[ CAS No. 64517-88-0 ]

Name: 64517-88-0|1,3-Dimethyl-1H-pyrazol-4-amine|97%
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Product Details of [ 64517-88-0 ]

CAS No. :	64517-88-0	MDL No. :	MFCD02055826
Formula :	C₅H₉N₃	Boiling Point :	231.5°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	111.15 g/mol	Pubchem ID :	4431056
Synonyms :

Calculated chemistry of of [ 64517-88-0 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.4
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	32.86
TPSA :	43.84 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) :	-7.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.09
Log Po/w (XLOGP3) :	-0.05
Log Po/w (WLOGP) :	0.32
Log Po/w (MLOGP) :	-0.27
Log Po/w (SILICOS-IT) :	0.08
Consensus Log Po/w :	0.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.96
Solubility :	12.2 mg/ml ; 0.11 mol/l
Class :	Very soluble
Log S (Ali) :	-0.42
Solubility :	42.3 mg/ml ; 0.38 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.76
Solubility :	19.1 mg/ml ; 0.172 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.44

Safety of [ 64517-88-0 ]

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

Application In Synthesis of [ 64517-88-0 ]

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

Upstream synthesis route of [ 64517-88-0 ]
Downstream synthetic route of [ 64517-88-0 ]

[ 64517-88-0 ] Synthesis Path-Upstream 1~3

1
[ 5334-39-4 ]
[ 74-88-4 ]
[ 64517-88-0 ]
[ 121983-36-6 ]

Reference： [1] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 000120

2
[ 3920-38-5 ]
[ 64517-88-0 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 9, p. 1705 - 1708[2] Zhurnal Obshchei Khimii, 1980, vol. 50, # 9, p. 2106 - 2109
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 10013 - 10030

3
[ 694-48-4 ]
[ 64517-88-0 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 9, p. 1705 - 1708[2] Zhurnal Obshchei Khimii, 1980, vol. 50, # 9, p. 2106 - 2109

[ 64517-88-0 ] Synthesis Path-Downstream 1~31

1
[ 64517-88-0 ]
[ 126230-40-8 ]
[ 126230-41-9 ]
[ 19846-93-6 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1989,vol. 25,p. 838 - 839
Khimiya Geterotsiklicheskikh Soedinenii,1989,vol. 25,p. 998 - 999
[2]Chemistry of Heterocyclic Compounds,1989,vol. 25,p. 838 - 839
Khimiya Geterotsiklicheskikh Soedinenii,1989,vol. 25,p. 998 - 999

2
[ 64517-88-0 ]
[ 124-40-3 ]
[ 137838-40-5 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1991,vol. 27,p. 926 - 931
Zhurnal Organicheskoi Khimii,1991,vol. 27,p. 1072 - 1078

3
[ 952059-84-6 ]
[ 64517-88-0 ]
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;	[7]; DMA was used as the reaction solvent. The reaction product was purified by trituration in a saturated aqueous sodium bicarbonate solution. The resultant solid was isolated, washed with water and dried under vacuum. The product gave the following characterising data :- 1HNMR Spectrum: (DMSOd6) 1.45 (t, 3H), 2.12 (s, 3H)5 3.69 (s, 3H)5 3.81 (s, 3H)5 3.84 (q, 2H)5 4.29 (q5 2H), 6.84 (d, IH), 7.46 (d, IH)5 7.79 (d, IH)5 7.81 s, IH), 8.03 (d, IH), 8.73 (s, IH)5 8.74 (d, IH)5 9.52 (s, IH); Mass Spectrum: M+H+ 449.

Reference： [1]Patent: WO2007/113548,2007,A1 .Location in patent: Page/Page column 168-169; 173

4
[ 952138-11-3 ]
[ 64517-88-0 ]
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;	[5]; 2-(6-Chlorobenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate was used in place of 2-(7-azabenzotriazol- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate(V) as the coupling agent. The product gave the following characterising data :- 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 3.66 (s, 2H), 3.70 (s, 3H), 3.78 (s, 3H), 6.77 (d, IH), 6.91 (m, IH), 7.06 (d, IH), 7.37 (d, IH), 7.81 (s, IH)5 8.08 (s, IH), 8.92 (s, IH), 9.44 (s, IH), 9.57 (d, IH); Mass Spectrum: M+H+ 438 and 440.

