[ CAS No. 6994-25-8 ] {[proInfo.proName]}

Name: 6994-25-8|Ethyl 3-amino-1H-pyrazole-4-carboxylate|95%
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Quality Control of [ 6994-25-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 6994-25-8 ]

CAS No. :	6994-25-8	MDL No. :	MFCD00005238
Formula :	C₆H₉N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YPXGHKWOJXQLQU-UHFFFAOYSA-N
M.W :	155.15	Pubchem ID :	81472
Synonyms :	3-Amino-4-ethoxycarbonylpyrazole

Calculated chemistry of [ 6994-25-8 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.33
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	39.08
TPSA :	81.0 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.96
Log Po/w (XLOGP3) :	0.64
Log Po/w (WLOGP) :	0.18
Log Po/w (MLOGP) :	-0.18
Log Po/w (SILICOS-IT) :	0.39
Consensus Log Po/w :	0.4

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.34
Solubility :	7.03 mg/ml ; 0.0453 mol/l
Class :	Very soluble
Log S (Ali) :	-1.92
Solubility :	1.88 mg/ml ; 0.0121 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.34
Solubility :	7.04 mg/ml ; 0.0454 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.71

Safety of [ 6994-25-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 6994-25-8 ]

* 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 [ 6994-25-8 ]
Downstream synthetic route of [ 6994-25-8 ]

[ 6994-25-8 ] Synthesis Path-Upstream 1~12

1
[ 6994-25-8 ]
[ 37622-90-5 ]

Yield	Reaction Conditions	Operation in experiment
80 g	With hydrogenchloride; acetic acid; sodium nitrite In water at 0℃; for 0.5 h;	Step three, Pyrazole-4-carboxylic acid ethyl ester: To the reaction flask was added 155 g of pyrazole-4-carboxylate and 500 ml of glacial acetic acid, Add 100 ml of hydrochloric acid at 0 ° C, And then dropping 70 g of sodium nitrite solution, After the reaction was carried out for 0.5 hour, 1500 ml of ethanol was added thereto and the mixture was refluxed and concentrated under reduced pressure. Adding DCM and water to stir the layers to obtain an organic layer, The organic layer was recrystallized using a mixed solvent of petroleum ether and ethyl acetate in a molar ratio of 1: 1, You can get 80g finished.

Reference： [1] Synthetic Communications, 2008, vol. 38, # 5, p. 674 - 683
[2] Patent: CN106518765, 2017, A, . Location in patent: Paragraph 0009

2
[ 591-50-4 ]
[ 6994-25-8 ]
[ 16078-71-0 ]
[ 16078-63-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide In 1,4-dioxane at 110℃; for 48 h; Inert atmosphere	General procedure: After standard evacuation and back-fill cycles with argon, a Schlenk tube fitted with a magnetic stirrer bar was charged with pyrazole derivative (1.29 mmol), aryl iodide (1.1 eq), K₃PO₄ (2 eq) and copper iodide (0.1 eq). N,N'-dimethyl-cyclohexane-1,2-diamine (0.2 eq) and anhydrous dioxane (3 mL) were then added under a stream of argon by syringe at room temperature. The sealed tube is stirred at 110 °C for 24-48 h. A 28percent solution of ammonia and water are added at room temperature to the reaction mixture. The resulting aqueous layer is extracted with DCM. The combined organic layers are dried on MgSO₄, filtered and evaporated under reduced pressure. The residue is triturated in an appropriate solvent or purified on silica gel.

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3867 - 3876

3
[ 6994-25-8 ]
[ 58347-48-1 ]

Reference： [1] Patent: WO2016/73895, 2016, A1,
[2] Patent: WO2017/176960, 2017, A1,

4
[ 591-50-4 ]
[ 6994-25-8 ]
[ 16078-71-0 ]
[ 16078-63-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide In 1,4-dioxane at 110℃; for 48 h; Inert atmosphere	General procedure: After standard evacuation and back-fill cycles with argon, a Schlenk tube fitted with a magnetic stirrer bar was charged with pyrazole derivative (1.29 mmol), aryl iodide (1.1 eq), K₃PO₄ (2 eq) and copper iodide (0.1 eq). N,N'-dimethyl-cyclohexane-1,2-diamine (0.2 eq) and anhydrous dioxane (3 mL) were then added under a stream of argon by syringe at room temperature. The sealed tube is stirred at 110 °C for 24-48 h. A 28percent solution of ammonia and water are added at room temperature to the reaction mixture. The resulting aqueous layer is extracted with DCM. The combined organic layers are dried on MgSO₄, filtered and evaporated under reduced pressure. The residue is triturated in an appropriate solvent or purified on silica gel.

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3867 - 3876

5
[ 6994-25-8 ]
[ 139308-52-4 ]

Reference： [1] Patent: WO2018/64119, 2018, A1,

6
[ 6994-25-8 ]
[ 754219-01-7 ]
[ 799835-39-5 ]

Reference： [1] Patent: US2018/170927, 2018, A1,

7
[ 6994-25-8 ]
[ 105486-72-4 ]

Reference： [1] Patent: WO2018/64119, 2018, A1,

8
[ 6994-25-8 ]
[ 1224944-77-7 ]

Reference： [1] Patent: WO2011/6074, 2011, A1,
[2] Patent: WO2012/34095, 2012, A1,
[3] Patent: US2016/159808, 2016, A1,
[4] Patent: TW2016/520, 2016, A,

9
[ 5941-55-9 ]
[ 6994-25-8 ]
[ 926663-00-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With caesium carbonate In N,N-dimethyl-formamide at 110℃; for 15 h; Stage #2: With acetic acid In N,N-dimethyl-formamide at 20℃;	Preparation B; Ethyl 5-chloropyrazolor 1 ,5-alpyrimidine-3-carboxylate; Step A: Preparation of ethyl 5-hvdroxypyrazolo[l,5-a1pyrimidine-3- carboxylate.; Ethyl 3-amino-lH-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (E)-ethyl 3- ethoxyacrylate (35.8 ml, 242 mmol) were mixed in DMF (537 mL). Cesium carbonate (78.7 g, 242 mmol) was added and the mixture heated to 110 ⁰C for 15 hours. The reaction mixture was cooled to ambient temperature and acidified with HOAc to pH 4. The resultant precipitate was filtered and washed with water and EtOAc, yielding the title compound as a fluffy white solid. Additional material was obtained by an aqueous workup. The filtrate was concentrated to remove the DMF, was diluted in EtOAc (500 mL) and washed with H₂O. The resultant precipitate in the EtOAc layer was filtered and washed with water and EtOAc to obtain additional product. The solids were pooled and dried in vacuum to afford ethyl 5- hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (33.3 g, 100 percent yield) as a fluffy white solid. MS (apci) m/z = 206.2 (M-H).

Reference： [1] Patent: WO2011/6074, 2011, A1, . Location in patent: Page/Page column 70

10
[ 1001-26-9 ]
[ 6994-25-8 ]
[ 926663-00-5 ]

Yield	Reaction Conditions	Operation in experiment
17.1 g	With caesium carbonate In N,N-dimethyl-formamide at 100℃;	A) ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (15.0 g) and ethyl 3-ethoxy-2-propenoate (21.0 mL) in N,N-dimethylformamide (322 mL) was added cesium carbonate (56.7 g). The reaction mixture was stirred overnight at 100° C., water was added, and acetic acid was sequentially added to adjust the pH to about 4. The obtained solid was collected by filtration, and washed with water to give the title compound (17.1 g). ¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (3H, t, J=7.0 Hz), 4.27 (2H, q, J=6.9 Hz), 6.14 (1H, d, J=7.9 Hz), 8.13 (1H, s), 8.56 (1H, d, J=7.9 Hz), 11.75 (1H, brs).
17.1 g	With caesium carbonate In N,N-dimethyl-formamide at 100℃;	The 3-amino -1H-pyrazole-4-carboxylic acid ethyl ester (15.0g) and 3-ethoxy-2-acrylic acid ethyl ester (21.0 ml) for N, N- dimethyl formamide (322 ml) is added in the solution cesium carbonate (56.7g). The reaction mixtures in 100 °C stirring overnight, add water, and adding acetic acid in order to adjust the pH to about 4. The collection of the solid by filtering, and by water cleaning and generates a title compound (17.1g).

Reference： [1] Patent: US2016/159808, 2016, A1, . Location in patent: Paragraph 1344; 1345; 1355; 1366; 1379; 1392
[2] Patent: TW2016/520, 2016, A, . Location in patent: Paragraph 0159; 0164

11
[ 6994-25-8 ]
[ 623-47-2 ]
[ 926663-00-5 ]

Reference： [1] Patent: WO2012/34095, 2012, A1, . Location in patent: Page/Page column 68

12
[ 6994-25-8 ]
[ 1353100-91-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With copper(ll) bromide; isopentyl nitrite In acetonitrile at 50℃;	To a 0° C. solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (5.0 g, 32 mmol) and copper (II) bromide (7.2 g, 32 mmol) in acetonitrile (65 mL) was slowly added isoamyl nitrite (12 mL, 86 mmol). The reaction was heated to 50° C. and stirred overnight. The reaction was cooled to room temperature and quenched with 1 N aqueous hydrochloric acid (150 mL). The mixture was extracted with ethyl acetate (3.x.100 mL). The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated to give the title compound as a brown oil that partially solidified under vacuum overnight (7.1 g, 100percent). ¹H NMR (400 MHz, CDCl₃, δ): 9.78 (br. s., 1H), 8.10 (br. s., 1H), 4.33 (q, J=7.22 Hz, 2H), 1.36 (m, 3H).
81%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20 - 70℃; for 3 h; Inert atmosphere	To a solution of terf-BuONO (156 mmol, 16.5 g) in acetonitrile (300 mL) was added CuBr₂ (156 mmol, 34.8 g). After the mixture was stirred at rt for 1 h under nitrogen, ethyl 3-amino-lH-pyrazole-4-carboxylate ( 129 mmol, 20.0 g) was added portionwise over 30 min. The reaction mixture was stirred at rt for 30 min and then was allowed to warm up to 70°C and was stirred for another 2 h. After cooling to rt, the solvent was removed under reduced pressure. The residue was diluted with EtOAc ( 1 L) and was washed with brine (200 mL x 3). The organic layer was dried over MgS0₄, filtered, and concentrated to afford ethyl 3-bromo-lH-pyrazole- 4-carboxylate (106 mmol, 23.2 g, 81 percent) and was used without any purification.LC-MS: m/z ES⁺= 219, 221.

Reference： [1] Patent: US2012/108619, 2012, A1, . Location in patent: Page/Page column 26
[2] Patent: WO2012/9009, 2012, A2, . Location in patent: Page/Page column 56
[3] Patent: WO2012/8999, 2012, A2, . Location in patent: Page/Page column 75
[4] Journal of Organic Chemistry, 2012, vol. 77, # 22, p. 10050 - 10057
[5] Patent: WO2014/188211, 2014, A1, . Location in patent: Page/Page column 78
[6] Patent: WO2018/64119, 2018, A1, . Location in patent: Paragraph 0499; 0505; 0935

[ 6994-25-8 ] Synthesis Path-Downstream 1~74

1
[ 42466-67-1 ]
[ 6994-25-8 ]

Reference： [1]Helvetica Chimica Acta,1956,vol. 39,p. 986,988

2
[ 2146-07-8 ]
[ 108-94-1 ]
[ 6994-25-8 ]
[ 103259-39-8 ]

Yield	Reaction Conditions	Operation in experiment
52%	With phosphorus pentoxide; N,N-dimethyl-cyclohexanamine at 180℃; for 20h;

Reference： [1]Nielsen, Soren V.; Pedersen, Erik B. [Liebigs Annalen der Chemie, 1986, # 10, p. 1728 - 1735]

3
[ 105-56-6 ]
[ 6994-25-8 ]
[ 115423-04-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite 1) CH₃COOH, water, 0 deg C, 20 min.; 2) ethanol, reflux, 4 h; Yield given. Multistep reaction;

Reference： [1]Kurasawa; Okamoto; Takada [Journal of Heterocyclic Chemistry, 1987, vol. 24, # 6, p. 1799 - 1801]

4
[ 19607-08-0 ]
[ 6994-25-8 ]
[ 136997-60-9 ]

Reference： [1]Pharmazie,1992,vol. 47,p. 580 - 581

5
[ 42466-67-1 ]
[ 64-17-5 ]
[ 7803-57-8 ]
[ 6994-25-8 ]

Reference： [1]Helvetica Chimica Acta,1956,vol. 39,p. 986,988

6
[ 94-05-3 ]
[ 1260243-04-6 ]

Yield	Reaction Conditions	Operation in experiment
66.78%	With hydrazine; In ethanol; for 4h;Reflux;	Ethylmethyloxymethyl nitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol; After 100 mL of hydrazine hydrate was added dropwise to the vessel, the vessel was placed in an electrothermal device and gradually heated to 80 C over a period of 30 minutes to give a mixture A; The mixture A was heated to reflux and refluxed for 4 hours. The ethanol was distilled off under reduced pressure and the remaining solid was evaporated. The solid was cooled to stand to precipitate a pale yellow solid which was filtered, washed and dried to give the intermediate 5-amino-lH-pyrazole-4-carboxylic acid ethyl ester. The article used in the washing process was cold Anhydrous ethanol. The product The mass of ethyl 5-amino-1H-pyrazole-4-carboxylate was 41.68 g. Yield: 66.78%
66.78%	With hydrazine hydrate; In ethanol; at 80℃; for 4.5h;	1.1) ethyl(ethoxymethylene)cyanoacetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;1.2) 100mL hydrated hydrazine was added to the container,Placing the container in an electric heating device,In the 30-minute range gradually heated to 80C ,To obtain a mixture A;1.3) The mixture A was heated to reflux,After 4 hours of refluxing,Distillation of ethanol, residual solids;1.4) The solid was cooled to stand to precipitate a pale yellow solid,The light yellow solid was filtered, washed, dried,To give ethyl 5-amino-lH-pyrazole-4-carboxylate;The articles used in the washing process are cold ethanol.The mass of the product 5-amino-lH-pyrazole-4-carboxylate was 41.68 g. Yield: 66.78%
66.78%	With hydrazine hydrate; In ethanol; at 80℃; for 4.5h;	1.1) ethyl(ethoxymethylene)cyanoacetate(68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanolin;1.2) After 100 mL of hydrazine hydrate was added to the vessel, the vessel was placed in an electric heating apparatus and gradually heated to 80 C over a period of 30 minutes to obtain a mixture A;1.3) The mixture A was heated to reflux and refluxed for 4 hours. The ethanol was evaporated under reduced pressure and the remaining solid was evaporated.1.4) The solid was cooled to stand to precipitate a pale yellow solid which was filtered, washed, dried,To give ethyl 5-amino-lH-pyrazole-4-carboxylate;The articles used in the washing process are cold ethanol.The mass of the product 5-amino-1H-pyrazole-4-carboxylatewas 41.68 g.Yield: 66.78%

