 6) δ: 5.66 (s, 1H), 2.57 (q, J= 7.6 Hz, 2H), 1.10 - 1.22 (m, 3H).[0352] 1Q: 1H NMR (400 MHz, DMSO-d6) δ: 11.29 (br. s., 1H), 6.44 (s, 2H), 5.63 (s, 1H), 4.67 (s, 1H), 1.82 - 1.94 (m, 1H), 0.85 - 0.95 (m, 2H), 0.65 - 0.75 (m, 2H).
87%	Stage #1: ethyl 3-ethoxy-3-iminopropanoate hydrochloride With sodium hydrogencarbonate In water; ethyl acetate Cooling with ice; Stage #2: 3⁽⁵⁾-aminopyrazole In ethanol at 80 - 85℃; Inert atmosphere;	1.A [0423] Step A: Commercially available HCl salt of ethyl 3-ethoxy-3-iminopropionate IA (25 g, 1.0 equivalent) was neutralized by adding it portion wise to a mixture of ice, saturated NaHCO3 and EtOAc with vigorous stirring for 5-10 minutes. The bi-layer was separated and the aqueous layer was extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and dried in vacuo. The colorless oil was dissolved in EtOH (1.0 M) and the solution was added to an ethanolic solution (0.5 M) of lH-pyrazol-5-amine (IB) (1.0 equivalent) , 3-methyl-lH-pyrazol-5-amine (IG) (1.0 equivalent), 3-ethyl-lH-pyrazol-5-amine (IL) (1.0 equivalent) or 3 -cyclopropyl- lH-pyrazol-5 -amine (IP) (1.0 equivalent). The mixture was heated to 80-85 0C under nitrogen for 15-24 h. The mixture was then filtered warm on a fritted funnel under nitrogen. The collected precipitate was washed once with cold EtOH and then Et2O under nitrogen. The product 1C (87%), IH (72%), IM (74%) or IQ (88%), respectively, was dried under vacuum and then used without further purification. [0424] 1C: 1H NMR (400 MHz, DMSO-J6) δ ppm 4.73 (s, 1 H) 5.91 (d, J=I.77 Hz, 1 H) 6.54 (s, 2 H) 7.62 (d, J=I.77 Hz, 1 H) 11.42 (br. s., 1 H). PATENT ASKl -5001 -WO[0425] IH: 1H NMR (400 MHz, DMSO-J6) δ ppm 2.20 (s, 3 H) 4.70 (s, 1 H) 5.75 (s, 1 H)6.54 (s, 2 H) 11.39 (br. s., 1 H); ESI-MS: m/z 164.9 (M+H)+.[0426] IM: IH NMR (400 MHz, DMSO-J6) δ: 5.66 (s, IH), 2.57 (q, J= 7.6 Hz, 2H), 1.10 -1.22 (m, 3H).[0427] IQ: 1H NMR (400 MHz, DMSO-J6) δ: 11.29 (br. s., IH), 6.44 (s, 2H), 5.63 (s, IH),4.67 (s, IH), 1.82 - 1.94 (m, IH), 0.85 - 0.95 (m, 2H), 0.65 - 0.75 (m, 2H).
74%	With triethylamine In isopropyl alcohol at 0℃; for 0.5h; Reflux;	1.A Step A: 5-Aminopyrazolo[1,5-a]pyrimidin-7(4H)-one To a suspension of 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (6.15 g, 0.031 mol) in isopropanol (100 mL) was added triethylamine (4.38 mL) at 0 ° C.And 3-aminopyrazole (2.87 g, 0.035 mol).After stirring for 30 minutes, the reaction was heated to reflux overnight.cool down,Collecting solids by filtration to obtain a product(3.50 g, 74%).

52%	Stage #1: ethyl 3-ethoxy-3-iminopropanoate hydrochloride With triethylamine In ethanol at 0 - 20℃; for 0.5h; Stage #2: 3⁽⁵⁾-aminopyrazole In ethanol at 80℃; for 16h;	457.A; 463.A Part A: 5-aminopyrazolo[1, 5-a]pyrimidin-7(4H)-one A solution of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (5 g, 25.6mmol) in ethanol (50 mL) cooled at 0 °C was added TEA (3.56 mL, 25.6 mmol)dropwise and the reaction mixture was stirred at room temperature for 30 mm. 1H- pyrazol-5-amine (2.336 g, 28.1 mmol) in ethanol (10 mL) was added dropwise to the reaction mixture and the mixture was heated 80°C for 16 h. The reaction mixture was cooled to room temperature and the white colored precipitate that formed wascollected by vacuum filtration, washed with an excess of cold ethanol (10 mL), and dried to give 5-ammnopyrazolo[1,5-ajpyrimidin-7(4B)-one (2 g, 13.32 mmol, 52% yield) as an off-white solid which was carried forward without further purification. LCMS (ESI) m/e 149.0 [(M-H)-, calcd for C6H5N40 149.11; LC/MS retention time (Method Al): tR = 0.21 mm.
	Stage #1: ethyl 3-ethoxy-3-iminopropanoate hydrochloride With sodium hydrogencarbonate In water; ethyl acetate Cooling with ice; Stage #2: 3⁽⁵⁾-aminopyrazole In ethanol Inert atmosphere; Reflux;	Method Z Sodium bicarbonate (3.9 g, 46.2 mmol) is added in small portions to a mixture of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (Z-l) (8.6 g, 44.0 mmol) in crushed ice (100 g) and ethyl acetate (50 mL) until the pH value reaches 8-9. The organic layer is separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers are dried over anhydrous MgSC>4 and filtered. The filtrate is concentrated in vacuo to afford a colourless oil which is added to a solution of lH-pyrazol-5-amine (3.65 g, 44.0 mmol) in ethanol (100 mL). The resulting mixture is then degassed and backfilled with argon (three cycles) and stirred at reflux overnight. The mixture is then filtered while it was still warm. The solid is rinsed with cold ethanol (25 mL) and ether (2 x 25 mL), and then dried in vacuo to afford 5-aminopyrazolo[l,5-a]pyrimidin-7(4H)-one (Z-2).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2011/41293, 2011, A1 Location in patent: Page/Page column 83-84
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2009/123986, 2009, A1 Location in patent: Page/Page column 148-149
[3]Current Patent Assignee: Zhang Li - CN108498515, 2018, A Location in patent: Paragraph 0018; 0020; 0021; 0022; 0023
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO; BIOCON LIMITED - WO2017/59080, 2017, A1 Location in patent: Page/Page column 226; 227; 237
[5]Current Patent Assignee: INFINITY PHARMACEUTICALS INC - WO2013/12915, 2013, A1 Location in patent: Paragraph 00665

27
[ 2065-75-0 ]
[ 1225387-53-0 ]
[ 875781-17-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	In acetic acid; for 6h;Heating; Reflux; Inert atmosphere of N2;	lH-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde(9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated <n="82"/>to reflux under N2 for 6 hours. The reaction mixture was cooled to room temperature and concentrated to give a solid. The crude solids were suspended in MeOH (200 mL) and absorbed onto silica gel (200 g). The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 5-bromo-lH- pyrazolo[3,4-b]pyridine as a solid (3.1 g, 25%).