Reference： [1]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 94-95; 101

5
[ 952138-15-7 ]
[ 64517-88-0 ]
C₂₃H₂₃N₅O₄ [ 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;	[6]; 2-(6-Chlorobenzotriazol-l-yl)-l,l,353-tetramethyluronium tetrafluoroborate was used in place of 2-(7-azabenzotriazol-l-yl)-l,l,353-tetramethyluronium hexafluorophosphate(V) as the coupling agent. The product gave the following characterising data :- 1H NMR Spectrum: (DMSOd6) 2.12 (s, 3H), 3.66 (s, 2H), 3.7 (s, 3H), 3.78 (s, 3H)5 4.02 (s, 3H)5 6.51 (d, IH), 6.88 (m, IH)5 7.03 (d, IH), 7.22 (s, IH)5 7.35 (d, IH)5 7.81 (s, IH), 8.77 (d, IH)5 9.43 (s, 2H); Mass Spectrum: M+H+ 434.

Reference： [1]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 94-95; 101

6
[ 694-48-4 ]
[ 64517-88-0 ]

Reference： [1]Journal of general chemistry of the USSR,1980,vol. 50,p. 1705 - 1708
Zhurnal Obshchei Khimii,1980,vol. 50,p. 2106 - 2109

7
[ 64517-88-0 ]
[ 1061358-71-1 ]
[ 1201934-67-9 ]

Yield	Reaction Conditions	Operation in experiment
45.5%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere;	2-[[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide (3.36 g, 10.19 mmol), l,3-dimethylpyrazol-4-amine (1.133 g, 10.19 mmol), palladium(II) acetate (0.183 g, 0.82 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.943 g, 1.63 mmol) and cesium carbonate (3.98 g, 12.23 mmol) were mixed together in dioxane (60 mL). The reaction was degassed with argon and was stirred at 90 0C for 3 hours under argon. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with <n="186"/>2 to 8 % MeOH in DCM. The solvent was evaporated to dryness to give an orange solid. This solid was recrystallised from acetonitrile and the resulting crystalline solid was collected by filtration, washed with acetonitrile and dried to a constant weight in a vacuum oven at 600C to afford the title compound (1.875 g, 4.64 mmol, 45.5 %) as a clear orange crystalline solid.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 184-185

8
[ 64517-88-0 ]
[ 1061358-81-3 ]
[ 1201933-67-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 24h;Inert atmosphere;	Example 1.012- [ [5-C yano-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll amino I -N-methyl- benzamide 2-[(2-Chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (200 mg, 0.70 mmol), palladium(II) acetate (12.53 mg, 0.06 mmol), l,3-dimethylpyrazol-4-amine (155 mg, 1.40 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (48.4 mg, 0.08 mmol) and cesium carbonate (273 mg, 0.84 mmol) were suspended in dioxane (5 mL). The mixture was purged for 5 minutes with nitrogen and then heated at 900C for 24 hours. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a solution of 7N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 1.01 (126 mg, 50% yield); 1U NMR spectrum: (300 MHz, DMSO) delta 2.12 (3H, s), 2.84 (3H, d), 3.77 (3H, s), 6.60 (IH, s), 7.21 (IH, ddd), 7.58 (2H, d), 7.79 (IH, d), <n="102"/>7.88 (IH, s), 8.35 (IH, s), 8.66 (IH, s), 8.72 (IH, d), 10.28 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 362.11.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 100-101

