[ CAS No. 1224944-77-7 ] {[proInfo.proName]}

Name: 1224944-77-7|Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate|97%
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Quality Control of [ 1224944-77-7 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1224944-77-7 ]

CAS No. :	1224944-77-7	MDL No. :	MFCD12407819
Formula :	C₉H₈ClN₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UOZKVCQDLXBWBG-UHFFFAOYSA-N
M.W :	225.63	Pubchem ID :	58063474
Synonyms :

Calculated chemistry of [ 1224944-77-7 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	54.08
TPSA :	56.49 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.6 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.2
Log Po/w (XLOGP3) :	1.51
Log Po/w (WLOGP) :	1.56
Log Po/w (MLOGP) :	1.45
Log Po/w (SILICOS-IT) :	1.22
Consensus Log Po/w :	1.59

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.44
Solubility :	0.826 mg/ml ; 0.00366 mol/l
Class :	Soluble
Log S (Ali) :	-2.3
Solubility :	1.12 mg/ml ; 0.00496 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.82
Solubility :	0.343 mg/ml ; 0.00152 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.08

Safety of [ 1224944-77-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1224944-77-7 ]

* 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 [ 1224944-77-7 ]
Downstream synthetic route of [ 1224944-77-7 ]

[ 1224944-77-7 ] Synthesis Path-Upstream 1~3

1
[ 926663-00-5 ]
[ 1224944-77-7 ]

Yield	Reaction Conditions	Operation in experiment
97.6%	for 2 h; Reflux	Step B: Preparation of ethyl 5 -chloropyrazolo [1,5 -alpyrimidine-3 -carboxylate.; Ethyl 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (22.7 g, 110 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove the excess POCI3. The residue was diluted in DCM (100 mL) and slowly added to a flask containing ice water. The mixture was separated and the aqueous layer extracted with DCM. The combined organics were dried with MgSO₄, filtered and concentrated to afford ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3- carboxylate (24.2 g, 97.6 percent yield) as a pale yellow solid. MS (apci) m/z = 225.9 (M+H).
61%	at 100℃; for 16 h;	POCl3 (30 mL, 322 mmol) was added to 30 (5.54 g,26.7 mmol) and the mixture was stirred at 100°C for 16 h.After POCl3 was removed under reduced pressure, the residuewas partitioned between EtOAc and NaHCO3 aqueous solution. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases werewashed with water and saturated aqueous NaCl, dried overanhydrous Na2SO4 and concentrated in vacuo. The residuewas purified by column chromatography (silica gel, hexane–ethyl acetate, 19 : 1 to 1 : 1) to afford 36 (3.69 g, 16.3 mmol,61percent) as a white solid. MS (ESI/APCI) m/z 226.1 [M+H]+.
14.05 g	With trichlorophosphate In acetonitrile at 10 - 110℃; for 4 h; Inert atmosphere	B) ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (18.0 g) was suspended in acetonitrile (40 mL), phosphorus oxychloride (40 mL) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere at 110° C. for 4 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and neutralized with aqueous sodium bicarbonate solution, and insoluble material was filtered off with Celite. The organic layer of the filtrate was purified by a silica gel pad, and the solvent was evaporated under reduced pressure. The precipitated solid was washed with ethyl acetate/diisopropyl ether to give the title compound (14.1 g). The mother liquor was further concentrated under reduced pressure and the resulting solid was washed with ethyl acetate/diisopropyl ether to give the title compound (2.40 g). ¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, t, J=7.2 Hz), 4.43 (2H, q, J=7.2 Hz), 6.99 (1H, d, J=7.2 Hz), 8.56 (1H, s), 8.63 (1H, d, J=7.2 Hz).

14.1 g

With trichlorophosphate In acetonitrile at 110℃; for 4 h;

The 5-hydroxy pyrazole [1,5-a] pyrimidine-3-carboxylic acid ethyl ester (18.0g) suspended in acetonitrile (40 ml), at room temperature add oxygen phosphorus chloride (40 ml), and to the mixture under nitrogen atmosphere to 110 °C stirring 4 hours. Cooling the reaction mixture, and the concentrated under reduced pressure. Aid hemostasis diluted with ethyl acetate and to neutralize the sodium bicarbonate aqueous solution, but insoluble material to celite filtration. The organic filtrate is purified by silicon rubber, and the evaporation of the solvent under reduced pressure. Precipitation of the solid in ethyl acetate/b isopropyl group ether cleaning in order to produce the title compound (14.1g). Mother liquor further for concentrated under reduced pressure, and the generated solid of using ethyl acetate/b isopropyl group ether cleaning in order to produce the title compound (2.40g).

Reference： [1] Patent: WO2011/6074, 2011, A1, . Location in patent: Page/Page column 70-71
[2] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 11, p. 1058 - 1077
[3] Patent: WO2012/34095, 2012, A1, . Location in patent: Page/Page column 68
[4] Patent: US2016/159808, 2016, A1, . Location in patent: Paragraph 1357; 1358; 1381; 1382; 1394; 1395
[5] Patent: TW2016/520, 2016, A, . Location in patent: Paragraph 0165
[6] Patent: WO2018/81417, 2018, A2, . Location in patent: Page/Page column 162; 163

2
[ 1260243-04-6 ]
[ 1224944-77-7 ]

Reference： [1] Patent: US2016/168156, 2016, A1,
[2] Patent: WO2017/4342, 2017, A1,
[3] Patent: WO2017/15367, 2017, A1,
[4] Patent: WO2013/59587, 2013, A1,
[5] Patent: EP2768509, 2017, B1,
[6] Patent: WO2017/7759, 2017, A1,
[7] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 11, p. 1058 - 1077

