876343-24-7|1-Ethyl-1H-pyrazol-4-amine| Ambeed

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Quality Control of [ 876343-24-7 ] Purity: 98% SDS Specification

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Product Details of [ 876343-24-7 ]

CAS No. :	876343-24-7
Formula :	C₅H₉N₃
M.W :	111.15
SMILES Code :	CCN1C=C(N)C=N1
MDL No. :	MFCD05861667
InChI Key :	HENLKZLWIDJRSC-UHFFFAOYSA-N
Pubchem ID :	7018640

Safety of [ 876343-24-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 876343-24-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	5
Fraction Csp3	0.4
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	32.7
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	43.84 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.09
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-0.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.49
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.27
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.05
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.22

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.83
Solubility	16.4 mg/ml ; 0.148 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.32
Solubility	53.7 mg/ml ; 0.483 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.78
Solubility	18.4 mg/ml ; 0.166 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.08 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.39

Application In Synthesis of [ 876343-24-7 ]

* 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.

Downstream synthetic route of [ 876343-24-7 ]

[ 876343-24-7 ] Synthesis Path-Downstream 1~55

1
[ 876343-24-7 ]
[ 952059-84-6 ]
C₂₄H₂₅N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 20℃; for 18h;	[3]; DMA was used as the reaction solvent. The product gave the following characterising data :- 1H NMR Spectrum: (DMSOd6) 1.32 (t5 3H)5 1.44 (t, 3H), 3.78 (s, 3H), 3.8 (s, 2H), 4.07 (q5 2H), 4.29 (q, 2H)5 6.83 (d, IH), 7.41 (s, IH)5 7.47 (d, IH), 7.79 (d, IH)5 7.86 (s, IH), 8.04 (d, IH)5 8.73 (s, IH)5 8.74 (d, IH)5 10.1 (s, IH); Mass Spectrum: M+H+ 449.

References: [1]Patent: WO2007/113548,2007,A1 .Location in patent: Page/Page column 168; 172.

2
[ 876343-24-7 ]
[ 952138-08-8 ]
N-(1-ethyl-1H-pyrazol-4-yl)-2-[2-methoxy-4-(1,6-naphthyridin-4-yloxy)phenyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 1; iV-(l-ethyl-lJ-pyrazol-4-yl)-2-[2-methoxy-4-(l,6-naphthyridin-4-yloxy)phenyl]acetamide; Diisopropylethylamine (0.417 ml) and 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.395 g) were added in turn to a stirred mixture of 2-[2-methoxy-4-(l,6-naphthyridin-4-yloxy)phenyl]acetic acid (0.27 g),4-amino-l -ethyl- 1/i-pyrazole (0.179 g) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The resultant mixture was evaporated and the residue was purified by reversed-phase preparative HPLC on a Waters 'Xbridge' Cl 8 column (5 microns silica, 19 mm diameter, 100 mm length) using a solvent gradient comprising 13:17 to 100:0 mixtures of acetonitrile and 0.02M aqueous ammonium carbonate as eluent for 4.5 minutes at a flow rate of 40 ml per minute. The material so obtained was further purified by column chromatography on silica using a solvent gradient from methylene chloride to a 9:1 mixture of methylene chloride and 7M methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.12 g); 1H NMR Spectrum: (DMSOd6) 1.33 (t, 3H), 3.61 (s, 2H), 3.77 (s, 3H), 4.07 (q, 2H), 6.75 (d, IH), 6.91 (m, IH), 7.06 (d, IH), 7.37 (d, IH), 7.42 (s, IH), 7.88 (s, IH), 7.92 (d, IH), 8.82 (d, IH), 8.9 (d, IH), 9.71 (s, IH), 10.05 (s, IH); Mass Spectrum: M+H+404.

References: [1]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 91.

3
[ 876343-24-7 ]
[ 952138-11-3 ]
C₂₂H₂₀ClN₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	[2]; 2-(6-Chlorobenzotriazol- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium tetrafluoroborate was used in place of 2-(7-azabenzotriazol-l-yl)-l,l53,3-tetramethyluronium hexafluorophosphate(V) as the coupling agent. The product gave the following characterising data :- 1H NMR Spectrum: (DMSOd6) 1.32 (t, 3H), 3.61 (s, 2H), 3.77 (s, 3H), 4.07 (q, 2H), 6.76 (d, IH), 6.92 (m, IH), 7.06 (d, IH), 7.38 (d, IH), 7.42 (s, IH)5 7.88 (s, IH), 8.08 (s, IH), 8.92 (d, IH), 9.57 (s, IH), 10.05 (s, IH); Mass Spectrum: M+H+ 438 and 440.

