[ CAS No. 28466-26-4 ] {[proInfo.proName]}

Name: 28466-26-4|4-Aminopyrazole|97%
Brand: Ambeed
SKU: A159049
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Quality Control of [ 28466-26-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 28466-26-4 ]

SDS Specification

Alternatived Products of [ 28466-26-4 ]

Product Details of [ 28466-26-4 ]

CAS No. :	28466-26-4	MDL No. :	MFCD01693729
Formula :	C₃H₅N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AXINVSXSGNSVLV-UHFFFAOYSA-N
M.W :	83.09	Pubchem ID :	78035
Synonyms :

Calculated chemistry of [ 28466-26-4 ]

Physicochemical Properties

Num. heavy atoms :	6
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	2.0
Molar Refractivity :	22.99
TPSA :	54.7 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) :	-7.58 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.16
Log Po/w (XLOGP3) :	-1.09
Log Po/w (WLOGP) :	0.0
Log Po/w (MLOGP) :	-1.13
Log Po/w (SILICOS-IT) :	0.56
Consensus Log Po/w :	-0.3

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.29
Solubility :	43.1 mg/ml ; 0.519 mol/l
Class :	Very soluble
Log S (Ali) :	0.43
Solubility :	224.0 mg/ml ; 2.7 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.76
Solubility :	14.3 mg/ml ; 0.173 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.2

Safety of [ 28466-26-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 28466-26-4 ]

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

Upstream synthesis route of [ 28466-26-4 ]
Downstream synthetic route of [ 28466-26-4 ]

[ 28466-26-4 ] Synthesis Path-Upstream 1~8

1
[ 2075-46-9 ]
[ 28466-26-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 12 h;	Under hydrogen (1 atm), to a solution of 4-nitropyrazole (1.13 g, 10 mmol) in methanol (10 mL) was added 10percent Pd—C (0.1 g). The mixture was stirred at 25° C. for 12 hours, and then filtrated, the filtrate was concentrated under reduced pressure to give compound 31-a (860 mg, yield: 100percent), which was used directly for the next step without purification.
100%	With palladium 10% on activated carbon; hydrogen In ethanol at 20℃;	5.0g 4-nitropyrazole was dissolved in 160mL of ethanol and 0.8g of 10percent Pd/C was added. The reaction was subjected to hydrogen and reacted overnight at room temperature. TLC was used to monitor reaction completion. By celite was filtered off Pd/C. Ethanol solvent was evaporated to give 3.6g of the pure intermediate 8 as a red solid, quantitative reaction.
99%	With palladium 10% on activated carbon; hydrogen In methanol for 16 h;	A suspension of 4-nitro-1H-pyrazole (2.05 g, 18.13 mmol), and Pd/C (10percent w/w palladium on activated carbon, 0.96 g, 0.90 mmol) in MeOH (20 mL) was stirred under H2 atmosphere (balloon) for 16 h. The reaction mixture was filtered through Celite, rinsed with MeOH (3x 30 mL) and concentrated, affording 1.50 g of 1H-pyrazol-4- amine (pale pink solid, 99percent yield). HPLC-MS (Method H): Ret, 1.16 min; ESI⁺-MS m/z: 84 (M+1).

95%	With hydrogen In ethanol at 20℃; for 3 h;	Compound Ia (15.0 g, 133 mmol) was added to a suspension of palladium on carbon 10percent (7.0 g, 6.65 mmol) in ethanol (100 mL). The mixture was shaken for 3 hours under hydrogen pressure (40 psi) at room temperature. The catalyst was removed by filtration through a pad of Celite^.(R). and the solvent was evaporated. Compound Ib was obtained as a burgundy oil (10.5 g, 126 mmol, 95percent) which was used in the following step without purification; GC/MS: m/z = 83 (100percent).
49%	With hydrogen In ethanol	A mixture of 4-nitro-l/f-pyrazole (1.13 g, 10 mmol), Pd/C (10percent, 57 mg) in ethanol (20 mL) was hydrogenated at 20-30 psi on a parr apparatu overnight. The reaction mixture was filtered through celite, washed with ethanol (10 mL). The filtrate was concentrated to get desired compound 0113-42 (404 mg, 49percent) as a brown solid. LC-MS: 84 [M+l]+; ¹H-NMR (400 MHz, DMSO-d₆) δ 3.11 (br s, 2H), 6.99 (s, 2H), 11.92 (s, IH).
3.6 g	With palladium 10% on activated carbon; hydrogen In ethanol at 20℃;	Dissolving 5.0 g of 4-nitropyrazole in 160 mL of ethanol, and then adding 0.8 g of 10 wtpercent Pd/C to the above solution; Hydrogen was introduced into the reaction solution and allowed to react overnight at room temperature; after the TLC detection reaction was completed, the insoluble matter was filtered off with diatomaceous earth; Evaporation of the ethanol solvent gave pure intermediate 2 as a red solid 3.6 g.

Reference： [1] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0252; 0253
[2] ChemMedChem, 2016, p. 1695 - 1699
[3] Patent: CN105418616, 2016, A, . Location in patent: Paragraph 0118; 0119
[4] Organic and Biomolecular Chemistry, 2013, vol. 11, # 3, p. 395 - 399
[5] Patent: WO2017/178510, 2017, A1, . Location in patent: Page/Page column 297
[6] Patent: WO2006/44821, 2006, A1, . Location in patent: Page/Page column 23
[7] Patent: WO2010/75542, 2010, A1, . Location in patent: Page/Page column 73
[8] Chemische Berichte, 1904, vol. 37, p. 3501
[9] Journal of the Chemical Society, 1945, p. 114
[10] Journal of the Chemical Society, 1925, vol. 127, p. 2939
[11] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5780 - 5793
[12] Patent: US6531475, 2003, B1,
[13] Patent: US6514982, 2003, B1,
[14] Patent: WO2007/99326, 2007, A1, . Location in patent: Page/Page column 108-109
[15] Patent: WO2008/8375, 2008, A2, . Location in patent: Page/Page column 83
[16] Patent: WO2009/93012, 2009, A1, . Location in patent: Page/Page column 20; 35
[17] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4350 - 4364
[18] Patent: WO2012/52459, 2012, A1, . Location in patent: Page/Page column 38-39
[19] Patent: WO2012/52458, 2012, A1, . Location in patent: Page/Page column 34
[20] Patent: WO2012/110986, 2012, A1, . Location in patent: Page/Page column 52-53
[21] Patent: WO2014/194242, 2014, A2, . Location in patent: Paragraph 00603-0605
[22] Patent: CN108864057, 2018, A, . Location in patent: Paragraph 0105; 0206-0208

2
[ 2075-46-9 ]
[ 28466-26-4 ]
[ 63680-90-0 ]

Reference： [1] Patent: US2015/111938, 2015, A1, . Location in patent: Paragraph 0018; 0019
[2] Patent: US2015/112073, 2015, A1, . Location in patent: Paragraph 0019-0020
[3] Patent: US2015/112074, 2015, A1, . Location in patent: Paragraph 0020; 0021

3
[ 2075-46-9 ]
[ 28466-26-4 ]

Reference： [1] Patent: US2015/112076, 2015, A1, . Location in patent: Paragraph 0008; 0020; 0021

4
[ 2075-46-9 ]
[ 28466-26-4 ]

Reference： [1] Tetrahedron Letters, 2017, vol. 58, # 1, p. 82 - 86

5
[ 116008-52-7 ]
[ 28466-26-4 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1927, vol. 457, p. 292

6
[ 7647-01-0 ]
[ 40769-81-1 ]
[ 28466-26-4 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1902, vol. 323, p. 281

7
[ 28466-26-4 ]
[ 3469-69-0 ]

Reference： [1] Chemische Berichte, 1904, vol. 37, p. 3501

8
[ 2075-46-9 ]
[ 28466-26-4 ]
[ 63680-90-0 ]

[ 28466-26-4 ] Synthesis Path-Downstream 1~88

1
[ 28466-26-4 ]
[ 121-60-8 ]
sulfanilic acid-(1H-pyrazol-4-ylamide) [ No CAS ]

Reference： [1]Journal of the Chemical Society,1945,p. 114

2
[ 28466-26-4 ]
[ 3469-69-0 ]

Reference： [1]Chemische Berichte,1904,vol. 37,p. 3501

3
[ 28466-26-4 ]
1H-pyrazole-4-diazonium ; chloride [ No CAS ]

Reference： [1]Journal of the Chemical Society,1925,vol. 127,p. 2939

4
[ 28466-26-4 ]
[ 448-61-3 ]
C₂₆H₂₀N₃⁽¹⁺⁾*BF₄^(1-)*BF₃*FH [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 1245 - 1254
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1509 - 1518

5
[ 28466-26-4 ]
[ 141-97-9 ]
3-(1H-pyrazol-4-ylamino)but-2-enoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With toluene-4-sulfonic acid; In benzene; for 1h;Heating / reflux;	Step 1C; A solution of Ib (10.5 g, 126 mmol), ethylacetoacetate (18.0 g, 140 mmol) and a catalytic amount of /?-toluenesulfonic acid monohydrate (1.3g, 6.65 mmol, 5%) in benzene (100 mL) was refluxed with a Dean-Stark trap for 1 hour. Solvents were removed under vacuum, and the imine was purified by running through a short silica chromatography column to afford compound Ic as a tan solid after evaporation of solvent (22.4 g, 125 mmol, 91%); GC/MS: m/z = 195 (100%).