Reference： [1]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 79-80

28
[ 1225387-53-0 ]
[ 115955-48-1 ]
[ 832740-68-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2735 - 2738

29
[ 922-67-8 ]
[ 1225387-53-0 ]
[ 29274-22-4 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; for 24h;Reflux;	4H-Pyrazolo[1 ,5-a]pyrimidin-5-one (17a); [00140] In anhydrous dioxane compound (16a) and methyl ester of acetylene carboxylic acid (1 equivalent) are dissolved. The mixture is refluxed for 24 h (TLC control). After cooling the formed precipitate is filtered off and recrystallized from ethyl acetate to give the title compound in moderate yield. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography to give additional product.1H NMR (DMSO-de, 400 MHz) delta (ppm) 5.78 (d, 1 H), 5.91 (d, 1 H), 7.71 (d, 1 H), 8.41 (m,1 H), 11.95 (s, 1 H). m/z (APCI+) 136 (M+H+)

Reference： [1]Patent: WO2010/63487,2010,A1 .Location in patent: Page/Page column 68

30
[ 1225387-53-0 ]
[ 105-53-3 ]
[ 57489-70-0 ]

Yield	Reaction Conditions	Operation in experiment
63.5%	With sodium; In ethanol; for 20.0h;Inert atmosphere; Reflux;	Under the protection of nitrogen, the sodium metal particles (7.62 g, 331.0 mmol) were slowly added to 150 mL of cold ethanol.When the sodium is completely dissolved, add 3-aminopyrazole (11.00g, 132.38mmol) and diethylmalonate (21.20g, 132.38mmol),The mixture was heated at reflux for 20 hours.After the reaction was completed, the reaction solution was cooled to room temperature, a large amount of solid was precipitated, filtered, and the filter cake was washed with a small amount of cold ethanol and dried.The obtained solid was re-dissolved in 400 mL of water, the insoluble matter was filtered off, and the solution was adjusted to pH 2 with concentrated hydrochloric acid.A large amount of solid precipitated, filtered with suction, washed with water to neutrality, and dried to obtain a pale yellow solid 5,7-dihydroxypyrazolo [1,5-a] pyrimidine (a) 12.70 g,The yield was 63.5%.
	With sodium ethanolate; In ethanol; at 80℃;	Dissolve 50 mmol of sodium ethoxide in 100 mL of EtOH and stirAnd then add 20mmolMalonateDiesterAnd 20 mmol of 3-aminopyrazole.Mix the mixture at 80 CThe mixture was heated under reflux for 18-20 hours to form a precipitate. After cooling to room temperature,The precipitate was collected by filtration and washed with EtOH.Dry under vacuum.After drying, the product is dissolved in 100 mL of water.The resulting solution was adjusted to pH = 2 with 12 mol/L HCl. Collecting solids by filtration,Wash with water,Pyrazolo[1,5-a]pyrimidine-5,7-diol is obtained.

Reference： [1]Patent: CN110483526,2019,A .Location in patent: Paragraph 0053; 0055-0056
[2]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 204 - 208
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 10312 - 10313
[4]Patent: CN110016036,2019,A .Location in patent: Paragraph 0022; 0023; 0024; 0025-0027; 0033-0037

31
[ 1225387-53-0 ]
[ 16182-04-0 ]
[ 34683-00-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	In ethyl acetate at 75℃; for 1h; Inert atmosphere;	ethyl [(1 H-pyrazol-5-yl)carbamothioyl]carbamate 1H-pyrazol-5-amine (58.7 g, 706 mmol; CAS 1820-80-0) was dissolved in ethyl acetate (420 ml_), under nitrogen, and stirred at 75°C. Ethyl carbonisothiocyanatidate (88 ml_, 750 mmol; CAS 16182-04-0) was added dropwise at 75°C and the mixture was stirred for 1h at 75°C. The mixture was cooled to 0°C, filtered, washed with ethyl acetate and the solid was dried under reduced pressure at 50°C to give 124 g (77 % yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.232 (7.32), 1.250 (16.00), 1.267 (7.44), 2.518 (0.40), 4.184 (2.18), 4.201 (6.76), 4.219 (6.67), 4.237 (2.07), 5.889 (0.89), 5.893 (0.82), 6.998 (1.81), 7.003 (2.83), 7.008 (1.72), 7.697 (2.70), 7.867 (0.72), 7.872 (0.75), 11.317 (2.61), 12.036 (2.75), 12.709 (1.55).
77%	In ethyl acetate at 75℃; for 1h; Inert atmosphere;	1.1 Step 1 : 1H-pyrazol-5-amine (58.7 g, 706 mmol; CAS 1820-80-0) was dissolved in ethyl acetate (420 ml_), under nitrogen, and stirred at 75°C. Ethyl carbonisothiocyanatidate (88 ml_, 750 mmol; CAS 16182-04-0) was added dropwise at 75°C and the mixture was stirred for 1h at 75°C. The mixture was cooled to 0°C, filtered, washed with ethyl acetate and the solid was dried under reduced pressure at 50°C to give 124 g (77 % yield) of ethyl [(1H-pyrazol-5-yl)carbamothioyl]carbamate.
77%	In ethyl acetate at 75℃; for 1h; Inert atmosphere;	1.1 Step 1 : 1H-pyrazol-5-amine (58.7 g, 706 mmol; CAS 1820-80-0) was dissolved in ethyl acetate (420 ml_), under nitrogen, and stirred at 75°C. Ethyl carbonisothiocyanatidate (88 ml_, 750 mmol; CAS 16182-04-0) was added dropwise at 75°C and the mixture was stirred for 1h at 75°C. The mixture was cooled to 0°C, filtered, washed with ethyl acetate and the solid was dried under reduced pressure at 50°C to give 124 g (77 % yield) of ethyl [(1 H-pyrazol-5-yl)carbamothioyl]carbamate.

56%	In ethyl acetate; benzene at 5 - 20℃; Inert atmosphere;	5.1.51. Mathyl 2H-pyrazol-3-ylaminocarbothioylcarbamate (46) To a stirred suspension of 34 (5.0 g, 60 mmol) in EtOAc (36 mL) and benzene (180 mL) was added dropwise a solution of ethoxycarbonyl isothiocyanate (7.9 g, 60 mmol) in benzene (60 mL) at 5 °C under argon atmosphere. After being stirred for 21 h at ambient temperature, the resulting precipitates were collected by filtration, and purified by recrystallization from EtOAc/hexane to give 46 (7.20 g, 56% yield) as an ivory powder. TLC Rf = 0.34 (MeOH/CH2Cl2, 1/9); 1H NMR (300 MHz, CDCl3) δ 11.92 (br s, 1H), 10.57 (br, 1H), 8.41 (br s, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.05 (br s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.34 (t, J =7.1 Hz, 3H).
	In ethyl acetate at 80℃; for 1h; Inert atmosphere;	lH-Pyrazol-5-amine (5 g, 0.06 mol) was dissolved in anhydrous EtOAc (35 mL) and the mixture was warmed to 80°C. Ethoxycarbonyl isothiocyanate (7.5 mL, 0.064 mol) was added dropwise and the mixture was stirred at 80°C under nitrogen for 1 h. The mixture was cooled in an ice-water bath and the precipitate was filtered off. The solids were washed with further EtOAc. The resulting pale yellow solid was dissolved in 2M aqueous sodium hydroxide solution (60 mL) and the mixture was stirred at r.t. for 3 h. The mixture was cooled to 0°C in an ice bath and 2N sulphuric acid (135 mL) was added. The resultant precipitate was filtered, washed with water (30 mL) and diethyl ether (20 mL), then dried in a vacuum oven, to afford the title compound (7.99 g, 79%)
	In dichloromethane at 0 - 25℃; for 12h; Inert atmosphere;	111.1 Step 1 : Ethyl N-(1 -pyrazol-5-ylcarbamothioyl)carbamate To a suspension of 3H-pyrazol-3 -amine (15.84 g, 190.62 mmol, 1 eq) in DCM (160 mL) was added ethoxycarbonyl isothiocyanate (25 g, 190.62 mmol, 22.52 mL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h under N2 atmosphere. The mixture was filtered. The filter cake was washed with DCM (20 mL x 2), dried to yield ethyl N-(lH-pyrazol-5-ylcarbamothioyl)carbamate (26 g, 109.22 mmol, 57.3% yield, 90% purity) as a white solid. NMR (400 MHz, CD3OD) δ ppm 7.59 (d, J= 2.2 Hz, 1H), 7.12 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.1Hz, 3H); ES- LCMS ffl/z 215.1 [M+H]+.
	In dichloromethane for 2h; Cooling with ice;	Under ice bath conditions,781mg (9.4mmol) 2H-3-aminopyrazole,Add 8.0mL of methylene chloride to the round bottom flask, slowly add 6.0mL containing 1232mg (9.4mmol) Ethyl isothiocyanatoformate in dichloromethane,Add 15.0mL of methylene chloride to dilute,Stir for 2h,The solvent was distilled off under reduced pressure to obtain a pale yellow solid.The obtained light yellow solid was dissolved with 19.3 mL of 2 mol / L NaOH aqueous solution,After stirring for 2h, 27.6mL 2mol / L H2SO4 aqueous solution was added,A white precipitate is produced immediately,After stirring well, filter,The filter cake was dried to obtain a white solid product,The yield is 90%
	In ethyl acetate for 2h; Cooling with ice;	Preparation of compound INT-3 Under ice bath conditions, ethoxycarbonyl isothiocyanate (9.47g, 72.2mmol) was added to the ethyl acetate solution (180mL) of 5-aminopyrazole INT-3a (6.00g, 72.2mmol),The resulting reaction liquid was stirred for 2 hours under ice bath conditions.The reaction solution was concentrated under reduced pressure to obtain orange-yellow solid compound INT-3b (15.5g, yield>99%), and the obtained crude product was directly used in the next reaction without purification.
	Stage #1: 3⁽⁵⁾-aminopyrazole; Ethoxycarbonyl isothiocyanate In tetrahydrofuran at 0 - 20℃; for 0.0333333h; Stage #2: In tetrahydrofuran at 100℃; for 0.0833333h; Microwave irradiation; Sealed tube;	3.2.1. Synthesis of 2-Thioxo-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one (3a) In a microwave vial, ethoxycarbonyl isothiocyanate (1.0 equiv.) was added dropwiseto a solution of 5-aminopyrazole 1a-n (1.0 equiv.) in dry THF (3 mL) at 0 °C. Aftercomplete addition, the mixture was stirred 2 min at room temperature and the vial wassealed, deposited in a microwave reactor and heated at 100 °C for 5 min. After cooling,NaOH 2N (2.0 equiv.) was added and the vessel was sealed again and irradiated at 80 °Cfor 3 min. After cooling, the resulting aqueous solution was acidified (pH < 5) with HCl2N then the precipitate was filtered off, washed with water up to neutral pH, trituratedwith Et2O then DCM and dried under vacuum to give 3a (4.601 g, 94%) as a white solid(4.601 g, 94%) from 1a (2.5 g, 29.20
	In dichloromethane for 2h; Cooling with ice;	Under the ice bath conditions, 5.9g (0.07mol) 2H-3-aminopyrazole, 50mL dichloromethane was added to the round-bottom flask, and 30mL of dichloromethane solution containing 9.3g (0.07mol) of ethyl isothiocyanatoformate was slowly added, and then 80mL of dichloromethane was added to dilute, stirred for 2h, and the solvent was evaporated under reduced pressure to obtain a yellowish solid. The resulting pale yellow solid was dissolved with 147mL 2mol/L of NaOH aqueous solution, stirred for 2h and then added 211mL 2mol/L of H2SO4aqueous solution, immediately produced a white precipitate, stirred thoroughly after filtration, dried filter cake to obtain a white solid product 1H-3H-pyrazolo [1,5-a] [1,3,5][1,3,5] triazine-4-one 10.6g, yield 90.6%,