9
[ 64517-88-0 ]
[ 1201935-65-0 ]
[ 1201934-35-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;	Example 4.128- [ [2- [(1 ,3-Dimethylpyrazol-4-yl)aminol -5-fluor o-4-pyridyll aminol -2-methyl-3,4- dihydroisog uinolin- 1-one A mixture of 8-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4- dihydroisoquinolin- 1-one (100 mg, 0.33 mmol), l,3-dimethylpyrazol-4-amine (48 mg, 0.43 mmol), sodium tert-butoxide (51.5 mg, 0.54 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (41.4 mg, 0.07 mmol) in anhydrous dioxane (3 mL) was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (32.7 mg, 0.057 mmol) was added. The mixture was heated at 15O0C for 30 minutes in a microwave reactor. MeOH was added and the mixture loaded onto an SCX column. The product was eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 4.12 (50.1 mg, 40% yield); 1H NMR spectrum (300 MHz, DMSO): delta 2.09 (3H, s), 2.95 (2H, t), 3.05 (3H, s), 3.55 (2H, t), 3.70 (3H, s), 6.83 - 6.85 (2H, m), 7.38 - 7.43 (2H, m), 7.85 (IH, s), 7.89 (2H, t), 11.24 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 381.56.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 159

10
[ 64517-88-0 ]
[ 1201935-29-6 ]
[ 1201933-69-8 ]

Yield	Reaction Conditions	Operation in experiment
30%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 1h;Inert atmosphere;	Example 1.032- [ [5-C yano-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -N-methoxy-N- methyl-benzamide A mixture of 2- [(2-chloro-5 -cyanopyridin-4-yl)amino] -N-methoxy-N- methylbenzamide (100 mg, 0.32 mmol), palladium(II) acetate (5.67 mg, 0.03 mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (21.92 mg, 0.04 mmol), 1,3- dimethylpyrazol-4-amine (70.2 mg, 0.63 mmol) and cesium carbonate (123 mg, 0.38 mmol) were suspended in dioxane (2 mL). The mixture was purged for 5 minutes with nitrogen and then heated at 900C for 1 hour. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then using a solution of 7N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 1.03 (37 mg, 30% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.02 (3H, s), 3.21 (3H, s), 3.47 (3H, s), 3.69 (3H, s), 6.08 (IH, s), 7.28 (IH, td), 7.41 (IH, d), 7.48 - 7.56 (2H, m), 7.77 (IH, s), 8.12 (IH, s), 8.22 (IH, s), 8.49 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 392.49.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 103

11
[ 64517-88-0 ]
[ 1201935-71-8 ]
[ 1201934-52-2 ]

Yield	Reaction Conditions	Operation in experiment
26%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; at 150℃; for 1h;Inert atmosphere; Microwave irradiation;	Example 4.28 7- [ [2- [(1 ,3-Dimethylpyrazol-4-yl)aminol -5-fluor o-4-pyridvH aminol -4-(4- isopropylpiperazin-l-yl)-2-methyl-isoindolin-l-one A mixture of 7-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-4-(4-propan-2- ylpiperazin-l-yl)-3H-isoindol-l-one (150 mg, 0.36 mmol), l,3-dimethylpyrazol-4-amine <n="171"/>(80 mg, 0.72 mmol), cesium carbonate (234 mg, 0.72 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (24.92 mg, 0.04 mmol) and palladium(II) acetate (6.45 mg, 0.03 mmol) was suspended in DMA (2 mL) under an atmosphere of nitrogen. The mixture was heated at 1500C for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was filtered and the filtrate evaporated. The residue was dissolved in MeOH (20 mL) and the solution made acidic (pH6) by the addition of 2M HCl. The mixture was loaded onto an SCX column and the product eluted first wit MeOH and then with a 0.7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated and the residue was then purified by preparative HPLC. Fractions containing product were combined and evaporated to afford example 4.28 (45.4 mg, 26% yield); 1H NMR spectrum (300 MHz, DMSO): delta 1.02 (6H, d), 2.11 (3H, s), 2.60 (4H, t), 2.70 (IH, m), 2.99 (4H,m), 3.06 (3H, s), 3.70 (3H, s), 4.48 (2H, s), 6.92 (IH, d), 7.15 (IH, d), 7.39 (IH, d), 7.86 - 7.93 (3H, m), 9.26 (IH, d); Mass spectrum: m/z (ESI+) (M+H)+ = 493.44.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 169-170