66.78%		Ethoxymethylenenitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;100mL of hydrazine hydrate drops into the container, the container is placed in an electric heating device, within a 30-minute range gradually warmed to 80 , to obtain a mixture A;The mixture A was heated to reflux, refluxed for 4 hours, vacuum distillation of ethanol, the remaining solids;The solid was allowed to cool to leave a pale yellow solid which was filtered, washed, dried,To obtain the intermediate ethyl 5-amino-1H-pyrazole-4-carboxylate;The washing process uses cold anhydrous ethanol.The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78%
66.78%		1.1)Ethoxymethylenenitrile ethyl acetate(68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanolin;1.2) 100mL hydrazine hydrate drops into the container, the container is placed in the electric device, gradually within 30 minutesThe temperature was raised to 80 C to obtain a mixture A1;1.3) The mixture A1 was heated to reflux, reflux for 4 hours, vacuum distillation of ethanol, the remaining solids;1.4) The solid was allowed to cool to leave a pale yellow solid which was filtered, washed and dried to give5-amino-1H-pyrazole-4-carboxylic acid ethyl ester;The washing process uses cold anhydrous ethanol.The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78%
66.78%	With hydrazine hydrate; In ethanol; at 80℃; for 4.5h;	1.1) Ethoxymethylenenitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;1.2) 100mL hydrazine hydrate drops into the container, the container is placed in an electric device,In a 30-minute range gradually warmed to 80 C, to obtain a mixture A;1.3) The mixture A was heated to reflux, reflux for 4 hours, vacuum distillation of ethanol, the remaining solids;1.4) The solid was allowed to cool to leave a pale yellow solid which was filtered, washed and dried to give5-amino-1H-pyrazole-4-carboxylic acid ethyl ester; the washing process used cold anhydrous ethanol. The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78%
52%	With hydrazine hydrate; In ethanol; for 3h;Reflux;	Step 2. Ethyl 5-amino-1H-pyrazole-4-carboxylate A solution of ethyl 2-cyano-3-ethoxyacrylate (21 g, 86.98 mmol, 1.00 equiv, 70%) and hydrazine hydrate (11 g, 176.00 mmol, 2.02 equiv, 80%) in ethanol (150 mL) was heated to reflux for 3 hours. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of dichloromethane. The organic layer was washed with 3*50 mL of water and dried over sodium sulfate, then concentrated under vacuum. This resulted in 7.2 g (52%) of ethyl 5-amino-1H-pyrazole-4-carboxylate as a yellow solid. LC-MS: (ES, m/z): 156 [M+H]+ 1H-NMR (300 MHz, CDCl3, ppm): 7.75 (s, 1H), 6.53 (s, 1H), 4.31-4.26 (q, J=5.4 Hz, 2H), 1.37-1.32 (t, J=5.4 Hz, 3H)
	With hydrazine hydrate; In ethanol; at 150℃; for 0.166667h;Microwave irradiation;	General procedure: Hydrazine monohydrate (26.7 mul, 0.55 mmol) was added to a solution of (ethoxymethylene)malonic acid derivatives 4a-d (0.50 mmol) in EtOH (0.5 ml), and the solution was subjected to microwave irradiation (4a: 80C, 4b: 150C, 4c,d: 120C; 150W; 10 min). Afterwards, water (0.5 ml), aldehydes 2a-j (0.55 mmol), TFA (7.7 mul, 0.10 mmol) and isocyanides 3a-d (0.55 mmol) were sequentially added to the solution, and the reaction was stirred for 10-60 min at room temperature. The precipitated product was filtered, washed with hexane or diethyl ether (1-3 ml) and dried in vacuo, yielding the corresponding final products 6-41 and 46-51. In case of 42-45, the crude reaction mixtures were purified by flash chromatography with hexane-EtOAc as eluent.
	With hydrazine hydrate; In ethanol; for 3h;Reflux;	To a mixture of 2-cyano-3-ethoxy-acrylic acid ethyl ester (10 g, 59 mmol) in ethanol (100 mL) was added hydrazine hydrate (3.6 g, 71 mmol). The mixture was stirred at reflux for 3 h before being concentrated in vacuo to afford the crude product. This material was used in subsequent reactions without further purification. MS m/z: 156 [M+H+].
	With hydrazine hydrate; In ethanol; at 80℃; for 4h;	ethyl (ethoxymethylene)cyanoacetate(68 g, 0.4 mol) was added to a vessel containing 200 ml of absolute ethanol1.2) After 100 ml of hydrazine hydrate was added dropwise to the vessel, the vessel was placed in an electrothermal apparatus and gradually cooled in the range of 30 minutesHeating the mixture to a temperature of 80 C to obtain a mixture A; heating the mixture A to reflux; after refluxing for 4 hours, distilling out the ethanol and vacuuming the remaining solid; cooling the solid to precipitate a pale yellow solid, filtering the pale yellow solid, washing, Dried to give the intermediate 5-amino-lH-pyrazole-4-carboxylic acid ethyl ester; the product used in the washing process was cold absolute ethanol.

Reference： [1]Patent: CN105949202,2016,A .Location in patent: Paragraph 0048-0053
[2]Patent: CN106008517,2016,A .Location in patent: Paragraph 0048; 0049; 0050; 0051; 0052; 0053
[3]Patent: CN106008519,2016,A .Location in patent: Paragraph 0048; 0049; 0050; 0051; 0052; 0053
[4]Patent: CN105949199,2016,A .Location in patent: Paragraph 0047-0052
[5]Patent: CN105949200,2016,A .Location in patent: Page/Page column 6; 7; 23
[6]Patent: CN105949201,2016,A .Location in patent: Paragraph 0048-0053
[7]Patent: US2012/277224,2012,A1 .Location in patent: Page/Page column 18
[8]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 821 - 826
[9]Beilstein Journal of Organic Chemistry,2014,vol. 10,p. 2338 - 2344
[10]Patent: US2015/65522,2015,A1 .Location in patent: Paragraph 0429; 0430
[11]Patent: ,2016, .Location in patent: Paragraph 0031; 0035

7
[ 138716-20-8 ]
[ 6994-25-8 ]
ethyl 7-(4-fluoroxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.56%	In acetic acid at 120℃; for 0.333333h; microwave irradiation;

Reference： [1]Ming, Li; Shuwen, Wang; Lirong, Wen; Huazheng, Yang; Xiuli, Zhang [Journal of Heterocyclic Chemistry, 2005, vol. 42, # 5, p. 925 - 930]

8
[ 6994-25-8 ]
[ 1001635-21-7 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride In tetrahydrofuran	4-Chloro-N-[5-chloro~2-(4-(4-methyl-1H-Dyrazol-3-yl)-4H-1,2λ- triazol-3-yl) pyridin-3-ylh 3-(trifluoromethyJ)benzenesulfonamide[00491] The titled compound was prepared according to general Method B using 4-chloro-N-(2-(hydrazinecarbonyl)-5-chloropyridin-3-yl)-3- (trifluoromethyl)benzenesulfonamide and 3-amino-4- hydroxymethylpyrazole((MS, 409 [M+H]+, which was generated in situ by reduction of ethyl 3-amino-1 H-pyrazole-4-carboxylate using LAH in THF): 1H NMR (400 MHz1 CDCI3) δ 8.28 (s, 1 H), 8.16 (d, 1 H), 8.13 (d, 1 H), 7.97 (d, 1 H), 7.94 (dd, 1 H)1 7.56 (d, 1 H), 7.42 (d. 1 H), 1.65 (s, 3H). MS (ES) [M+H]+ expected 518.0, found 518.0.

Reference： [1]Current Patent Assignee: CHEMOCENTRYX INC - WO2008/8375, 2008, A2 Location in patent: Page/Page column 112-113

9
[ 67382-37-0 ]
[ 6994-25-8 ]
ethyl 7-(2,5-dimethyl-thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With acetic acid at 110℃;

Reference： [1]Baraldi, Pier Giovanni; Fruttarolo, Francesca; Tabrizi, Mojgan Aghazadeh; Romagnoli, Romeo; Preti, Delia; Ongini, Ennio; El-Kashef, Hussein; Carrion, Maria Dora; Borea, Pier Andrea [Journal of Heterocyclic Chemistry, 2007, vol. 44, # 2, p. 355 - 361]

10
[ 123367-27-1 ]
[ 6994-25-8 ]
ethyl 7-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid	65 Ethyl 7-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate EXAMPLE 65 Ethyl 7-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of 3.52 g. of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one and 3.10 g. of ethyl 3-aminopyrazole-4-carboxylate in 50 ml. of glacial acetic acid is refluxed for 15 hours. The solvent is removed and the residue worked up as for Example 53 to give 3.0 g. of crystals, m.p. 209°-210° C.

Reference： [1]Current Patent Assignee: PFIZER INC - US4281000, 1981, A

11
[ 6994-25-8 ]
[ 115955-48-1 ]
[ 765292-65-7 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid; at 80.0℃;	to a solution of 3-dimethylamino-1-(3-nitro-phenyl)-propenone (3 mmol) in acetic acid is added 3 amino-4 carbethoxyprazole (3.1 mmol) and heated at 80 C. overnight. The solution is concentrated and the tan solid obtained is taken to the next step without further purification.
	With acetic acid; at 80.0℃;	Step 2: 7-(3-Nitro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester to a solution of 3-Dimethylamino-1-(3-nitro-phenyl)-propenone (3 mmol) in acetic acid is added 3 amino-4 carbethoxyprazole (3.1 mmol) and heated at 80 C. overnight. The solution is concentrated and the tan solid obtained is taken to the next step without further purification.

Reference： [1]Patent: US2007/219183,2007,A1 .Location in patent: Page/Page column 11
[2]Patent: US2007/219186,2007,A1 .Location in patent: Page/Page column 22

12
[ 94-05-3 ]
[ 6994-25-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrazine hydrate In ethanol at 20℃; for 6h;	4.2.1. 3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (2a) Hydrazine (0.02 mmol) and 2-cyano-3-ethoxy-acrylic acid ethyl ester (0.02 mmol) were dissolved in EtOH (50 mL). The reaction mixture was stirred at room temperature for 6 h. After removal of solvent under reduced pressure, the crude oil was crystallized in isopropylic ether. The precipitate was filtrated, washed and dried to give 2a as a yellow powder; purity 100%; yield: 95%. mp: 102-103 °C; 1H NMR: (300 MHz, CDCl3): δ ppm 1.32 (t, J = 7 Hz, 3H), 4.32 (q, J = 7 Hz, 2H), 6.88 (s, 2H), 7.78 (s, 1H); 13C NMR (75 MHz, CDCl3) δ ppm 14.8, 60.2, 98.2, 136.3, 154.3, 164.9; LCMS (EI(+)) m/z = 156 [M + H] +.
93%	With hydrazine hydrate In ethanol at 20℃; for 18h;
79%	With hydrazine hydrate In ethanol Reflux;	1.1 step 1: preparation of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester will 2-cyano-3-ethoxy acrylic acid ethyl ester (15.8g, 93.39mmol) was dissolved in ethanol, hydrazine hydrate (5.37ml, 85%) was added dropwise, and the reaction was refluxed overnight, concentrate, ethyl acetate and water extraction, the ethyl acetate layers are combined, dry over anhydrous sodium sulfate, concentrate to dryness to give a yellow solid 11.5g. Yield: 79%.

72.5%	With hydrazine hydrate In ethanol at 20℃; for 3h;	Step A: ethyl 3-amino-1H-pyrazole-4-carboxylate To a solution of ethyl 2-cyano-3-ethoxyacrylate (20 g, 118 mmol) in EtOH (200 mL) was added N2H4.H2O (6.12 g, 120 mmol, 98% purity). The reaction solution was stirred at 20 °C for 3 h, then concentrated under reduced pressure. The residue was triturated with MTBE (200 mL) to give the title compound (13.3 g, 72.5% yield) as a yellow solid. LCMS: m/z 156.1 (M+H)+(ES+).1H NMR (CDCl3): d 9.68 (s, 1H), 7.57 (d, 1H), 4.30 (br s, 2H), 4.23 (q, 2H), 1.32 (t, 3H).
68%	With hydrazine hydrate In ethanol for 12h; Reflux;
	Multi-step reaction with 2 steps 1: toluene / 1 h / Reflux 2: hydrogenchloride / ethanol; water / 1 h / Reflux
1.5 g	With hydrazine hydrate In ethanol at 0℃; for 8h;	1.2 Step two, Synthesis of 3-amino-pyrazole-4-carboxylic acid ethyl ester Step two, Synthesis of 3-amino-pyrazole-4-carboxylic acid ethyl ester: 170 g of ethyl ethoxymethylenecyanoacetate was dissolved in 1300 ml of ethanol, At a temperature of 0 degrees Celsius, 63 g of hydrazine hydrate with a mass fraction of 80% Keep the reaction at 0 degrees Celsius for 8 hours, The solvent is then subjected to vacuum distillation, To obtain 150 g of solid 3-amino-pyrazole-4-carboxylic acid ethyl ester;

Reference： [1]Location in patent: experimental part Deprez-Poulain, Rebecca; Cousaert, Nicolas; Toto, Patrick; Willand, Nicolas; Deprez, Benoit [European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3867 - 3876]
[2]Toto, Patrick; Chenault, Jacques; Hakmaoui, Ahmed El; Akssira, Mohamed; Guillaumet, Gerald [Synthetic Communications, 2008, vol. 38, # 5, p. 674 - 683]
[3]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - CN111217816, 2020, A Location in patent: Paragraph 0158; 0161-0164
[4]Current Patent Assignee: ROCHE HOLDING AG - WO2021/32588, 2021, A1 Location in patent: Page/Page column 164
[5]Yokokawa, Fumiaki; Wang, Gang; Chan, Wai Ling; Ang, Shi Hua; Wong, Josephine; Ma, Ida; Rao, Srinivasa P. S.; Manjunatha, Ujjini; Lakshminarayana, Suresh B.; Herve, Maxime; Kounde, Cyrille; Tan, Bee Huat; Thayalan, Pamela; Ng, Seow Hwee; Nanjundappa, Mahesh; Ravindran, Sindhu; Gee, Peck; Tan, Maria; Wei, Liu; Goh, Anne; Chen, Pei-Yu; Lee, Kok Sin; Zhong, Chen; Wagner, Trixie; Dix, Ina; Chatterjee, Arnab K.; Pethe, Kevin; Kuhen, Kelli; Glynne, Richard; Smith, Paul; Bifani, Pablo; Jiricek, Jan [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 5, p. 451 - 455]
[6]La Rosa, Salvatore; Benicchi, Tiziana; Bettinetti, Laura; Ceccarelli, Ilaria; Diodato, Enrica; Federico, Cesare; Fiengo, Pasquale; Franceschini, Davide; Gokce, Ozgun; Heitz, Freddy; Lazzeroni, Giulia; Luthi-Carter, Ruth; Magnoni, Letizia; Miragliotta, Vincenzo; Scali, Carla; Valacchi, Michela [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984]
[7]Current Patent Assignee: SHANGHAI MICRO MEGA - CN106518765, 2017, A Location in patent: Paragraph 0009