Reference： [1]Current Patent Assignee: Helmholtz Association; BAYER AG - WO2021/116178, 2021, A1 Location in patent: Paragraph 249; 370
[2]Current Patent Assignee: BAYER AG; Helmholtz Association - WO2021/176045, 2021, A1 Location in patent: Page/Page column 212
[3]Current Patent Assignee: BAYER AG; Helmholtz Association - WO2021/176049, 2021, A1 Location in patent: Page/Page column 301
[4]Location in patent: experimental part Saito, Tetsuji; Obitsu, Tetsuo; Minamoto, Chiaki; Sugiura, Tsuneyuki; Matsumura, Naoya; Ueno, Sonoko; Kishi, Akihiro; Katsumata, Seishi; Nakai, Hisao; Toda, Masaaki [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 20, p. 5955 - 5966]
[5]Current Patent Assignee: UCB - WO2015/193169, 2015, A1 Location in patent: Page/Page column 47
[6]Current Patent Assignee: IKENA ONCOLOGY INC - WO2018/195397, 2018, A2 Location in patent: Paragraph 00733-00734
[7]Current Patent Assignee: SHAANXI NORMAL UNIVERSITY - CN110950871, 2020, A Location in patent: Paragraph 0071; 0072
[8]Current Patent Assignee: XIAMEN BIOTIME BIOTECHNOLOGY; ADLAI NORTYE BIOPHARMA; HANGZHOU ADLAI NORTYE BIOMEDICAL TECH - CN112028891, 2020, A Location in patent: Paragraph 0125-0127
[9]Besson, Thierry; Elie, Jonathan; Fruit, Corinne [Molecules, 2021, vol. 26, # 12]
[10]Current Patent Assignee: UNIV SHAANXI NORMAL - CN114181217, 2022, A Location in patent: Paragraph 0038-0039

32
[ 1225387-53-0 ]
[ 105-53-3 ]
pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.2%	With sodium In ethanol at 80℃; for 5h;	4.2 General synthetic procedure for compounds 5-chloro-7-subtitutedphenoxypyrazolo[1,5-a]pyrimidines (4-9) 3-Aminopyrazole (1) (20mmol, 1equiv) and diethyl malonate (22mmol, 1.1equiv) were added to a freshly made solution of sodium metal (40mmol, 2equiv) in ethanol (60mL). The mixture was heated to 80°C and stirred for 5h. After the reaction, the solution was cooled to room temperature and filtered. The obtained solid was washed with ethanol and dissolved in water (30mL). Then the solution was acidified to pH 1∼2 using concentrated HCl in an ice-bath. The precipitate was filtered, washed with water and dried to give light yellow powder ( 2, yield 73.2%, EI-MS: 152.2 [M+H], 174.3 [M+Na]) that was directly used in next step.
	Stage #1: 3⁽⁵⁾-aminopyrazole; diethyl malonate With sodium ethanolate In ethanol for 24h; Reflux; Stage #2: With hydrogenchloride In water	5.1.2. 5,7-Dichloropyrazolo[1,5-a]pyrimidine (38a) To a stirred solution of sodium ethoxide in EtOH, which was prepared from sodium (2.77 g, 120 mmol) and EtOH (90 mL) by the conventional method, were added diethyl malonate (9.64 g, 60 mmol) at ambient temperature and then 3-aminopyrazole (5.0 g, 60 mmol). The reaction mixture was refluxed for 24 h. After cooling to room temperature, the precipitates were collected by filtration and dissolved in water. The aqueous solution was acidified with 2 N HCl (pH ∼2). The resulting precipitates were collected by filtration and dried under reduced pressure to afford 4H-pyrazolo[1,5-a]pyrimidine-5,7-dione (6.56 g) as a white powder, which was used for the next reaction without further purification. MS (FAB, Pos) m/z 152 (M+H)+CommentA stirred suspension of 4H-pyrazolo[1,5-a]pyrimidine-5,7-dione (6.56 g) and N,N-diethylaniline (8.3 mL, 52 mmol) in phosphorus oxychloride (30 mL) was refluxed for 4 h. After cooling, the reaction mixture was poured into ice-water, stirred for 30 min, neturalized with saturated aqueous sodium carbonate and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/hexane (1/10) to give 38a (6.60 g, 81% yield in 2steps) as a yellow solid.