Reference： [1]Patent: WO2006/44821,2006,A1 .Location in patent: Page/Page column 23
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 5780 - 5793

6
[ 28466-26-4 ]
[ 141-97-9 ]
[ 91591-72-9 ]

Yield	Reaction Conditions	Operation in experiment
	p-toluenesulfonic acid monohydrate; In benzene;	Imine (I1) A solution of <strong>[28466-26-4]4-aminopyrazole</strong> (10) (10.5 g, 126 mmol), ethylacetoacetate (18.0 g, 140 mmol, 1.05 eq.) and a catalytic amount of para-toluenesulfonic acid monohydrate (1.3 g, 6.65 mmol, 5%) in 100 mL of benzene was refluxed with a Dean-Stark trap for about 1 hour. The end of reaction checked by TLC (Ethylacetate/Hexane 1/1, <strong>[28466-26-4]4-aminopyrazole</strong> Rf=0.1, imine Rf=0.5, UV active, brown after overnight). Solvents were removed under vacuum and the imine was purified by running through a short silica chromatography column to give the desired product (11) as a tan solid (22.4 g, 125 mmol, 91%). GC/MS: m/z=195 (100%).

Reference： [1]Patent: US6531475,2003,B1

7
[ 832684-43-2 ]
[ 28466-26-4 ]
[ 1019970-63-8 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1999 - 2002

8
[ 28466-26-4 ]
[ 97-94-9 ]
[ 16243-57-5 ]

Reference： [1]Journal of the American Chemical Society,1966,vol. 88,p. 1842 - 1844
[2]Gmelin Handbuch der Anorganischen Chemie,Gmelin Handbook: B: B-Verb.5, 1.2, page 2 - 7

9
[ 28466-26-4 ]
[ 170097-67-3 ]
[ 1035224-89-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Intermediate 25: 1 ,1-Dimethylethyl 6-[(1 /-/-pyrazol-4-ylamino)carbonyl1-3,4-dihydro- 2(1 HVisoalphauinolinecarboxylate; To a solution of 1 H-pyrazol-4-amine (1.87 g, 22.5 mmol), N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (5.18 g, 27 mmol), 1-hydroxybenzotriazole hydrate (3.65 g, 27 mmol) and triethylamine (6.3 ml_, 45 mmol) in DMF was added 2- [(I J-dimethylethyOoxylcarbonylJ-i ^^^-tetrahydro-theta-isoquinolinecarboxylic acid (5.62 g, 20.3 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, the residue was dissolved in MeOH and potassium hydroxide (5.04 g, 90 mmol), water (100 ml.) was added and the mixture was heated at 500C for 15 min. The MeOH was evaporated under reduced pressure and the solid which crystallized was filtered and recrystallized from acetonitrile to give the title compound as a solid (3.7 g, 48%). LC/MS: m/z 341 (M-H)+, Rt: 2.80 min.

Reference： [1]Patent: WO2008/74824,2008,A2 .Location in patent: Page/Page column 41

10
[ 4795-29-3 ]
[ 7154-73-6 ]
[ 2038-03-1 ]
[ 4572-03-6 ]
[ 27757-85-3 ]
[ 109-12-6 ]
[ 3731-53-1 ]
[ 107-10-8 ]
[ 7663-77-6 ]
[ 6628-04-2 ]
[ 2620-50-0 ]
polystyrene carboxaldehyde resin [ No CAS ]
[ 5071-96-5 ]
[ 617-89-0 ]
[ 28466-26-4 ]
[ 42185-03-5 ]
[ 453-71-4 ]
[ 19293-58-4 ]
[ 75-04-7 ]
[ 62-53-3 ]
[ 1003-03-8 ]
[ 51387-90-7 ]
[ 74-89-5 ]
[ 100-46-9 ]
[ 4152-90-3 ]
[ 68-41-7 ]
C₉H₈FN₂O₃Pol [ No CAS ]
C₁₀H₁₀FN₂O₃Pol [ No CAS ]
C₁₁H₁₂FN₂O₃Pol [ No CAS ]
C₁₄H₁₀FN₂O₃Pol [ No CAS ]
C₁₁H₈FN₄O₃Pol [ No CAS ]
C₁₂H₈FN₄O₃Pol [ No CAS ]
C₁₃H₁₀FN₂O₄Pol [ No CAS ]
C₁₅H₁₂FN₂O₃Pol [ No CAS ]
C₁₄H₁₁FN₃O₃Pol [ No CAS ]
C₁₃H₁₄FN₂O₃Pol [ No CAS ]
C₁₃H₁₀FN₂O₃PolS [ No CAS ]
C₁₃H₁₆FN₂O₄Pol [ No CAS ]
C₁₃H₁₄FN₂O₄Pol [ No CAS ]
C₁₆H₁₄FN₂O₄Pol [ No CAS ]
C₁₁H₉FN₃O₅Pol [ No CAS ]
C₁₅H₁₁ClFN₂O₃Pol [ No CAS ]
C₁₇H₁₇FN₃O₃Pol [ No CAS ]
C₁₄H₁₇FN₃O₃Pol [ No CAS ]
C₁₄H₁₇FN₃O₄Pol [ No CAS ]
C₁₅H₁₉FN₃O₃Pol [ No CAS ]
C₁₆H₁₂FN₂O₅Pol [ No CAS ]
C₁₈H₁₃FN₃O₃Pol [ No CAS ]
C₁₅H₁₇FN₃O₄Pol [ No CAS ]
C₁₆H₂₂FN₄O₃Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A library of compounds in which R4 was various groups having the formula [CONHR »] was prepared by the process described above using 4-fluoro-3-nitrobenzoic acid, as follows: [72] Aldehyde resin was mixed with a primary amine (R17-NH2) in [DICHLOROETHANE] (DCE), triethylorthoformate (TEOF), and DMF (containing [1%] acetic acid) in a 1: 1: 1 ratio. After shaken overnight, sodium triacetoxyborohydride (20 eq. ) dissolved in DMF was added (Abdel-Magid, A. F. , et al., Tetrahedron Lett, 3 1: 5595-5598 (1990) ). After the mixture was shaken at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL), [MEOH] [(3 X 5] mL), DMF [(3 X 5] mL), [MEOH] [(3 X 5] mL), and [CH2CL2] [(3 X 5] mL). The resin was washed twice with 5 mL DMF containing [1%] Hunig's base. To the filtered resin was added a mixture of 4-fluoro-3-nitrobenzoic acid (FNBA, 10 eq. ) and diisopropylcarbodiimide (DIC, 5 eq. ) in 2: 1 DMF : DCM. After shaking at room temperature overnight, the resin was filtered and washed with DMF (3 x 5 mL) and [CH2C12] (3 x 5 mL). [73] The resin was shaken with a primary amine [(R2-NH2)] in DMF for 8 hrs, filtered, and washed with DMF (6 x 5 mL), [MEOH] [(3 X 5] mL), and CH2C12 (3 x 5 mL). The aryl nitro group was reduced by the addition of tin (II) chloride dihydrate (20 eq. , >2 M) and N-methyl morpholine (NMM, 20 eq. ) in N-methyl pyrrolidinone (NMP). After shaken at room temperature overnight, the resin was filtered and washed with NMP (3 x 5 mL), [MEOH] (3 x 5 mL), and [CH2CI2 (3 X 5] mL). The resulting resin was shaken at room temperature with cyanogen bromide (5 eq. ) overnight, filtered, and washed with CH2Cl2 (3 x 5 mL), [MEOH] (3 x 5 mL), and CH2CI2 (3 x 5 mL). To produce a free amine, the resin was shaken for 30 min. in CHCl2 with the addition of sodium methoxide in methanol, filtered, and washed with CH2Cl2 [(4 X 5] mL). [[74]] In the final diversification step, the resin was heated at 500 C in DMF with a mono- substituted epoxide [[RLCH (-CH2O-)].] After shaking for 2 to 4 days the resin was filtered and washed with DMF (5 x 5 mL), [MEOH] [(3 X 5] mL), and CH2Cl2 (3 x 5 mL). T he resin-bound benzimidazole was cleaved from the solid-support by treatment with TFA: [CH2C12] (2: 3) for 1 hour at room temperature.