13
[ 2065-75-0 ]
[ 6994-25-8 ]
[ 1027511-41-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: 2-Bromo-malonaldehyde; 3-amino-4-pyrazolecarboxylic acid ethyl ester With acetic acid In ethanol at 70℃; for 0.5h; Stage #2: With sodium hydroxide; water monomer In ethanol; dichloromethane	54 INTERMEDIATE 54; Ethyl 6-bromopyrazolo[l,5-α]pyrimidine-3-carboxylate; A solution of bromomalonaldehyde (1.00 g, 6.66 mmol) in EtOH (15 mL) at 70 0C was treated with ethyl 3-amino-lH-pyrazole-4-carboxylate (1.04 g, 6.66 mmol) and ηOAc (5 mL) and the mixture was stirred at 70 0C for 30 min. DCM (150 mL) and IM NaOH (30 mL) were added and the phases separated. The aqueous layer was extracted with DCM, the combined organic phases dried and concentrated to give the title compound (1.66 g, 92%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.08 Hz, 3 H) 4.45 (q, J=7.08 Hz, 2 H) 8.55 (s, 1 H) 8.76 (d, 1 H) 8.91 (d, J=2.20 Hz, 1 H). MS (ESI+) m/z = 270/272.
63%	With acetic acid In ethanol at 70℃; for 2h;	61.A Step A. Ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate To a mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (3.0 g, 19.34 mmol) and 2- bromomalonaldehyde (3.21g, 21.26 mmol) in ethanol (10 mL) was added acetic acid (30 mL). The mixture was stirred for 2h at 70 oC. The reaction was concentrated to dryness. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate solution was added. The organic phase was extracted and dried over sodium sulfate before concentration to dryness. The residue was then purified by silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (3.3 g, 63%) as a white solid. MS (ESI): m/z = 270.0 [M+1]+.
63%	With acetic acid In ethanol at 70℃; for 2h;

60%	With acetic acid In ethanol at 70℃; for 3h;	4.1.2 General procedure for the synthesis of ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylates (2a-n) General procedure: The mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (775mg, 5.0mmol, 1.0eq.) and diketone or dialdehydecompounds (5.25mmol, 1.05eq.) in AcOH (4mL) and EtOH (4mL) was stirred at 70 for 3h. The mixture was concentrated in vacuo and then partitioned between 50mL EtOAc and 50mL NaHCO3 aqueous solution. The organic layer was collected, and the aqueous phase was extracted with 30mL EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residues were purified by column chromatography (silica gel, petroleum ether (b.p. 60-90 )/ethyl acetate, 20:1 to 3:1) to obtain the intermediates. Ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (2aa). Yield: 60%. Yellow solid. M.P. 140.7-142.8 . 1H NMR (300MHz, DMSO-d6) δ (ppm): 9.75 (d, J=2.1Hz, 1H), 8.89 (d, J=2.1Hz, 1H), 8.59 (s, 1H), 4.28 (q, J=7.0Hz, 2H), 1.29 (t, J=7.0Hz, 3H). 13C NMR (75MHz, DMSO-d6) δ (ppm): 161.4, 153.7, 147.7, 145.2, 137.4, 105.7, 102.3, 59.8, 14.4. IR νmax (neat): 3062, 2976, 1708, 1539, 1375, 1259, 1209, 1195, 1050, 902, 806, 782, 695. HRMS (ESI+):m/z[2M+Na]+ calcd. for C18H16Br2N6O4Na+, 560.9492; found, 560.9492 (error 0ppm).
60%	With acetic acid In ethanol at 70℃; for 3h;	4.1.2 General procedure for the synthesis of ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylates (2a-n) General procedure: The mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (775mg, 5.0mmol, 1.0eq.) and diketone or dialdehydecompounds (5.25mmol, 1.05eq.) in AcOH (4mL) and EtOH (4mL) was stirred at 70 for 3h. The mixture was concentrated in vacuo and then partitioned between 50mL EtOAc and 50mL NaHCO3 aqueous solution. The organic layer was collected, and the aqueous phase was extracted with 30mL EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residues were purified by column chromatography (silica gel, petroleum ether (b.p. 60-90 )/ethyl acetate, 20:1 to 3:1) to obtain the intermediates. Ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (2aa). Yield: 60%. Yellow solid. M.P. 140.7-142.8 . 1H NMR (300MHz, DMSO-d6) δ (ppm): 9.75 (d, J=2.1Hz, 1H), 8.89 (d, J=2.1Hz, 1H), 8.59 (s, 1H), 4.28 (q, J=7.0Hz, 2H), 1.29 (t, J=7.0Hz, 3H). 13C NMR (75MHz, DMSO-d6) δ (ppm): 161.4, 153.7, 147.7, 145.2, 137.4, 105.7, 102.3, 59.8, 14.4. IR νmax (neat): 3062, 2976, 1708, 1539, 1375, 1259, 1209, 1195, 1050, 902, 806, 782, 695. HRMS (ESI+):m/z[2M+Na]+ calcd. for C18H16Br2N6O4Na+, 560.9492; found, 560.9492 (error 0ppm).
15 g	With acetic acid In ethanol at 70℃; for 1h;	Intermediate 3 To a solution of of 2-Bromo-malonaldehyde (9.73 g; 64 mmol) in EtOH (100 mL) at 70° C., 3-amino-4-carbethoxypyrazole (10 g, 64 mmol) and AcOH (100 mL) were added and the mixture stirred at 70° C. for 1 h. Solvents were evaporated, the residue treated with DCM (100 mL) and a 1N solution of NaOH (100 mL). Phases were separated, organics washed with a saturated solution of NaCl, dried over sodium sulphate and evaporated. The crude was purified flash cromatography (eluent 10:1 PE/EtOAc) to obtain 15 g of the title compound as white solid. LC-MS (Method 2): Rt=0.98 min MS (ESI pos): m/z=271 (M+H)+

Reference： [1]Current Patent Assignee: KANCERA AB - WO2008/116898, 2008, A1 Location in patent: Page/Page column 97
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2017/108723, 2017, A2 Location in patent: Page/Page column 342
[3]Bryan, Marian C.; Drobnick, Joy; Gobbi, Alberto; Kolesnikov, Aleksandr; Chen, Yongsheng; Rajapaksa, Naomi; Ndubaku, Chudi; Feng, Jianwen; Chang, Willy; Francis, Ross; Yu, Christine; Choo, Edna F.; Dement, Kevin; Ran, Yingqing; An, Le; Emson, Claire; Huang, Zhiyu; Sujatha-Bhaskar, Swathi; Brightbill, Hans; Dipasquale, Antonio; Maher, Jonathan; Wai, John; McKenzie, Brent S.; Lupardus, Patrick J.; Zarrin, Ali A.; Kiefer, James R. [Journal of Medicinal Chemistry, 2019, vol. 62, # 13, p. 6223 - 6240]
[4]Abdukirim, Elyar; Cheng, Kai-Wen; Chou, Tsui-Fen; Huo, Ran; Kang, Guifeng; Li, Shan; Wang, Feng; Zhang, Gang; Zhu, Yingying [Bioorganic and Medicinal Chemistry, 2022, vol. 62]
[5]Abdukirim, Elyar; Cheng, Kai-Wen; Chou, Tsui-Fen; Huo, Ran; Kang, Guifeng; Li, Shan; Wang, Feng; Zhang, Gang; Zhu, Yingying [Bioorganic and Medicinal Chemistry, 2022, vol. 62]
[6]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2017/101411, 2017, A1 Location in patent: Paragraph 0425; 0426; 0427; 0428

14
[ 6994-25-8 ]
[ 152873-64-8 ]
[ 1204926-19-1 ]

Yield	Reaction Conditions	Operation in experiment
5%	With acetic acid for 4h; Reflux;	12 N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-lH-pyrazol-4-yl)-6- fluoropyrazolo[ 1 ,5-a]pyrimidine-3-carboxamide A solution of (2Z)-3-(diethylamino)-2-fluoro-2-propenal (326 mg, 2.25 mmol- synthesised according to the literature procedure: K. Funabiki, T. Ohtsuki, T. lshihara and. Yamanaka, Chem. Lett., 1994, 1075-78.) and ethyl 3-amino-l H-pyrazole-4- carboxylate (698 mg, 4.50 mmol) in acetic acid (6 ml) was heated under reflux for 4 h. The mixture was allowed to cool to room temperature and concentrated under vacuum afford a pale yellow solid. The resultant residue was treated with 2M aqueous NaOH (15 ml) then extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate in pentane). Appropriate fractions were combined and evaporated to afford ethyl 6-fluoropyrazolo[l,5-a]pyrimidine-3- carboxylate (24mg, 5%) as a pale yellow solid. LC/MS (Method K, ESI): [M+H]+ = 325, RT = 3.89 min; 1H NMR (400 MHz, CDC13): δ 8.82 (d, J= 2.7 Hz, 1H), 8.72 (dd, J= 3.6, 2.7 Hz, 1H), 8.60 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).
	Stage #1: 3-amino-4-pyrazolecarboxylic acid ethyl ester; (Z)-3-(diethylamino)-2-fluoroacrylaldehyde With acetic acid for 2h; Reflux; Stage #2: With sodium hydroxide In dichloromethane; water	15 Description 15Ethyl 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate A solution of (2Z)-3-(diethylamino)-2-fluoro-2-propenal (660 mg, 4.55 mmol-synthesized according to the literature procedure: K. Funabiki, T. Ohtsuki, T. Ishihara and H. Yamanaka, Chem. Lett., 1994, 1075-78.) and ethyl 3-amino-1H-pyrazole-4-carboxylate (1058 mg, 6.82 mmol) in acetic acid (5 ml) was heated at reflux for 1 h. Additional ethyl 3-amino-1H-pyrazole-4-carboxylate (200 mg) was added and the solution heated at reflux for a further 1 h. Concentration under vacuum gave a pale yellow solid that was suspended in DCM (25 ml) and 2M aqueous NaOH (25 ml). The organic layers were isolated using a phase separator, then washed with 2M aqueous HCl (25 ml), and isolated using a phase separator. Concentration under vacuum gave a pale yellow solid (530 mg). Flash chromatography (silica; Flash 12M; 2% [2M NH3 in MeOH] in DCM) and concentration of the desired fractions gave the title compound as a pale yellow solid (464 mg).m/z (API-ES) 325 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.1 Hz, 3H), 4.45 (q, J=7.1 Hz, 2H), 8.60 (s, 1H), 8.72 (dd, J=3.6, 2.7 Hz, 1H), 8.82 (d, J=2.7 Hz, 1H)19F NMR (377 MHz, CHLOROFORM-d) δ ppm -149.6 (s)

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2018/166993, 2018, A2 Location in patent: Page/Page column 112
[2]Current Patent Assignee: BIOGEN IDEC INC. - US2010/16330, 2010, A1 Location in patent: Page/Page column 12

15
[ 23975-61-3 ]
[ 6994-25-8 ]
[ 1260243-03-5 ]

Yield	Reaction Conditions	Operation in experiment
27%	With acetic acid for 4h; Reflux;

Reference： [1]Location in patent: experimental part Yoshida, Masato; Mori, Akira; Inaba, Atsuhiro; Oka, Masahiro; Makino, Haruhiko; Yamaguchi, Masashi; Fujita, Hisashi; Kawamoto, Tomohiro; Goto, Mika; Kimura, Hiroyuki; Baba, Atsuo; Yasuma, Tsuneo [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 24, p. 8501 - 8511]

16
[ 1495-03-0 ]
[ 6994-25-8 ]
[ 1260243-05-7 ]

Yield	Reaction Conditions	Operation in experiment
34%	With acetic acid for 4h; Reflux;

17
[ 1260243-04-6 ]
[ 23975-60-2 ]
[ 1260243-02-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 8501 - 8511

18
[ 5941-55-9 ]
[ 6994-25-8 ]
[ 926663-00-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		Preparation B; Ethyl 5-chloropyrazolor 1 ,5-alpyrimidine-3-carboxylate; Step A: Preparation of ethyl 5-hvdroxypyrazolo[l,5-a1pyrimidine-3- carboxylate.; Ethyl 3-amino-lH-pyrazole-4-carboxylate (25.0 g, 161 mmol) and (E)-ethyl 3- ethoxyacrylate (35.8 ml, 242 mmol) were mixed in DMF (537 mL). Cesium carbonate (78.7 g, 242 mmol) was added and the mixture heated to 110 0C for 15 hours. The reaction mixture was cooled to ambient temperature and acidified with HOAc to pH 4. The resultant precipitate was filtered and washed with water and EtOAc, yielding the title compound as a fluffy white solid. Additional material was obtained by an aqueous workup. The filtrate was concentrated to remove the DMF, was diluted in EtOAc (500 mL) and washed with H2O. The resultant precipitate in the EtOAc layer was filtered and washed with water and EtOAc to obtain additional product. The solids were pooled and dried in vacuum to afford ethyl 5- hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (33.3 g, 100 % yield) as a fluffy white solid. MS (apci) m/z = 206.2 (M-H).
95.6%		To a reactor was charged K3PO4 (4104 g granular, 19.3 moles), ethyl 3-amino-lH-pyrazole-4-carboxylate (2000 g, 12.9 moles), and DMF (18.8 kg) and the mixture was agitated. After 20 min, (£)- <strong>[5941-55-9]ethyl 3-ethoxyacrylate</strong>, (2230 g, 15.5 moles) was added and the mixture was heated to 110- 115 C internal temperature (IT). After the reaction was judged to be complete based on consumption of starting material, heating was ceased. The mixture was allowed to stir and cool overnight. Aqueous hydrochloric acid (3 M, 13 L) was added over ~ 2 h. DI water (6 L) was added and the mixture was allowed to stir overnight. The mixture was filtered through polypropylene filter cloth (PPFC) and the residue was washed with water (3 x 5 vol, 3 x 10 L). The solid was placed in trays and oven dried under vacuum at 55 C for 3 days and then 45 C for 4 days to constant wei ht of (2553 g 95.6%).