Reference： [1]Tian, Ye; Du, Deping; Rai, Diwakar; Wang, Liu; Liu, Huiqing; Zhan, Peng; De Clercq, Erik; Pannecouque, Christophe; Liu, Xinyong [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 7, p. 2052 - 2059]
[2]Location in patent: experimental part Saito, Tetsuji; Obitsu, Tetsuo; Minamoto, Chiaki; Sugiura, Tsuneyuki; Matsumura, Naoya; Ueno, Sonoko; Kishi, Akihiro; Katsumata, Seishi; Nakai, Hisao; Toda, Masaaki [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 20, p. 5955 - 5966]

33
[ 6279-86-3 ]
[ 1225387-53-0 ]
[ 56-40-6 ]
[ 1134906-94-7 ]

Yield	Reaction Conditions	Operation in experiment
11%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In ethanol; at 180℃; for 0.333333h;Microwave irradiation;	Example 2N-r(7-hvdroxy-5-oxo-4,5-dihvdropyrazolori,5-alpyrimidin-6-yl)carbonyllglvcine A mixture of lH-pyrazol-5-amine (0.20 g, 2.40 mmol), triethyl methanetricarboxylate (0.51 mL, 2.40 mmol), glycine (0.27 g, 3.60 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.68 mL, 4.80 mmol) in ethanol (5.0 mL) was heated to 180 0C for 20 minutes in a Biotage Initiator microwave synthesizer. The mixture was purified via preparative HPLC (YMC 75 X 30 mm column, 0.1% TFA in water and 0.1% TFA in acetonitrile) to afford the title compound as a yellow solid (0.065 g, 11%). 1H NMR (400 MHz, OMSO-d6) delta ppm 13.0 (s, 2 H) 9.87 (t, J=5.6 Hz, 1 H) 7.85 (d, J=2.0 Hz, 1 H) 6.01 (d, J=LO Hz, 1 H) 4.16 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 253 [M+H]+.

Reference： [1]Patent: WO2009/39323,2009,A1 .Location in patent: Page/Page column 14

34
[ 1225387-53-0 ]
[ 40876-98-0 ]
6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With hydrogenchloride; acetic acid; In water; at 80℃; for 14h;	5-Aminopyrazole (25 g) and diethyl oxalacetate sodium salt (74.4 g) were dissolved under cooling in 1 N hydrochloric acid. 68.75 ml_ of glacial acetic acid were added and the mixture was stirred at 80C for 14 h. The mixture was cooled to room temperature and the formed precipite was filtered off and titurated in ethyl acetate to give 16.06 g (26%) of the desired product.LC/MS (Method LC1 ): Rt = 0.86 min; m/z = 208.07 [M+H]+.
26%	With hydrogenchloride; acetic acid; In water; at 80℃; for 14h;	(a) 6-Hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester 5-Aminopyrazole (25 g) and diethyl oxalacetate sodium salt (74.4 g) were dissolved under cooling in 1N hydrochloric acid. 68.75 mL of glacial acetic acid were added and the mixture was stirred at 80 C. for 14 h. The mixture was cooled to room temperature and the formed precipite was filtered off and titurated in ethyl acetate to give 16.06 g (26%) of the desired product. LC/MS (Method LC1): Rt=0.86 min: m/z=208.07 [M+H]+.

Reference： [1]Patent: WO2013/60636,2013,A1 .Location in patent: Page/Page column 181
[2]Patent: US2013/150340,2013,A1 .Location in patent: Paragraph 0866; 0867; 0868

35
[ 80410-57-7 ]
[ 127-17-3 ]
[ 1225387-53-0 ]
[ 1443283-11-1 ]

Yield	Reaction Conditions	Operation in experiment
23.7 mg		To 2 g (1 1 mmol) of <strong>[80410-57-7]3-methoxy-4-nitrobenzaldehyde</strong> in 150 ml of anhydrous ethanol in a sealed tube are added 1 .17 g (13.3 mmol) of pyruvic acid and 1 .1 g (15.5 mmol) of 1 H-pyrazol-5-amine. The reaction medium is heated at 80C for 18 hours and then concentrated under reduced pressure. The residue is dissolved in 160 ml of a 3/1 DMSO/methanol mixture, to which are added 80 g of Dowex 1 x8-400 resin. The reaction medium is stirred at room temperature for 1 hour and then filtered. The resin is rinsed several times with DMSO and then with methanol, and finally treated for 30 minutes in a 10% solution of TFA in methanol. After filtration, the organic phase is concentrated under reduced pressure. The residue obtained is taken up in 100 ml of ethanol and 40 ml of acetic acid. 300 mg of zinc powder are added. The reaction medium is stirred at room temperature. 1 g of zinc powder are added after 15 minutes. The reaction medium is filtered and then concentrated under reduced pressure. After purification by column chromatography on C-18 reverse-phase silica gel, eluting with an acetonitrile/H2O/0.1 % TFA mixture, 23.7 mg of a lyophilizate are obtained. MH+: 285 1H NMR (600 MHz, DMSO-d6): delta 8.28 (s, 1 H), 8.08 (s, 1 H), 7.67 (d, J = 2.1 Hz, 1 H), 7.59 (dd, JA = 8.4 Hz, JB = 1 .9 Hz, 1 H), 6.77 (d, J = 8.2 Hz, 1 H), 3.91 (s, 3 H)

Reference： [1]Patent: WO2013/87744,2013,A1 .Location in patent: Page/Page column 23

36
[ 1225387-53-0 ]
[ 6630-33-7 ]
[ 235-30-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With copper(l) iodide; potassium carbonate; ethylenediamine In N,N-dimethyl-formamide at 110℃; for 3h;	To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.

Reference： [1]Gao, Lin; Song, Yunping; Zhang, Xinying; Guo, Shenghai; Fan, Xuesen [Tetrahedron Letters, 2014, vol. 55, # 36, p. 4997 - 5002]

37
[ 59142-68-6 ]
[ 1225387-53-0 ]
C₁₀H₆FN₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With copper(l) iodide; potassium carbonate; ethylenediamine In N,N-dimethyl-formamide at 110℃; for 3h;	General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.

Reference： [1]Gao, Lin; Song, Yunping; Zhang, Xinying; Guo, Shenghai; Fan, Xuesen [Tetrahedron Letters, 2014, vol. 55, # 36, p. 4997 - 5002]

38
[ 824-54-4 ]
[ 1225387-53-0 ]
[ 1621628-69-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With copper(l) iodide; potassium carbonate; ethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 3h;	General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b?3ll were obtained in a similar manner.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 4997 - 5002

39
[ 94569-84-3 ]
[ 1225387-53-0 ]
[ 1621628-72-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With copper(l) iodide; potassium carbonate; ethylenediamine In N,N-dimethyl-formamide at 110℃; for 3h;	General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.

Reference： [1]Gao, Lin; Song, Yunping; Zhang, Xinying; Guo, Shenghai; Fan, Xuesen [Tetrahedron Letters, 2014, vol. 55, # 36, p. 4997 - 5002]

40
[ 1225387-53-0 ]
[ 102684-91-3 ]
C₁₁H₆F₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With copper(l) iodide; potassium carbonate; ethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 3h;	General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 4997 - 5002

41
[ 15930-53-7 ]
[ 1225387-53-0 ]
C₁₁H₇N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper(l) iodide; potassium carbonate; ethylenediamine In N,N-dimethyl-formamide at 110℃; for 3h;	General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.

Reference： [1]Gao, Lin; Song, Yunping; Zhang, Xinying; Guo, Shenghai; Fan, Xuesen [Tetrahedron Letters, 2014, vol. 55, # 36, p. 4997 - 5002]

42
[ 128071-75-0 ]
[ 1225387-53-0 ]
pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With copper(l) iodide; potassium carbonate; ethylenediamine In N,N-dimethyl-formamide at 110℃; for 3h;	General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 °C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.

Reference： [1]Gao, Lin; Song, Yunping; Zhang, Xinying; Guo, Shenghai; Fan, Xuesen [Tetrahedron Letters, 2014, vol. 55, # 36, p. 4997 - 5002]

43
[ 1006-39-9 ]
[ 1225387-53-0 ]
C₁₁H₈FN₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With copper(l) iodide; potassium carbonate; ethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 5h;	General procedure: To a solution of 2-bromobenzaldehyde (1a, 1 mmol) and 1H-pyrazol-5-amine (2a, 1.2 mmol) in DMF (5 mL) were added K2CO3 (2 mmol), CuI (0.2 mmol) and ethylenediamine(0.2 mmol). The mixture was stirred at 110 C until a complete conversion as indicated by TLC. It was cooled to room temperature and added with saturated brine, then extracted with ethyl acetate. The combined organic phase was concentrated under vacuum. The crude product was purified by columnchromatography eluting with petroleum ether/ethyl acetate (10:1) to give the desired product 3a. Products 3b-3ll were obtained in a similar manner.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 4997 - 5002

44
[ 27007-53-0 ]
[ 1225387-53-0 ]
7-chloropyrazolo[1,5-a]quinazolin-5(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With copper(l) iodide; caesium carbonate; In water; at 100℃; for 6h;Inert atmosphere;	General procedure: To a solution of Cs2CO3 (2 mmol) in H2O (5 mL) were added methyl 2-bromobenzoate (1a, 1 mmol), 1H-pyrazol-5-amine (2a, 1.2 mmol), and CuI (0.2 mmol). The mixture was stirred at 100 C under nitrogen atomasphere until a complete conversion as indicated by TLC. It was cooled to room temperature and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 3a. Products 3b-3t and 6 were obtained in a similar manner.