Reference： [1]Patent: WO2003/105779,2003,A2 .Location in patent: Page 26

11
[ 28466-26-4 ]
[ 1174665-59-8 ]
[ 1174665-63-4 ]

Yield	Reaction Conditions	Operation in experiment
40%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 40℃; for 2h;	To a solution of intermediate (1c), 2-[5-carboxy-2-oxo-1-(2-trimethylsilanyl- ethoxymethyl)-1 ,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, (3g, 6.2mmol) in tetrahydrofuran (10OmL) was added intermediate (2f), 1 H-pyrazol-4- ylamine (0.62g, 7.46mmol), 1-hydroxybenzotriazole hydrate (1.09g, 8.07mmol), N, N- diisopropylethylamine (2.4g, 3.24mL, 18.6mmol) and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (1.55g, 8.07mmol). The reaction mixture was heated at 4O0C for 2 hours. The reaction mixture was cooled and partitioned between ethyl acetate and aqueous saturated sodium hydrogen bicarbonate solution. The ethyl acetate layer was separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane - 66% ethyl acetate / hexane (gradient) to afford the desired title compound as a yellow solid, 1.36g, 40%.

Reference： [1]Patent: WO2009/93012,2009,A1 .Location in patent: Page/Page column 20; 35

12
[ 28466-26-4 ]
[ 30082-45-2 ]
[ 1018445-75-4 ]

Yield	Reaction Conditions	Operation in experiment
7.8%		Example 150 3-[(2-chlorophenoxy)methyl]-N-1H-pyrazol-4-ylbenzamide 3-[(2-Chlorophenoxy)methyl]benzoic acid was suspended in tetrahydrofuran (50 mL), and oxalyl chloride (1.03 mL) and N,N-dimethylformamide (catalytic amount) were added. After stirring at room temperature for 30 min, the mixture was added dropwise to a suspension of <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (1.0 g) in N,N-dimethylacetamide (50 mL). After stirring at room temperature for 5 hr, ethyl acetate was added, and the mixture was washed 3 times with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography and recrystallized from ethyl acetate/hexane to give the object product (280 mg, 7.8%). 1H NMR (300 MHz, DMSO-d6) delta ppm 5.29 (s, 2H) 6.93-7.02 (m, 1H) 7.22-7.35 (m, 2H) 7.46 (dd, J=1.51, 7.91 Hz, 1H) 7.56 (t, J=7.72 Hz, 1H) 7.63-7.70 (m, 1H) 7.85 (brs, 2H) 7.89-7.95 (m, 1H) 8.02-8.06 (m, 1H) 10.47 (s, 1H) 12.63 (brs, 1H)

Reference： [1]Patent: US2009/325956,2009,A1 .Location in patent: Page/Page column 41

13
[ 28466-26-4 ]
[ 89-32-7 ]
[ 1230878-52-0 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 7902 - 7904

14
[ 28466-26-4 ]
[ 1268520-96-2 ]
[ 1279724-69-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1270 - 1274

15
[ 28466-26-4 ]
C₁₁H₁₁N₃O₂ [ No CAS ]
[ 1279724-70-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1270 - 1274

16
[ 28466-26-4 ]
[ 1268520-84-8 ]
[ 1279724-71-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1270 - 1274

17
[ 28466-26-4 ]
[ 1239981-00-0 ]
[ 1239979-08-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2064 - 2070

18
[ 28466-26-4 ]
[ 62176-31-2 ]
[ 1285514-22-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Neat 1 H-pyrazol-4-amine (55.2 mg, 0.66 mmol) was added in one charge to a stirred solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method D; 170 mg, 0.55 mmol), EDC (318 mg, 1.66 mmol) and HOBT (254 mg, 1.66 mmol) in N,N-dimethylformamide (4 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. Water (30 ml) was added, and the mixture was extracted with ethyl acetate (50 ml x 2). The organic layers were combined, dried over MgSO,,, and concentrated in vacuo. The residue was washed with ethyl acetate yield the title compound as a brown solid. 180 mg.1HNMR (400 MHz, DMSO-c/6): 5.26 (s, 2H), 7.24 (d, 1 H), 7.35-7.45 (m, 4H), 7.52 (d, 2H), 7.65-7.68 (m, 1 H), 7.77 (d, 1 H), 7.93 (s, 1 H), 10.21 (s, 1 H), 12.66 (s, 1 H).MS (electrospray): m/z [M+H]+ = 372

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 119

19
[ 28466-26-4 ]
[ 1237517-77-9 ]
[ 1285514-46-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Neat 1 H-pyrazol-4-amine (49.0 mg, 0.59 mmol) was added in one charge to a stirred solution of 2-[(phenylmethyl)oxy]-5-(4-pyndinyl)benzoic acid (may be prepared as described in Description 79; 150 mg, 0.49 mmol), EDC (283 mg, 1.47 mmol) and HOBT (226 mg, 1.47 mmol) in dimethylformamide (4 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. 30 ml water was added, and the mixture was extracted with ethyl acetate (70 ml x 2). The organic layers were combined, dried over MgS04l and concentrated in vacuo. The residue was further purified by pre-HPLC (Gilson GX-281 ; Shimadzu 15mueta? 250*20mm; A: l OmMolNH4HC03/Water; B: CH3CN) to yield the title compound as a white solid. 50 mg.1HNMR (400 MHz, DMSO-cfe): 5.34 (s, 2H), 7.34-7.44 (m, 4H), 7.55 (d, 2H), 7.74 (d, 4H), 7.95-7.98 (m, 1 H), 8.09 (d, 1 H), 8.62 (d, 2H), 10.25 (s, 1 H), 12.65 (s, 1 H).MS (electrospray): m/z [M+H]+ = 371

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 129

20
[ 28466-26-4 ]
[ 78471-43-9 ]
[ 1315544-56-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 1.5h;	As shown in step 5-i of Scheme 5, methyl 4-bromo-2-(bromomethyl)benzoate (Compound 2018, 2.08 g, 6.75 mmol; prepared by reacting l-(4-bromo-2- methylphenyl)ethanone with NBS),lH-pyrazol-4-amine (561 mg, 6.75 mmol), and DIEA (873 mg, 1.18 mL, 6.75 mmol) were combined in DMF (7.78 mL) and heated at 110 C for 90 min. The reaction mixture was diluted with MeOH (60 mL) and the resulting white crystaline solid was collected by filtration and dried under vacuum to give 5-bromo-2-(lH- pyrazol-4-yl)isoindolin-l-one (Compound 2019, 1.21 g, 4.35 mmol, 64% yield): ESMS (Mu+Eta) 279.99

Reference： [1]Patent: WO2011/87776,2011,A1 .Location in patent: Page/Page column 56-57; 58

21
[ 28466-26-4 ]
[ 1315544-68-3 ]
[ 1315544-69-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃;	As shown in step 11-v of Scheme 11, Compound 2038 (76 mg, 0.306 mmol) was dissolved in 1 mL of DMF and added dropwise to a stirring solution of lH-pyrazol-4-amine (63.6 mg, 0.766 mmol) and DIEA (59.4 mg, 801 mu, 0.46 mmol) in 1 mL of DMF. The reaction was stirred at room temperature for 2 hours and then heated overnight at 80 C. After the addition of 10 mL of methanol, the mixture was allowed to cool to produce a solid. The solid was collected by filtration and washed with 3 mL of methanol. The solid was dried overnight under high vacuum to give 2-chloro-3-methyl-6-(lH-pyrazol-4-yl)-6,7-dihydro-5H- pyrrolo[3,4-6]pyridin-5-one (Compound 2039, 35 mg, 0.141 mmol, 46% yield). ESMS (M+l) 249.08.

Reference： [1]Patent: WO2011/87776,2011,A1 .Location in patent: Page/Page column 69; 70

22
[ 28466-26-4 ]
[ 1315544-59-2 ]
[ 1315544-60-5 ]

Yield	Reaction Conditions	Operation in experiment
32%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 22h;	As shown in step 6-iii of Scheme 6, lH-pyrazol-4-amine (149 mg, 1.79 mmol), methyl 2-(bromomethyl)-4-(5,6-dimethoxy-3-pyridyl)-6-methyl-benzoate (680 mg, 1.79 mmol) and DIEA (231 mg, 312 mu^, 1.79 mmol) were combined in DMF (5 mL), heated to 90C for 6 hours, and allowed to cool to room temperature over 16 hours. The reaction mixture was taken up in EtO Ac/water and the organic layer washed with water, brine, dried, and concentrated under reduced pressure to yield a foam. The foam was recrystallized in DCM/MeOH. The resulting solid was collected by filtration, washed with DCM, and dried under vacuum to provide 5-(5,6-dimethoxy-3-pyridyl)-7-methyl-2-(lH-pyrazol-4- yl)isoindolin-l-one (Compound 2024, 115 mg). The filtrate from the recrystallization was concentrated under reduced pressure and the residue purified by silica gel chromatography (20 to 100% EtO Ac/hex) to yield an additional 88 mg of Compound 2024 (total yield 203 mg, 0.66 mmol, 32% yield): ESMS (Mu+Eta) 351.26; 1H NMR (DMSO-d6) delta 12.83 (s, 1Eta), 8.10 (m, 2Eta), 7.88 (s, 1Eta), 7.74 (s, 1Eta), 7.61 (s, 2Eta), 4.83 (s, 2Eta), 3.92 (s, 3Eta), 3.91 (s, 3Eta), 2.72 (s, 3Eta).