References: [1]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 94-96.

4
[ 876343-24-7 ]
[ 952138-15-7 ]
N-(1-ethyl-1H-pyrazol-4-yl)-2-[2-methoxy-4-(7-methoxy-1,6-naphthyridin-4-yloxy)phenyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	[3]; 2-(6-Chlorobenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate was used in place of 2-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) as the coupling agent. The product gave the following characterising data :- H NMR Spectrum: (DMSOd6) 1.32 (t, 3H), 3.6 (s, 2H), 3.77 (s, 3H), 4.02 (s, 3H), 4.07 (q, 2H), 6.51 (d, IH), 6.88 (m, IH), 7.03 (d, IH), 7.23 (s, IH), 7.36 (d, IH), 7.42 (s, IH), 7.88 (s, IH), 8.77 (d, IH), 9.43 (s, IH), 10.04 (s, IH); Mass Spectrum: M+H4 434.

References: [1]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 94-95; 98.

5
[ 876343-24-7 ]
[ 876343-11-2 ]
C₁₆H₁₉N₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol; at 120℃;	EXAMPLE 187: 4-[4-(l-EthyMNo.-pyrazol-4-ylamino)-7No.-pyrroIo[2,3-"npyrimidin-6-yI]-3,6-dihydro-2No.-pyridine-l-carboxylic acid fcrf-butyl ester.; [527] A mixture of 4-(4-chloro-7No.-pyrrolo[2,3 -d]pyrimidin-6-yl)-3 ,6-dihydro-2No.-pyridine-1-carboxylic acid fert-butyl ester (HOmg, 0.33mmol) and l-ernyl-4-amino-l./:/'-pyrazole (44mg, 0.39mmol) in 1-butanol (3mL) was heated at 120°C overnight, LC-MSshowed the desired product and some de-Boc product. After the mixture was cooled to rt, itwas diluted with methylene chloride (3mL), then AyV-diisopropylethylamine (0.1 ImL,0.66mmol) and di-tert-butyldicarbonate (72mg, 0.33mmol) were added, the resulting mixturewas stirred at rt for 30min. The mixture was diluted with EtOAc (30mL), then washed withbrine (20mL), and dried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was crystallized with EtOAc to give, the title compound asan off-white solid. LC-MS (ES, Pos.): 410 [MH*]. 'HNMR (CDC13, 400 MHz): 8 = 1.51 (s,9H), 1.56 (t, J = 7.3 Hz, 3H), 2.50 (m, 2H), 3.66 (m, 2H), 4.16 (m, 2H), 4.22 (q, J = 7.3 Hz,2H), 6.04 (s, 1H), 6.17 (s, 1H), 6.57 (s, 1H), 7.56 (s, 1H), 7.95 (s, 1H), 8.38 (s, 1H), 10.96 (brs, 1H).

References: [1]Patent: WO2006/17443,2006,A2 .Location in patent: Page/Page column 122-123.

6
[ 58793-45-6 ]
[ 876343-24-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;palladium 10% on activated carbon; In ethanol; under 2585.81 Torr; for 3h;Inert atmosphere;	Example 111b l-Ethyl-lH-pyrazol-4-amine 111b CGI PHARM6 0WOA 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 468 mg dry weight) and a solution of 111a (1.90 g, 13.5 mmol) in ethanol (100 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 3 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2 x 25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a quantitative yield of 111b (1.50 g) as a purple oil: ]H NMR (300 MHz, CDC13) delta 7.15 (s, 1H), 7.02 (s, 1H), 4.05 (q, 2H, / = 7.2 Hz), 2.88 (br s, 2H), 1.43 (t, 3H, / = 7.2 Hz); MS (ESI+) m/z 112.1 (M+H).
96%	With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; for 12h;	Under hydrogen (1 atm), to a solution of compound 40-b (1.0 g, 7.1 mmol) in methanol (10 mL) was added 10% 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 40-a (760 mg, yield: 96%), which was used directly for the next step without purification. LC-MS (ESI): m/z=112 [M+H]+.
93%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 6h;	Example 123b 1-Ethyl-1H-pyrazol-4-amine 123b A 100-mL single-neck round-bottomed flask was purged with hydrogen and charged with 123a (4.5 g, 31.9 mmol), 10% palladium on carbon (10% wet, 2.0 g), and methanol (50 mL). The mixture was stirred at room temperature for 6 h. The catalyst was removed by filtration through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford 123b (3.3 g, 93%). MS-ESI: [M+H]+ 112.0