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2426 - 2435

45
[ 35450-36-3 ]
[ 1225387-53-0 ]
7-methoxypyrazolo[1,5-a]quinazolin-5(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With copper(l) iodide; caesium carbonate; In water; at 100℃; for 6h;Inert atmosphere;	General procedure: To a solution of Cs2CO3 (2 mmol) in H2O (5 mL) were added methyl 2-bromobenzoate (1a, 1 mmol), 1H-pyrazol-5-amine (2a, 1.2 mmol), and CuI (0.2 mmol). The mixture was stirred at 100 C under nitrogen atomasphere until a complete conversion as indicated by TLC. It was cooled to room temperature and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 3a. Products 3b-3t and 6 were obtained in a similar manner.

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2426 - 2435

46
[ 6942-36-5 ]
[ 1225387-53-0 ]
7-nitropyrazolo[1,5-a]quinazolin-5(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With copper(l) iodide; caesium carbonate; In water; at 100℃; for 6h;Inert atmosphere;	General procedure: To a solution of Cs2CO3 (2 mmol) in H2O (5 mL) were added methyl 2-bromobenzoate (1a, 1 mmol), 1H-pyrazol-5-amine (2a, 1.2 mmol), and CuI (0.2 mmol). The mixture was stirred at 100 C under nitrogen atomasphere until a complete conversion as indicated by TLC. It was cooled to room temperature and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 3a. Products 3b-3t and 6 were obtained in a similar manner.

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2426 - 2435

47
[ 100959-22-6 ]
[ 1225387-53-0 ]
8-nitropyrazolo[1,5-a]quinazolin-5(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With copper(l) iodide; caesium carbonate; In water; at 100℃; for 6h;Inert atmosphere;	General procedure: To a solution of Cs2CO3 (2 mmol) in H2O (5 mL) were added methyl 2-bromobenzoate (1a, 1 mmol), 1H-pyrazol-5-amine (2a, 1.2 mmol), and CuI (0.2 mmol). The mixture was stirred at 100 C under nitrogen atomasphere until a complete conversion as indicated by TLC. It was cooled to room temperature and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 3a. Products 3b-3t and 6 were obtained in a similar manner.

Reference： [1]Synthetic Communications,2015,vol. 45,p. 2426 - 2435

48
[ 1225387-53-0 ]
[ 934758-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; copper(l) chloride; isopentyl nitrite; In water; acetonitrile; at 0 - 20℃; for 180h;Inert atmosphere;	To a souUon of 1H-pyrazo-5-amne (23.6 g, 284 mmo) n CH3CN (1 L) under a nitrogen atmosphere were added HC (140 m, 1420 mmo, 32%) and copper chorde (56.3 g, 568 mmo) at 0C, sopenty ntrte (80 mL 568 mmo) was added at 0C and the mixture was stirred at 0C for 2 days. sopenty nitrite (20 m, 0.5 eq) was added and the mixture was stirred at RT for another 5.5 days. The reaction mixture was sowy poured into ammonium hydroxide (1 L, 25%) and extracted with AcOEt. The organic phase was separated and the aqueous phase was extracted with AcOEt. The combined organic ayers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by sWca ge co?umn chromatography (hexane / TBME from 1:0 to 4:6) to afford 5-choro-1H-pyrazoe. Mz = 103/105 [M+H]+, Rt = 0.48 mm (UPLC Method B2), 1H NMR (600 MHz, DMSO-d6) : 6 ppm: 1300 (bs, IH), 7.79 (t, IH), 6.29 (t, IH), isoarny acoho :4.28 (t, IH), 3.41 (q, 2H), 1.30 (q, 2H), 0.85 (d, 6H).

Reference： [1]Patent: WO2015/181747,2015,A1 .Location in patent: Page/Page column 38; 39

49
[ 6141-13-5 ]
[ 1225387-53-0 ]
C₁₁H₉N₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 1035 - 1039

50
[ 4640-67-9 ]
[ 1225387-53-0 ]
[ 16182-04-0 ]
[ 1448466-58-7 ]

Yield	Reaction Conditions	Operation in experiment
57%		To a solution of <strong>[4640-67-9]3-(4-fluorophenyl)-3-oxopropanenitrile</strong> (1 g, 6.13 mmol) in ethanol (11 mL) was added hydrazine hydrate (1.82 mL, 36.8 mmol). The reaction mixture was stirred at 100C in a sealed vessel for 6 h. The solvents were evaporated in vacuo and the residue was extracted with EtOAc and brine. The organic solvents were dried over magnesium sulphate and evaporated in vacuo. The residue (1.18 g) was dissolved in EtOAc (anhydrous), then the procedure for Intermediate 1 was applied. The title compound (914 mg, 57%) was isolated as a white powder. C NMR delta (DMSO-d6, 75 MHz) 173.19, 163.01 (d, JCF 245.0 Hz), 154.61, 141.81, 141.59, 128.63 (2C, d, JCF 8.4 Hz), 127.97, 115.94 (2C, d, JCF 21.6 Hz), 86.88. MS (m/z) 263 [M+H]+.

Reference： [1]Patent: WO2015/193169,A1 .Location in patent: Page/Page column 49
Patent: ,2015, .Location in patent: Page/Page column 49

51
[ 874-14-6 ]
[ 1225387-53-0 ]
[ 1224944-43-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium ethanolate; In ethanol; at 75℃;Inert atmosphere;	10405] A solution of 1H-pyrazol-5-amine and 1,3-dimeth- ylpyrimidine-2,4(1H,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer,steam pot, a reflux condenser, a J-Kem temperature probe and an N2 adaptor for positive N2 pressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOR under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wt percent solution in EtOR), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOR. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1 .5 area percent of 1H-pyrazol-5-amine was observed by TRK1PM1 HPLC tofollow the progression of the reaction using 20 tL of slurry diluted in 4 mE deionized water and 5 tE injection at 220 mm10406] After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mE/g) of heptane and then refluxed at 70° Celsius for 1 hout The slurry was then cooled to room temperature overnight. The solid was collected by filtrationa tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4 mE/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[1 ,5-a] -pyrimidin-5-olate was obtained in 93-96percent yield (corrected) and larger than 99.5 area percent observed by HPEC (1 mgmE dilution in deionized water, TRK1PM1 at 220 nm).
	With sodium ethanolate; In ethanol; at 75℃;Inert atmosphere;	A solution of lH-pyrazol-5-amine and 1,3-dimethylpyrimidine-2,4(lH,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an N2 adaptor for positive N2 pressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOH under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wtpercent solution in EtOH), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOH. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1.5 area percent of 1H-pyrazol-5-amine was observed by TRK1PM1 E1PLC to follow the progression of the reaction using 20 pL of slurry diluted in 4 mL deionized water and 5 pL injection at 220 nm. After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mL/g) of heptane and then refluxed at 70° Celsius for 1 hour. The slurry was then cooled to room temperature overnight. The solid was collected by filtration on a tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4mL/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[l,5-a]-pyrimidin-5-olate was obtained in 93-96percent yield (corrected) and larger than 99.5 area percent observed by HPLC (1 mg/mL dilution in deionized water, TRK1PM1 at 220 nm).