3
[ 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,

[ 1224944-77-7 ] Synthesis Path-Downstream 1~20

1
[ 1218935-59-1 ]
[ 1224944-77-7 ]
[ 1260845-57-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium fluoride; In dimethyl sulfoxide; at 180℃; for 2h;	A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.30 g, 5.76 mmol), <strong>[1218935-59-1](R)-2-(2,5-difluorophenyl)pyrrolidine</strong> (Intermediate 5, 1.13 g, 6.6 mmol) and KF (1.67 g, 28.8 mmol) in DMSO (19 mL) was stirred at 180 C. for 2 hours. After being cooled to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to afford ethyl (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (2.11 g, 98%) as a yellow solid. MS: 372.90 [MH+]
79.7%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 100℃; for 15h;	Preparation C; (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolori,5-alpyrimidine-3-carboxylic acid; Step A: Preparation of (R)-ethyl 5-(2-(2.5-difluorophenv0pyrrolidin-l- yl)pyrazolo[ 1 ,5-a"\|pyrimidine-3-carboxylate.; A mixture of ethyl 5-chloropyrazolo[l,5- a]pyrimidine-3-carboxylate (Preparation B, 2.00 g, 8.86 mmol), (R)-2-(2,5- difluorophenyl)pyrrolidine (Preparation A, 1.62 g, 8.86 mmol), diisopropylethylamine (3.09 mL, 17.7 mmol) and butan-1-ol (2.95 ml, 8.86 mmol) was heated at 100 0C for 15 hours. The reaction mixture was cooled to ambient temperature and was diluted with EtOAc (30 mL) and water (10 mL). Undissolved solid was filtered and washed with Et2O to afford the title compound as a light orange solid (2.13 g). The organic layer was separated from the filtrate, washed with brine (10 mL) and dried over MgSO4. The solution was filtered and concentrated to provide additional solid that was purified by silica chromatography using gradient elution with 50-100% EtOAc/hexanes. This afforded the title compound (0.50 g) as a light yellow solid. The combined yield was 2.63 g, 79.7 %. MS (apci) m/z = 373.1 (M+H).

Reference： [1]Patent: US2016/168156,2016,A1 .Location in patent: Paragraph 0340; 0341
[2]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 71

2
[ 1224944-77-7 ]
[ 1260845-67-7 ]
C₂₀H₂₁FN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 160℃; for 72.0h;sealed tube;	Preparation G; (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-l-yl)pyrazolo[l,5-alpyrimidine-3-carboxylic acid; In a sealed tube, ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3-carboxylate(Preparation B, 500 mg, 2.22 mmol), <strong>[1260845-67-7](R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine hydrochloride</strong> salt (513 mg, 2.22 mmol), and diisopropylethylamine (0.774 mL, 4.43 mmol) were combined in isopropanol (2 mL) and heated at 160 0C for 3 days. 2N NaOH (6 mL) and MeOH (5 mL) were added and the reaction mixture stirred at ambient temperature for 24 hours, followed by heating to 40 0C for 3 hours. The reaction was partially concentrated, treated with saturated aqueous NH4Cl (10 mL) and the mixture extracted with EtOAc. The combined organic extracts were filtered, concentrated and the residue purified by reverse phase chromatography eluting with 0-60% acetonitrile/water to yield the title compound as a pink solid (254 mg, 32.2% yield). MS (apci) m/z = 357.0 (M+H).

Reference： [1]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 73

3
[ 1224944-77-7 ]
[ 1260847-45-7 ]
[ 1260847-48-0 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In N,N-dimethyl-formamide for 0.166667h; Stage #2: (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	222.C Step C: Preparation of (RVethyl 5-(2-(2-chloro-5-fluoropyridin-3- yDpyrrolidin- 1 -yl)pyrazolo[ 1 ,5-a"\|pyrimidine-3-carboxylate:; To a solution of ethyl 5- hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 275 mg, 1.33 mmol) in anhydrous DMF (5 mL) was added (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (646 mg, 1.46 mmol). The heterogeneous mixture was stirred for 10 minutes before adding DIEA (1.16 mL, 6.6 mmol), followed by addition of (R)-2-chloro-5-fluoro-3-(pyrrolidin-2-yl)pyridine dihydrochloride (363 mg, 1.33 mmol). The reaction was stirred at ambient temperature overnight to reach completion. The mixture was partitioned between 10% citric acid (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed successively with water (20 mL), saturated NaHCθ3 (20 mL), water (20 mL) and brine (3 x 20 mL), then dried (Na2SO4) and concentrated to afford the crude product as an orange foam. The crude material was purified on a 25 g Biotage SNAP silica cartridge eluting with 1% MeOH/DCM to afford the desired product as cream-colored foam (0.35 g, 68%). MS (apci pos) m/z = 390.0 (M+H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/6074, 2011, A1 Location in patent: Page/Page column 163

4
[ 926663-00-5 ]
[ 1224944-77-7 ]

Yield	Reaction Conditions	Operation in experiment
97.6%	With trichlorophosphate; for 2.0h;Reflux;	Step B: Preparation of ethyl 5 -chloropyrazolo [1,5 -alpyrimidine-3 -carboxylate.; Ethyl 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (22.7 g, 110 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove the excess POCI3. The residue was diluted in DCM (100 mL) and slowly added to a flask containing ice water. The mixture was separated and the aqueous layer extracted with DCM. The combined organics were dried with MgSO4, filtered and concentrated to afford ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3- carboxylate (24.2 g, 97.6 % yield) as a pale yellow solid. MS (apci) m/z = 225.9 (M+H).
61%	With trichlorophosphate; at 100℃; for 16.0h;	POCl3 (30 mL, 322 mmol) was added to 30 (5.54 g,26.7 mmol) and the mixture was stirred at 100C for 16 h.After POCl3 was removed under reduced pressure, the residuewas partitioned between EtOAc and NaHCO3 aqueous solution. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases werewashed with water and saturated aqueous NaCl, dried overanhydrous Na2SO4 and concentrated in vacuo. The residuewas purified by column chromatography (silica gel, hexane-ethyl acetate, 19 : 1 to 1 : 1) to afford 36 (3.69 g, 16.3 mmol,61%) as a white solid. MS (ESI/APCI) m/z 226.1 [M+H]+.
		[000230] Ethyl 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (1-9) (0.43 g, 2.0 mmol) was treated with POCl3 (3 mL) and heated to 100 C for 1 hour then cooled to room temperature. The reaction was evaporated to dryness, quenched with cold aqueous NaHC03 and extracted with DCM (3 x 25 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and reduced to dryness. Crude product was purified by column chromatography on silica gel with hexanes/EtOAc gradient as eluant to afford ethyl 5-chloropyrazolo[l,5- a]pyrimidine-3-carboxylate (1-10). 1H NMR (400MHz, DMSO-d6) delta 8.61 (d, J = 1.2 Hz, 1 H),8.54 (s, 1 H), 6.97 (d, J = 7.2 Hz, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 6.8 Hz, 3 H). MS m/z 226.1 (M+l)+.