12
[ 64517-88-0 ]
[ 1201935-38-7 ]
[ 1201933-75-6 ]

Yield	Reaction Conditions	Operation in experiment
26%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 1h;Inert atmosphere;	Example 1.096-[(l.,3-Dimethylpyrazol-4-yl)aminol-4-[[7-(4-isopropylpiperazin-l-yl)-2-methyl-3- oxo-isoindolin-4-yll aminol pyridine-3-carbonitrile 6-Chloro-4-[[2-methyl-3-oxo-7-(4-propan-2-ylpiperazin-l-yl)-lH-isoindol-4- yl]amino]pyridine-3-carbonitrile (100 mg, 0.24 mmol), palladium(II) acetate (4.23 mg, 0.02 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (16.34 mg, 0.03 mmol), l,3-dimethylpyrazol-4-amine (52.3 mg, 0.47 mmol) and cesium carbonate (92 mg, 0.28 mmol) were suspended in dioxane (2 mL). The mixture was purged for 5 minutes with <n="112"/>nitrogen and then heated at 900C for 1 hour. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a solution of 7N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 1.09 (31 mg, 26% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 1.02 (6H, d), 2.09 (3H, s), 2.60 (4H, t), 2.68 - 2.73 (IH, m), 3.01 (4H, t), 3.06 (3H, s), 3.72 (3H, s), 4.49 (2H, s), 6.72 (IH, s), 7.14 (IH, d), 7.39 (IH, d), 7.86 (IH, s), 8.30 (IH, s), 8.65 (IH, s), 9.26 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 500.33.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 110-111

13
[ 64517-88-0 ]
[ 1201935-41-2 ]
[ 1201933-78-9 ]

Yield	Reaction Conditions	Operation in experiment
18%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In tetrahydrofuran; 1,4-dioxane; at 140℃; for 0.666667h;Microwave irraidiation;	Example 48 2-({5-Chloro-2-[(1,3-dimethyl-1H-pyrazol-4-yl)-amino]-4-pyridinyl}amino)-N-(methyloxy)benzamide A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (250 mg, 0.8 mmol), <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> (187 mg, 1.68 mmol), cesium carbonate (783 mg, 2.4 mmol) and dioxane/THF (3:1 ml). The reaction mixture was degassed under nitrogen for 10 min and palladium (II) acetate (9 mg, 0.04 mmol) and BINAP (50 mg, 0.08 mmol) were added. The mixture was stirred in a microwave at 140 C. for 40 min. It was evaporated and the residue dissolved in MeOH was filtered thru celite and thru an Acrodisc and purified further using preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). Fractions were combined and evaporated. Ether was added to the residue and a tan precipitate crashed out. It was filtered off and dried under vacuum at 40 C. for 2 days to afford the desired product (55 mg, 18%) as a tan solid. LC-MS (ES) m/z=387.1, [M+H]+=389.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.93 (br. s., 1H) 9.51 (br. s., 1H) 8.03 (s, 1H) 7.96 (s, 1H) 7.82 (s, 1H) 7.51-7.61 (m, 3H) 7.07-7.15 (m, 1H) 6.68 (s, 1H) 3.70 (d, J=4.29 Hz, 6H) 2.07 (s, 3H).
5%	With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;	Example 3.01 l-rrS-Chloro-l-rfU-dimethylpyrazoM-vDaminol^-pyridyllaminol-N-methoxy- benzamide 2-[(2,5-dichloropyridin-4-yl)amino]-N-methoxybenzamide (0.1 g, 0.32 mmol), 1,3- dimethylpyrazol-4-amine (0.053 g, 0.48 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.037 g, 0.06 mmol) and sodium tert-butoxide (0.046 g, 0.48 mmol) were suspended in dioxane (5 mL) and purged with nitrogen. Bis(dibenzylideneacetone)palladium (0.029 g, 0.050 mmol) was added and the mixture was heated at 1500C for 30 minutes in a microwave reactor. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a solution of 0.35N NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 3.01 (6.0 mg, 5% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.06 (3H, s), 3.69 - 3.71 (6H, m), 6.66 (IH, s), 7.08 - 7.13 (IH, m), 7.50 - 7.60 (4H, m), 7.80 (IH, s), 7.95 - 7.99 (2H, m), 9.43 (IH, s), 11.87 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 387.03 and 389.02.