Reference： [1]Patent: US2017/281632,2017,A1 .Location in patent: Paragraph 0405; 0406
[2]Patent: US2016/137654,2016,A1 .Location in patent: Paragraph 0237-0238

52
[ 491-38-3 ]
[ 1225387-53-0 ]
2-(pyrazolo[1,5-a]pyrimidin-7-yl)phenol [ No CAS ]
2-(pyrazolo[1,5-a]pyrimidin-5-yl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 59% 2: 23%	With sodium methylate In dimethyl sulfoxide at 100℃; Microwave irradiation;	1 2.3. General procedure for the synthesis of 2-(pyrazolo[1,5-a]pyrimidin-5-yl)phenols (3) and 2-(pyrazolo[1,5-a]pyrimidin-5-yl)phenols (4) Chromone (1; 1 mmol), 3-aminopyrazole (2a; 1.5 mmol) or 3-amino-5-methyl pyrazole (2b; 2 mmol), and CH3ONa (135 mg,2.5 mmol) were dissolved in dried DMSO (15 mL). The resultingmixture was heated under microwave irradiation for 10 min at100 C. After that the mixture was poured into brine (100 mL) andwas adjusted to pH 6e7 with 20% HCl. The formed precipitatewas filtered. Further purified via column chromatography on silicagel (dichloromethane) gave product 3 and 4.

Reference： [1]Zhang, Jin; Peng, Ju-Fang; Wang, Tao; Wang, Ping; Zhang, Zun-Ting [Journal of Molecular Structure, 2016, vol. 1120, p. 228 - 233]

53
[ 22927-13-5 ]
[ 127-17-3 ]
[ 1225387-53-0 ]
C₁₅H₁₃N₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 11079 - 11097

54
[ 26510-52-1 ]
[ 1225387-53-0 ]
5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With acetic acid; at 120℃; for 14h;Inert atmosphere;	(a) Ethyl 3-oxo-3-(pyridin-2-yl)propanoate (500mg, 2.6mmol) was taken in AcOH (6mL) in a 50mL round bottom flask under N2. To it was added 1H-pyrazol-3-amine (258mg, 3.1mmol). The reaction mixture was heated at 120C for 14h. The reaction mixture was then evaporated to dryness using toluene as an azeotropic solvent and triturated with diethyl ether. This was finally dried under high vaccum which affored 66c as a colourless solid (420mg, 77%). This was then used in the next step without any further purification. MS (ESI) m/z 213.08 [M+H+].

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3922 - 3946

55
[ 20026-96-4 ]
[ 1225387-53-0 ]
7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one [ No CAS ]

Reference： [1]ACS Combinatorial Science,2018,vol. 20,p. 256 - 260

56
[ 709648-68-0 ]
[ 1225387-53-0 ]
6-(4-bromophenyl)pyrazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With acetic acid In ethanol at 100℃; for 1h;	Step 1: To a solution of 1H-pyrazol-5-amine (25, 2.20 g, 26.4 mmol) in EtOH (25 mL)/AcOH (25 mL) was added 2-(4-bromophenyl)malonaldehyde (24, 6.0 g, 26.4 mmol) and the mixture was heated at 100 °C for 1 hr. The reaction mixture was cooled with ice bath and the precipitate was filtered under reduced pressure and further washed with 1/1 EtOH/AcOH. The collected solid was further dried under high vacuum to give the desired product 26 (2.15 g, 81%) as an off-white solid.

Reference： [1]Jiang, Jian-kang; Huang, Xiuli; Shamim, Khalida; Patel, Paresma R.; Lee, Arthur; Wang, Amy Q.; Nguyen, Kimloan; Tawa, Gregory; Cuny, Gregory D.; Yu, Paul B.; Zheng, Wei; Xu, Xin; Sanderson, Philip; Huang, Wenwei [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 20, p. 3356 - 3362]

57
[ 75-24-1 ]
[ 696-42-4 ]
[ 1225387-53-0 ]
5-fluoro-N'-(1H-pyrazol-5-yl)pyridine-3-carboxamidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[696-42-4]5-fluoropyridine-3-carbonitrile</strong> (1 g, 7.78 mmol, 1 eq) and lH-pyrazol-5-amine (775.80 mg, 9.34 mmol, 1.2 eq) in xylene (15 mL) was stirred at 70 C for 30 min, then AlMe3 (2 M, 7.78 mL, 2 eq) (2 M in toluene, 19.45 mL, 1 eq) was added in one portion at 70 C. The mixture was stirred at 100 C for 12 h. The reaction mixture was concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from DCM/MeOH= 100/1 to 10/1, TLC: DCM/MeOH= 10/1, Rf = 0.3) to yield 5-fluoro-/V-(lH-pyrazol-5-yl)pyridine-3- carboxamidine (700 mg, 2.73 mmol, 35.1% yield, 80.0% purity) as a yellow solid. NMR (400 MHz, CD3OD) delta ppm 8.89 (s, 1H), 8.59 (d, J= 2.7 Hz, 1H), 8.06 (d, J= 9.3 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 6.16 (d, J = 2.2 Hz, 1H); ES-LCMS m/z 206.3 [M+H]+.

Reference： [1]Patent: WO2018/195397,2018,A2 .Location in patent: Paragraph 00929-00930

58
[ 598-21-0 ]
[ 1225387-53-0 ]
2-bromo-N-(1H-pyrazol-5-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.8%	With sodium carbonate In tetrahydrofuran at 0℃; for 1h;	1 4.1.6. General procedure for the synthesis of intermediates 16i-k General procedure: Different five-membered heterocyclic amines (1.72 mmol) and sodiumcarbonate (0.36 g, 3.44 mmol) were added to anhydrous tetrahydrofuran(10 mL) at 0 °C. Then, 15b (0.35 g, 1.72 mmol) dissolved in5 mL of tetrahydrofuran was added. Stirring was continued for an additional1 h in the ice bath (monitored by TLC). The organic phase wasfiltered and the diethyl ether (10 mL) was added to the filtrate. Finally,the solid was precipitated from the filtrate to afford the intermediates16i-k.

Reference： [1]Wang, Zhao; Yu, Zhao; Kang, Dongwei; Zhang, Jian; Tian, Ye; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng; Liu, Xinyong [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 3, p. 447 - 456]

59
[ 2065-75-0 ]
[ 53617-36-0 ]
[ 1225387-53-0 ]
6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyrazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a suspension of 2-bromomalonaldehyde (0.30 g, 1.96 mmol) and suitably substituted cyclic amines (2.94 mmol) in 1,4-dioxane (2 ml), Hunig's base (0.5 ml, 2.94 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. After this time, lH-Pyrazol-5- amine (0.06 ml, 0.98 mmol) was added and the reaction mixture was heated in a microwave for lh at 100 °C. It was then cooled to room temperature, concentrated and directly subjected to flash silica gel column chromatography via Biotage silica gel column (gradient: 10percent H3 in MeOH/CH2Cl2 = 0/100 to 15/100) to give the desired product.

Reference： [1]Patent: WO2018/200855,2018,A1 .Location in patent: Paragraph 00424-00425; 00438

60
[ 873-83-6 ]
[ 443-69-6 ]
[ 1225387-53-0 ]
5-fluoro-1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With acetic acid In water at 90℃; for 7h; Green chemistry;	General procedure for synthesis of spiro-fused 3,4′-pyrazolo [4′,3′:5,6]pyrido[2,3-d]pyrimidine derivatives General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 °C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF. 5-Fluoro-1′,9′-dihydrospiro[indoline-3,4′-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine]-2,5′,7′(6′H,8′H)-trione (4a) White solid; yield: 330.1 mg (97 %); m.p. >280 °C.IR (KBr) (ν, cm-1): 3428, 3236, 1726, 1630, 1603, 1546, 1522, 1485, 1401, 1314,1186, 1125, 800, 690, 609, 565. 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.34(s, 1H, NH), 10.56 (s, 1H, NH), 10.25 (s, 1H, NH), 10.17 (s, 1H, NH), 9.26 (s, 1H,NH), 7.14 (s, 1H, ArH), 6.90 (td, J1 = 4.8 Hz, J2 = 2.4 Hz, 1H, ArH), 6.77 (dd,J1 = 8.4 Hz, J2 = 4.4 Hz, 1H, ArH), 6.74 (dd, J1 = 8.0 Hz, J2 = 2.4 Hz, 1H, ArH).13C NMR (100 MHz, DMSO-d6) (δ, ppm): 180.3, 162.6, 159.8, 157.4, 150.3, 148.5,145.2, 140.3 (d, JCF = 7.2 Hz), 138.0, 125.6, 113.7 (d, JCF = 22.9 Hz), 111.1 (d,JCF = 24.3 Hz), 110.1 (d, JCF = 8.0 Hz), 103.3, 84.6, 48.2. HRMS (ESI-TOF) m/zcalculated for C15H9FN6NaO3:363.0618, found [M + Na]+: 363.0627.