14.05 g	With trichlorophosphate; In acetonitrile; at 10 - 110℃; for 4.0h;Inert atmosphere;	B) ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (18.0 g) was suspended in acetonitrile (40 mL), phosphorus oxychloride (40 mL) was added at room temperature, and the mixture was stirred under a nitrogen atmosphere at 110 C. for 4 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and neutralized with aqueous sodium bicarbonate solution, and insoluble material was filtered off with Celite. The organic layer of the filtrate was purified by a silica gel pad, and the solvent was evaporated under reduced pressure. The precipitated solid was washed with ethyl acetate/diisopropyl ether to give the title compound (14.1 g). The mother liquor was further concentrated under reduced pressure and the resulting solid was washed with ethyl acetate/diisopropyl ether to give the title compound (2.40 g). 1H NMR (300 MHz, CDCl3) delta 1.42 (3H, t, J=7.2 Hz), 4.43 (2H, q, J=7.2 Hz), 6.99 (1H, d, J=7.2 Hz), 8.56 (1H, s), 8.63 (1H, d, J=7.2 Hz).
14.1 g	With trichlorophosphate; In acetonitrile; at 110℃; for 4.0h;	The 5-hydroxy pyrazole [1,5-a] pyrimidine-3-carboxylic acid ethyl ester (18.0g) suspended in acetonitrile (40 ml), at room temperature add oxygen phosphorus chloride (40 ml), and to the mixture under nitrogen atmosphere to 110 C stirring 4 hours. Cooling the reaction mixture, and the concentrated under reduced pressure. Aid hemostasis diluted with ethyl acetate and to neutralize the sodium bicarbonate aqueous solution, but insoluble material to celite filtration. The organic filtrate is purified by silicon rubber, and the evaporation of the solvent under reduced pressure. Precipitation of the solid in ethyl acetate/b isopropyl group ether cleaning in order to produce the title compound (14.1g). Mother liquor further for concentrated under reduced pressure, and the generated solid of using ethyl acetate/b isopropyl group ether cleaning in order to produce the title compound (2.40g).
	With trichlorophosphate; In acetonitrile; at -74℃;Inert atmosphere; Large scale;	To a flask, under nitrogen, outfitted with mechanical stirring, J-Kem temperature probe, and condenser was added <strong>[926663-00-5]ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate</strong> (2319 g, 11.2 moles), acetonitrile (9200 mL), and phosphoryl trichloride (1230 mL, 13.4 mmol). The reaction mixture was heated to -74 C (IT) until it was judged complete by HPLC. The reaction was cooled to -30 C. While cooling, a separate flask was outfitted with mechanical stirring and a J-Kem temperature probe. Water (37 L) was added to this and the water was cooled to below 15 C. The reaction mixture was added portion-wise producing a mixture . The chlorination reactor was rinsed with 4: 1 water/MeCN (2 L) and the rinse was added to the mixture. To the mixture was added MeCN (1 L) The transfer line was rinsed with 4: 1 water/MeCN (2 L), and the rinse was added to the mixture. The mixture was cooled back to below 20 C and a solution of tribasic phosphate (2312 g, 10.9 mol) in water (4.0 L) was added portion-wise at a rate to keep the IT below 25 C. The slurry was stirred at ambient temperature overnight. The slurry was filtered (PPFC) and rinsed with 4: 1 water/MeCN (6 L). The cake was rinsed a second time with water (7.0 L). The solid was placed in trays and dried in a vacuum oven at 50 C for 36 - 72 h to give 8.
	With trichlorophosphate; In acetonitrile; at 74℃;Large scale;	To a flask, under nitrogen, outfitted with mechanical stirring, J-Kem temperature probe, and condenser was added ethyl 5-hydroxypyrazolo[l,5-a]pyrimidine-3-carboxylate (2319 g, 11.2 moles), acetonitrile (9200 mL), and phosphoryl trichloride (1230 mL, 13.4 mmol). The reaction mixture was heated to -74 C (IT) until it was judged complete by HPLC. The reaction was cooled to -30 C. While cooling, a separate flask was outfitted with mechanical stirring and a J-Kem temperature probe. Water (37 L) was added to this and the water was cooled to below 15 C. The reaction mixture was added portion-wise producing a mixture. The chlorination reactor was rinsed with 4: 1 water/MeCN (2 L) and the rinse was added to the mixture. To the mixture was added MeCN (1 L). The transfer line was rinsed with 4: 1 water/MeCN (2 L), and the rinse was added to the mixture. The mixture was cooled back to below 20 C and a solution of tribasic phosphate (2312 g, 10.9 mol) in water (4.0 L) was added portion-wise at a rate to keep the IT below 25 C. The slurry was stirred at ambient temperature overnight. The slurry was filtered (PPFC) and rinsed with 4: 1 water/MeCN (6 L). The cake was rinsed a second time with water (7.0 L). The solid was placed in trays and dried in a vacuum oven at 50 C for 36 - 72 h to ive 8.

Reference： [1]Patent: WO2011/6074,2011,A1 .Location in patent: Page/Page column 70-71
[2]Chemical and Pharmaceutical Bulletin,2017,vol. 65,p. 1058 - 1077
[3]Patent: WO2012/34095,2012,A1 .Location in patent: Page/Page column 68
[4]Patent: US2016/159808,2016,A1 .Location in patent: Paragraph 1357; 1358; 1381; 1382; 1394; 1395
[5]Patent: TW2016/520,2016,A .Location in patent: Paragraph 0165
[6]Patent: WO2018/81417,2018,A2 .Location in patent: Page/Page column 162; 163
[7]Patent: WO2019/84285,2019,A1 .Location in patent: Page/Page column 205; 206

5
[ 1224944-77-7 ]
[ 34486-24-3 ]
[ 1224944-78-8 ]