Reference： [1]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 70
[2]Patent: WO2019/84285,2019,A1 .Location in patent: Page/Page column 205

19
[ 326-06-7 ]
[ 6994-25-8 ]
ethyl 5-phenyl-7-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With acetic acid for 4h; Reflux;	1.A Step A: A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione 1 (6.97 g, 32.24 mmol) and ethyl 3-aminopyrazole-4-carboxylate 2 (5.0 g, 32.22 mmol) in AcOH (100 mL) was refluxed for 4 h. The mixture was cooled to room temperature and concentrated and precipitated crystals were collected by filtration to give 8.63 g (79%) of the title compound as yellow crystals. 1H NMR (CDCl3, 200 MHz): 1.47 (3H, t, J=7.0 Hz), 4.47 (2H, q, J=7.0 Hz), 7.54-7.61 (3H, m), 7.80 (1H, s), 8.23-8.28 (2H, m), 8.68 (1H, s).
77%	With acetic acid Reflux;
	In acetic acid for 0.0833333h; Microwave irradiation;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US9447100, 2016, B2 Location in patent: Page/Page column 57; 58
[2]Lepri, Susan; Nannetti, Giulio; Muratore, Giulia; Cruciani, Gabriele; Ruzziconi, Renzo; Mercorelli, Beatrice; Palù, Giorgio; Loregian, Arianna; Goracci, Laura [Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4337 - 4350]
[3]Location in patent: experimental part Mulakayala, Naveen; Reddy, Upendar; Chaitanya; Hussain, Manzoor; Kumar, Chitta Suresh; Golla, Narayanaswamy [Journal of the Korean Chemical Society, 2011, vol. 55, # 4, p. 719 - 722]

20
[ 720-94-5 ]
[ 6994-25-8 ]
[ 351989-80-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 451 - 455
[2]Journal of the Korean Chemical Society,2011,vol. 55,p. 719 - 722

21
[ 18931-61-8 ]
[ 6994-25-8 ]
[ 313249-39-7 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid for 0.35h; Microwave irradiation;
	With acetic acid at 110℃;

Reference： [1]Location in patent: experimental part Mulakayala, Naveen; Reddy, Upendar; Chaitanya; Hussain, Manzoor; Kumar, Chitta Suresh; Golla, Narayanaswamy [Journal of the Korean Chemical Society, 2011, vol. 55, # 4, p. 719 - 722]
[2]Yokokawa, Fumiaki; Wang, Gang; Chan, Wai Ling; Ang, Shi Hua; Wong, Josephine; Ma, Ida; Rao, Srinivasa P. S.; Manjunatha, Ujjini; Lakshminarayana, Suresh B.; Herve, Maxime; Kounde, Cyrille; Tan, Bee Huat; Thayalan, Pamela; Ng, Seow Hwee; Nanjundappa, Mahesh; Ravindran, Sindhu; Gee, Peck; Tan, Maria; Wei, Liu; Goh, Anne; Chen, Pei-Yu; Lee, Kok Sin; Zhong, Chen; Wagner, Trixie; Dix, Ina; Chatterjee, Arnab K.; Pethe, Kevin; Kuhen, Kelli; Glynne, Richard; Smith, Paul; Bifani, Pablo; Jiricek, Jan [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 5, p. 451 - 455]

22
[ 582-65-0 ]
[ 6994-25-8 ]
[ 333761-24-3 ]

Reference： [1]Journal of the Korean Chemical Society,2011,vol. 55,p. 719 - 722

23
[ 591-50-4 ]
[ 6994-25-8 ]
[ 16078-71-0 ]
[ 16078-63-0 ]

Yield	Reaction Conditions	Operation in experiment
40%; 28%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 110℃; for 48h;Inert atmosphere;	General procedure: After standard evacuation and back-fill cycles with argon, a Schlenk tube fitted with a magnetic stirrer bar was charged with pyrazole derivative (1.29 mmol), aryl iodide (1.1 eq), K3PO4 (2 eq) and copper iodide (0.1 eq). N,N'-dimethyl-cyclohexane-1,2-diamine (0.2 eq) and anhydrous dioxane (3 mL) were then added under a stream of argon by syringe at room temperature. The sealed tube is stirred at 110 C for 24-48 h. A 28% solution of ammonia and water are added at room temperature to the reaction mixture. The resulting aqueous layer is extracted with DCM. The combined organic layers are dried on MgSO4, filtered and evaporated under reduced pressure. The residue is triturated in an appropriate solvent or purified on silica gel.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3867 - 3876

24
[ 5436-21-5 ]
[ 6994-25-8 ]
[ 62908-85-4 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of ethyl 3-amino-4-pyrazolecarboxylate (1.0 g, 6.4 mmol) and acetylacetaldehyde dimethyl acetal (1.7 g, 13 mmol) in toluene (5 mL) was heated at reflux overnight. The resulting mixture was cooled and purified by flash chromatography (hexane /ethyl acetate) to obtain 0.7 g of the ester. The ester was then dissolved in a mixture of methanol and water (1/1, 10 mL) and sodium hydroxide (0.7 g) and heated at reflux overnight. The reaction mixture was cooled, neutralized with an aqueous solution of hydrochloric acid (6 M) to pH 7 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 5-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid without further purifications.

Reference： [1]Patent: US2012/15962,2012,A1 .Location in patent: Page/Page column 67

25
[ 5436-21-5 ]
[ 6994-25-8 ]
[ 1016505-59-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; at 60.0℃; for 0.25h;	A mixture of ethyl 3-amino-4-pyrazolecarboxylate (250 mg), acetylacetaldehyde dimethyl acetale (200 μL) and concentrated hydrochloric acid (0.5 mL) was heated at 60 C. for 15 minutes. The resulting mixture was cooled and the solid which crashed out was collected by filtration, washed with ethyl acetate and dried in a vacuum oven to give 200 mg of 7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.

Reference： [1]Patent: US2012/15962,2012,A1 .Location in patent: Page/Page column 68

26
[ 2605-14-3 ]
[ 6994-25-8 ]
[ 1355241-15-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 30h;	A mixture of 3-amino-1 H-pyrazole-4-carboxyiic acid ethyl ester (730 mg, 4.71 mmol), potassium carbonate (1 .3g, 9.42 mmol) and 2-Ch.oro-6-rnethoxy benzothiazole (940 mg, 4.71 mmol) in DMF (20 mL) was stirred for 30 h at SO'C poured into water and extracted with dichioromethane. The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated. The residue was purified by chromatography on silica gel to give 738 mg (49%) of 3-amino-1-(6-methoxy- benzothiazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester.1H-NIVIR (300 MHz, CDCI3): delta = 8.69 (s, 1 H), 7.78 (d, 1 H), 7.33 (d, 1 H), 7.10 (dd, 1 H), 5.1 (br s, 2H), 4.37 (q, 2H), 3,92 (s, 3H), 1.41 (t, 3H) ppm. ESI-MS m/z 319 (M+1 ).

Reference： [1]Patent: WO2012/7510,2012,A1 .Location in patent: Page/Page column 48

27
[ 6994-25-8 ]
[ 1353100-91-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With copper(ll) bromide; isopentyl nitrite; In acetonitrile; at 50℃;	To a 0 C. solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (5.0 g, 32 mmol) and copper (II) bromide (7.2 g, 32 mmol) in acetonitrile (65 mL) was slowly added isoamyl nitrite (12 mL, 86 mmol). The reaction was heated to 50 C. and stirred overnight. The reaction was cooled to room temperature and quenched with 1 N aqueous hydrochloric acid (150 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated to give the title compound as a brown oil that partially solidified under vacuum overnight (7.1 g, 100%). 1H NMR (400 MHz, CDCl3, delta): 9.78 (br. s., 1H), 8.10 (br. s., 1H), 4.33 (q, J=7.22 Hz, 2H), 1.36 (m, 3H).
81%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 70℃; for 3h;Inert atmosphere;	To a solution of terf-BuONO (156 mmol, 16.5 g) in acetonitrile (300 mL) was added CuBr2 (156 mmol, 34.8 g). After the mixture was stirred at rt for 1 h under nitrogen, ethyl 3-amino-lH-pyrazole-4-carboxylate ( 129 mmol, 20.0 g) was added portionwise over 30 min. The reaction mixture was stirred at rt for 30 min and then was allowed to warm up to 70C and was stirred for another 2 h. After cooling to rt, the solvent was removed under reduced pressure. The residue was diluted with EtOAc ( 1 L) and was washed with brine (200 mL x 3). The organic layer was dried over MgS04, filtered, and concentrated to afford ethyl 3-bromo-lH-pyrazole- 4-carboxylate (106 mmol, 23.2 g, 81 %) and was used without any purification.LC-MS: m/z ES+= 219, 221.
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 70℃; for 2.5h;Inert atmosphere;	Example 29[00239] Example 29 presents the preparation of Cmpd 29, N-(5-fluoropyrimidin-2-yl)- 4,5,6,7-tetrahydropyrazolo[3',4':6,7]cyclohepta[1,2-d][1 ,3]thiazol-2-amine (Table II, Compound No. 29)[00240] To a solution of t-BuONO (124 g, 1.20 mol) in 3 L MeCN was added CuBr2 (279 g, 1.20 mol). The mixture was stirred at room temperature for 1 h under nitrogen, then compound 29a (160g, 1.03 mol) was added in portions over 30 min. The mixture was stirred at room temperature under nitrogen for 30 min, then heated to 70C and stirred for an additional 2h. After cooling to r.t., the solvent was removed in vacuo. The residue was diluted with EtOAc (3 L) and washed with brine (400 mL.x3). The organic layer was dried over MgS04, filtered, and concentrated to afford the crude product 29b (200 g, 89% yield) used directly in the next step without purification.

	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 70℃; for 2.75h;Inert atmosphere;	To a solution of tert-butyl nitrite (3.04 mL, 25.6 mmol) in anhydrous MeCN (80 mL) was added copper(ll) bromide (5.71 g, 25.6 mmol). The mixture was stirred at ambient temperature for 1 hour under N2, then ethyl 3-amino-lH-pyrazole-4-carboxylate (3.39 g, 21.85 mmol) added in portions over 15 min. The mixture was stirred at ambient temperature for 30 min, then heated at 70 C for 2 hrs. The reaction was allowed to cool and the acetonitrile removed under vacuum. The residue was dissolved in EtOAc (250 mL) and washed with brine (3 x 100 mL), dried (MgSO,^), filtered and concentrated to a dark green solid (5.64 g, 18.02mmol, 82% yield, 70% purity). The product was used directly in the next step without purification. [M+H]+ = 219/221
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 70℃; for 12h;Inert atmosphere;	[0499] to a solution of t-buono (3.8 ml, 30.94 mmol) in CH3CN (60 ml) was added cubr2 (6.91 g, 30.94 mmol). The mixture was stirred at 25 C for 1 h under N2. Then compound 30a (4 g, 25.78 mmol) was added protionwise. The mixture was then heated to 70 C and stirred for 12 hrs. The reaction was washed with H2O (100 ml), extracted with EtOAc (100 ml x 2). The organics were collected, dried with Na2SO4, filtered and concentrated to afford intermediate compound 30b (6 g, crude) as black brown oil. MS (ESI) m/z (m+ h)+ 218.9, 220.9.

Reference： [1]Patent: US2012/108619,2012,A1 .Location in patent: Page/Page column 26
[2]Patent: WO2012/9009,2012,A2 .Location in patent: Page/Page column 56
[3]Patent: WO2012/8999,2012,A2 .Location in patent: Page/Page column 75
[4]Journal of Organic Chemistry,2012,vol. 77,p. 10050 - 10057
[5]Patent: WO2014/188211,2014,A1 .Location in patent: Page/Page column 78
[6]Patent: WO2018/64119,2018,A1 .Location in patent: Paragraph 0499; 0505; 0935

28
[ 6994-25-8 ]
[ 623-47-2 ]
[ 926663-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In ethanol; at 140℃; for 0.333333h;Microwave irradiation;	nthesis of ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3-carboxylate (1-10); 1-9 1-10; [000229] A solution of ethyl 3-amino-lH-pyrazole-4-carboxylate (1.28 g, 8.3 mmol) and ethyl propiolate (0.89 g, 9.1 mmol) in EtOH/AcOH, 5: 1 (20 mL) was heated under microwave conditions at 140 C for 20 minutes. The crude reaction mixture was reduced to dryness and recrystallized from EtOH to afford ethyl 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (1-9) as a white crystalline solid. Alternatively, the crude reaction mixture could be purified by column chromatography on silica with hexanes/EtOAc gradient as eluant. 1H NMR (400MHz, DMSO-dg) delta 11.8 (s, 1 H), 8.58 (d, J = 7.6 Hz, 1 H), 8.14 (s, 1 H), 6.15 (d, J = 7.6 Hz, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 1.30 (t, J = 6.8 Hz, 3 H). MS m/z 208.1 (M+l)+.

Reference： [1]Patent: WO2012/34095,2012,A1 .Location in patent: Page/Page column 68

29
[ 6994-25-8 ]
[ 1374257-98-3 ]
[ 1374258-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; potassium iodide; sodium nitrite / water / 20 °C 2: caesium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2012/108619, 2012, A1

30
[ 41739-23-5 ]
[ 6994-25-8 ]
[ 438218-16-7 ]
C₁₁H₁₁F₂N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid at 110℃;

Reference： [1]Location in patent: experimental part Patnaik, Samarjit; Zheng, Wei; Choi, Jae H.; Motabar, Omid; Southall, Noel; Westbroek, Wendy; Lea, Wendy A.; Velayati, Arash; Goldin, Ehud; Sidransky, Ellen; Leister, William; Marugan, Juan J. [Journal of Medicinal Chemistry, 2012, vol. 55, # 12, p. 5734 - 5748]

31
[ 6994-25-8 ]
1-cyclopropyl-4,4-difluoro-1,3-butanedione [ No CAS ]
C₁₃H₁₃F₂N₃O₂ [ No CAS ]
[ 512825-94-4 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid at 110℃;

32
[ 207974-17-2 ]
[ 6994-25-8 ]
[ 1384973-07-2 ]

Yield	Reaction Conditions	Operation in experiment
87.6%	In toluene for 6h; Reflux;	8 Example 8: Synthesis of 5-(2, 6-difluorophenyl)-6-(pyridin-3-ylmethylthio)-lH-pyrazolor3,4- dlpyrimidin-4(5H)-one (A565 (27)):A565 (27)Scheme 9: 5-(2,6-difluorophenyl)-6-(pyridin-3-ylmethylthio)-lH-pyrazolo[3,4- d]pyrimidin-4(5H)-one (A565 (27))[0143] Synthesis of 5-(2,6-difluorophenyl)-6-thioxo-6,7-dihydro-lH-pyrazolor3,4- dlpyrimidin-4(5H)-one(26). A mixture of ethyl 5-amino-lH-pyrazole-4-carboxylate (755 mg, 5 mmol) and l,3-difluoro-2-isothiocyanatobenzene (855 mg, 5 mmol) in dry toluene 5mL was refluxed for 6h, then cooled. Intermediate was precipitated spontaneously and were collected as pure products. A suspension of intermediate in 4% aqueous sodium hydroxide (4 mL) was refluxed until no more of the starting material could be detected by TLC or LC-MS (l-2h). After cooling, the solution was neutralized with 4 hydrochloricacid and then extracted with ethyl acetate (3 x20mL). After drying over anhydrous magnesium sulfate, the solvent was removed and the white solid residue was purified by flash column chromatography to give pure product (M+l)+ = 281 (1.226g, white powder, 87.6%).