Reference： [1]Dai, Lei; Mao, Kaimin; Pan, Zhengbing; Rong, Liangce [Research on Chemical Intermediates, 2019, vol. 45, # 2, p. 769 - 788]

61
[ 873-83-6 ]
[ 317-20-4 ]
[ 1225387-53-0 ]
7-fluoro-1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With acetic acid; In water; at 90℃; for 7h;Green chemistry;	General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF.

Reference： [1]Research on Chemical Intermediates,2019,vol. 45,p. 769 - 788

62
[ 873-83-6 ]
[ 7477-63-6 ]
[ 1225387-53-0 ]
7-chloro-1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With acetic acid In water at 90℃; for 7h; Green chemistry;	General procedure for synthesis of spiro-fused 3,4′-pyrazolo [4′,3′:5,6]pyrido[2,3-d]pyrimidine derivatives General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 °C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF.

Reference： [1]Dai, Lei; Mao, Kaimin; Pan, Zhengbing; Rong, Liangce [Research on Chemical Intermediates, 2019, vol. 45, # 2, p. 769 - 788]

63
[ 873-83-6 ]
[ 608-05-9 ]
[ 1225387-53-0 ]
5-methyl-1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With acetic acid In water at 90℃; for 7h; Green chemistry;	General procedure for synthesis of spiro-fused 3,4′-pyrazolo [4′,3′:5,6]pyrido[2,3-d]pyrimidine derivatives General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 °C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF.

Reference： [1]Dai, Lei; Mao, Kaimin; Pan, Zhengbing; Rong, Liangce [Research on Chemical Intermediates, 2019, vol. 45, # 2, p. 769 - 788]

64
[ 873-83-6 ]
[ 91-56-5 ]
[ 1225387-53-0 ]
1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With acetic acid In water at 90℃; for 7h; Green chemistry;	General procedure for synthesis of spiro-fused 3,4′-pyrazolo [4′,3′:5,6]pyrido[2,3-d]pyrimidine derivatives General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 °C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF.

Reference： [1]Dai, Lei; Mao, Kaimin; Pan, Zhengbing; Rong, Liangce [Research on Chemical Intermediates, 2019, vol. 45, # 2, p. 769 - 788]

65
[ 443-69-6 ]
[ 6642-31-5 ]
[ 1225387-53-0 ]
5-fluoro-6',8'-dimethyl-1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With acetic acid In water at 90℃; for 7h; Green chemistry;	General procedure for synthesis of spiro-fused 3,4′-pyrazolo [4′,3′:5,6]pyrido[2,3-d]pyrimidine derivatives General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 °C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF.

Reference： [1]Dai, Lei; Mao, Kaimin; Pan, Zhengbing; Rong, Liangce [Research on Chemical Intermediates, 2019, vol. 45, # 2, p. 769 - 788]

66
[ 317-20-4 ]
[ 6642-31-5 ]
[ 1225387-53-0 ]
7-fluoro-6',8'-dimethyl-1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With acetic acid; In water; at 90℃; for 7h;Green chemistry;	General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF.

Reference： [1]Research on Chemical Intermediates,2019,vol. 45,p. 769 - 788

67
[ 7477-63-6 ]
[ 6642-31-5 ]
[ 1225387-53-0 ]
7-chloro-6',8'-dimethyl-1',9'-dihydrospiro[indoline-3,4'-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]-2,5',7'(6'H,8'H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With acetic acid In water at 90℃; for 7h; Green chemistry;	General procedure for synthesis of spiro-fused 3,4′-pyrazolo [4′,3′:5,6]pyrido[2,3-d]pyrimidine derivatives General procedure: A mixture of isatins 1 (1 mmol), substituted 1H-pyrazol-5-amine 2 (1 mmol), 6-aminopyrimidine-2,4(1H,3H)-dione 3 or 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 5 (1 mmol), H2O(6 mL), and HOAc (2 mL) was placed in a 25-mL flask andstirred at 90 °C (monitored by thin layer chromatography (TLC)) for about 7 h. Afterreaction completion, the mixture was cooled to room temperature and the precipitateobtained by filtration. Compounds 4 or 6 were further purified by recrystallizationfrom DMF.

Reference： [1]Dai, Lei; Mao, Kaimin; Pan, Zhengbing; Rong, Liangce [Research on Chemical Intermediates, 2019, vol. 45, # 2, p. 769 - 788]

68
[ 6341-92-0 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
6-chloro-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

69
[ 6341-92-0 ]
3-ethylisoxazol-5(4H)-one [ No CAS ]
[ 1225387-53-0 ]
6-chloro-3'-ethyl-6',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

70
[ 6326-79-0 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
6-bromo-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

71
[ 6326-79-0 ]
3-ethylisoxazol-5(4H)-one [ No CAS ]
[ 1225387-53-0 ]
6-bromo-3'-ethyl-6',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

72
[ 17630-76-1 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
5-chloro-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

73
3-ethylisoxazol-5(4H)-one [ No CAS ]
[ 17630-76-1 ]
[ 1225387-53-0 ]
5-chloro-5'-(1-(hydroxyimino)propyl)-1',7'-dihydrospiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

74
[ 91-56-5 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

75
[ 443-69-6 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
5-fluoro-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

76
[ 317-20-4 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
7-fluoro-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With Amberlyst-15; In methanol; at 80℃; for 5h;	General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Tetrahedron Letters,2019,vol. 60

77
[ 317-20-4 ]
3-ethylisoxazol-5(4H)-one [ No CAS ]
[ 1225387-53-0 ]
3'-ethyl-7-fluoro-6',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With Amberlyst-15; In methanol; at 80℃; for 5h;	General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Tetrahedron Letters,2019,vol. 60

78
[ 20780-74-9 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
7-bromo-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

79
[ 39755-95-8 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
5-methoxy-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

80
[ 608-05-9 ]
[ 1076-59-1 ]
[ 1225387-53-0 ]
5-methyl-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With Amberlyst-15 In methanol at 80℃; for 5h;	Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 °C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound.

Reference： [1]Niu, Qingqing; Xi, Junhua; Li, Lei; Li, Li; Pan, Chengli; Lan, Meijun; Rong, Liangce [Tetrahedron Letters, 2019, vol. 60, # 43]

81
2-methylamino-2-methylthio-1-nitroethene [ No CAS ]
[ 1225387-53-0 ]
[ 5527-95-7 ]
4-(4-chloro3-fluorophenyl)-N-methyl-5-nitro-4,7-dihydro-2H-pyrazolo[3,4-b]pyridin-6-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With toluene-4-sulfonic acid In acetonitrile at 80℃; for 5h;

Reference： [1]Ji, Yifan; Li, Li; Zhu, Guangzhou; Zhou, Ya; Lu, Xinchi; He, Wenjing; Gao, Lijiu; Rong, Liangce [Journal of Heterocyclic Chemistry, 2020, vol. 57, # 4, p. 1781 - 1796]

82
[ 346-34-9 ]
[ 102721-76-6 ]
[ 1225387-53-0 ]
4-fluoro-6'-(methylamino)-5'-nitro-2',7'-dihydrospiro(indoline-3,4'-pyrazolo[3,4-b]pyridin)-2-one [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2020

83
phenyl (6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamic acid ester [ No CAS ]
[ 1225387-53-0 ]
[ 76-05-1 ]
(x)C₂HF₃O₂*C₁₄H₁₆N₈O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: phenyl (6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)carbamic acid ester; 3⁽⁵⁾-aminopyrazole With triethylamine In N,N-dimethyl-formamide at 50℃; for 12h; Stage #2: trifluoroacetic acid In water; acetonitrile	1-(6-(4-Isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(pyridin-2-yl)urea (11h) General procedure: General Method B: 11c (30mg, 0.0929mmol), pyridin-2-amine (26mg, 0.28mmol), and Et3N (38mg, 0.37mmol) were placed in a round-bottom flask, followed by addition of DMF (2mL). The mixture was heated up at 50°C for 12h. Water (4mL) was added and the mixture was purified by reverse phase HPLC to afford 11h as a solid of TFA salt (22.9mg, 56%).