Reference： [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 29
[2]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 116

14
[ 64517-88-0 ]
[ 1201935-48-9 ]
[ 1201934-01-1 ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;	Example 3.226-[[5-Chloro-2-[(l,3-dimethylpyrazol-4-yl)aminol-4-pyridyllaminol-4-methyl-2,3- dihydro- 1 ,4-benzoxazepin-5-one 6-[(2,5-Dichloropyridin-4-yl)amino]-4-methyl-2,3-dihydro- 1 ,4-benzoxazepin-5- one (118mg, 0.35 mmol), l,3-dimethylpyrazol-4-amine (58.2 mg, 0.52 mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (40.4 mg, 0.07 mmol) and sodium tert- butoxide (50.3 mg, 0.52 mmol) were suspended in dioxane (5 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (32.0 mg, 0.056 mmol) was added. The mixture was heated at 1500C for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product was eluted first with MeOH and then using a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC. Fractions containing product were combined and evaporated to afford example 3.22 (39.0 mg, 27 % yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.06 (3H, s), 3.12 (3H, s), 3.50 (2H, t), 3.69 (3H, s), 4.32 (2H, t), 6.66 (IH, s), 6.77 - 6.80 (IH, m), 7.32 - 7.34 (IH, m), 7.46 (IH, t), 7.80 (IH, s), 7.93 (IH, s), 7.98 (IH, s), 9.00 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 413.05 and 415.02.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 132

15
[ 64517-88-0 ]
[ 1201935-55-8 ]
[ 1201934-15-7 ]

Yield	Reaction Conditions	Operation in experiment
14%	With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;	Example 3.357- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -2-methyl- isoindolin-1-one <n="144"/>7-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3H-isoindol-l-one (156 mg, 0.51 mmol), l,3-dimethylpyrazol-4-amine (84 mg, 0.76 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (58.6 mg, 0.10 mmol) and sodium tert-butoxide (73.0 mg, 0.76 mmol) were suspended in dioxane (5 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (46.4 mg, 0.081 mmol) was added and the mixture heated at 1500C for 30 minutes in a microwave reactor. The mixture was allowed to cool to room temperature and then loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC. Fractions containing product were combined and evaporated to afford example 3.35 (27.0 mg, 14% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 2.11 (3H, s), 3.07 (3H, s), 3.71 (3H, s), 4.47 (2H, s), 7.00 (IH, s), 7.15 (IH, d), 7.44 - 7.47 (IH, m), 7.54 (IH, d), 7.87 (IH, s), 8.00 (IH, s), 8.14 (IH, s), 9.53 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 383.05 and 385.02.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 142-143

16
[ 64517-88-0 ]
[ 1201935-57-0 ]
[ 1201934-18-0 ]