Reference： [1]Current Patent Assignee: AGILENT TECHNOLOGIES INC - WO2012/97196, 2012, A1 Location in patent: Page/Page column 45

33
[ 1495-03-0 ]
[ 6994-25-8 ]
[ 1260243-05-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With acetic acid for 6h; Reflux;	Intermediate 1 : Ethyl 5-(4-ethylphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine- 3-carboxylateA mixture of ethyl 3-aminopyrazole-4-carboxylate (ALDRICH, 0.635 g, 4.090 mmol) and 1- (4-ethyl-phenyl)-4,4,4-trifluoro-butane-1 ,3-dione (ARTCHEM, 1 g, 4.090 mmol) in AcOH (10 mL) was heated at reflux for 6 h. After cooling to rt the reaction mixture was poured onto ice (60 g). The solid formed was filtered off, triturated with hexane and dried to afford a pale yellow solid (950 mg, 2.61 mmol, 64%). 1H NMR (400 MHz, CDCI3) δ ppm: 8.66 (s, 1 H), 8.18 (d, 2H), 7.77 (s, 1 H), 7.39 (d, 2H), 4.47 (q, 2H), 2.76 (q, 2H), 1 .47 (t, 3H), 1.30 (t, 3H). [ES+ MS] m/z 364 (M+H)+.
64%	In acetic acid for 6h; Reflux;	Intermediate 1: Ethyl 5-(4-ethylphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 3-aminopyrazole-4-carboxylate (ALDRICH, 0.635 g, 4.090 mmol) and 1-(4-ethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (ARTCHEM, 1 g, 4.090 mmol) in AcOH (10 mL) was heated at reflux for 6 h. After cooling to rt the reaction mixture was poured onto ice (60 g). The solid formed was filtered off, triturated with hexane and dried to afford a pale yellow solid (950 mg, 2.61 mmol, 64%). 1H NMR (400 MHz, CDCl3) δ ppm: 8.66 (s, 1H), 8.18 (d, 2H), 7.77 (s, 1H), 7.39 (d, 2H), 4.47 (q, 2H), 2.76 (q, 2H), 1.47 (t, 3H), 1.30 (t, 3H). [ES+MS] m/z 364 (M+H)+.
64%	In acetic acid for 6h; Reflux;	General procedure for the synthesis of tetrahydropyrazolopyrimidine derivatives 1a-3a General procedure: Ethyl esters of THPPs 1a-3a were synthesized as previously described [1]. For the synthesis of compound 1a, a mixture of ethyl 3-aminopyrazole-4-carboxylate (0.635 g, 4.090 mmol) and 1-(4-ethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (1 g, 4.090 mmol) in AcOH (10 mL) was heated under reflux for 6 h. After cooling to room temperature the reaction mixture was poured onto ice (60 g). The solid formed was filtered off, triturated with hexane and dried to afford a pale yellow solid (950 mg, 2.61 mmol, 64%).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/143522, 2012, A1 Location in patent: Page/Page column 25-26
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2014/38989, 2014, A1 Location in patent: Paragraph 0246
[3]Fernandez-Alvaro, Elena; Esquivias, Jorge; Perez-Sanchez, Maria; Dominguez De Maria, Pablo; Remuinan-Blanco, Modesto J. [Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 100, p. 1 - 6]

34
[ 57965-22-7 ]
[ 6994-25-8 ]
[ 832136-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid at 110℃;

Reference： [1]Yokokawa, Fumiaki; Wang, Gang; Chan, Wai Ling; Ang, Shi Hua; Wong, Josephine; Ma, Ida; Rao, Srinivasa P. S.; Manjunatha, Ujjini; Lakshminarayana, Suresh B.; Herve, Maxime; Kounde, Cyrille; Tan, Bee Huat; Thayalan, Pamela; Ng, Seow Hwee; Nanjundappa, Mahesh; Ravindran, Sindhu; Gee, Peck; Tan, Maria; Wei, Liu; Goh, Anne; Chen, Pei-Yu; Lee, Kok Sin; Zhong, Chen; Wagner, Trixie; Dix, Ina; Chatterjee, Arnab K.; Pethe, Kevin; Kuhen, Kelli; Glynne, Richard; Smith, Paul; Bifani, Pablo; Jiricek, Jan [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 5, p. 451 - 455]

35
[ 6994-25-8 ]
[ 165328-11-0 ]
[ 438218-13-4 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid at 110℃;

36
[ 6994-25-8 ]
[ 1352903-61-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 0.08 h / 20 °C 1.2: 1 h / 80 °C 2.1: sodium acetate; bromine / water; ethanol / 5 h / 20 °C 3.1: hydrogenchloride / ethanol / 1 h / 50 °C
3.65 g	With N-Bromosuccinimide In acetonitrile at 10 - 35℃; for 2h;	126.A A) ethyl 3-amino-5-bromo-1H-pyrazole-4-carboxylate A) ethyl 3-amino-5-bromo-1H-pyrazole-4-carboxylate To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (4.65 g) in acetonitrile (100 mL) was added N-bromosuccinimide (5.87 g) at room temperature by small portions, and the reaction mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous sodium thiosulfate solution, and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the resulting solid was washed with diisopropyl ether/ethyl acetate to give the title compound (3.65 g). MS (API+): [M+H]+234.0, 236.0.
	Multi-step reaction with 3 steps 1: 1 h / 80 °C 2: sodium acetate; bromine / water; ethanol / 5 h / 20 °C 3: hydrogenchloride / ethanol / 1 h / 20 - 50 °C

Reference： [1]Kumar, P. Mahesh; Kumar, K. Siva; Meda, Chandana L.T.; Reddy, G. Rajeshwar; Mohakhud, Pradeep K.; Mukkanti; Krishna, G. Rama; Reddy, C. Malla; Rambabu; Kumar, K. Shiva; Priya, K. Krishna; Chennubhotla, Keerthana Sarma; Banote, Rakesh Kumar; Kulkarni, Pushkar; Parsa, Kishore V.L.; Pal, Manojit [MedChemComm, 2012, vol. 3, # 6, p. 667 - 672]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2016/159808, 2016, A1 Location in patent: Paragraph 1564; 1565
[3]Bharath, Yarlagadda; Rao, Mandava V. Basaveswara; Pal, Manojit [Letters in drug design and discovery, 2017, vol. 14, # 10, p. 1206 - 1214]

37
[ 62679-61-2 ]
[ 6994-25-8 ]
[ 438219-16-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	With acetic acid Reflux;

Reference： [1]Lepri, Susan; Nannetti, Giulio; Muratore, Giulia; Cruciani, Gabriele; Ruzziconi, Renzo; Mercorelli, Beatrice; Palù, Giorgio; Loregian, Arianna; Goracci, Laura [Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4337 - 4350]

38
[ 6994-25-8 ]
[ 315180-15-5 ]
3-amino-1-(6-fluoro-pyridin-3-yl methyl)-1H-pyrazole-4-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate In ethanol at 80℃; for 1.5h;	27.A A. 3-Amino-l-(6-fluoro-pyridin-3-ylmethyl)-lH-pyrazole-4-carboxylic acid ethyl ester To a stirred solution of 3-amino-lH-pyrazole-4-carboxylic acid ethyl ester (1.785 g, 11.51 mmol) in ethanol (10 mL) was added sodium ethoxide (1.566 g, 23.01 mmol). After 5 min a solution of 5- (chloromethyl)-2-fluoropyridine (1.675 g, 11.51 mmol) in EtOH (3 mL) was added and the reaction heated to 80 °C. After 90 min the reaction mixture was reduced in volume under vacuum and then diluted with EtOAc (200 mL) and water (100 mL). The organics were isolated and washed with brine (100 mL), dried over magnesium sulfate, filtered and solvent removed. The crude product was purified by chromatography (80 g column, slowly 0-40% (3:1 EtOAcMeCN) in isohexanes). The undesired regioisomer 5-amino-l-(6-fluoro-pyridin-3-ylmethyl)-lH-pyrazole-4-carboxylic acid ethyl ester was isolated from the first set of fractions (768 mg, 2.76 mmol, 24 % yield) as an oil that solidified to a waxy solid on standing. The desired isomer 3-amino-l-(6-fluoro-pyridin-3-ylmethyl)-lH-pyrazole-4-carboxylic acid ethyl ester (712 mg, 2.61 mmol, 22.7% yield) was isolated as a waxy solid from the second set of fractions. [M+H]+ =265

Reference： [1]Current Patent Assignee: KALVISTA PHARMACEUTICALS INC - WO2014/188211, 2014, A1 Location in patent: Page/Page column 96

39
[ 6994-25-8 ]
[ 607-97-6 ]
ethyl 6-ethyl-5-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With acetic acid In acetic acid for 12h; Inert atmosphere; Reflux;	56.2 Ethyl 6-ethyl-5-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate Step 2 Ethyl 6-ethyl-5-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate To a mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (100 mg, 0.65 mmol) in acetic acid (5 mL) was added 2-ethyl-3-oxo-butyric acid ethyl ester (102 mg, 0.65 mmol). The mixture was stirred at reflux for 12 h under nitrogen before cooling to room temperature. The solvent was removed in vacuo to afford a crude residue. The crude product was purified on silica gel (petroleum ether:ethyl acetate=8:5) to afford the desired product (110 mg, 70% yield). MS m/z: 250 [M+H+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; MORPHOSYS AG - US2015/65522, 2015, A1 Location in patent: Paragraph 0431; 0432

40
[ 2065-75-0 ]
[ 6994-25-8 ]
[ 1027511-41-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With acetic acid In ethanol at 70℃; for 0.5h;	[00790] Ethyl 6-brom BMT) [00791] A solution of 2-bromopropanedial (5.11 g, 33.8 mmol, CASNo. 2065-75-0) in EtOH (75 mL) at 70 °C was treated with ethyl 5-amino-1H-pyrazole-4-carboxylate (5.00 g, 32.2 mmol, CASNo. 6994-25-8) and AcOH (25 mL). The mixture was stirred at 70 °C for 0.5 hour. On completion, the reaction mixture was cooled, filtered and concentrated in vacuo to give the title compound (8.00 g, 85% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.8 Hz, 1H), 8.70 (d, J = 2.8 Hz, 1H), 8.49 (s, 1H), 4.40 (q, J = 7.0 Hz, 2H) 296 (6H) 137 (t J = 72 Hz 3H) LC MS (ESI+) m/z 2923 (M+N)+
52%	With acetic acid In ethanol at 70℃; for 1h; Inert atmosphere;

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2021/158634, 2021, A1 Location in patent: Paragraph 00790-00791
[2]Robb, Graeme R.; Boyd, Scott; Davies, Christopher D.; Dossetter, Alexander G.; Goldberg, Frederick W.; Kemmitt, Paul D.; Scott, James S.; Swales, John G. [MedChemComm, 2015, vol. 6, # 5, p. 926 - 934]

41
[ 1001-26-9 ]
[ 6994-25-8 ]
[ 926663-00-5 ]

Yield	Reaction Conditions	Operation in experiment
17.1 g	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;	A) ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (15.0 g) and <strong>[1001-26-9]ethyl 3-ethoxy-2-propenoate</strong> (21.0 mL) in N,N-dimethylformamide (322 mL) was added cesium carbonate (56.7 g). The reaction mixture was stirred overnight at 100° C., water was added, and acetic acid was sequentially added to adjust the pH to about 4. The obtained solid was collected by filtration, and washed with water to give the title compound (17.1 g). 1H NMR (300 MHz, DMSO-d6) delta 1.28 (3H, t, J=7.0 Hz), 4.27 (2H, q, J=6.9 Hz), 6.14 (1H, d, J=7.9 Hz), 8.13 (1H, s), 8.56 (1H, d, J=7.9 Hz), 11.75 (1H, brs).
17.1 g	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;	The 3-amino -1H-pyrazole-4-carboxylic acid ethyl ester (15.0g) and <strong>[1001-26-9]3-ethoxy-2-acrylic acid ethyl ester</strong> (21.0 ml) for N, N- dimethyl formamide (322 ml) is added in the solution cesium carbonate (56.7g). The reaction mixtures in 100 °C stirring overnight, add water, and adding acetic acid in order to adjust the pH to about 4. The collection of the solid by filtering, and by water cleaning and generates a title compound (17.1g).

Reference： [1]Patent: US2016/159808,2016,A1 .Location in patent: Paragraph 1344; 1345; 1355; 1366; 1379; 1392
[2]Patent: TW2016/520,2016,A .Location in patent: Paragraph 0159; 0164

42
[ 6994-25-8 ]
[ 315180-15-5 ]
3-amino-1-(6-fluoro-pyridin-3-yl methyl)-1H-pyrazole-4-carboxylic acid ethyl ester [ No CAS ]
5-amino-1-(6-fluoro-pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 17% 2: 23%	With potassium carbonate In acetonitrile at 20℃; Inert atmosphere;	F F.3-amino-1-(6-fluoro-pyridin-3-yl methyl)-1H-pyrazole-4-carboxylic acid ethyl ester 5-Chloromethy2fluoropyridine (375 mg, 2.58 mmo) was taken up in acetonitrie (25 mL) and potassium carbonate (534 mg, 3.87 mmo) added. (400 mg, 2.58 mmo) was dissoved in acetonitrHe (50 mL) and added dropwise over 3 hrs and the reaction stirred at rt untU compete consumption of starting materiaL The so’vent was removed under vacuum and the residue taken up in ethy acetate (60 mL) and washed with water (20 mL). The organic ayer was dried (MgSO,), fi[tered and evaporated. The residue was purified by automated flash chromatography &uting with 0 100% of a mixture of ethy’ acetate and acetonitrie (2:1 ratio) in petroeurn ether to afford two regioisomers. The first regioisomer coflected was identified as 5-amino-1-(6-fluoro-pyridine-3-ylmethyl)-1H-pyrazoe-4carboxyic acid ethy ester (154 mg, 23% yi&d). The second regioisomer was identified as the tite compound (115 mg, 17% yi&d).[MH]= 264.9

Reference： [1]Current Patent Assignee: KALVISTA PHARMACEUTICALS INC - WO2016/83818, 2016, A1 Location in patent: Page/Page column 54

43
[ 6994-25-8 ]
[ 315180-15-5 ]
3-amino-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 °C / Inert atmosphere 2: 1,4-dioxane / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: KALVISTA PHARMACEUTICALS INC - WO2016/83818, 2016, A1

44
[ 6994-25-8 ]
[ 58347-48-1 ]