89%	With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h;	A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for5 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material in 89% yield; 1H NMR: (DMSOd6) 1.27 (t, 3H), 3.77 (br s, 2H), 3.92 (q, 2H), 6.87 (s, IH), 7.01 (s, IH).
89%	With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h;	A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material in 89% yield; 1HNMR: (DMSOd6) 1.27 (t, 3H), 3.77 (br s, 2H), 3.92 (q, 2H), 6.87 (s, IH), 7.01 (s, IH).
89%	With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h;	A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material in 89% yield; 1H NMR: (DMSOd6) 1.27 (t, 3H), 3.77 (br s, 2H), 3.92 (q, 2H), 6.87 (s, 1H), 7.01 (s, 1H).
89%	With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h;	A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material in 89% yield; 1H NMR Spectrum: (DMSOd6) 1.27 (t, 3H), 3.77 (br s, 2H), 3.92 (q, 2H), 6.87 (s, IH), 7.01 (s, IH).
89%	With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h;	A mixture of a portion (0.8 g) of the material so obtained, platinum oxide (0.1 g), ethyl acetate (10 ml) and ethanol (30 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material in 89% yield; 1H NMR Spectrum: (DMSOd6) 1.27 (t, 3H), 3.77 (br s, 2H), 3.92 (q, 2H), 6.87 (s, IH), 7.01 (s, IH).
87%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 2h;	Synthesis of Compound 5.2. Into a 250-mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed 5.1 (1.9 g, 13.46 mmol, 1.00 equiv), methanol (100 mL), and palladium on carbon (200 mg). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The reaction was stirred 2 h at room temperature under an atmosphere of hydrogen (balloon). Then the solids were filtered off and the organics were concentrated in vacuo. This afforded 1.3 g (87%) of 5.2 as red oil.
	With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate;	4-Amino-l-ethyl-lfl-pyrazole"; [529] To a solution of l-ethyl-4-nitro-lF-pyrazole (59mg, 0.42mmol) in ethylacetate (2mL) and ethanol (2mL) was added W% Pd-C (20mg), and the resulting mixture wasstirred under hydrogen atmosphere overnight. TLC showed the reaction was complete. Thecatalyst was removed by filtration through a pad of celite, and the filtrate was concentratedunder reduced pressure to give the title compound as red oil. *H NMR (CDC13, 400 MHz): 8= 1.43 (t, J= 7.3 Hz, 3H), 2.90 (br s, 2H), 4.05 (q, J= 7.3 Hz, 2H), 7.02 (d, J= 0.8 Hz, 1H),7.15(d,J=0.8Hz, 1H).
260 mg	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;	To a solution of 4-nitro-lH-pyrazole (500 mg, 4.42 mmol) in anhydrous THF (20 mL) was added NaH (60% dispersion in mineral oil, 353 mg, 8.84 mmol) in portions at 0C . The resulting mixture was stirred at 0C for 10 min. Then 1-bromoethane (723 mg, 6.64mmol) in anhydrous THF (2 mL) was added dropwise at 0C . The mixture was stirred at ambient temperature for 16 h. Then reaction was quenched with H20 (20 mL) and the volatiles were removed under reduced pressure. The resulting aqueous layer was extracted with EA (2*30 mL). The combined extracts were concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) and then Pd/C (10%, 100 mg) was added. The mixture was stirred at ambient temperature under hydrogen atmosphere for 16 h. The catalyst was filtered off. The filtrate was concentrated and the residue was purified via ISCO (eluted with MeOH in H20 0-100%) to afford the title compound as brown oil (260 mg, 52.9% yield, 2 steps). MS (m/z): 112.1 (M+H)+.
260 mg	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;	To a solution of 4-nitro-lH-pyrazole (500 mg, 4.42 mmol) in anhydrous THF (20 mL) was added NaH (60% dispersion in mineral oil, 353 mg, 8.84 mmol) in portions at 0 C. The resulting mixture was stirred at 0 C for 10 min. Then 1-bromoethane (723 mg, 6.64 mmol) in anhydrous THF (2 mL) was added dropwise at 0 C. The mixture was stirred at ambient temperature for 16 h. Then reaction was quenched with H20 (20 mL) and the volatiles were removed under reduced pressure. The resulting aqueous layer was extracted with EA (2*30 mL). The combined extracts were concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) and then Pd/C (10%, 100 mg) was added. The mixture was stirred at ambient temperature under hydrogen atmosphere for 16 h. The catalyst was filtered off. The filtrate was concentrated and the residue was purified via ISCO (eluted with MeOH in H20 0-100%) to afford the title compound as brown oil (260 mg, 52.9% yield, 2 steps). MS (m/z): 112.1 (M+H)+.
	With hydrazine hydrate; palladium 10% on activated carbon; In ethanol; at 80℃; for 0.166667h;	General procedure: 80% hydrazine hydrate (1 mL) and 10% palladium charcoal (0.04 g) were added to a solution of 2a (2 mmol) in ethanol (5 mL). The reaction was hated to 80C for 10 min and filltered by celite. The filtrate was dried by sodium sulfate, and concentrated in vacuum to afford compound 3a, which were used without further purification.
	With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; under 760.051 Torr; for 12h;	Palladium 10% on carbon (0.1 g) was added to a solution of compound 13-c (1.0 g, 7.1 mmol) in methanol (10 mL) under hydrogen gas atmosphere (1 atm). The mixture was reacted at 25 C. for 12 hours, then filtered and the filtrate was concentrated under reduced pressure to give compound 13-b (760 mg, yield 96%), which was directly used for the next step without purification. LC-MS (ESI): m/z=112[M+H]+.