Yield	Reaction Conditions	Operation in experiment
17%	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;bis(dibenzylideneacetone)-palladium(0); In toluene; at 140℃; for 0.333333h;Microwave irradiation; Inert atmosphere;	A 20-mL microwave vial was charged with ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.28 g, 5.67 mmol, 1 equiv), <strong>[34486-24-3]2-amino-6-(trifluoromethyl)pyridine</strong> (1.10 g, 6.81 mmol, 1.2 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.22 mmol, 4 mol %), tris(dibenzylideneacetone) dipalladium(0) (104 mg, 0.11 mmol, 2 mol %), sodium tert-butoxide (652 mg, 6.81 mmol, 1.2 equiv) and toluene (12 mL). The vial was sealed and the contents degassed, purged with argon and then heated in a microwave reactor at 140 C. for 20 minutes. After cooling, the mixture was diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water and saturated aqueous sodium chloride solution, dried over anydrous sodium sulphate, filtered, and concentrated under vacuum. The resultant residue was purified by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in dichloromethane) to give 344 mg (17%) of ethyl 5-(6-(trifluoromethyl)pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate as an orange solid. LCMS (ESI) m+H=352.1; 1H NMR (300 MHz, DMSO-d6) delta: 11.06 (s, 1H), 9.16 (d, 1H), 8.94 (d, 1H), 8.39 (s, 1H), 8.10 (t, 1H), 7.57 (d, 1H), 7.05 (d, 1H), 4.31 (q, 2H), 1.40 (t, 3H).

Reference： [1]Patent: US2012/22043,2012,A1 .Location in patent: Page/Page column 88-89

6
[ 1224944-77-7 ]
[ 1314712-96-3 ]
[ 1364889-12-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1,4-dioxane at 110℃; for 12h;	Synthesis of ethyl 5-(2-(3-fluorophenyl)-5-oxopyrrolidin-l-yl)pyrazolofl,5-a]pyrimidine-3- rboxylate (X-19); 1-35 1-10 X-19[000303] To a degassed solution of 5-(3-fluorophenyl)pyrrolidin-2-one (1-35) (44 mg, 0.2 mmol), Cul (3 mg, 16 μιηο) and potassium carbonate (61 mg, 0.4 mmol) in 1,4-dioxane (0.5 mL) was added ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3-carboxylate (1-10) (50 mg, 0.2 mmol) and N,N'-dimethylcyclohexane-l,2-diamine (4 μ, 22 μιηο). The reaction was heated at 110 °C for 12 hours and partitioned with DCM/H20 upon cooling. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by preparative LCMS to yield 5-(2-(3-fluorophenyl)-5-oxopyrrolidin-l-yl)pyrazolo[l,5- a]pyrimidine-3-carboxylate (X-19). 1H NMR (400MHz, DMSO- 6) δ 9.11 (d, J = 8.0 Hz, 1 H), 8.44 (s, 1 H), 8.18 (d, J = 7.6 Hz, 1 H), 7.35 - 7.19 (m, 3 H), 7.03 (bt, J = 8.8 Hz, 1 H), 5.84 (d, J = 6.4 Hz, 1 H), 4.23 (q, J = 6.0 Hz, 2 H), 2.26 - 2.88 (m, 1 H), 2.71 - 2.64 (m, 1 H), 2.00 - 1.95 (m, 1 H), 1.26 (t, J = 6.8 Hz, 3 H). MS m/z 369.1 (M+l)+.

Reference： [1]Current Patent Assignee: IRM LLC - WO2012/34095, 2012, A1 Location in patent: Page/Page column 94-95

7
[ 1224944-77-7 ]
[ 365996-30-1 ]
ethyl 5-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 90℃; for 8h;Sealed tube;	Step 1: A mixture of ethyl 5-chloropyrazolo[1,5-ajpyrimidine-3-carboxylate (500 mg, 2.2 mmol) and <strong>[365996-30-1]tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate</strong> (475 mg, 2.2 mmol) in ethanol (5mL) was taken in a 25 mL sealed tube, and the mixture was heated at 90 C for 8 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (20-30%) to yield ethyl 5 -(((1R,25)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)pyrazolo[ 1,5 - ajpyrimidine-3-carboxylate as a solid. 1H NMR (DMSO-d6, 400 MHz): ö 8.48 (d, J 7.5 Hz,1H), 8.12 (s, 1H), 7.48 (d, J 7.3 Hz, 1H), 6.61 (d, J 8.3 Hz, 1H), 6.45 (d, J 7.5 Hz, 1H), 4.31-4.22 (m, 1H), 4.17 (q, J 6.7 Hz, 2H), 4.03-4.01 (m, 1H), 1.85-1.48 (m, 8H), 1.36 (s, 9H),1.31 (t, J 6.7 Hz, 3H). MS calc’d [M+Hj 404.2, found 404.4.
	In ethanol; at 90℃; for 8h;Sealed tube;	Into a 25 mL sealed tube were added ethyl 5-chloropyrazolo[l ,5-a]pyrimidine-3- carboxylate (500 mg, 2.2 mmol), tert-butyl ((15',2i?)-2-aminocyclohexyl)carbamate (475 mg, 2.2 mmol) and ethanol (5 mL) and the resulting solution was stirred at 90 C for 8 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with ethyl acetate in petroleum ether (20- 30%) to yield ethyl 5-(((li?,2^-2-((ter^butoxycarbonyl)amino)cyclohexyl)amino)pyrazolo[l,5- a]pyrimidine-3-carboxylate as a solid. NMR (DMS0 , 400 MHz): δ 8.48 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.48 (d, J = 7.3 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 7.5 Hz, 1H), 4.31 -4.22 (m, 1H), 4.17 (q, J = 6.7 Hz, 2H), 4.03-4.01 (m, 1H), 1.85-1.48 (m, 8H), 1.36 (s, 9H), 1.31 (t, J = 6.7 Hz, 3H). MS calc'd [M+H]+ 404.2, found 404.4.