Reference： [1]Patent: WO2016/73895,2016,A1
[2]Patent: WO2017/176960,2017,A1

45
[ 6290-50-2 ]
8-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1-one [ No CAS ]
[ 6994-25-8 ]
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-5-(methoxymethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 12.1 mg 2: 51 mg	Stage #1: 1-methoxypentane-2,4-dione; ethyl 5-amino-1H-pyrazole-4-carboxylate With acetic acid at 110℃; for 1h; Microwave irradiation; Stage #2: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 72h; Stage #3: 8-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1-one With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;	219; 220 N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxamide A mixture of ethyl 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylate(isomer 1) and ethyl 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxylate(isomer 2) (1.35 g, 5.42 mmol, ratio of isomers ca 1:1) was stirred in a mixture of lithiumhydroxide (27 ml, 27 mmol, 1 M aqueous solution), tetrahydrofuran (35 ml) and methanol(9.4 ml) for 3 days at room temperature. For work-up, aqueous hydrochloric acid (2 M) was added and the precipitate formed was collected by filtration. The filtrated was extracted with ethyl acetate (3x), washed with brine, filtrated through a silicon filter and concentrated to give the title compounds as mixture of isomers (ca 1:1) (820 mg, 69%) which was used in the nextstep without further purification. N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxamide Benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (206 mg, 396 limol)and N,N-diisopropylethylamine (290 iii, 1 .7 mmol) were added to a mixture of 8-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1-one (isomer 1) (100 mg, 330 limol) and amixture of regioisomers of 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylicacid (isomer 1) and 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylic acid (isomer 2) (91.3 mg, 413 limol) in N,N-dimethylformamide (3.7 ml) and the mixture was stirred at room temperature for 12 h. For work-up, the mixture was concentrated and the residue was purified by preparative HPLC [Instrument: Waters Autopurificationsystem SOD;column: Waters XBrigde 018 5iim lOOx3Omm; eluent A: water + 0.2% Vol. ammonia (32%), eluent B: acetonitrile; gradient: 0,00-0,50 mm 10% B (25->70m1/min), 0,51-5,50 mm io20% B (70m1/min), temperature: Rt; DAD scan: 21 0-400 nm; MS ESI-Pos., scan range 160-1000 m/z] to give N-[(trans)-2-(2-chloro-4-fluorophenyl)- 1 -oxo-2-azaspiro[4.5]dec-8-yl]-7- (methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxamide (12.1 mg R = 3.9-4.3mm) and N-[(trans)-2-(2-chloro-4-fluorophenyl)- 1 -oxo-2-azaspiro[4.5]dec-8-yl]-5- (methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxam ide (51 .0 mg R = 3.2-3.5 mm).N-[(trans)-2-(2-chloro-4-fluorophenyl)- 1 -oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxymethyl)-5- methylpyrazolo[1 ,5-a]pyrim idine-3-carboxamide:LC-MS (Method 2): R = 1.23 mm; MS (ESIpos): m/z = 500 [M+H]1HNMR (400 MHz, DMSO-d6) 6 [ppm]: 1.681 (2.15), 1.689 (2.43), 1.706(1.32), 2.172 (2.51), 2.189 (1.38), 2.323 (0.87), 2.327 (1.22), 2.331 (0.87),2.665 (0.93), 2.669 (1.26), 2.674 (0.93), 2.695 (11.88), 3.521 (16.00), 3.614(2.47), 3.648 (1.32), 4.962 (4.36), 4.965 (4.20), 7.165 (2.70), 7.310 (0.95),7.339 (0.69), 7.470 (1.24), 7.485 (1.30), 7.492 (1.03), 7.507 (0.97), 7.579(1 .24), 7.601 (1.24), 7.608 (1.22), 7.981 (1 .07), 8.000 (1.03), 8.504 (4.93).(1.56), 2.1552.523 (2.41),(1.40), 3.6327.317 (1.03),(1.22), 7.587 1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 0.000 (1.29), 1.473 (0.49), 1.489(1.69), 1.693 (1.93), 1.710 (1.27), 2.000 (0.60), 2.008 (0.64), 2.020 (0.44),2.041 (0.56), 2.151 (1.06), 2.168 (1.98), 2.185 (1.13), 2.543 (0.76), 2.806(6.16), 3.311 (0.85), 3.468 (16.00), 3.620 (1.13), 3.637 (1.97), 3.654 (1.09),7.243 (2.01), 7.245 (1.99), 7.289 (0.50), 7.297 (0.52), 7.311 (0.76), 7.318(0.58), 7.339 (0.67), 7.470 (1.07), 7.485 (1.15), 7.492 (0.94), 7.507 (0.87),7.584 (1.10), 7.598 (1.08), 7.605(1.11), 7.960 (0.85), 7.979 (0.83), 8.561 (4.95).(0.44), 1.6842.031 (0.60),(6.01), 2.8084.669 (6.75),(0.84), 7.3327.576 (1.10),Isolated as side-product in the synthesis of N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2- azaspiro[4. 5]dec-8-yl]-7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxamide (51.0 mg R = 3.2-3.5 mm)LC-MS (Method 2): R = 1.17 mm; MS (ESIpos): m/z = 500.3 [M÷H]

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 207; 208; 495; 496

46
[ 6290-50-2 ]
trans-4-amino-N-(2-chloro-4-fluorophenyl)cyclohexanecarboxamide hydrochloride [ No CAS ]
[ 6994-25-8 ]
N-{trans-4-[(2-chloro-4-fluorophenyl)carbamoyl]cyclohexyl}-5-(methoxymethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]
N-{trans-4-[(2-chloro-4-fluorophenyl)carbamoyl]cyclohexyl}-7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-methoxypentane-2,4-dione; ethyl 5-amino-1H-pyrazole-4-carboxylate With acetic acid at 110℃; for 1h; Microwave irradiation; Stage #2: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 72h; Stage #3: trans-4-amino-N-(2-chloro-4-fluorophenyl)cyclohexanecarboxamide hydrochloride With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	110; 111 N-{trans-4-[(2-chloro-4-fluorophenyl)carbamoyl]cyclohexyl }-5-(methoxymethyl)-7- methylpyrazolo[1 ,5-a] pyrimidine-3-carboxamideand N-{trans-4-[(2-chloro-4-fluorophenyl)carbamoyl]cyclohexyl}-7-(methoxymethyl)-5-methylpyrazolo[1,5-a] pyrimidine-3-carboxamide A mixture of ethyl 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylate(isomer 1) and ethyl 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxylate(isomer 2) (1.35 g, 5.42 mmol, ratio of isomers ca 1:1) was stirred in a mixture of lithiumhydroxide (27 ml, 27 mmol, 1 M aqueous solution), tetrahydrofuran (35 ml) and methanol(9.4 ml) for 3 days at room temperature. For work-up, aqueous hydrochloric acid (2 M) was added and the precipitate formed was collected by filtration. The filtrated was extracted with ethyl acetate (3x), washed with brine, filtrated through a silicon filter and concentrated to give the title compounds as mixture of isomers (ca 1:1) (820 mg, 69%) which was used in the nextstep without further purification. (benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate (226 mg, 0.434 mmol) was added to a mixture of 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylic acid (isomer 1) and 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylic acid(isomer 2) (80 mg, 0.362 mmol) and trans-4-amino-N-(2-chloro-4- fluorophenyl)cyclohexanecarboxam ide hydrochloride (100 mg, 0.325 mmol) and N-ethyl-Nisopropylpropan-2-amine (252 hI, 1 .45 mmol) in 5.0 ml N,N-dimethylformamide and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with dichlormethane. The organic phase was filtrated thorugh asilicone filter, concentrated and the residue was purified by preparative HPLC (Method 8) to give the title compound (50.0 mg) together with N-{trans-4-[(2-chloro-4- fluorophenyl)carbamoyl]cyclohexyl}-7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrim idine-3- carboxamide (30.0 mg) (see Example 111).LC-MS (Method 1): R = 1.12 mm; MS (ESIpos) m/z = 474.4 [M+H].1HNMR (400 MHz, DMSO-d6): 6 [ppm] = 9.49 (5, 1H), 8.56 (5, 1H), 7.94 (d, 1H), 7.61 (dd,1H), 7.50 (dd, 1H), 7.29-7.16 (m, 2H), 4.66 (5, 2H), 3.86-3.67 (m, 1H), 3.46 (5, 3H), 2.80 (5,3H), 2.16-2.02 (m, 2H), 2.01 -1 .91 (m, 2H), 1.68-1.49 (m, 2H), 1.43-1.28 (m, 2H). Isolated as product in the synthesis of N-{trans-4-[(2-chloro-4- fluorophenyl)carbamoyl]cyclohexyl}-5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3- carboxamide (Example 110).LC-MS (Method 1): R = 1 .17 mm; MS (ESIpos) m/z = 474.4 [M+H].l[jj (400 MHz, DMSO-d6): 6 [ppm] = 9.49 (5, 1H), 8.50 (5, 1H), 7.96 (d, 1H), 7.61 (dd,1H), 7.50 (dd, 1H), 7.22 (td, 1H), 7.16 (br. s, 1H), 4.96 (d, 2H), 3.88-3.69 (m, 1H), 3.52 (5,3H), 2.68 (5, 3H), 2.13-1.86 (m, 4H), 1.68-1.48 (m, 2H), 1.45-1.27 (m, 2H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 207; 208; 412; 413

47
[ 6290-50-2 ]
8-amino-2-(2-chloro-4,6-difluorophenyl)-2-azaspiro[4.5]decan-1-one [ No CAS ]
[ 6994-25-8 ]
N-[(trans)-2-(2-chloro-4,6-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]
N-[(trans)-2-(2-chloro-4,6-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-5-(methoxymethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 19.9 mg 2: 61.7 mg	Stage #1: 1-methoxypentane-2,4-dione; ethyl 5-amino-1H-pyrazole-4-carboxylate With acetic acid at 110℃; for 1h; Microwave irradiation; Stage #2: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 72h; Stage #3: 8-amino-2-(2-chloro-4,6-difluorophenyl)-2-azaspiro[4.5]decan-1-one With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;	241; 242 N-[(trans)-2-(2-chloro-4,6-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide A mixture of ethyl 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylate(isomer 1) and ethyl 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxylate(isomer 2) (1.35 g, 5.42 mmol, ratio of isomers ca 1:1) was stirred in a mixture of lithiumhydroxide (27 ml, 27 mmol, 1 M aqueous solution), tetrahydrofuran (35 ml) and methanol(9.4 ml) for 3 days at room temperature. For work-up, aqueous hydrochloric acid (2 M) was added and the precipitate formed was collected by filtration. The filtrated was extracted with ethyl acetate (3x), washed with brine, filtrated through a silicon filter and concentrated to give the title compounds as mixture of isomers (ca 1:1) (820 mg, 69%) which was used in the nextstep without further purification. Benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (218 mg, 419 limol)and N,N-diisopropylethylamine (300 iii, 1 .7 mmol) were added to a mixture of 8-amino-2-(2-chloro-4,6-difluorophenyl)-2-azaspiro[4.5]decan-1-one (isomer 1) (200 mg, 55 % purity, 349iimol) and a mixture of regioisomers of 5-(methoxymethyl)-7-methylpyrazolo[1 5-a]pyrim idine-3-carboxylic acid (isomer 1) and 7-(methoxymethyl)-5-methylpyrazolo[1 ‘5- a]pyrimidine-3-carboxylic acid (isomer 2) (92.8 mg, 419 limol) in N,N-dimethylformamide (3.9 ml) and the mixture was stirred at room temperature for 12 h. For work-up, the mixture was concentrated and the residue was purified by preparative HPLC [Instrument: WatersAutopurificationsystem; column: Waters XBrigde 018 5i lOOx3Omm; eluent A: water + 0.2 Vol-% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0.00-0.50 mm 38% B (25->70m1/min), 0.51-5.50 mm 38-60% B (70m1/min), DAD scan: 21 0-400 nm] to give N-[(trans)2-(2-chloro-4, 6-dif luorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (19.9 mg, 11% yield, R = 4.54 -4.79 mm)and N-[(trans)-2-(2-chloro-4,6-difluorophenyl)- 1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxam ide (61 .7 mg, 34% yield, R = 3.78-4.03 mm)N-[(trans)-2-(2-chloro-4,6-difluorophenyl)- 1 -oxo-2-azaspiro[4.5]dec-8-yl]-7-(methoxym ethyl)5-methylpyrazolo[1 , 5-a]pyrim idine-3-carboxam ide:LC-MS (Method 2): R = 1.24 mm; MS (ESIpos): m/z = 518 [M÷H]1HNMR (400 MHz, DMSO-d6) 6 [ppm]: 1.469 (0.51), 1.481 (0.55), 1.499 (0.61), 1.510(0.58), 1.671 (1.16), 1.681 (1.29), 1.694 (1.25), 1.710 (0.75), 1.722 (0.45), 1.994 (0.66),2.003 (0.68), 2.013 (0.46), 2.025 (0.65), 2.035 (0.59), 2.059 (0.55), 2.197 (0.88), 2.214(1.81), 2.232 (1.04), 2.327 (0.43), 2.518 (1.24), 2.523 (0.88), 2.669 (0.47), 2.693 (11.36),3.521 (16.00), 3.540 (0.41), 3.547 (0.75), 3.633 (0.68), 3.640 (0.43), 3.651 (0.50), 3.657(0.56), 4.961 (3.83), 4.964 (3.79), 7.165 (2.56), 7.504 (0.44), 7.511 (0.63), 7.527 (0.60),7.535 (1.09), 7.542 (0.87), 7.546 (0.77), 7.549 (0.58), 7.554 (0.66), 7.558 (0.88), 7.564 (0.87), 7.568 (0.73), 7.571 (0.43), 7.575 (0.49), 7.983 (0.96), 8.002 (0.92), 8.504 (4.99),8.514 (0.41). Isolated as side product in the synthesis of N-[(trans)-2-(2-chloro-4,6-difluorophenyl)-1 -oxo-2- azaspiro[4. 5]dec-8-yI]-7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxamide:(61 .7 mg, 34% yield, R = 3.78-4.03 mm)LC-MS (Method 2): R = 1.18 mm; MS (ESIpos): m/z = 518 [M÷H][ppm]:1.694(0.55),2.804(0.45),7.536(0.81),(0.51), 1.4831.722 (0.44),(1.74), 2.2243.527 (0.58),(6.91), 7.2427.547 (0.71),(0.48), 7.960(0.56), 1.4931.994 (0.61),(0.99), 2.5183.532 (0.47),(2.03), 7.2447.550 (0.54),(0.89), 7.9791HNMR (400 MHz, DMSO-d6) 6 (0.53), 1.672 (1.08), 1.682 (1.21), 2.003 (0.64), 2.026 (0.60), 2.035(1.05), 2.523 (0.69), 2.802 (5.97),3.551 (0.69), 3.636 (0.64), 3.654(2.05), 7.512 (0.57), 7.528 (0.53),7.554 (0.63), 7.558 (0.80), 7.565(0.85), 8.560 (4.95).1 .453 (0.47), 1 .464(1.17), 1.710 (0.74),2.190 (0.84), 2.207(6.34), 3.463 (16.00),3.660 (0.54), 4.665(0.99), 7.543 (0.80),7.568 (0.68), 7.575