References: [1]Patent: WO2012/31004,2012,A1 .Location in patent: Page/Page column 84-85.
[2]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0296; 0298.
[3]Patent: US2013/116246,2013,A1 .Location in patent: Paragraph 0354; 0356.
[4]Patent: WO2007/99317,2007,A1 .Location in patent: Page/Page column 105.
[5]Patent: WO2007/99335,2007,A1 .Location in patent: Page/Page column 95.
[6]Patent: US2009/76075,2009,A1 .Location in patent: Page/Page column 37.
[7]Patent: WO2007/113548,2007,A1 .Location in patent: Page/Page column 143.
[8]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 94.
[9]Patent: WO2017/4134,2017,A1 .Location in patent: Paragraph 00290.
[10]Patent: WO2006/17443,2006,A2 .Location in patent: Page/Page column 123.
[11]Patent: WO2014/139145,2014,A1 .Location in patent: Page/Page column 31; 32.
[12]Patent: WO2014/139465,2014,A1 .Location in patent: Page/Page column 32; 33.
[13]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 145 - 151.
[14]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2382 - 2390.
[15]Patent: US2018/208604,2018,A1 .Location in patent: Paragraph 0245-0246.
[16]ChemMedChem,2018,vol. 13,p. 2558 - 2566.

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; In ethanol; ethyl acetate; for 5h;	General procedure: The 1 - (2 - methoxy ethyl) -4 - nitro - 1H - pyrazole (5 g, 29.21 mmol) dissolved in ethanol (25 ml) and ethyl acetate (25 ml) in, add Raney nickel (500 mg), under the hydrogen environment reaction 5 hours. Diatomite filter, evaporating the filtrate, a brown solid 3.6 g, yield 87percent.

8
[ 876343-24-7 ]
[ 947688-86-0 ]
N-(1-ethyl-1H-pyrazol-4-yl)-2-[5-(6,7-dimethoxy-quinazolin-4-yloxy)-3-methoxy-pyridin-2-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 17 - 25℃; for 18h;	Example 7lambdar-(l-ethyl-lH-pyrazol-4-yl)-2-[5-(6,7-dimethoxyquinazolin-4-yloxy)-3-methoxypyridin-2- yl]acetamideDiisopropylethylamine (0.263 ml) and 2-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.186 g) were added in turn to a stirred mixture of 2-[5-(6,7-dimethoxyquinazolin-4-yloxy)-3-methoxypyridin-2-yl]acetic acid(0.14 g), 4-amino-lH-l-ethylpyrazole (0.072 g) and DMF (1.5 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The resultant mixture was concentrated by evaporation and the residue was purified by preparative etaPLC using a Waters 'Xterra' reversed-phase column (5 microns silica, 19 mm diameter, 10 mm length) using decreasingly polar mixtures of water (containing 0.2percent ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound (0.085 g); 1H NMR: (DMSOd6) 1.33 (t, 3H), 3.78 (s, 2H), 3.8 (s, 3H), 3.99 (s, 3H), 4.0 (s, 3H), 4.06 (q, 2H), 7.41 (d, IH), 7.54 (d, IH), 7.58 (s, IH), 7.86 (s, IH), 8.11 (d, IH), 8.59 (s, IH), 10.13 (br s, IH); Mass Spectrum: M+H+ 465.

References: [1]Patent: WO2007/99317,2007,A1 .Location in patent: Page/Page column 109.