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 683 - 688
[2]Patent: WO2016/144846,2016,A1 .Location in patent: Page/Page column 157; 158
[3]Patent: WO2016/144844,2016,A1 .Location in patent: Page/Page column 48

8
[ 1224944-77-7 ]
[ 1802222-53-2 ]
[ 1802221-21-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 100℃;	14 Ethyl (R)-5-( ( l -(5-fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[ /, 5-a]pyrimidine-3-carboxylate To a solution of (i?)-2-(l-Aminoethyl)-4-fluorophenol hydrochloride (15.7 g, 82.0 mmol) and DIE A (63.5 g, 491.0 mmol) in -BuOH (150 mL) was added ethyl 5- chloropyrazolo[l,5-a]pyrimidine-3-carboxylate (15.1 g, 66 mmol). After stirring at l00°C overnight, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried with Na2S04 and concentrated, and the residue was purified by column chromatography eluted with DCM/MeOH = 50/1 to afford the title compound as a yellow solid (22.7g, 100%). NMR (400 MHz, DMSO-76): 5 1.27 (t, 7 = 7.2 Hz, 3H), 1.45 (d, 7 = 6.8 hz, 3H), 4.17 (q, 7= 7.2 Hz, 1H), 5.48-5.59 (m, 1H), 6.46 (d, 7= 8.0 Hz, 1H), 6.77-6.90 (m, 2H), 7.07 (dd, 7= 3.2, 9.6 Hz, 1H), 8.12 (s, 1H), 8.24 (d, 7= 8.0 Hz, 1H), 8.52 (d, 7= 7.6 Hz, 1H), 9.58 (brs, 1H). ESI-MS (EI+, m/z): 345.1.
99%	With N-ethyl-N,N-diisopropylamine In ethanol at 70℃; for 1.5h;	A8 Example A8 [0304] To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.25 g, 5.54mmol) and (R)-2-(1-aminoethyl)-4-fluorophenol HC1 salt (purchased from NetChem, Inc.)in EtOH (15.83 mL) was added Hunig’s base (3.58 g, 27.70 mmol) and heated to 70 °C for 1.5 hour. The reaction was rotovaped to dryness, suspended in water, and extracted with DCM (5 x 50 mL). The combined extracts were dried with Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (40 g), 0-5% methanol in dichloromethane) provided A8 (1.89 g, 5.49 mmol, 99% yield).
78.76%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 120℃; for 2h;	3.1 Step 1 : Preparation of ethyl (tf)-5-((l-(5-fluoro-2- hydroxyphenyl)ethyl)amino)pyrazolo[ 1 ,5-a]pyrimidine-3-carboxylate (3) [0260] To a solution of (tf)-2-(l-aminoethyl)-4-fluorophenol (2) (85 g, 443.56 mmol, 1.00 eq.) and ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3-carboxylate (1) (100.08 g, 443.56 mmol, 1.00 eq.) in n-BuOH (2 L) was added DIEA (343.96 g, 2.66 mol, 6.00 eq.). The mixture was stirred at 120 °C for 2 hrs. TLC (PE:EtOAc=l : l) showed the reaction was completed. The reaction mixture was diluted with H20 (500 mL) at 16 °C, and extracted with EtOAc (500 mLx3). The combined organic layers were washed with brine (500 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=10/l to 1 :3) to give ethyl (K)-5-((l-(5- fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylate (3) (122 g, 349.34 mmol, 78.76% yield, ee>99% purity) as a white solid. 1HNMR (CDC13 , 400MHz) δ 9.28 (br. s., IH), 8.26 (s, IH), 8.14 (d, =7.5 Hz, IH), 6.95 - 6.89 (m, 2H), 6.87 - 6.80 (m, IH), 6.18 (d, =7.5 Hz, IH), 5.98 (d, =8.3 Hz, IH), 5.71 - 5.54 (m, IH), 4.50 - 4.35 (m, 2H), 1.60 (d, =6.8 Hz, 3H), 1.42 (t, J=7.2 Hz, 3H).

46.69%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 120℃; for 2h;	A.6 Step 6. Preparation of ethyl (R)-5-((l-(5-fluoro-2- hydroxyphenyl)ethyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylate (A-l). To a solution of A-l-5 (1.10 g, 7.09 mmol, 1.00 eq.) and A-1-8 (1.60 g, 7.09 mmol, 1.00 eq.) in n-BuOH (30.00 mL) was added DIEA (5.50 g, 42.53 mmol, 6.00 eq.). The mixture was stirred at 120 °C for 2 hrs. The reaction mixture was quenched by addition of water (20 mL) at ambient temperature, and extracted with EtOAc (20 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=10/l to 1 :3) to provide A-1 (1.15 g, 3.31 mmol, 46.69% yield, ee>97% purity) as a white solid.
31%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 5h;	1.D Step D: Step D: ethyl (R)-5-((1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyri midine-3-carboxylate 5.3g (27.9mmol, 1.0eq) (R)-2-(1-aminoethyl)-4-fluorophenol hydrochloride, 6.29g (27.9mmol, 1.0eq) ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate and diisopropylethylamine (DIEA) (12mL, 167mmol, 6.0eq) were dissolved in 60 ml N,N-dimethylformamide (DMF). The mixture was heated to 120°C for 5 hours. TLC analysis showed that the reaction was complete, and the solvent was removed by concentration. Water (100mL) and ethyl acetate (200mL) were added for extraction. The combined organic layers were washed twice with water and saturated brine in turn, and dried over anhydrous Na2SO4. The solvent was removed by concentration to afford the crude product, which was purified by silica gel column chromatography (2.9g, 31% yield). 1H NMR (400 MHz, CDCl3) δ 9.17(brs, 1H), 8.24(s, 1H), 8.14 (d, J = 8.0Hz, 1H), 6.93-6.90(m, 2H), 6.83(d, J = 8.0Hz, 1H), 6.13 (d, J = 8.0 Hz, 1H), 5.81 (d, J = 8.0 Hz, 1H), 5.64 (t, J = 8.0 Hz, 1H), 4.42(q, J = 8.0 Hz, 2H), 1.61(d, J = 8.0 Hz, 3H), 1.41 (t, 3H).

Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2020/69106, 2020, A1 Location in patent: Paragraph 00199; 00205
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/112806, 2015, A3 Location in patent: Paragraph 0304
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/7759, 2017, A1 Location in patent: Paragraph 0245; 0259; 0260
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/4342, 2017, A1 Location in patent: Paragraph 0443
[5]Current Patent Assignee: PRIMEGENE BEIJING - EP3786167, 2021, A1 Location in patent: Paragraph 0093; 0102-0104

9
[ 1014717-10-2 ]
[ 1224944-77-7 ]
[ 1646543-38-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With copper(l) iodide; palladium diacetate; triphenylphosphine In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere;	Ethyl 5-(Pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (38) A mixture of ethyl 36 (300 mg, 1.33 mmol), lithium 4-methyl-1-(pyridin-2-yl)-2,6,7-trioxa-1-borabicyclo[2.2.2]-octan-1-uide (37) (566 mg, 2.66 mmol), Ph3P (139 mg,0.532 mmol), copper(I) iodide (127 mg, 0.665 mmol) andPd(OAc)2 (29.9 mg, 0.133 mmol) in DMF (5 mL) was stirredat 80°C for 2 h under Ar. The mixture was filtered througha cake of basic silica gel pad (eluted with ethyl acetate), followed by a cake of silica gel pad (eluted with ethyl acetate).The appropriate fractions were concentrated in vacuo. Theresulting solid was triturated with hot ethyl acetate and insoluble materials were filtered off. After concentration of thefiltrate, the residue was purified by column chromatography(basic silica gel, hexane-ethyl acetate, 100 : 0 to 3 : 7) to give38 (309 mg, 1.15 mmol, 87%) as a pale yellow solid after trituration with diisopropyl ether. 1H-NMR (300 MHz, CDCl3) δ:1.47 (3H, t, J=7.1 Hz), 4.46 (2H, q, J=7.1 Hz), 7.40-7.47 (1H,m), 7.86-7.95 (1H, m), 8.25 (1H, d, J=7.4 Hz), 8.59 (1H, s),8.71-8.76 (2H, m), 8.80 (1H, d, J=7.4 Hz). MS (ESI/APCI) m/z269.1 [M+H]+.
309 mg	With copper triiodide; palladium diacetate; triphenylphosphine In ethyl acetate; N,N-dimethyl-formamide at 80℃; for 2h;	72.C C) ethyl 5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate C) ethyl 5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg), lithium 4-methyl-1-(pyridin-2-yl)-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide (566 mg), triphenylphosphine (139 mg), copper triiodide (127 mg), palladium acetate (29.9 mg) and N,N-dimethylformamide (5.00 mL) was heated at 80° C. for 2 hr. The reaction mixture was filtered through a silica gel pad (NH and SiO2), and concentrated under reduced pressure. To the residue was added ethyl acetate, and the resulting insoluble solid was collected by filtration, purified by silica gel chromatography (NH, ethyl acetate/hexane), and crystallized from diisopropyl ether to give the title compound (309 mg). 1H NMR (300 MHz, CDCl3) δ 1.47 (3H, t, J=7.1 Hz), 4.46 (2H, q, J=7.1 Hz), 7.40-7.47 (1H, m), 7.86-7.95 (1H, m), 8.25 (1H, d, J=7.4 Hz), 8.59 (1H, s), 8.71-8.76 (2H, m), 8.80 (1H, d, J=7.4 Hz).

Reference： [1]Mikami, Satoshi; Kawasaki, Masanori; Ikeda, Shuhei; Negoro, Nobuyuki; Nakamura, Shinji; Nomura, Izumi; Ashizawa, Tomoko; Kokubo, Hironori; Hoffman, Isaac Dylan; Zou, Hua; Oki, Hideyuki; Uchiyama, Noriko; Hiura, Yuuto; Miyamoto, Maki; Itou, Yuuki; Nakashima, Masato; Iwashita, Hiroki; Taniguchi, Takahiko [Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 11, p. 1058 - 1077]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2016/159808, 2016, A1 Location in patent: Paragraph 1396; 1397

10
[ 886503-15-7 ]
[ 1224944-77-7 ]
ethyl 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium fluoride In dimethyl sulfoxide at 180℃; for 2h;	7.C Step C: ethyl 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.00 g, 4.43 mmol), 2-(2,5-difluorophenyl)pyrrolidine (Intermediate 2, 853 mg, 4.65 mmol) and KF (1.28 g, 22.1 mmol) in DMSO (14 mL) was stirred at 180° C. for 2 hours. After being cooled to room temperature, the reaction mixture was poured into water. The mixture was stirred for 30 min. A precipitated solid was collected by filtration and dried under vacuum to afford ethyl 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.51 g, 91%) as a yellow solid. 1H-NMR (CDCl3, Varian, 400 MHz): δ 1.30-1.49 (3H, m), 1.98-2.18 (3H, m), 2.43-2.58 (1H, m), 3.95-4.20 (2H, m), 4.25-4.48 (2H, m), 5.18-5.23 (1H, m), 5.82-5.94 (1H, m), 6.68-6.80 (1H, m), 6.86-6.98 (1H, m), 7.00-7.12 (1H, m), 8.08-8.22 (1H, m), 8.29 (1H, s).

Reference： [1]Current Patent Assignee: HAN DOK INC.; CMG PHARMACEUTICAL CO LTD - US2016/168156, 2016, A1 Location in patent: Paragraph 0240; 0246; 0247

11
[ 1206640-82-5 ]
[ 1224944-77-7 ]
ethyl 5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.8 g	With potassium phosphate; bis[di-tert-butyl-(4-dimethylaminophenyl)-phosphine]dichloropalladium(ll); In water; toluene; at 100℃; for 16h;Inert atmosphere;	C) ethyl 5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixed solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.0 g), <strong>[1206640-82-5]1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (3.24 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (0.628 g) and potassium phosphate (2.82 g) in toluene (81 mL) and water (8.1 mL) was stirred under an argon stream at 100 C. for 16 hr. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.8 g). MS (API+): [M+H]+308.1.

Reference： [1]Patent: US2016/159808,2016,A1 .Location in patent: Paragraph 1383; 1384

12
[ 1224944-77-7 ]
[ 1212996-56-9 ]
[ 2058228-15-0 ]

Yield	Reaction Conditions	Operation in experiment
871.4 mg	With N-ethyl-N,N-diisopropylamine In ethanol at 80℃; for 64h;	M.6 Step 6: To a solution of 58-7 (469.7 mg, 2.76 mmol) and 5-chloropyrazolo[l,5- a]pyrimidine-3-carboxylate (778 mg, 3.45 mmol) in EtOH (14.0 mL) was added Hiinig's base (2.96 g, 22.9 mmol, 4.0 niL). The solution was heated at 80 °C for 64 hours. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica (40 g), 50- 100% ethyl acetate in hexane) provided 58-8 (871.4 mg, 2.42 mmol, 87% yield).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2017/4342, 2017, A1 Location in patent: Paragraph 0538