Reference： [1]Patent: WO2011/87776,2011,A1 .Location in patent: Page/Page column 59; 60

23
[ 28466-26-4 ]
[ 3946-32-5 ]
[ 1310822-80-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 4350 - 4364

24
[ 109-04-6 ]
[ 28466-26-4 ]
[ 1369433-24-8 ]

Reference： [1]Synlett,2012,p. 285 - 289

25
[ 626-55-1 ]
[ 28466-26-4 ]
[ 1369433-25-9 ]

Reference： [1]Synlett,2012,p. 285 - 289

26
[ 108-86-1 ]
[ 28466-26-4 ]
phenyl-(1H-pyrazol-4-yl)-amine [ No CAS ]

Reference： [1]Synlett,2012,p. 285 - 289

27
[ 883985-18-0 ]
[ 28466-26-4 ]
[ 1355221-44-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 262 - 266

28
[ 28466-26-4 ]
[ 18063-02-0 ]
[ 1153946-38-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 20℃;Cooling with ice; Inert atmosphere;	1/-/-Pyrazol-4-amine (for a preparation see intermediate 1 ; 0.54 g, 6.5 mmol) was dissolved in acetonitrile (25 ml) with triethylamine (1.81 ml, 13.0 mmol) to give a red- purple suspension which was cooled in an ice-water bath. To the suspension was added a solution of 2,6-difluorobenzoyl chloride (Aldrich; 0.817 ml, 6.5 mmol) in acetonitrile (25 ml) dropwise over 15 min. The mixture was stirred cold under nitrogen. The reaction was stirred and allowed to warm slowly towards room temperature over 2 h, then at room temperature for 30 min. The reaction mixture was partitioned between EtOAc and water (-100 ml each). The aqueous phase was extracted with further EtOAc (2 x 50 ml). The combined organic extracts were dried (MgS04) and concentrated in vacuo. The residue (1.41 g) was purified on silica (50 g) using 0-100% EtOAc-cyclohexane then 0-20% methanol- EtOAc. Relevant fractions were concentrated in vacuo to give some pure product (0.925 g) and some less pure material (0.50 g). The latter material was re-purified on silica (20 g) using EtOAc to give further pure product (0.366 g). The two batches of pure product were combined to give the title compound (1.28 g) as a pale cream solid; LCMS (System 1): MH+= 224, tRET = 2.08 min.
		Intermediate 6: 2,6-Difluoro-N-1H-pyrazol-4-ylbenzamide.1H-Pyrazol-4-amine (for a preparation see intermediate 5; 0.54 g, 6.5 mmol) was dissolved in acetonitrile (25 ml) with triethylamine (1.81 ml, 13.0 mmol) to give a red- purple suspension which was cooled in an ice-water bath. To the suspension was added a solution of 2,6-difluorobenzoyl chloride (Aldrich; 0.817 ml, 6.5 mmol) in acetonitrile (25 ml) dropwise over 15 min. The mixture was stirred cold under nitrogen. The reaction was stirred and allowed to warm slowly towards room temperature over 2 h, then at room temperature for 30 min. The reaction mixture was partitioned between EtOAc and water (-100 ml each). The aqueous phase was extracted with further EtOAc (2 x 50 ml). The combined organic extracts were dried (MgS04) and concentrated in vacuo. The residue (1.41 g) was purified on silica (50 g) using 0-100% EtOAc-cyclohexane then 0-20% methanol- EtOAc. Relevant fractions were concentrated in vacuo to give some pure product (0.925 g) and some less pure material (0.50 g). The latter material was re-purified on silica (20 g) using EtOAc to give further pure product (0.366 g). The two batches of pure product were combined to give the title compound (1.28 g) as a pale cream solid; LCMS (System1): MH+= 224, tRET = 2.08 min.

Reference： [1]Patent: WO2012/52459,2012,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2012/52458,2012,A1 .Location in patent: Page/Page column 34-35

29
[ 28466-26-4 ]
[ 1332598-47-6 ]
[ 1365989-32-7 ]

Yield	Reaction Conditions	Operation in experiment
20%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 2h;Inert atmosphere; Microwave irradiation;	To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), lH-pyrazol-4 -amine (0.018 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2C03 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160 C for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HC03 to give the desired product as a white solid (12 mg, 20% yield). ¾ NMR (500 MHz, CH3OH-£¾: delta 8.27 (d, J= 5.5Hz, 1H), 8.12 (br, 1H), 7.74 (br, 1H), 7.64-7.58 (m, 3H), 7.41-7.40 (d, J= 5.5Hz, 1H). LCMS (Method A): RT = 4.94 min, m/z: 362.0 [M+H+].

Reference： [1]Patent: WO2012/35039,2012,A1 .Location in patent: Page/Page column 82-83

30
[ 98-03-3 ]
[ 28466-26-4 ]
[ 1156353-14-8 ]

Yield	Reaction Conditions	Operation in experiment
72%		To a 0C stirring mixture of lH-pyrazol-4-amine (250 mg, 3.008 mmol) and thiophene-2- carbaldehyde (281 uL, 3.008 mmol) in methanol and acetic acid (5.0 ml, 10: 1 ratio) was added 5-ethyl-2-methylpyridine borane complex (444 uL, 3.008 mmol). The ice bath was removed and the flask was attached to a bubbler to allow gas evolution and expansion. The reaction was stirred overnight at room temp. Most of the volatiles were evaporated in vacuo. With the aid of a 0C chilling bath, a 10 M solution of NaOH in water was carefully added. The ice bath was removed and stirring was continued for nearly 1 hour. The aqueous layer was extracted with DCM (3 x), washed with brine, and dried over MgS04 and concentrated. The obtained crude product was left under vacuum to remove the volatiles. The obtained viscous oil was diluted with DCM and evaporated under a gentle stream of nitrogen overnight. Solid crystals of the amine separated out and were washed with three aliquots of Hex:EtOAc = 9: 1. In this way, 391 mg (2.181 mmol; 72%) of the desired product were obtained in more than 97% purity by 1H-NMR analysis. 1H NMR (400 MHz, DMSO-d6) delta 4.21 (d, J= 5.6 Hz, 1H), 4.92 (t, J= 6.0 Hz, 1H), 6.94 (dd, J= 5.1, 3.4 Hz, 1H), 7.10 - 6.99 (m, 3H), 7.36 (dd, J= 5.1, 1.2 Hz, 1H), 12.05 (br s, 1H).

Reference： [1]Patent: WO2012/61698,2012,A2 .Location in patent: Page/Page column 95; 96

31
[ 28466-26-4 ]
[ 914220-25-0 ]
[ 1394162-31-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: To a solution of 5-(m-tolyl)oxazole-4-carboxylic acid (1 1.18 g) in DCM (65 mL), HOBT (1 1 .15 g, 0.083 mol) and EDC (15.8 g, 0.083 mol) was added at 0 C. This suspension was stirred at this temperature for 10 min, then it was added to a suspension was of 1 /-/-pyrazol-4-amine (5.48 g) and DIPEA (17.65 mL) in DCM (50 mL). The resulting mixture was allowed to warm to rt and was stirred at rt for 18 h. Percipitation of the desired compound was obtained by the addition of water. The solid was filtered and dried to yield the title compound. LC-MS conditions B: tR = 0.63 min, [M+H]+ = 269.13.