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 207; 208; 515; 516; 517

48
[ 6290-50-2 ]
trans-4-amino-N-(2-chloro-4,6-difluorophenyl)cyclohexanecarboxamide hydrochloride [ No CAS ]
[ 6994-25-8 ]
N-{trans-4-[(2-chloro-4,6-difluorophenyl)carbamoyl]cyclohexyl}-5-(methoxymethyl)-7-methylpyrazolo[1,5-a] pyrimidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-methoxypentane-2,4-dione; ethyl 5-amino-1H-pyrazole-4-carboxylate With acetic acid at 110℃; for 1h; Microwave irradiation; Stage #2: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 72h; Stage #3: trans-4-amino-N-(2-chloro-4,6-difluorophenyl)cyclohexanecarboxamide hydrochloride With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	112 N-{trans-4-[(2-chloro-4,6-difluorophenyl)carbamoyl]cyclohexyl}-5-(methoxymethyl)-7-methylpyrazolo[1,5-a] pyrimidine-3-carboxamide General procedure: A mixture of ethyl 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylate(isomer 1) and ethyl 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxylate(isomer 2) (1.35 g, 5.42 mmol, ratio of isomers ca 1:1) was stirred in a mixture of lithiumhydroxide (27 ml, 27 mmol, 1 M aqueous solution), tetrahydrofuran (35 ml) and methanol(9.4 ml) for 3 days at room temperature. For work-up, aqueous hydrochloric acid (2 M) was added and the precipitate formed was collected by filtration. The filtrated was extracted with ethyl acetate (3x), washed with brine, filtrated through a silicon filter and concentrated to give the title compounds as mixture of isomers (ca 1:1) (820 mg, 69%) which was used in the nextstep without further purification. (benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate (226 mg, 0.434 mmol) was added to a mixture of 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylic acid (isomer 1) and 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylic acid(isomer 2) (80 mg, 0.362 mmol) and trans-4-amino-N-(2-chloro-4- fluorophenyl)cyclohexanecarboxam ide hydrochloride (100 mg, 0.325 mmol) and N-ethyl-Nisopropylpropan-2-amine (252 hI, 1 .45 mmol) in 5.0 ml N,N-dimethylformamide and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with dichlormethane. The organic phase was filtrated thorugh asilicone filter, concentrated and the residue was purified by preparative HPLC (Method 8) to give the title compound (50.0 mg) together with N-{trans-4-[(2-chloro-4- fluorophenyl)carbamoyl]cyclohexyl}-7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrim idine-3- carboxamide (30.0 mg) (see Example 111). Was prepared in analogy to the synthesis of N-{trans-4-[(2-chloro-4-fluorophenyl)carbamoyl]cyclohexyl}-5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxamide trans-4-am ino-N-(2-chloro-4,6-difluorophenyl)cyclohexanecarboxam idehydrochloric acid salt (37.0 mg, 114 limol) as starting material to give the title compound (41.0 mg).LC-MS (Method 1): R = 1 .07 mm; MS (ESIpos) m/z = 492.3 [M+H].1HNMR (400 MHz, DMSO-d6): 6 [ppm] = 9.61 (5, 1H), 8.55 (5, 1H), 7.95 (d, 1H), 7.50-7.37(m, 2H), 7.23 (br. s, 1 H), 4.66 (5, 2H), 3.87-3.70 (m, 1 H), 3.46 (5, 3H), 2.80 (5, 3H), 2.47-2.40 (m, 1H), 2.13-1.88 (m, 4H), 1.67-1.51 (m, 2H), 1.43-1.30 (m, 2H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 207; 208; 414

49
[ 6290-50-2 ]
[ 6994-25-8 ]
ethyl 5-(methoxymethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]
ethyl 7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid at 110℃; for 1h; Microwave irradiation; Overall yield = 80 mg;	I33 ethyl 5-(methoxymethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate and ethyl 7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (1.00 g, 6.45 mmol) and 1- methoxypentane-2,4-dione (1.68 g, 12.9 mmol, GAS No. 6290-50-2) in acetic acid (5.0 ml) was heated for 1 h at 1100 in a microwave reactor (Biotage Initator). Upon cooling to room temperature, the reaction mixture was portioned between water and dichlormethane and theorganic phase was washed with water, filtrated through a silicone filter and concentrated under vacuum. The crude product was purified by flash chromatography (50 g Snap Gartrigde, hexanes/ethyl acetate 1:1) to yield the title compound as mixture of isomers fraction 1 (1 .35 g, 5.42 mmol, 1:1 mixture of isomerl / isomer 2) and fraction 2 (80 mg, 0.32 mmol, 85:15 mixture of isomer 1/isomer 2). Fraction 2:LG-MS (Method 2): R = 0.89 mm (Isomer 1); 0.91 mm (isomer 2);1HNMR (400 MHz, DMSO-d6 isomer 1): 6 [ppm] = 8.62 (5, 1H), 7.31-7.26 (m, 1H), 4.61 (5,2H), 4.33-4.25 (m, 2H), 3.44 (5, 3H), 2.80 (d, 3H), 1 .31 (t, 3H).1HNMR (400 MHz, DMSO-d6 isomer 2, characteristic signals): 6 [ppm] = 8.63 (5, 1H), 7.61(5, 1 H), 4.01 (5, 3H), 2.68 (5, 3H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 207

50
[ 6290-50-2 ]
[ 6994-25-8 ]
5-(methoxymethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid [ No CAS ]
7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-methoxypentane-2,4-dione; ethyl 5-amino-1H-pyrazole-4-carboxylate With acetic acid at 110℃; for 1h; Microwave irradiation; Stage #2: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 72h; Overall yield = 69 %; Overall yield = 820 mg;	I34 5-(methoxymethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid and 7-(methoxymethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of ethyl 5-(methoxymethyl)-7-methylpyrazolo[1 ,5-a]pyrim idine-3-carboxylate(isomer 1) and ethyl 7-(methoxymethyl)-5-methylpyrazolo[1 ,5-a]pyrimidine-3-carboxylate(isomer 2) (1.35 g, 5.42 mmol, ratio of isomers ca 1:1) was stirred in a mixture of lithiumhydroxide (27 ml, 27 mmol, 1 M aqueous solution), tetrahydrofuran (35 ml) and methanol(9.4 ml) for 3 days at room temperature. For work-up, aqueous hydrochloric acid (2 M) was added and the precipitate formed was collected by filtration. The filtrated was extracted with ethyl acetate (3x), washed with brine, filtrated through a silicon filter and concentrated to give the title compounds as mixture of isomers (ca 1:1) (820 mg, 69%) which was used in the nextstep without further purification.

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/177658, 2016, A1 Location in patent: Page/Page column 207; 208

51
[ 1260243-04-6 ]
[ 7307-04-2 ]
ethyl 7-tert-butyl-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With acetic acid; at 110℃; for 1h;Microwave irradiation;	A mixture of <strong>[1260243-04-6]ethyl 5-amino-1H-pyrazole-4-carboxylate</strong> (546 mg, 3.52 mmol) and 5,5- dimethylhexane-2,4-dione (1 .03 g, 97 % purity, 7.03 mmol) in acetic acid (2.7 ml) was heated for 1 h at 11 OC in a microwave reactor (Biotage In itator). Upon cooling to room temperature, the reaction mixture was portioned between water and dichlormethane and the organic phase was washed with water, filtrated through a silicone filter and concentrated undervacuum. The crude product was purified by flash chromatography (25 g Snap Cartrigde, hexanes/ethyl acetate gradient) to yield the title compound (850 mg, 93% yield). LC-MS (Method 1): R = 1 .25 mm; MS (ESipos) m/z = 262.2 [M+H].1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.281 (2.05), 1.299 (4.51), 1.316 (2.11), 1.375(0.78), 1.558 (16.00), 2.619 (8.39), 4.252 (0.66), 4.270 (2.08), 4.288 (2.05), 4.305 (0.61),7.072 (2.38), 8.569 (2.97).

Reference： [1]Patent: WO2016/177658,2016,A1 .Location in patent: Page/Page column 208; 209

52
[ 6994-25-8 ]
[ 50488-42-1 ]
C₁₂H₁₁F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 2-bromo-5- (trifluoromethyl)pyridine (2.25 g, 0.01 mol), C52CO3 (6.52 g, 0.02 mol) in DMF (20 mL) was stirred for 1 hour at 100 C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The cmde product was purified via silica gel chromatography (PE-EA) to give desired compound asyellow solid (1.95 g, 65%). ESI MS m/z = 301.2 [M+Hf ?HNMR (300 MHz, DMSO-d6) oe1.31 (m, 3H), 4.14-4.40 (m, 2H), 5.96 (d, J= 4.0 Hz, 2H), 7.86 (m, 1H), 8.36 (m, 1H), 8.74 (d, J = 3.7 Hz, 1H), 8.83 (d, J 2.8 Hz, 1H).
65%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 2-bromo-5- (trifluoromethyl)pyridine (2.25 g, 0.01 mol), Cs2CO3 (6.52 g, 0.02 mol) in DMF (20 mL) was stirred for 1 hour at 100C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give desired compound as yellow solid (1.95 g, 65%). ESI MS m/z = 301.2 [M+H]+.1H NMR (300 MHz, DMSO-d6) delta 1.31 (m, 3H), 4.14- 4.40 (m, 2H), 5.96 (d, J = 4.0 Hz, 2H), 7.86 (m, 1H), 8.36 (m, 1H), 8.74 (d, J = 3.7 Hz, 1H), 8.83 (d, J = 2.8 Hz, 1H).

Reference： [1]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 332; 333
[2]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 302

53
[ 5414-19-7 ]
[ 936841-73-5 ]
[ 6994-25-8 ]
C₁₆H₁₇F₃N₄O₃ [ No CAS ]
C₁₆H₁₇F₃N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 5-fluoro-2- (trifluoromethyl)pyridine (1.65 g, 0.01 mol), C52CO3(4.89 g, 0.015 mol) in DMF (8 mL) was stirred for 1 hour at 100 C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The cmde product was purified via silica gel chromatography (PE-EA) to give the mixture of desired compounds as ayellow solid (1.04 g, 35%). ESI MS m/z = 301.1[M+Hjt; NaH (168 mg, 4.2 mmol) was added to the solution of the compound from step a (1.04 g, 3.5mmol) and 1-bromo-2-(2-bromoethoxy)ethane (966 mg, 4.2 mmol) in DMF (20 mL) at 0 C.The mixture was stirred overnight. The mixture was quenched with water, extracted with EA(x3). The organic layers were combined and washed with brine (x2), dried, concentrated. Thecrude product was purified via silica gel chromatography (PE-EA) to give the mixture ofdesired compounds as a white solid (280 mg, 22%). ESI MS m/z = 371.2 [M+Hf.

Reference： [1]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 337; 338

54
[ 936841-73-5 ]
[ 6994-25-8 ]
5-amino-1-(5-trifluoromethyl-pyrid-2-yl)-4-ethoxycarbonyl-pyrazole [ No CAS ]
C₁₂H₁₁F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 5-fluoro-2- (trifluoromethyl)pyridine (1.65 g, 0.01 mol), C52CO3(4.89 g, 0.015 mol) in DMF (8 mL) was stirred for 1 hour at 100 C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The cmde product was purified via silica gel chromatography (PE-EA) to give the mixture of desired compounds as ayellow solid (1.04 g, 35%). ESI MS m/z = 301.1[M+Hjt

Reference： [1]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 337; 338

55
[ 936841-73-5 ]
[ 6994-25-8 ]
C₁₆H₁₇F₃N₄O₃ [ No CAS ]

Reference： [1]Patent: WO2017/15449,2017,A1

56
[ 10602-37-6 ]
[ 6994-25-8 ]
ethyl 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.17 g	With hydrogenchloride In 1,4-dioxane; ethanol at 80℃;	Intermediate 1 To a solution of 3-amino-4-carbethoxypyrazole (4 g, 25.27 mmol) in absolute EtOR (40 mE), 1,1,3,3-Tetra- ethoxy-2-methyl-propane (6.34 g, 26.53 mmol) was added followed by 13.90 mE of a 1M solution of HC1 in dioxane. The mixture was heated at 80 C overnight. Solvents were evaporated, then DCM and water were added. Phases were separated, organics washed with a saturated solution of NaC1, dried over sodium sulphate and evaporated to obtain 5.17 g of the title compoundEC-MS (Method 2): R=0.73 mm MS (ESI pos): mlz=206 (M+H)

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2017/101411, 2017, A1 Location in patent: Paragraph 0417; 0418; 0419; 0420

57
[ 6994-25-8 ]
[ 152873-64-8 ]
[ 1204926-19-1 ]

Yield	Reaction Conditions	Operation in experiment
26%	With acetic acid at 80℃; for 1h;	54.C; 55.C Step C. Ethyl 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of (Z)-3-(diethylamino)-2-fluoroacrylaldehyde (400 mg, 2.76 mmol) and ethyl 5- amino-1H-pyrazole-4-carboxylate (428 mg, 2.76 mmol) in acetic acid (5 mL) was stirred at 80 oC for 1h. After concentration in vacuo, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether(1:5) as eluting solvents to afford ethyl 6-fluoropyrazolo[1,5- a]pyrimidine-3-carboxylate (180 mg, 26%) as a yellow solid. MS (ESI): m/z = 210.1 [M+1]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2017/108723, 2017, A2 Location in patent: Page/Page column 333

58
[ 17649-86-4 ]
[ 6994-25-8 ]
ethyl 7-methyl-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With piperidine; acetic acid In water for 20h; Reflux;	To a solution of 4,4-bis(methylthio)but-3-en-2-one (0.5 g, 3.08 mmol) in a mixture of acetic acid/water (3:1, 48 mL) was added ethyl 3-amino-1H-pyrazole-4-carboxylate (0.36 g, 2.37 mmol) and a catalytic amount of piperidine (2 drops). The resulting solution was heated at reflux for 20 h then, after cooling, water was added (10 mL). The precipitated solid wascollected by filtration and recrystallized from a mixture of PE/ether (3:1) to furnish ethyl 7- methyl-5-(methylthio)pyrazolo[ 1,5 -aj pyrimidine-3-carboxylate (500 mg, 62%) as a yellow solid.

Reference： [1]Current Patent Assignee: BIAL R D INVESTMENTS - WO2017/176960, 2017, A1 Location in patent: Paragraph 00297

59
[ 6994-25-8 ]
[ 119741-57-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogenchloride; sodium nitrite / water / 0.42 h / 0 °C 1.2: 0.83 h 2.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 2.2: 15 h / 20 °C 3.1: N,N-dimethyl-formamide / 6 h / 140 °C 4.1: trifluoroacetic acid / dichloromethane / 3 h / 20 °C

Reference： [1]Current Patent Assignee: ATTUNE PHARMACEUTICALS INC - WO2018/11628, 2018, A1

60
[ 6994-25-8 ]
[ 105486-72-4 ]

Reference： [1]Patent: WO2018/64119,2018,A1

61
[ 6994-25-8 ]
[ 139308-52-4 ]

Reference： [1]Patent: WO2018/64119,2018,A1

62
[ 6994-25-8 ]
[ 85290-76-2 ]

Reference： [1]Patent: WO2018/64119,2018,A1

63
[ 6994-25-8 ]
[ 754219-01-7 ]
[ 799835-39-5 ]

Reference： [1]Patent: US2018/170927,2018,A1

64
[ 5414-19-7 ]
[ 936841-73-5 ]
[ 6994-25-8 ]
ethyl 3-morpholino-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate [ No CAS ]
ethyl 5-morpholino-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 5-fluoro-2- (trifluoromethyl)pyridine (1.65 g, 0.01 mol), Cs2CO3(4.89 g, 0.015 mol) in DMF (8 mL) was stirred for 1 hour at 100 C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give the mixture of desired compounds as a yellow solid (1.04 g, 35%). ESI MS m/z = 301.1[M+H]+. Exam les 444 and 445 ste b: NaH (168 mg, 4.2 mmol) was added to the solution of the compound from step a (1.04 g, 3.5 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (966 mg, 4.2 mmol) in DMF (20 mL) at 0 C. The mixture was stirred overnight. The mixture was quenched with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give the mixture of desired compounds as a white solid (280 mg, 22%). ESI MS m/z = 371.2 [M+H]+.