9
[ 948594-29-4 ]
[ 876343-24-7 ]
N-(1-ethylpyrazol-4-yl)-2-[5-(6,7-dimethoxyquinolin-4-yloxy)pyrimidin-2-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2-hydroxy-pyridine N-oxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 17 - 55℃; for 16h;	Example 1; iV-(l-ethylpyrazol-4-yl)-2-[5-(6,7-dimethoxyquinolin-4-yIoxy)pyrimidin-2-yl]acetamide; l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.123 g) was added to a stirred mixture of 2- [4-(6,7-dimethoxyquinolin-4-yloxy)pyrimidin-2-yl] acetic acid (0.11 g), 4-amino-l-ethyl-lH-pyrazole (0.09 g), diisopropylethylamine (0.225 ml), 2-hydroxypyridine iV-oxide (0.071 g) and DMF (2 ml) at ambient temperature. The resultant mixture was stirred and heated to 550C for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient of 10:0 to 9:1 mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.1 g); 1H NMR: (DMSOd6) 1.33 (t, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 3.99 (s, 2H), 4.07 (q, 2H), 6.65 (d, IH), 7.43 (m, IH), 7.52 (s, IH), 7.9 (s, IH), 8.54 (d, IH), 8.86 (s, 2H); Mass Spectrum: M+H+ 435.

References: [1]Patent: WO2007/99335,2007,A1 .Location in patent: Page/Page column 93.

10
[ 876343-24-7 ]
[ 947762-94-9 ]
[ 947762-93-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	EXAMPLE 1 N-(1-ethylpyrazol-4-yl)-2-[5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl]acetamide Diisopropylethylamine (0.154 ml), <strong>[876343-24-7]4-amino-1-ethyl-1H-pyrazole</strong> (0.098 g) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.335 g) were added in turn to a stirred mixture of 2-[5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl]acetic acid (0.25 g) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was purified by preparative HPLC using a Waters 'betaBasic Hypersil' reversed-phase column (5 microns silica, 30 mm diameter, 250 mm length) and decreasingly polar mixtures of water (containing 0.2percent ammonium carbonate) and acetonitrile as eluent. The product so obtained was triturated under a 19:1 mixture of diethyl ether and ethanol. The resultant solid was dried under vacuum. There was thus obtained the title compound (0.076 g); 1H NMR: (DMSOd6) 1.3 (t, 3H), 3.85 (s, 2H), 3.9 (s, 3H), 3.95 (s, 3H), 4.1 (q, 2H), 6.5 (d, 1H), 7.4 (m, 2H), 7.5 (m, 2H), 7.75 (m, 1H), 7.9 (s, 1H), 8.5 (m, 2H); Mass Spectrum: M+H+ 434.

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3050 - 3055.
[2]Patent: US2009/76075,2009,A1 .Location in patent: Page/Page column 35.

11
[ 876343-24-7 ]
[ 87486-34-8 ]
[ 1202932-39-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 2h;	Example 123c 5-Bromo-3-(1-ethyl-1H-pyrazol-4-ylamino)-1-methylpyrazin-2(1H)-one 123c A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 123b (500 mg, 4.5 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.40 g, 9.0 mmol), DIPethyl acetate (3 mL), and isopropanol (50 mL). The mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 123c (802 mg, 60percent) as a white solid. MS-ESI: [M+H]+ 298.0
57%	In isopropyl alcohol; at 120℃; for 1h;	Example 17 A solution of the aminopyrazole (0.28 g, 2.5 mmol) and the dibromopyrazinone (0.74 g, 1.1 equiv) were heated to 120° C. in isopropanol for 1 h. The reaction mixture was cooled to RT, and the product was isolated by filtration (0.43 g, 57percent).

References: [1]Patent: US2013/116246,2013,A1 .Location in patent: Paragraph 0354; 0357.
[2]Patent: US2010/4231,2010,A1 .Location in patent: Page/Page column 71-72.

12
[ 876343-24-7 ]
[ 463-71-8 ]
[ 1006471-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 0℃;	Example 4. Compounds of formula IV[0077] 4-Isothiocyanato-l -methyl- lH-pyrazole (Compound 1012), 4-isothiocyanato-l,3- dimethyl-lH-pyrazole (Compound 1013), and l-ethyl-4-isothiocyanato-lH-pyrazole (Compound 1014) were prepared from 1 -methyl- lH-pyrazol-4-amine, l,3-dimethyl-lH-pyrazol-4-amine (from Matrix Chemical Co.), and 1 -ethyl- lH-pyrazol-4-amine (from Oakwood Products), respectively, by reacting the pyrazolamine with thiophosgene at O0C in the presence of pyridine.CH,[1012] [1013] [1014]

References: [1]Patent: WO2010/138665,2010,A1 .Location in patent: Page/Page column 26.

13
[ 876343-24-7 ]
[ 19335-11-6 ]
(1S,2S,3R,4R)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide [ No CAS ]
[ 1258558-02-9 ]