Reference： [1]Patent: WO2012/110986,2012,A1 .Location in patent: Page/Page column 53

32
[ 28466-26-4 ]
[ 1403888-69-6 ]
C₂₂H₂₀N₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; methanol; at 140℃; for 0.0833333h;Microwave irradiation;	Example No. 121Preparation of (8-Methoxy-3H-pyrazolo [3 , 4-c] quinolin-4-yl) - (lH-pyrazol-4-yl) -amine4-chloro-8-methoxy-2- (4-methoxybenzyl) -2H-pyrazolo [3,4- c]quinoline (0.16 mmol) and lH-pyrazol-4 -amine (2 eq.,0.3 mmol) were suspended in MeOH (dry, 3mL) in a microwave vial (2-5mL) , HC1 in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140C. The reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3mL) . The reaction mixture was irradiated in a microwave reactor for 5 min at 140C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from water/t-BuOH 4/1. exact mass: 280.1224 g/molHPLC-MS: analytical method Brt: 1.54 min - found mass: 281.1 (m/z+H)

Reference： [1]Patent: WO2012/143143,2012,A1 .Location in patent: Page/Page column 235-236

33
[ 28466-26-4 ]
[ 1694-31-1 ]
[ 1314389-50-8 ]

Yield	Reaction Conditions	Operation in experiment
		lH-Pyrazol-4-amine (10.4 g, 125 mmol) was dissolved in concentrated HCl (36.8 mL)/water (186 mL) and cooled to 0C. A solution of sodium nitrite (9.05g, 131 mmol) in water (122 mL) was added dropwise while maintaining the internal temperature below 4C. On complete addition, the mixture was stirred at 0C for 30 min. The resulting diazonium chloride solution was added via a pipette to a solution of tert-butyl acetoacetate (21.8 mL, 131 mmol) and sodium acetate (124 g, 1.51 mol) in water (122 mL) and EtOH (122 mL) at 0C. The resulting mixture was stirred between 0-1 C for two hours. The solid was filtered and dried in-vacuo to afford terf -butyl 3-oxo-2-[lH-pyrazol-4-yldiazenyl]butanoate as a yellow-brownish powder. LRMS (ESI) calc'd for CI 1Eta17Nu403 [M+H]+: 253, Found: 253.

Reference： [1]Patent: WO2011/84402,2011,A1 .Location in patent: Page/Page column 116-117

34
[ 28466-26-4 ]
[ 1044941-24-3 ]
[ 1422982-30-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 18h;	To a stirred mixture of 6-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-3-ca rboxylic acid (57.2 g, 0.154 mol), HATU (64.4 g, 0.169 mol), and diisopropylethylamine (69.7 g, 0.539 mol) in CH2Cl2 (1500mL) was added a solution of <strong>[28466-26-4]1H-pyrazole-4-amine</strong> (22.4 g, 0.270 mol) in DMF (500 mL) dropwise. The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water. MTBE was added to the mixture, and after separation, the aqueous layer was extracted with MTBE three times. The combined organic layers were washed by water three times and saturated brine once, dried over Na2SO4 . After concentration, the residue was triturated with MTBE to afford 55 g of desired product as an off white solid. (Yield: 82%).

Reference： [1]Patent: WO2013/24011,2013,A1 .Location in patent: Page/Page column 54

35
[ 28466-26-4 ]
[ 58793-45-6 ]
[ 1338718-34-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 41 5-Chloro-1-ethyl-4-nitro-1H-pyrazole Following the procedure for Intermediate 5 starting with 1-ethyl-4-nitropyrazole gave 5-chloro-1-ethyl-4-nitro-1H-pyrazole as a colorless solid (1.3 g, 74%). 1H-NMR (400 MHz, CDCl3) delta 8.16 (s, 1H), 4.26 (q, J=7 Hz, 2H), 1.50 (t, J=7 Hz, 3H).

Reference： [1]Patent: US2014/88117,2014,A1 .Location in patent: Page/Page column

36
[ 28466-26-4 ]
[ 1190380-62-1 ]
[ 1338718-36-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 43 5-Chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole Following the procedure for Intermediate 5 starting with 1-cyclopropylmethyl-4-nitropyrazole gave 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole as a colorless oil (1.16 g, 56%). 1H-NMR (400 MHz, CDCl3) delta 8.17 (s, 1H), 4.07 (d, J=7 Hz, 2H), 1.39-1.28 (m, 1H), 0.66-0.59 (m, 2H), 0.50-0.40 (m, 2H).

Reference： [1]Patent: US2014/88117,2014,A1 .Location in patent: Page/Page column

37
[ 28466-26-4 ]
[ 108-24-7 ]
[ 6647-92-3 ]

Yield	Reaction Conditions	Operation in experiment
54%	at 0 - 20℃;	Intermediate Example 17.N-( 1 H-pyrazol-4-yl)acetamide Acetic anhydride (0.7 ml, 8.433 mmol.) was added dropwise at 0 C to 1H- pyrazol-4-amine (0.7 g, 8.433 mmol). The mixture was stirred for 30 min at RT and quenched by the addition of crushed ice. The mixture was extracted with ethyl acetate The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 54 % yield. (0.6 g). LC- MS (ESI): Calculated mass: 125.0; Observed massl26.0 [M+H] + (rt: 0.115 min).
54%	at 20℃; for 0.5h;	Acetic anhydride (0.7 ml, 8.433 mmol) was added dropwise at 0 C. to <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (0.7 g, 8.433 mmol). The mixture was stirred for 30 min at RT and quenched by the addition of crushed ice. The mixture was extracted with ethyl acetate The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 54% yield. (0.6 g). LC-MS (ESI): Calculated mass: 125.0; Observed mass 126.0 [M+H]+ (rt: 0.115 min).

Reference： [1]Patent: WO2013/53983,2013,A1 .Location in patent: Page/Page column 38
[2]Patent: US2015/11548,2015,A1 .Location in patent: Paragraph 0157

38
[ 28466-26-4 ]
[ 3196-15-4 ]
C₈H₁₃N₃O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2743 - 2749

39
[ 28466-26-4 ]
[ 4489-34-3 ]
[ 1450821-84-7 ]

Reference： [1]Synthesis,2013,vol. 45,p. 1764 - 1784

40
[ 28466-26-4 ]
1-methyl-5-(5-ethyl-6,8-dioxaspiro[2.5]octan-7-yl)-4-nitro-pyrazole [ No CAS ]
2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 12 2-Ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one Following the procedure for Intermediate 5 starting from 1-methyl-5-(5-ethyl-6,8-dioxaspiro[2.5]octan-7-yl)-4-nitro-pyrazole gave 2-ethyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one as a colourless solid (240 mg, 13% over two steps). 1H NMR (400 MHz, CDCl3) delta 8.04 (s, 1H), 5.67 (dd, J=11.0, 2.4 Hz, 1H), 4.02 (s, 3H), 3.94 (dd, J=10.2, 5.2 Hz, 1H), 3.04 (td, J=13.3, 3.3 Hz, 1H), 2.79-2.63 (m, 3H), 2.20-2.12 (m, 1H), 2.05-1.92 (m, 1H), 1.67-1.57 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Reference： [1]Patent: US2014/88117,2014,A1 .Location in patent: Page/Page column

41
[ 3934-20-1 ]
[ 28466-26-4 ]
[ 1595291-18-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In isopropyl alcohol; at 50℃;	The mixture of 2, 4 -dichloro-pyrimidine (200 mg, 2.41 mmol), lH-pyrazol-4- ylamine (431 mg, 2.89 mmol), and TEA (730 mg, 7.23 mmol) in z'-PrOH (8 mL) was stirred at 50 overnight. After cooling, the reaction mixture was concentrated. The crude product was used directly for the next step without purification

Reference： [1]Patent: WO2014/55999,2014,A2 .Location in patent: Paragraph 0220

42
[ 28466-26-4 ]
[ 1612171-85-3 ]
[ 1612164-51-8 ]

Yield	Reaction Conditions	Operation in experiment
8%	With trifluoroacetic acid; In tert-butyl alcohol; at 100℃; for 48h;Sealed tube;	A mixture of N-(2-chloropyrimidin-4-yl)-l-isopropyl-lH-imidazo[4,5-c]pyridin-6-amine (Example 12, Step 4) (51.1 mg, 0.177 mmol), lH-pyrazol-4-amine (23.9 mg, 0.288 mmol), trifluoroacetic acid (10.0 mu^, 0.129 mmol) and fert-butanol (1.5 mL, 16 mmol) was heated in a sealed vial at 100 C for 2 days. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product (20.3 mg) was purified via reverse-phase HPLC and lyophilized to yield 4.6 mg (8%) of the title compound. LCMS (ESI): RT (min) = 3.051, [M+H]+ = 336.2, method = B; lH NMR (400 MHz, DMSO-d6) delta 12.43 (s, 1H), 9.72 (s, 1H), 8.83 (s, 1H), 8.66 (d, J = 1.0 Hz, 1H), 8.38 (s, 1H), 8.01 (d, J = 5.7 Hz, 1H), 6.67 (s, 1H), 4.62 (br s, 1H), 1.51 (d, J = 6.6 Hz, 6H).