Reference： [1]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 307

65
[ 936841-73-5 ]
[ 6994-25-8 ]
C₁₂H₁₁F₃N₄O₂ [ No CAS ]
C₁₂H₁₁F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (1.55 g, 0.01 mol), 5-fluoro-2- (trifluoromethyl)pyridine (1.65 g, 0.01 mol), Cs2CO3(4.89 g, 0.015 mol) in DMF (8 mL) was stirred for 1 hour at 100 C. The mixture was diluted with water, extracted with EA (x3). The organic layers were combined and washed with brine (x2), dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give the mixture of desired compounds as a yellow solid (1.04 g, 35%). ESI MS m/z = 301.1[M+H]+.

Reference： [1]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 307

66
[ 5018-30-4 ]
[ 6994-25-8 ]
C₁₀H₁₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.70%	With ethanol; sodium ethanolate; for 20h;Reflux;	To a solution of Int-3 (50 g, 322.58 mmol, 1.0 eq) in ethanol (250 mL) was added Int-3.1 (104.5 g, 645.16 mmol, 2.0 eq) followed by drop wise addition of sodium ethoxide (75 mL, 21% ethanol solution, 3.0 eq). Reaction mixture was stirred with heating under reflux for 20 h. After completion of reaction, reaction mixture was concentrated under reduced pressure to obtain residue which was dissolved in water, acidified with concentrated hydrochloric acid to pH?3-4. Precipitated solid was filtered, washed with water, diethyl ether and dried well to obtain pure Int-3.1 (43 g, Yield: 52.70%; MS (ES): m/z 254.07 [M+H]+).

Reference： [1]Patent: US2020/131201,2020,A1 .Location in patent: Paragraph 0438-0440

67
[ 6994-25-8 ]
[ 105772-13-2 ]
ethyl 3-amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
347.2 g	With potassium phosphate monohydrate In acetonitrile at 80℃; for 6.5h; Inert atmosphere;	Synthesis of ethyl 3-amino-1-[(frans)-4-cyanotetrahydropyran-3-yl]pyrazole- 4-carboxylate (V) A jacketed glass reactor (5L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with dry acetonitrile (750 ml_), potassium phosphate tribasic monohydrate (38.3 g, 0.16 mol) and ethyl 3-amino-1 H-pyrazole-4-carboxylate (IV) (500 g, 3.19 mol). The resulting mixture was heated to 80 °C and 3,6- dihydro-2H-pyran-4-carbonitrile (III) (462 g, 4.15 mol) was quickly added via an addition funnel. The addition funnel was rinsed with acetonitrile (250 ml_) which was also added to the reaction mixture. The reaction mixture was reacted for 6.5 h at 80 °C under vigorous stirring before heating was stopped and the reaction mixture further stirred overnight. After concentration of the reaction mixture under reduced pressure a yellow slurry was obtained. The obtained material was diluted with ethyl acetate (5 L) and the resulting solution was extracted with aqueous 1 M hydrochloric acid (3 c 1.5 L)was washed once with brine (1 L),was filtered over a filter filled with a pad of magnesium sulfate and was concentrated under reduced pressure to afford a yellow oil. The yellow oil was taken up in methanol (1.36 L), the resulting mixture was warmed up to 40 °C under stirring to ensure homogenization. The solution was then cooled to 25 °C and was seeded at this temperature with 2.0 g pure seeds before being gently stirred at -20 °C overnight. The precipitate formed was filtered off, was washed with pre chilled methanol (1 L) and was dried under reduced pressure at 40 °C to give an off- white solid. The isolated white solid was heated to reflux in 2-propanol (1 L) for 1 h and the mixture was slowly allowed to reach room temperature under gentle stirring overnight. The precipitate formed was filtered off, was washed with 2- propanol (300 ml_) and was dried under reduced pressure at 40 °C to afford the desired product (V) as off-white solid (347. 2 g, 1.20 mol). HPLC Method A: Ret. Time: 0.75 min; m/z 265 NMR (600 MHz, CDCI3) d (ppm): 7.82 (s, 1 H); 4.28 (2H, J = 7.1 Hz, q); 4.14 (1 H, J = 4.3, 9.0 Hz, dt); 4.08 (1 H, J = 4.2, 12.0 Hz, dd); 4.00 (1 H, J = 4.0, 12.1 Hz, td); 3.90 (1 H, J = 8.7, 12.0 Hz, dd); 3.55 - 3.50 (1 H, m); 3.62 - 3.44 (2H, m); 2.20 - 2.10 (1 H, m); 2.06 - 1.94 (1 H, m); 1.34 (3H, J = 7.1 Hz, t)

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2020/120673, 2020, A1 Location in patent: Page/Page column 25-26

68
[ 6994-25-8 ]
[ 105772-13-2 ]
ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate [ No CAS ]
ethyl 3-amino-1-[(3S,4R)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-amino-4-pyrazolecarboxylic acid ethyl ester; 3,6-dihydro-2H-pyran-4-carbonitrile With potassium phosphate monohydrate In acetonitrile at 80℃; for 6.5h; Inert atmosphere; Stage #2: Resolution of racemate;	Chiral separation of ethyl 3-amino-1-[(frans)-4-cyanotetrahydropyran-3- yl]pyrazole-4-carboxylate (V) to ethyl 3-amino-1-[(3S,4/?)-4-cyanotetrahydro- 2H-pyran-3-yl]-1 H-pyrazole-4-carboxylate (VI) A jacketed glass reactor (5L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with dry acetonitrile (750 ml_), potassium phosphate tribasic monohydrate (38.3 g, 0.16 mol) and ethyl 3-amino-1 H-pyrazole-4-carboxylate (IV) (500 g, 3.19 mol). The resulting mixture was heated to 80 °C and 3,6- dihydro-2H-pyran-4-carbonitrile (III) (462 g, 4.15 mol) was quickly added via an addition funnel. The addition funnel was rinsed with acetonitrile (250 ml_) which was also added to the reaction mixture. The reaction mixture was reacted for 6.5 h at 80 °C under vigorous stirring before heating was stopped and the reaction mixture further stirred overnight. After concentration of the reaction mixture under reduced pressure a yellow slurry was obtained. The obtained material was diluted with ethyl acetate (5 L) and the resulting solution was extracted with aqueous 1 M hydrochloric acid (3 c 1.5 L)was washed once with brine (1 L),was filtered over a filter filled with a pad of magnesium sulfate and was concentrated under reduced pressure to afford a yellow oil. The yellow oil was taken up in methanol (1.36 L), the resulting mixture was warmed up to 40 °C under stirring to ensure homogenization. The solution was then cooled to 25 °C and was seeded at this temperature with 2.0 g pure seeds before being gently stirred at -20 °C overnight. The precipitate formed was filtered off, was washed with pre chilled methanol (1 L) and was dried under reduced pressure at 40 °C to give an off- white solid. The isolated white solid was heated to reflux in 2-propanol (1 L) for 1 h and the mixture was slowly allowed to reach room temperature under gentle stirring overnight. The precipitate formed was filtered off, was washed with 2- propanol (300 ml_) and was dried under reduced pressure at 40 °C to afford the desired product (V) as off-white solid (347. 2 g, 1.20 mol). HPLC Method A: Ret. Time: 0.75 min; m/z 265 NMR (600 MHz, CDCI3) d (ppm): 7.82 (s, 1 H); 4.28 (2H, J = 7.1 Hz, q); 4.14 (1 H, J = 4.3, 9.0 Hz, dt); 4.08 (1 H, J = 4.2, 12.0 Hz, dd); 4.00 (1 H, J = 4.0, 12.1 Hz, td); 3.90 (1 H, J = 8.7, 12.0 Hz, dd); 3.55 - 3.50 (1 H, m); 3.62 - 3.44 (2H, m); 2.20 - 2.10 (1 H, m); 2.06 - 1.94 (1 H, m); 1.34 (3H, J = 7.1 Hz, t) Separation of the mixture of enantiomers (V) to the single enantiomer (VI) was achieved by chiral chromatography.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2020/120673, 2020, A1 Location in patent: Page/Page column 25-27

69
[ 6994-25-8 ]
1-cyclopropyl-4,4-difluoro-1,3-butanedione [ No CAS ]
[ 512825-94-4 ]

Yield	Reaction Conditions	Operation in experiment
56%	With acetic acid at 110℃; for 16h; Sealed tube;

Reference： [1]Manetti, Fabrizio; Stecca, Barbara; Santini, Roberta; Maresca, Luisa; Giannini, Giuseppe; Taddei, Maurizio; Petricci, Elena [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 5, p. 832 - 838]

70
[ 6994-25-8 ]
[ 1394003-51-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / acetonitrile; tetrahydrofuran / 0 - 20 °C 2: acetic acid / 68 h / 70 °C
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide / acetonitrile; tetrahydrofuran / 0 - 20 °C 2: acetic acid / 18 h / 70 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2021/32992, 2021, A1
[2]Current Patent Assignee: PFIZER INC - WO2022/180397, 2022, A1

71
[ 6994-25-8 ]
[ 1374258-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sulfuric acid / water / 0.5 h / 0 °C 1.2: 0.5 h / 0 °C 1.3: 14.5 h / 0 - 25 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 25 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2021/55326, 2021, A1

72
[ 454-89-7 ]
[ 6994-25-8 ]
ethyl 2,4-bis(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a][1,3,5]triazine-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonium iodide In 1,2-dichloro-benzene at 140℃; for 8h;
85%	With ammonium iodide In 1,2-dichloro-benzene at 140℃; for 8h; Green chemistry;	32 Example 32 In a 35 mL reaction flask, 1v (174mg, 1mmol), 2a (77.6mg, 0.5mmol), ammonium iodide (72.5mg, 0.5mmol) and o-dichlorobenzene (2mL) were added, and then placed in a 140 °C metal bath with open stirring for 8h. 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL×3), and then the organic phase was washed sequentially with a mass concentration of 10%Na2S2O3solution and saturated saline, and the anhydrous sodium sulfate was dried. Filtered, screwed dry, separated by silica gel column (petroleum ether /ethyl acetate = 20/1, v/v) to give a yellowish solid product of 3 v (204 mg, 85%).

Reference： [1]Gao, Qinghe; Wu, Manman; Zhang, Le; Xu, Pengju; Wang, He; Sun, Zhenhua; Fang, Lizhen; Duan, Yingchao; Bai, Suping; Zhou, Xiangyu; Han, Mingxin; Zhang, Jixia; Lv, Jieli [Journal of Organic Chemistry, 2021, vol. 86, # 23, p. 17265 - 17273]
[2]Current Patent Assignee: XINXIANG MEDICAL UNIVERSITY - CN113801119, 2021, A Location in patent: Paragraph 0011; 0096-0098

73
[ 5973-71-7 ]
[ 6994-25-8 ]
ethyl 2,4-bis(3,4-dimethylphenyl)pyrazolo[1,5-a][1,3,5]triazine-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With ammonium iodide In 1,2-dichloro-benzene at 140℃; for 8h;
84%	With ammonium iodide In 1,2-dichloro-benzene at 140℃; for 8h; Green chemistry;	34 Example 34 In a 35 mL reaction flask, 1x (134 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added, and then placed in a 140 °C metal bath with open stirring for 8 h. 50mL of water was added to quench the reaction, extracted with ethyl acetate (50mL×3), and then the organic phase was washed sequentially with a mass concentration of 10%Na2S2O3solution and saturated table salt water, and the anhydrous sodium sulfate was dried. Filtered, screwed dry, separated by silica gel column (petroleum ether / ethyl acetate = 15/1, v/v) to give a light brown solid product 3x (168.1 mg, 84%).

74
[ 6994-25-8 ]
[ 1540-34-7 ]
[ 1988248-24-3 ]

Yield	Reaction Conditions	Operation in experiment
51%	With acetic acid In ethanol at 70℃; for 3h;	4.1.2 General procedure for the synthesis of ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylates (2a-n) General procedure: The mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (775mg, 5.0mmol, 1.0eq.) and diketone or dialdehydecompounds (5.25mmol, 1.05eq.) in AcOH (4mL) and EtOH (4mL) was stirred at 70 for 3h. The mixture was concentrated in vacuo and then partitioned between 50mL EtOAc and 50mL NaHCO3 aqueous solution. The organic layer was collected, and the aqueous phase was extracted with 30mL EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residues were purified by column chromatography (silica gel, petroleum ether (b.p. 60-90 )/ethyl acetate, 20:1 to 3:1) to obtain the intermediates.
51%	With acetic acid In ethanol at 70℃; for 3h;	4.1.2 General procedure for the synthesis of ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylates (2a-n) General procedure: The mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (775mg, 5.0mmol, 1.0eq.) and diketone or dialdehydecompounds (5.25mmol, 1.05eq.) in AcOH (4mL) and EtOH (4mL) was stirred at 70 for 3h. The mixture was concentrated in vacuo and then partitioned between 50mL EtOAc and 50mL NaHCO3 aqueous solution. The organic layer was collected, and the aqueous phase was extracted with 30mL EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residues were purified by column chromatography (silica gel, petroleum ether (b.p. 60-90 )/ethyl acetate, 20:1 to 3:1) to obtain the intermediates.

Reference： [1]Abdukirim, Elyar; Cheng, Kai-Wen; Chou, Tsui-Fen; Huo, Ran; Kang, Guifeng; Li, Shan; Wang, Feng; Zhang, Gang; Zhu, Yingying [Bioorganic and Medicinal Chemistry, 2022, vol. 62]
[2]Abdukirim, Elyar; Cheng, Kai-Wen; Chou, Tsui-Fen; Huo, Ran; Kang, Guifeng; Li, Shan; Wang, Feng; Zhang, Gang; Zhu, Yingying [Bioorganic and Medicinal Chemistry, 2022, vol. 62]

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[ 6994-25-8 ] Synthesis Path-Upstream 1~12

[ 6994-25-8 ] Synthesis Path-Downstream 1~74

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Esters

Amines

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Pyrazoles

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[ 6994-25-8 ]

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