Yield	Reaction Conditions	Operation in experiment
21%	With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;	Example 3.387- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -4-(4- 5 isopropylpiperazin-l-yl)-2-methyl-isoindolin-l-one A mixture of 7-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-4-(4-propan-2- ylpiperazin-l-yl)-3H-isoindol-l-one (0.20 g, 0.46 mmol), l,3-dimethylpyrazol-4-amine (0.061 g, 0.55 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.053 g, 0.0910 mmol) and sodium te/t-butoxide (0.066 g, 0.69 mmol) was suspended in dioxane (5 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (0.042 g, 0.073 mmol) was added. The mixture was heated at 1500C for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first using MeOH and then with a 0.35M <n="148"/>solution ofNH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by preparative HPLC and fractions containing product were combined and evaporated to afford example 3.38 (0.050 g, 21% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 1.00 - 1.03 (6H, m), 2.10 (3H, s), 2.55 - 2.62 (4H, m), 2.65 - 2.72 (IH, m), 2.98 - 3.01 (4H, m), 3.06 (3H, s), 3.71 (3H, s), 4.48 (2H, s), 6.91 (IH, s), 7.14 (IH, d), 7.41 (IH, d), 7.85 (IH, s), 7.95 (IH, s), 8.07 (IH, s), 9.32 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 509.06.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 146-147

17
[ 64517-88-0 ]
[ 1201935-59-2 ]
[ 1201934-20-4 ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;	Example 3.392- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -3-fluoro-N- methyl-benzamide l,3-Dimethylpyrazol-4-amine (53.1 mg, 0.48 mmol), 2-[(2,5-dichloropyridin-4- yl)amino]-3-fluoro-N-methylbenzamide (lOOmg, 0.32 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (36.8 mg, 0.06 mmol) and sodium tert-butoxide (45.9 mg, 0.48 mmol) were suspended in dioxane (3 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (28 mg, 0.049 mmol) was added and the mixture was heated at 1500C for 30 minutes in a microwave reactor. The mixture was allowed to cool to room temperature and then loaded onto an SCX column. The product was eluted first with MeOH and then with a 0.7M solution OfNH3 in MeOH and pure fractions were evaporated. The residue was purified by preparative HPLC to afford example 3.39 (37.7 mg, 30% yield); 1H NMR spectrum: (300 MHz, DMSO) delta IH NMR (300.132 MHz, DMSO) delta 2.02 (3H, s), 2.75 (3H, s), 3.67 (3H, s), 5.84 (IH, d), 7.31 (IH, td), 7.45 - 7.54 (2H, m), 7.74 (IH, s), 7.88 (IH, s), 7.91 (IH, s), 8.63 - 8.95 (2H, m); Mass spectrum: m/z (ESI+) (M+H)+ = 389.3 and 391.3.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 148

18
[ 64517-88-0 ]
[ 1201935-60-5 ]
[ 1201934-21-5 ]

Yield	Reaction Conditions	Operation in experiment
38%	With sodium t-butanolate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 150℃; for 0.5h;Microwave irradiation; Inert atmosphere;	Example 3.402- [ [5-Chloro-2- [(1 ,3-dimethylpyrazol-4-yl)aminol -4-pyridyll aminol -6-fluoro-N- methyl-benzamide l,3-Dimethylpyrazol-4-amine (70.8 mg, 0.64 mmol), 2-[(2,5-dichloropyridin-4- yl)amino]-6-fluoro-N-methylbenzamide (100 mg, 0.32 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (36.8 mg, 0.06 mmol) and sodium tert-butoxide (45.9 mg, 0.48 mmol) were suspended in dioxane (3 mL). The mixture was degassed with nitrogen and then bis(dibenzylideneacetone)palladium (28 mg, 0.049 mmol) was added and the mixture heated at 1500C for 1 hour in a microwave reactor. The mixture was allowed to cool to room temperature and the mixture was acidified with a 2M solution of HCl in MeOH. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 0.7M solution OfNH3 in MeOH. Fractions containing product were combined and evaporated to afford example 3.40 (46.4 mg, 38% yield); 1H NMR spectrum: (300 MHz, DMSO) delta 1.99 (3H, s), 2.71 (3H, d), 3.62 (3H, s), 6.53 (IH, d), 6.92 (IH, m), 7.26 (IH, d), 7.42 (IH, td), 7.73 (IH, s), 7.87 (IH, s), 7.93 (IH, s), 8.49 (IH, m), 8.68 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 389.3 and 391.3.