Reference： [1]Patent: WO2014/81718,2014,A1 .Location in patent: Page/Page column 106; 107

43
[ 28466-26-4 ]
(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid [ No CAS ]
(2S,3R,4R)-1-acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)-N-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8 mg	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃; for 1.5h;	To a solution of (2S,3R,4R)- I -acetyl-2-cyclopropyl-3-methyl-4-((6-methylpyridin-2-yl)amino)- 1,2,3,4- tetrahydroquinoline-6-carboxylic acid (for a preparation see Example 247, 50 mg, 0.132 mmol) andHATU (90 mg, 0.198 mmol) in N,N-dimethylformamide (DMF)(1 mL)was added IH-pyrazol-4-amine (13 mg, 0.158 mmol) followed by DIPEA (0.097 mL, 0.553 mmol). The reaction mixture was stirred at rt for 90 mm, then purified directly by MDAP (HpH). The solvent was evaporated in vacuo to give the product (8 mg). LCMS (2 mm High pH): Rt = 0.88 mi [MH] = 445.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 358

44
[ 28466-26-4 ]
C₁₉H₂₅ClN₄OS [ No CAS ]
N₄-((1r,4r)-4-morpholinocyclohexyl)-N₂-(1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; at 150℃; for 2h;Microwave irradiation;	[00606] Synthesis of compound 1-78. Compound 1-78 was prepared from compounds 3.4 and 96.2 using protocol described in Example 94. . LCMS (ES, m/z): 440 [M+H]+; 1H-NMR (300 MHz, DMSO) delta 8.87 (1H, s), 7.82 (1H, brs), 7.52 (1H, brs), 5.71 (1H, d), 4.05-3.89 (1H, m), 3.58 (4H, brs), 3.01-2.95 (2H, m), 2.84-2.79 (2H, m), 2.50 (4H, m), 2.42-2.34 (2H, m), 2.26- 2.18 (1H, m), 2.05 (2H, d), 1.92 (2H, d), 1.47-1.30 (4H, m). [00599] Example 94. Synthesis of 2-(4-((4-(((lr,4r)-4-morpholinocyclohexyl)amino)-6,7- dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-2-yl)amino)-lH-pyrazol-l-yl)acetate, Example 1-76 [00600] To a solution of intermediate 3.4 (50 mg, 0.13 mmol, 1.00 equiv) and 2-(4-amino- lH-pyrazol-l-yl)acetic acid (36 mg, 0.26 mmol, 2.00 equiv) in isopropanol (5 mL) was added hydrochloric acid (4 M in dioxane, 0.1 mL) at room temperature. The reaction was stirred for 2 h at 140 C and irradiated in microwave. The resulting mixture was concentrated under vacuum and resulting crude was purified to yield compound 1-76 as a yellow solid. LCMS (ES, m/z) 540 [M+H]+. 1H NMR (300 MHz, d6-OMSO, ppm): delta 8.99 (s, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 7.26-7.06 (m, 1H), 5.79-5.71 (m, 1H), 4.99-4.91 (m, 3H), 4.01-3.99 (m, 1H), 3.77-51 (m, 4H), 3.05-2.98 (m, 2H), 2.83-2.73 (m, 2H), 2.61-2.53 (m, 5H), 2.40-2.35 (m, 2H), 2.01-1.94 (m, 2H), 1.49-1.35 (m, 4H), 1.20-1.15 (m, 6H).

Reference： [1]Patent: WO2014/194242,2014,A2 .Location in patent: Paragraph 00599-00600; 00603; 00606

45
[ 28466-26-4 ]
[ 504-02-9 ]
[ 39689-08-2 ]
9-[5-(1H-benzimidazol-2-ylsulfanyl)-2-furyl]-1,4,5,6,7,9-hexahydropyrazolo[4,3-b]quinolin-8-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 362 - 375

46
[ 28466-26-4 ]
[ 888720-29-4 ]
C₉H₈N₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4546 - 4552

47
[ 28466-26-4 ]
[ 10108-64-2 ]
Cd(μ-4-aminopyrazole)(μ-Cl)₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	In water; at 120℃; for 24h;High pressure;	A mixture of CdCl2 (0.1mmol, 18.3mg) and <strong>[28466-26-4]4-aminopyrazole</strong> (4-Hampz, 0.2mmol, 16.2mg) in H2O (10mL) was heated in a 23mL Teflon-lined reactor at 120C for 24h. After being cooled to room temperature, pale yellow crystals of 1 were collected by filtration, washed with water, and dried in air (54% yield based on Cd). Anal. Calc. for C3H5CdCl2N3 (%): C, 13.53; H, 1.89; N, 15.77. Found: C, 13.57; H, 1.94; N, 15.83.

Reference： [1]Journal of Molecular Structure,2015,vol. 1089,p. 135 - 145

48
[ 28466-26-4 ]
[ 108-24-7 ]
[ 6647-91-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	With triethylamine; In dichloromethane; at 5 - 30℃; for 21h;	N-(1-acetyl-1H-pyrazol-4-yl)acetamide A 250-mL 3-neck flask was charged with <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (5 g, 60.2 mmol) and dichloromethane (50 mL). The resulting suspension was cooled to 5 C. and triethylamine (TEA, 9.13 g, 90.0 mmol) was added, followed by acetic anhydride (Ac2O, 7.37 g, 72.2 mmol) at <20 C. The reaction was stirred at room temperature for 18 h, at which point thin layer chromatography [Eluent: ethyl acetate] analysis indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30 C. for an additional 3 hours to give a dark solution, at which point thin layer chromatography analysis indicated that only a trace of starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as eluent. The fractions containing pure product were combined and concentrated to dryness to afford an off-white solid. The solid was dried under vacuum at room temperature for 18 hours (5.55 g, 55%): 1H NMR (400 MHz, DMSO-d6) delta 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1 H), 7.83 (d, J=0.7 Hz, 1H), 2.60 (s, 3H), 2.03 (s, 3H); EIMS m/z 167 ([M]+).
55%	With triethylamine; In dichloromethane; at 5 - 30℃; for 21h;	Example CE-1 RRN 64N-(1-acetyl-1H-pyrazol-4-yl)acetamide [0049] <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (5 g, 60.2 mmol) and dichloromethane (50 mL). The resulting suspension was cooled to 5 C. and triethylamine (TEA, 9.13 g, 90.0 mmol) was added, followed by acetic anhydride (7.37 g, 72.2 mmol) at <20 C. The reaction was stirred at room temperature for 18 hours, at which point thin layer chromatography [Eluent: ethyl acetate] analysis indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30 C. for an additional 3 hours to give a dark solution, at which point thin layer chromatography analysis indicated that only a trace of starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as eluent. The fractions containing pure product were combined and concentrated to dryness to afford an off-white solid. The solid was dried under vacuum at room temperature for 18 hours (5.55 g, 55%): [0051] 1H NMR (400 MHz, DMSO-d6) delta 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1H), 7.83 (d, J=0.7 Hz, 1H), 2.60 (s, 3H), 2.03 (s, 3H); EIMS m/z 167 ([M]+).
55%	With triethylamine; In dichloromethane; at 5 - 20℃; for 18h;	10054] A 250-mE 3-neck flask was charged with 1H-pyra- zol-4-amine (5 g, 60.2 mmol) and dichioromethane (50 mE). The resulting suspension was cooled to 5 C. and triethylamine (9.13 g, 90.0 mmol) was added, followed by acetic anhydride (7.37 g, 72.2 mmol) at <20 C. The reaction was stirred at room temperature for 18 hours, at which point thin layer chromatography [Eluent: ethyl acetate] analysis indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30 C. for an additional 3 hours to give a dark solution, at which point thin layer chromatography analysis indicated that only a trace of starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as eluent. The fractions containing pure product were combined and concentrated to dryness to afford an off-white solid. The solid was dried under vacuum at room temperature for 18 hours (5.55 g, 55%): ?H NMR (400 MHz, DMSO-d5) oe 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1H), 7.83 (d, J=0.7 Hz, 1H), 2.60 (s, 3H), 2.03 (s, 3H); ElMS mlz 167 ([M]j.