13
[ 1224944-77-7 ]
[ 2097002-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: triethylamine / ethanol / 19 h / 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C / Inert atmosphere; Large scale 3.1: triethylamine / dichloromethane / 1 h / 5 - 15 °C 4.1: copper(l) iodide; palladium; diisopropylamine / toluene / 1 h / 60 °C / Inert atmosphere 4.2: 1 h / Inert atmosphere 5.1: Pd/C; hydrogen / methanol / 2585.81 Torr 6.1: sodium hydroxide / isopropyl alcohol / 75 °C 7.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 20 °C
	Multi-step reaction with 7 steps 1.1: triethylamine / ethanol / 19 h / 20 °C / Large scale 2.1: hydrogenchloride / 1,4-dioxane / 60 °C / Large scale 3.1: triethylamine / dichloromethane / 1 h / 15 °C / Large scale 4.1: copper(l) iodide; diisopropylamine / toluene / 1 h / 60 °C / Large scale 4.2: 1 h / 60 °C / Large scale 5.1: palladium on activated charcoal; hydrogen / methanol / 2585.81 Torr 6.1: sodium hydroxide; water / isopropyl alcohol / 75 °C 7.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: ELI LILLY & CO; PFIZER INC - WO2018/81417, 2018, A2
[2]Current Patent Assignee: ELI LILLY & CO - WO2019/84285, 2019, A1

14
[ 1224944-77-7 ]
[ 62908-85-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1522 - 1531
[2]Patent: WO2021/158634,2021,A1

15
[ 26734-08-7 ]
[ 1224944-77-7 ]
ethyl 5-[(3-hydroxy-3-methylbutyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 1h; Inert atmosphere;	1 Step 1 - Ethyl 5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidine-3- carboxylate To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 886 umol, CAS 1244844-77-7) and 4-amino-2-methyl-butan-2-ol (91.4 mg, 886 umol, CAS 26734-08-7) in ACN (2 mL) was added DIPEA (229 mg, 1.77 mmol). The mixture was stirred at 60 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (250 mg, 96% yield) as colorless oil. LC-MS (ESI+) m/z 293.1 (M+H)+.

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/113233, 2020, A1 Location in patent: Paragraph 00962; 003445-003447

16
[ 1224944-77-7 ]
[ 178312-62-4 ]
[ 2434847-33-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 1h; Inert atmosphere;	1 Step 1 - Ethyl 5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.50 g, 11.1 mmol), 1,4-oxazepane;hydrochloride (1.60 g, 11.6 mmol, HCl) and DIPEA (4.30 g, 33.2 mmol) in MeCN (35 mL) was stirred at 60 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted in ethyl acetate (50 mL) and water (80 mL). The mixture was acidified by saturated critic acid aqueous until the pH=7. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was concentrated in vacuo to give the title compound (3.00 g, 93% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) d 8.70 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.21 - 4.15 (m, 2H), 4.06 - 3.69 (m, 6H), 3.64 (t, J = 5.6 Hz, 2H), 1.92 - 1.89 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H).

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/113233, 2020, A1 Location in patent: Paragraph 00962; 003797-003799; 004158-004160

17
[ 112461-31-1 ]
[ 1224944-77-7 ]
ethyl 5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 2h; Inert atmosphere;	1 Step 1 - Ethyl 5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxylate To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 1.33 mmol, CAS 1224944-77-7) and 6-oxa-3-azabicyclo[3.1.1]heptane (216.34 mg, 1.60 mmol, HCl, CAS 1414958-33-0) in ACN (5 mL) was added DIPEA (515 mg, 3.99 mmol, 694 uL). The reaction mixture was stirred at 60 °C for 2 hours. The mixture was concentrated in vacuo to give the title compound (0.85 g, 90% yield) as yellow oil. LC-MS (ESI+) m/z 289.1 (M+H)+.

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/113233, 2020, A1 Location in patent: Paragraph 00962; 004337-004339

18
[ 280-13-7 ]
[ 1224944-77-7 ]
ethyl 5-[8-oxa-3-azabicyclo[3.2.1]octan-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 1h;Inert atmosphere;	To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.80 g, 7.98 mmol, CAS 1224944-77-7), (1S,5R)-8-oxa-3-azabicyclo[3.2.1]octane (1.79 g, 12.0 mmol, CAS 280-13-7) in ACN (30 mL) was added DIPEA (4.12 g, 31.9 mmol). The mixture was stirred at 60 C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase flash (0.1% FA condition) to give the title compound (2.20 g, 91% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) d 8.74 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.47 (d, J = 2.4 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.17 (d, J = 12.4 Hz, 2H), 1.92 - 1.80 (m, 2H), 1.75 - 1.63 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

Reference： [1]Patent: WO2020/113233,2020,A1 .Location in patent: Paragraph 00962; 004791-004793

19
[ 1224944-77-7 ]
[ 1260845-81-5 ]
[ 1260845-79-1 ]

Yield	Reaction Conditions	Operation in experiment
99.7%	With N-ethyl-N,N-diisopropylamine In ethanol at 40 - 45℃;	1 method 1: At room temperature, add 3L of absolute ethanol,Compound I-1 (300.00g, 1.29mol) and compound II-1 (390.91g, 1.29mol) are stirred uniformly,Then add DIPEA (349.95g, 2.71mol), after the addition, the reaction system is heated to 4045 and stirred for 46h,HPLC or TLC monitors that the reaction is complete, the reaction system is cooled to room temperature, and the reaction solution is added to the vigorously stirred 0.7eq citric acid aqueous solution (31.5L),The pH value of the aqueous solution is controlled between 3 and 5, stirred for 0.5 to 1 h, a large amount of solids are precipitated, and filtered by suction.The solid is rinsed with 1L water, and air-dried at 5055 for 16h496.5 g of compound III-1 was obtained.Yield: 99.7%, purity>98%.The product can also be used directly in the next reaction without drying.