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 150

19
[ 64517-88-0 ]
[ 463-71-8 ]
[ 1001500-07-7 ]

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]

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

20
[ 64517-88-0 ]
[ 887341-00-6 ]
(1S,2S,3R,4R)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide [ No CAS ]
[ 1258557-55-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 134 (1S,2S,3R,4R)-3-({5-chloro-2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide The title compound was prepared as described in Example 1, substituting <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> for 1-methyl-1H-pyrazol-4-amine in Example 1B along with substitution of (+)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide for (+/-)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2,4,5-trichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine in Example 1A. 1H NMR (400 MHz, DMSO-d6, T=90 C.) ppm 1.34-1.47 (m, 1H) 2.06-2.16 (m, 4H) 2.73 (s, 1H) 2.87 (s, 1H) 3.71 (s, 3H) 4.03-4.15 (m, 1H) 6.21 (dd, J=5.49, 3.05 Hz, 1H) 6.31 (dd, J=5.65, 2.90 Hz, 1H) 7.42 (d, J=7.63 Hz, 1H) 7.65 (s, 1H) 7.81 (s, 1H) 7.87 (s, 1H); MS (ESI(+)) m/e 374 (M+H)+.

Reference： [1]Patent: US2010/317680,2010,A1

21
[ 64517-88-0 ]
[ 887341-00-6 ]
(1S,2S,3R,4R)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide [ No CAS ]
[ 1258557-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 135 (1S,2S,3R,4R)-3-({5-bromo-2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide The title compound was prepared as described in Example 1, substituting <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> for 1-methyl-1H-pyrazol-4-amine in Example 1B along with substitution of (+)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide for (+/-)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2,4-dichloro-5-bromopyrimidine for 2,4-dichloro-5-fluoropyrimidine in Example 1A. 1H NMR (400 MHz, DMSO-d6) ppm 1.37-1.43 (m, 1H) 2.05-2.17 (m, 4H) 2.49-2.53 (m, 1H) 2.72 (s, 1H) 2.86 (s, 1H) 3.70 (s, 3H) 4.03-4.14 (m, 1H) 6.20 (dd, J=5.80, 3.05 Hz, 1H) 6.30 (dd, J=5.65, 2.90 Hz, 1H) 7.38 (d, J=7.93 Hz, 1H) 7.64 (s, 1H) 7.88 (s, 1H) 7.91 (s, 1H); MS (ESI(+)) m/e 418, 420 (M+H)+.

Reference： [1]Patent: US2010/317680,2010,A1

23
[ 64517-88-0 ]
[ 98-58-8 ]
[ 900366-32-7 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;	4-Bromo-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prepared from 4-bromobenzenesulfonyl chloride (396 mg, 1.55 mmol) and <strong>[64517-88-0]4-amino-1,3-dimethyl-1H-pyrazole</strong> (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (469 mg, 1.42 mmol, 92%). OH (D-6 DMSO, 300K) 9.44 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.57 (2H, d J 8.7 Hz), 7.39 (1H, s), 3.65 (3H, s), 1.70 (3H, s). m/z (ES+, 70V) 332.0 (MH+).

Reference： [1]Patent: US2011/312921,2011,A1

24
[ 64517-88-0 ]
[ 351003-54-8 ]
[ 1215011-63-4 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine;	4-Bromo-2,6-dichloro-N-(1,3-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and <strong>[64517-88-0]4-amino-1,3-dimethyl-1H-pyrazole</strong> (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a pale pink solid (501 mg, 1.26 mmol, 82%). deltaH (CDCl3, 300K) 7.65 (2H, s), 7.31 (1H, s), 6.77 (1H, s), 3.78 (3H, s), 2.04 (3H, s). m/z (ES+, 70V) 399.9 (MH+).

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 57,p. 9855 - 9869
[2]Patent: US2011/312921,2011,A1

25
[ 948570-72-7 ]
[ 64517-88-0 ]
[ 1374784-90-3 ]