Reference： [1]Huang, Chaoying; Li, Jia; Lyu, Xilin; Wang, Huan; Wang, Peipei; Wang, Zengtao; Zang, Yi; Zhang, Shiyan; Zhao, Yujun [European Journal of Medicinal Chemistry, 2020, vol. 195]

84
[ 91007-16-8 ]
[ 1225387-53-0 ]
5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With acetic acid at 70℃; for 6h;
74.9%	With acetic acid at 70℃; for 4h;	35.2 Example 35 Step 2 To a suspension of ethyl 4-ethyl-3-oxo-hexanoate (4.4 g, 23.62 mmol) in acetic acid (11 mL) at 70° C. was added 1H-pyrazol-5-amine (4.71 g, 56.7 mmol) in two portions (the second portion was added after 2 hours of stirring the first portion) over a 4 hour period. Upon consumption of SM as indicated by TLC, the reaction was cooled to rt and the solvent was evaporated in a rotary evaporator. The residue was treated with ethyl acetate and filtered to give 5-(1-ethylpropyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (3.7 g, 17.7 mmol, 74.9% yield) as an off-white solid.

Reference： [1]Richters, André; Doyle, Shelby K.; Freeman, David B.; Lee, Christina; Leifer, Becky S.; Jagannathan, Sajjeev; Kabinger, Florian; Koren, Jošt Vrabič; Struntz, Nicholas B.; Urgiles, Julie; Stagg, Ryan A.; Curtin, Brice H.; Chatterjee, Deep; Mathea, Sebastian; Mikochik, Peter J.; Hopkins, Tamara D.; Gao, Hua; Branch, Jonathan R.; Xin, Hong; Westover, Lori; Bignan, Gilles C.; Rupnow, Brent A.; Karlin, Kristen L.; Olson, Calla M.; Westbrook, Thomas F.; Vacca, Joseph; Wilfong, Chris M.; Trotter, B. Wesley; Saffran, Douglas C.; Bischofberger, Norbert; Knapp, Stefan; Russo, Joshua W.; Hickson, Ian; Bischoff, James R.; Gottardis, Marco M.; Balk, Steven P.; Lin, Charles Y.; Pop, Marius S.; Koehler, Angela N. [Cell Chemical Biology, 2021, vol. 28, # 2, p. 134 - 14,147]
[2]Current Patent Assignee: KRONOS BIO INC - US2020/131189, 2020, A1 Location in patent: Paragraph 0134-0135

85
[ 105161-33-9 ]
[ 1225387-53-0 ]
pyrazolo(1,5-a)pyrimidine-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogenchloride In methanol at 20℃; for 72h;	1.1; 2.1 reaction step one: compound 2 (4.77 g, 34 mmol) was dissolved in 100 mL of methanol and 2.77 mL of concentrated hydrochloric acid, and compound 1 (1.4 g, 16.7 mmol) was dissolved in 6.7 mL of methanol at room temperature, and then added dropwise to the above solution. After stirring for three days at room temperature, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate = 5: 2) to obtain target compound 3 (light yellow solid, 3.62 g, yield) Rate 92%).

Reference： [1]Current Patent Assignee: ANHUI QUSHI PHARMACEUTICAL TECH - CN113149995, 2021, A Location in patent: Paragraph 0023-0024; 0027-0028

86
[ 100-52-7 ]
[ 1225387-53-0 ]
1-morpholino-2-nitroethylene [ No CAS ]
6-nitro-7-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With boron trifluoride diethyl etherate In butan-1-ol at 120℃; for 2h;	3.1. 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines 4,6,8; General procedure 1 General procedure: To a suspension 2 mmol (1.0 equiv.) of corresponding aminoazole 1, 2 mmol (1.0 equiv.)of nitroalkene 2, and 2 mmol (1.0 equiv.) of aldehyde 3 in 5 mL of n-BuOH, was added3 mmol (1.5 equiv., 0.37 mL) of BF3Et2O. The reaction mixture was heated on oil bathat 120 °C for 2 h. The resulting solution was cooled to room temperature and stirred for15 min. The obtained precipitate was filtered off, washed with 15 mL of i-PrOH. Theprecipitate was suspended in 50 mL of water, stirred for 5 min, filtered off again, andwashed with 15 mL of water.

Reference： [1]Balyakin, Ilya A.; Chupakhin, Oleg N.; Lyapustin, Daniil N.; Rusinov, Vladimir L.; Shchepochkin, Alexander V.; Ulomsky, Evgeny N. [Molecules, 2021, vol. 26, # 16]

87
2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl}-2-methylpropanenitrile [ No CAS ]
[ 1225387-53-0 ]
(R)-2-(2-((1H-pyrazol-5-yl)amino)-6-(3-methylmorpholino)pyridin-4-yl)-2-methylpropanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; Cs₂CO₃ In 1,4-dioxane at 110℃; for 10h; Inert atmosphere;	22.1 To a solution of 2- {2-chloro-6- [ (3R) -3-methylmorpholin-4-yl] pyridin-4-yl} -2-methylpropanenitrile (60 mg, 0.21 mmol) and 1H-pyrazol-5-amine (35 mg, 0.42 mmol) in Dioxane (3 mL) were added BrettPhos-Pd-G3 (19 mg, 0.21 mmol) and Cs2CO3(210 mg, 0.64 mmol) . The mixture was stirred at 110 for 10 h under N2atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL) , then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-HPLC (C18, 10-95%, MeOH in H2O with 0.1%HCOOH) to give the desired product (60 mg, yield: 85%) . LC/MS (ESI) : m/z 327 [M+H]+.1H NMR (400 MHz, DMSO) δ 12.10 (s, 1H) , 9.02 (s, 1H) , 7.53 (d, J = 2.2 Hz, 1H) , 6.59 (s, 1H) , 6.30 (d, J = 1.9 Hz, 1H) , 6.08 (d, J = 1.0 Hz, 1H) , 4.32 (d, J = 6.5 Hz, 1H) , 3.93 (dd, J = 11.2, 3.3 Hz, 1H) , 3.79 (d, J =12.8 Hz, 1H) , 3.73 (d, J = 11.2 Hz, 1H) , 3.62 (dd, J = 11.3, 2.9 Hz, 1H) , 3.47 (td, J =11.8, 3.0 Hz, 1H) , 3.06 (td, J = 12.6, 3.7 Hz, 1H) , 1.63 (s, 6H) , 1.13 (d, J = 6.6 Hz, 3H) .

Reference： [1]Current Patent Assignee: SHANGHAI ANTENGENE LTD; ANTENGENE DISCOVERY - WO2022/2245, 2022, A1 Location in patent: Paragraph 00292

88
[ 13323-81-4 ]
[ 61040-78-6 ]
[ 1225387-53-0 ]
[ 1112914-91-6 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium hydroxide In toluene at 110℃; for 18h; chemoselective reaction;

Reference： [1]Hu, Qiyan; Huang, Fei; Qin, Feng; Tang, Lin; Xu, Dongping; Zhang, Wu [Applied Organometallic Chemistry, 2022]

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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1225387-53-0 ] {[proInfo.proName]}

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[ 1225387-53-0 ] Synthesis Path-Upstream 1~16

[ 1225387-53-0 ] Synthesis Path-Downstream 1~88

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