55%	With triethylamine; In dichloromethane; at 20 - 30℃; for 21h;	10055] A 250-mL 3-neck flask was charged with iH-pyrazol-4-amine (5 g, 60.2 mmol) and dichloromethane (50 mL). The resulting suspension was cooled to 5 C. and triethylamine (9.i3 g, 90.0 mmol) was added, followed by acetic anhydride (7.37 g, 72.2 mmol) at <20 C. The reaction was stirred at room temperature for i 8 hours, at which point thin layer chromatography (Eluent: ethyl acetate) analysis indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30 C. for an additional 3 hours to give a dark solution, at which point thin layer chromatography analysis indicated that only a trace of starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as eluent. The fractions containing pure product were combined and concentrated to dryness to afford an off-white solid. The solid was dried under vacuum at room temperature for i 8 hours (5.55 g, 55%):10056] ?H NMR (400 MHz, DMSO-d5) oe iO.30 (s, iH),8.39 (d, J=0.7 Hz, iH), 7.83 (d, J=0.7 Hz, iH), 2.60 (s, 3H),2.03 (s, 3H); ElMS mlz i67 ([M]j.
55%	With triethylamine; In dichloromethane; at 5 - 20℃; for 21h;	A 250-mL 3-neck flask was charged with <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (5 g, 60.2 mmol) and dichloromethane (50 mL). The resulting suspension was cooled to 5 C. and triethylamine (9.13 g, 90.0 mmol) was added, followed by acetic anhydride (7.37 g, 72.2 mmol) at <20 C. The reaction was stirred at room temperature for 18 hours, at which point thin layer chromatography [Eluent: ethyl acetate] analysis indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30 C. for an additional 3 hours to give a dark solution, at which point thin layer chromatography analysis indicated that only a trace amount of starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as eluent. The fractions containing pure product were combined and concentrated to dryness to afford an off-white solid. The solid was dried under vacuum at room temperature for 18 hours (5.55 g, 55%): 1H NMR (400 MHz, DMSO-d6) delta 10.30 (s, 1H), 8.39 (d, J=0.7 Hz, 1H), 7.83 (d, J=0.7 Hz, 1H), 2.60 (s, 3H), 2.03 (s, 3H); EIMS m/z 167 ([M]+).

Reference： [1]Patent: US2015/111938,2015,A1 .Location in patent: Paragraph 0043; 0044
[2]Patent: US2015/112073,2015,A1 .Location in patent: Paragraph 0049-0051
[3]Patent: US2015/112074,2015,A1 .Location in patent: Paragraph 0053; 0054
[4]Patent: US2015/112075,2015,A1 .Location in patent: Paragraph 0054; 0055; 0056
[5]Patent: US2015/112076,2015,A1 .Location in patent: Paragraph 0076; 0077

49
[ 2075-46-9 ]
[ 28466-26-4 ]
[ 63680-90-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylsilane; 5% palladium on Al2O3; In ethanol; water; at 15℃; for 72h;Inert atmosphere;	Example 1 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2100 mL) and dried under vacuum at 20 C. to afford a white solid (?10:1 mixture of 1a and 1H-pyrazole-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H) EIMS m/z 117 ([M]+).
	With hydrogenchloride; triethylsilane; 5% palladium on Al2O3; In ethanol; water; at 15℃; for 73h;Inert atmosphere;	Example 1 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) [0019] nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 weight %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37%, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2×100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2×100 mL) and dried under vacuum at 20 C. to afford a white solid (10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H) EIMS: m/z 117.
	With hydrogenchloride; triethylsilane; Pd/Al2O3; In ethanol; water; at 15℃; for 73h;	Example 1 3-Chloro-1H-pyrazol-4-amine hydrochloride (1a) A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2100 mL) and dried under vacuum at 20 C. to afford a white solid (?10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+).

Reference： [1]Patent: US2015/111938,2015,A1 .Location in patent: Paragraph 0018; 0019
[2]Patent: US2015/112073,2015,A1 .Location in patent: Paragraph 0019-0020
[3]Patent: US2015/112074,2015,A1 .Location in patent: Paragraph 0020; 0021

50
[ 2075-46-9 ]
[ 28466-26-4 ]
3-chloro-1H-pyrazol-4-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylsilane; palladium/alumina; In ethanol; water; at 15℃; for 73h;	A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added a second time and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added a third time and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with Acetonitrile (2100 mL) and dried under vacuum at 20 C. to afford a white solid (?10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+).

Reference： [1]Patent: US2015/112076,2015,A1 .Location in patent: Paragraph 0008; 0020; 0021

51
[ 28466-26-4 ]
4-chloro-7-nitroisobenzofuran-1,3-dione [ No CAS ]
4-chloro-7-nitro-2-(1H-pyrazol-4-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With acetic acid; at 100℃; for 18h;	Synthesis of LXVI:To a stirred solution of compound XXV (2.5 g, 10 mmol) in acetic acid (50 mL) was added<strong>[28466-26-4]1H-pyrazol-4-amine</strong> (LXV; 2.2 g, 20 mmol) and the reaction mixture heated at 100C for 18 h. The reaction mixture was cooled to room temperature and the acetic acid removed underreduced pressure to obtain crude product. The crude product was washed with ethanol to afford4-chloro-7-nitro-2-(1H-pyrazol-4-yl)isoindoline-1,3-dione as a yellow solid (LXVI; 2.5 g, 78%yield). ?H NMR (400MHz, DMSO-d6): V 13.18(s, 1H), 8.29-8.27 (d, J 8Hz, 1H), 8.13-8.11(d, J= 8 Hz, 2H), 7.84 (bs, 1H). MS (M+1): 292.93.

Reference： [1]Patent: WO2015/97121,2015,A1 .Location in patent: Page/Page column 134

52
[ 28466-26-4 ]
4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid [ No CAS ]
tert-butyl (trans-2-(4-(1H-pyrazol-4-ylcarbamoyl)phenyl)cyclopropyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.3 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	A) tert-butyl (trans-2-(4-(1H-pyrazol-4-ylcarbamoyl)phenyl)cyclopropyl)carbamate To a solution of 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid (50.7 mg) and <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (18.2 mg) in DMF (0.91 mL) were added 1-hydroxybenzotriazole (37.1 mg) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (52.6 mg). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (56.3 mg). MS (API+): [M+H]+ 343.3.

Reference： [1]Patent: US2015/266881,2015,A1 .Location in patent: Paragraph 0956; 0957

53
[ 28466-26-4 ]
C₁₆H₁₅ClN₆O₂S₂ [ No CAS ]
2-(3-(4-(2-((1H-pyrazol-4-yl)amino)thieno[3,2-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With toluene-4-sulfonic acid; In butan-1-ol; at 120℃; for 3h;	Compound 31-a (130 mg, 1.5 mmol) and compound 5 (222 mg, 0.5 mmol) were dissolved in n-butanol (10 mL), p-toluene sulfonic acid monohydrate (344 mg, 2.0 mmol) was added. The mixture was heated to 120 C. and stirred for 3 hours. After cooled to room temperature, the mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL), then extracted with dichloromethane (10 mL×3). The organic layers were combined, washed with water (10 mL×3) and saturated brine (10 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated. The residue was purified by preparation HPLC (mobile phase:water (0.04% trifluoroacetic acid), acetonitrile; gradient: 32%-62%) to give compound T-31 (143 mg, yield: 61%). LC-MS (ESI): m/z=470 [M+H]+. (0255) 1H-NMR (400 MHz, DMSO-d6) delta: 9.43 (s, 1H), 8.81 (s, 1H), 8.37 (s, 1H), 8.34 (d, J=4.0 Hz, 1H), 7.87 (s, 2H), 739 (d, J=4.0 Hz, 1H), 4.57 (d, J=8 Hz, 2H), 4.27 (d, J=8 Hz, 2H), 3.91 (s, 4H), 3.24 (q, J=6 Hz, 2H), 1.25 (t, J=6 Hz, 3H) ppm

Reference： [1]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0252; 0254; 0255

54
[ 3934-20-1 ]
[ 28466-26-4 ]
[ 1595291-13-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine; In isopropyl alcohol; at 50℃;	Example 57 2-chloro-N-(lH-pyrazol-4-yl)pyrimidin-4-amine The mixture of 2, 4 -dichloro-pyrimidine (200 mg, 2.41 mmol), lH-pyrazol-4- ylamine (431 mg, 2.89 mmol), and TEA (730 mg, 7.23 mmol) in z'-PrOH (8 mL) was stirred at 50 overnight. After cooling, the reaction mixture was concentrated. The crude product was used directly for the next step without purification.

Reference： [1]Patent: WO2015/157556,2015,A1 .Location in patent: Paragraph 0248

55
[ 28466-26-4 ]
[ 122-51-0 ]
1-(1H-pyrazol-4-yl)-1H-tetrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium azide; acetic acid; at 90℃;	General procedure: A mixture of the appropriate aminopyrazole 1 (0.01 mol), NaN3 (0.78 g, 0.012 mol), andtriethyl orthoformate (1.60 ml, 0.015 mol) or triethylorthoacetate (1.74 ml, 0.015 mol) in glacial acetic acid(10 ml) was stirred for 3-4 h at 90. The reaction mixturewas cooled and poured into ice water (50 ml). In the case ofcompounds 2a-c, 4b, the precipitate that formed wasfiltered off, washed with water, and recrystallized from EtOH. In the case of compounds 2d, 3a, 4a,c, the aqueouslayer was extracted with ethyl acetate (3×15 ml), and theorganic layer was dried over anhydrous Na2SO4. Thesolvent was removed at reduced pressure, and the solidresidue was recrystallized from EtOH.