Reference： [1]Current Patent Assignee: CHENGDU BRILLIANT PHARMACEUTICAL CO LTD - CN113045575, 2021, A Location in patent: Paragraph 0132-0139

20
[ 601515-79-1 ]
[ 1224944-77-7 ]
ethyl 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 3h; Inert atmosphere;	Step 1 - Ethyl 5 - hi R.4 R ) - 2 - ox a-5 -a zab i c yd o 12.2.11 h e n t a n - 3 -y 11 p yrazo i o 1.5 - alpyrimidine -3-carboxylate To a solution of ethyl 5-chiorop>Taztdo[1,5-a]pyrimidine-3-carboxylate (200 mg, 886 umol, CAS?/ 1224944 77-7) and (1 R,4R)-2-oxa-5-azabicyclo(2.2.1 Jheptane (144 mg, 1.06 mmol. HCi salt, CAS 661470-56-0) in ACNf (5.00 mL) was added DIPEA (343 mg, 2.66 mmol). The mixture was stirred at 60 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo, then diluted with water (5 mL) and extracted wi th EA (2 X 10 mL). The combined organic layers were washed with brine (2 X 30 L), dried over ajSCL, concentrated in vacuo to give the title compound (180 mg, 70 % yield) as a white solid. NMR (400 MHz, CDCb) 68.38 - 8.18 (m, 2H), 6.12 (s, 1 H), 5.46 (s, 1H), 4.77 (s, 1H), 4.34 (q, ./- 7.2 Hz, 2H), 4.06 - 3.87 (m, 2H), 3.75 - 3.3S (m, 2H), 2.09 - 1.90 (m, 211), 1.38 (t, J- 7.2 Hz, 3H).
70%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 3h;	1 Step 1 - Ethyl 5-[(lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[l,5-a]pyrimidine -3-carboxylate [0012] To a solution of ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3-carboxylate (200 mg, 886 pmol, CAS 1224944-77-7) and (lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (144 mg, 1.06 mmol, HC1 salt, CAS 661470-56-0) in ACN (5.00 mL) was added DIPEA (343 mg, 2.66 mmol). The mixture was stirred at 60 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo, then diluted with water (5 mL) and extracted with EA (2 X 10 mL). The combined organic layers were washed with brine (2 X 30 mL), dried over Na2S04, concentrated in vacuo to give the title compound (180 mg, 70 % yield) as a white solid. NMR (400 MHz, CDCL) d 8.38 - 8.18 (m, 2H), 6.12 (s, 1H), 5.46 (s, 1H), 4.77 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.06 - 3.87 (m, 2H), 3.75 - 3.38 (m, 2H), 2.09 - 1.90 (m, 2H), 1.38 (t, J= 7.2 Hz, 3H).
70%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 3h; Inert atmosphere;	Step 1 - Ethyl 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine -3- carboxylate To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 886 umol, CAS 1224944-77-7) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (144 mg, 1.06 mmol, HCl salt, CAS 661470-56-0) in ACN (5.00 mL) was added DIPEA (343 mg, 2.66 mmol). The mixture was stirred at 60 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo, then diluted with water (5 mL) and extracted with EA (2 X 10 mL). The combined organic layers were washed with brine (2 X 30 mL), dried over Na2SO4, concentrated in vacuo to give the title compound (180 mg, 70 % yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.38 - 8.18 (m, 2H), 6.12 (s, 1H), 5.46 (s, 1H), 4.77 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.06 - 3.87 (m, 2H), 3.75 - 3.38 (m, 2H), 2.09 - 1.90 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H).

70%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 3h;	1 Step 1 - Ethyl 5-[(lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[l,5-a]pyrimidine -3-carboxylate To a solution of ethyl 5-chloropyrazolo[l,5-a]pyrimidine-3-carboxylate (200 mg, 886 pmol, CAS 1224944-77-7) and (lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (144 mg, 1.06 mmol, HC1 salt, CAS 661470-56-0) in ACN (5.00 mL) was added DIPEA (343 mg, 2.66 mmol). The mixture was stirred at 60 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo, then diluted with water (5 mL) and extracted with EA (2 X 10 mL). The combined organic layers were washed with brine (2 X 30 mL), dried over Na2S04, concentrated in vacuo to give the title compound (180 mg, 70 % yield) as a white solid. NMR (400 MHz, CDCL) d 8.38 - 8.18 (m, 2H), 6.12 (s, 1H), 5.46 (s, 1H), 4.77 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.06 - 3.87 (m, 2H), 3.75 - 3.38 (m, 2H), 2.09 - 1.90 (m, 2H), 1.38 (t, J= 7.2 Hz, 3H).
70%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 3h; Inert atmosphere;	Step 1 - Ethyl 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine -3- carboxylate To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 886 umol, CAS 1224944-77-7) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (144 mg, 1.06 mmol, HCl salt, CAS 661470-56-0) in ACN (5.00 mL) was added DIPEA (343 mg, 2.66 mmol). The mixture was stirred at 60 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo, then diluted with water (5 mL) and extracted with EA (2 X 10 mL). The combined organic layers were washed with brine (2 X 30 mL), dried over Na2SO4, concentrated in vacuo to give the title compound (180 mg, 70 % yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.38 - 8.18 (m, 2H), 6.12 (s, 1H), 5.46 (s, 1H), 4.77 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.06 - 3.87 (m, 2H), 3.75 - 3.38 (m, 2H), 2.09 - 1.90 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H).
70%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 3h;	1 Step 1 - Ethyl 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine -3- carboxylate. To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 886 μmol, CAS 1224944-77-7) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (144 mg, 1.06 mmol, HCl salt, CAS 661470-56-0) in ACN (5.00 mL) was added DIPEA (343 mg, 2.66 mmol). The mixture was stirred at 60 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo, then diluted with water (5 mL) and extracted with EA (2 X 10 mL). The combined organic layers were washed with brine (2 X 30 mL), dried over Na2SO4, concentrated in vacuo to give the title compound (180 mg, 70 % yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.38 - 8.18 (m, 2H), 6.12 (s, 1H), 5.46 (s, 1H), 4.77 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.06 - 3.87 (m, 2H), 3.75 - 3.38 (m, 2H), 2.09 - 1.90 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H).

Reference： [1]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2021/127190, 2021, A1 Location in patent: Paragraph 00512; 001040-001042
[2]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2021/247899, 2021, A1 Location in patent: Paragraph 0012
[3]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2021/247897, 2021, A1 Location in patent: Paragraph 00426; 00472-00474
[4]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2021/247899, 2021, A1 Location in patent: Paragraph 0012
[5]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2021/247897, 2021, A1 Location in patent: Paragraph 00426; 00472-00474
[6]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2022/125790, 2022, A1 Location in patent: Paragraph 00666; 00667

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