Reference： [1]Chemistry of Heterocyclic Compounds,2015,vol. 51,p. 695 - 703
Khim. Geterotsikl. Soedin.,2015,vol. 51,p. 695 - 703,9

56
[ 28466-26-4 ]
(S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1,3-oxazole-4-carboxylic acid [ No CAS ]
(S)-tert-butyl (1-(4-((1H-pyrazol-4-yl)carbamoyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-5-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 10h;	Step 1: (S) -Tert-butyl (1- (4- ( (1H-pyrazol-4-yl) carbamoyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazol-5-yl) ethyl) carbamate[1998]To 15 mL of dichloromethane were added (S) -5- (1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (250 mg, 0.53 mmol) , <strong>[28466-26-4]4-aminopyrazole</strong> (53 mg, 0.64 mmol) , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol) and 1-hydroxy-7-azabenzotriazole (182 mg, 1.33 mmol) . To the mixture was added N, N-diisopropylethylamine (0.37 mL, 2.14 mmol) dropwise at 0 . The resulting mixture was stirred at rt for 10 hours. The reaction mixture was washed with water (10 mL × 2) and the organic layer was dried over anhydrous sodium sulfate. The organic solvent was removed and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 1/1) to give a white solid (138 mg, 47) .[1999]1H NMR (400 MHz, CDCl3) : delta ppm 7.96 (s, 2H) , 7.62 -7.59 (m, 1H) , 7.58 (s, 1H) , 7.24 (d, J 8.4 Hz, 1H) , 6.70 (t, JF-H 75.0 Hz, 1H) , 5.36 -5.32 (m, 1H) , 3.98 (d, J 6.9 Hz, 2H) , 1.56 (d, J 7.0 Hz, 3H) , 1.43 (s, 9H) , 1.35 -1.32 (m, 1H) , 0.71 -0.66 (m, 2H) , 0.43 -0.39 (m, 2H) and MS-ESI: m/z 478.8 [M-55]+.

Reference： [1]Patent: WO2015/161830,2015,A1 .Location in patent: Paragraph 00705

57
[ 28466-26-4 ]
((1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone [ No CAS ]
cyclopropyl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With hydrogenchloride; In isopropyl alcohol; at 140℃; for 1h;Microwave irradiation;	Example 49 cyclopropyl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone To a solution of ((1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclo-propyl)methanone (Preparation 28, 100 mg, 0.342 mmol) and 1-H-pyrazol-4-amine (100 mg, 0.54 mmol) in iPrOH (5 mL) was added cHCl (2 drops) and the reaction was heated to 140 C. under microwave irradiation for 1 hour. The reaction was cooled, concentrated in vacuo and purified by silica gel column chromatography eluting with 5% MeOH in DCM followed by preparative HPLC (Purification Method B) to afford the title compound (34 mg, 29%). 1H NMR (400 MHz, DMSO-d6): delta ppm 0.77 (br s, 4H), 1.63 (br s, 1H), 1.74 (br s, 2H), 2.01 (d, 2H), 2.94-3.10 (m, 2H), 3.87-4.27 (m, 2H), 4.53-4.84 (m, 2H), 6.10 (d, 1H), 7.53 (br s, 1H), 7.78 (br s, 1H), 7.92 (d, 1H), 8.86 (br s, 1H), 12.36 (br s, 1H). MS m/z 340 [M+H]+

Reference： [1]Patent: US2016/52930,2016,A1 .Location in patent: Paragraph 0452; 0453

58
[ 28466-26-4 ]
[ 15761-38-3 ]
tert-butyl (1-((1H-pyrazol-4-yl)amino)-1-oxopropan-2-yl)carbamate [ No CAS ]

Reference： [1]ChemMedChem,2016,p. 1695 - 1699

59
[ 28466-26-4 ]
[ 47375-34-8 ]
tert-butyl (1-((1H-pyrazol-4-yl)amino)-3-(4-(tert-butoxy)phenyl)-1-oxopropan-2-yl)carbamate [ No CAS ]

Reference： [1]ChemMedChem,2016,p. 1695 - 1699

60
[ 28466-26-4 ]
[ 13726-84-6 ]
tert-butyl 5-((1H-pyrazol-4-yl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate [ No CAS ]

Reference： [1]ChemMedChem,2016,p. 1695 - 1699

61
[ 28466-26-4 ]
[ 24424-99-5 ]
tert-butyl N-(1H-pyrazol-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 48h;	3.0g of compound 8 was dissolved in NaHCO3/THF (7.5g/160mL) mixed solution and added 8.6g of Boc2O. It was reacted at room temperature for 2 days. After distilling off the solvent it was dissolved in ethyl acetate, washed with water, aqueous citric acid solution, and saturated sodium chloride solution three times each 100mL. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The crude product was washed with n-hexane to obtain 5.0g of the pure intermediate 9 as a pink solid, yield: 75%.
75%	With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 48h;	3.0 g of <strong>[28466-26-4]4-amino-1H-pyrazole</strong> (2) was dissolved in a 7.5 g / 160 mL NaHCO3 / tetrahydrofuran mixed solution, 8.6 g of di-tert-butyl dicarbonate was added and reacted at room temperature for 2 days. The solvent was evaporated to dryness on a rotary evaporator, and then dissolved with ethyl acetate, and washed three times with water, aqueous citric acid, and saturated sodium chloride solution; The organic phase was dried over anhydrous magnesium sulfate over night and filtered and evaporated After the crude product was washed with n-hexane, a pure 5.0 g of a pink solid 3 was obtained in a yield of 75%.
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2.5h;Inert atmosphere;	fe/t-Butyl- lH-pyrazol-4-ylcarbamate (1027a) (0823) 1 /-/-pyrazol-4-amine di-ferf-butyl dicarbonate 1027a (0824) [00378] Under argon atmosphere, to a solution of lH-pyrazol-4-amine (2 g, 28.9 mmol) and -tert- butyl dicarbonate (6.3 g, 28.9 mmol) in 100 mL of anhydrous THF was added triethylamine (1.68 mL, 12 mmol) at 0C. After stirring for 30 min, the temperature was raised to RT and the mixture was stirred for 2 h. The reaction mixture was condensed under reduced pressure, and then dispersed into 50 mL of EtOAc, washed with water, evaporated, dried over anhydrous MgS04, and evaporated to dryness. The mixture was purified with flash column chromatography with an eluent of EtOAc/hexane in a 1 : 1 v/v ratio, and then the condensed compounds were then recrystallized using EtOAc/hexane (1: 1 v/v) to give a target product. NMR (CDC13, 400 MHz) delta 7.63 (s, 2H, ArH), 6.29 (bs, 1Eta, NH), 1.51 (s, 9Eta, C(CH3)3); MS (ESI) mJz 182.1 [M - H]

Reference： [1]Patent: CN105418616,2016,A .Location in patent: Paragraph 0120; 0121
[2]Patent: CN108864057,2018,A .Location in patent: Paragraph 0105; 0206; 0209-0210
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 3898 - 3923
[4]Patent: WO2017/214634,2017,A1 .Location in patent: Paragraph 00378

62
[ 941685-26-3 ]
[ 28466-26-4 ]
4-(1H-pyrazol-4-ylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 150℃; for 2h;Microwave irradiation;	0.2g of compound 2 and 0.11g of <strong>[28466-26-4]4-aminopyrazole</strong> were dissolved in n-butanol. 0.27g of N,N-diisopropylethylamine was added to the solution and was heated at 150C under microwave for 2h. After completion of the reaction, the solvent was evaporated to dryness using a rotary evaporator under reduced pressure to obtain a crude product. The product was purified by column chromatography (dichloromethane:methanol = 20:1) to give 0.15g of compound 3 as a yellow solid, yield: 65%.

Reference： [1]Patent: CN105418616,2016,A .Location in patent: Paragraph 0108; 0109

63
[ 28466-26-4 ]
[ 1341200-80-3 ]
5-chloro-N4-(4-chlorophenyl)-N2-(1H-pyrazol-4-yl)pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With trifluoroacetic acid; In butan-1-ol; at 150℃; for 2h;Microwave irradiation;	0.3 g of intermediate 2a and 0.18 g of <strong>[28466-26-4]4-aminopyrazole</strong> were dissolved in n-butanol,To the solution was added 2-3 drops of trifluoroacetic acid,The reaction was carried out at microwave at 150 C for 2 h,After the reaction,The solvent was evaporated to dryness by a reduced pressure rotary evaporator to obtain a crude product. The crude product was obtained by column chromatography using a column of dichloromethane: methanol = 30: 1 by volume to give compound 3a,0.15 g as a white solid,Yield: 42%

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 950 - 955
[2]Patent: CN106349224,2017,A .Location in patent: Paragraph 0099; 0100

64
[ 28466-26-4 ]
[ 280581-45-5 ]
5-chloro-N4-phenyl-N2-(1H-pyrazol-4-yl)pyrimidine-2,4-diamine [ No CAS ]