1124-16-9|5-Amino-1-isopropyl-3-methylpyrazole| Ambeed

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Structure of 1124-16-9

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Quality Control of [ 1124-16-9 ] Purity: 95% SDS Specification

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Product Details of [ 1124-16-9 ]

CAS No. :	1124-16-9
Formula :	C₇H₁₃N₃
M.W :	139.20
SMILES Code :	CC(C)N1N=C(C)C=C1N
MDL No. :	MFCD00514520
InChI Key :	OCSWHADWFJTNAZ-UHFFFAOYSA-N
Pubchem ID :	121018

Safety of [ 1124-16-9 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301
Precautionary Statements:	P301+P310
Class:	6.1
UN#:	2811
Packing Group:	Ⅲ

Computational Chemistry of [ 1124-16-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	5
Fraction Csp3	0.57
Num. rotatable bonds	1
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	42.47
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.	1.67
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	0.99
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.36
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.	0.87
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	0.49
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.08

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.63
Solubility	3.26 mg/ml ; 0.0234 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.	-1.5
Solubility	4.41 mg/ml ; 0.0317 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	-1.23
Solubility	8.14 mg/ml ; 0.0585 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.	-6.45 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)	1.68

Application In Synthesis of [ 1124-16-9 ]

* 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 [ 1124-16-9 ]

[ 1124-16-9 ] Synthesis Path-Downstream 1~35

1
[ 17422-74-1 ]
[ 1124-16-9 ]
[ 78831-28-4 ]

References: [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 607 - 612.

2
[ 59507-92-5 ]
[ 1124-16-9 ]
[ 78831-10-4 ]

References: [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 619 - 622.

3
[ 73829-57-9 ]
[ 1124-16-9 ]
[ 73829-61-5 ]

References: [1]Chemistry of Heterocyclic Compounds,1980,vol. 16,p. 1160 - 1165.
Khimiya Geterotsiklicheskikh Soedinenii,1980,vol. 16,p. 1524 - 1529.

4
[ 1124-16-9 ]
[ 73829-57-9 ]

References: [1]Chemistry of Heterocyclic Compounds,1980,vol. 16,p. 1166 - 1171.
Khimiya Geterotsiklicheskikh Soedinenii,1980,vol. 16,p. 1530 - 1535.

6
[ 4971-56-6 ]
[ 86-81-7 ]
[ 1124-16-9 ]
C₂₁H₂₅N₃O₅ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5183 - 5192.

7
[ 1124-16-9 ]
[ 77696-55-0 ]

References: [1]Chemistry of Heterocyclic Compounds,1980,vol. 16,p. 1166 - 1171.
Khimiya Geterotsiklicheskikh Soedinenii,1980,vol. 16,p. 1530 - 1535.

8
[ 1201935-41-2 ]
[ 1124-16-9 ]
[ 1224887-10-8 ]

Yield	Reaction Conditions	Operation in experiment
15%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; at 160℃; for 0.666667h;Microwave irradiation;	Example 41a 2-[(5-Chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-N-(methyloxy)benzamide A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (70 mg, 0.224 mmol), {<strong>[1124-16-9]3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine</strong> (70 mg, 0.503 mmol) and cesium carbonate (230 mg, 0.706 mmol). The reaction mixture was degassed with nitrogen for 10 min. At same time, BINAP (50 mg, 0.080 mmol) and palladium(II) acetate (10 mg, 0.045 mmol) were added. The reaction mixture was heated in a microwave at 160° C. for 40 min. The crude material was purified on reverse-phase HPLC (Gilson) eluding with CH3CN/H2O with 0.1percent formic acid which gave a title compound (15 mg, 15percent); MS: M (C20H23ClN6O2)=414.89, (M+H)+=415, 416; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 9.42 (br. s., 1H) 8.71 (br. s., 1H) 8.02 (s, 1H) 7.54 (br. s., 1H) 7.06 (t, J=7.5 Hz, 1H) 6.48 (s, 1H) 6.32 (br. s., 1H) 5.86 (s, 1H) 4.47 (dt, J=13.4, 6.7 Hz, 1H) 3.92 (s, 3H) 2.26 (s, 3H) 1.41-1.43 (d, J=6.6 Hz, 2H).
15%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; at 160℃; for 0.666667h;Inert atmosphere; Microwave irradiation;	2-[(5-Chloro-2-[3-methyl- 1 -(1 -methylethyl)- 1 H-pyrazol-5-yllami no)-4-pyridi nyl)aminol-N( methyloxy)benzamideA microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N- (methyloxy)benzamide (70 mg, 0.224 mmol), {3-methyl-1-(1-methylethyl)-1H-pyrazol-5- amine (70 mg, 0.503 mmol) and cesium carbonate (230 mg, 0.706 mmol). The reactionmixture was degassed with nitrogen for 10 mm. At same time, BINAP (50 mg, 0.080 mmol) and palladium(ll) acetate (10 mg, 0.045 mmol) were added. The reaction mixture was heated in a microwave at 160 °C for 40 mm. The crude material was purified on reverse-phase HPLC (Gilson) eluting with CH3CNH20 with 0.1percent formic acid which gave a title compound (15mg, 15percent); MS: M(C20H23C1N602) = 414.89, (M+H) = 415, 416; 1H NMR(400 MHz, CHLOROFORM-d) 6 ppm 9.42 (br. s., 1 H) 8.71 (br. s., 1 H) 8.02 (s, 1 H) 7.54 (br. s., 1H) 7.06 (t, J=7.5 Hz, 1 H) 6.48 (s, 1 H) 6.32 (br. s., 1 H) 5.86 (s, 1 H) 4.47 (dt, J=13.4, 6.7 Hz, 1 H) 3.92 (s, 3 H) 2.26 (s, 3 H) 1.41 - 1.43 (d, J = 6.6 Hz, 2H).

References: [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 23-24.
[2]Patent: WO2013/3575,2013,A1 .Location in patent: Page/Page column 53.

9
[ 1224888-03-2 ]
[ 1124-16-9 ]
[ 1224888-04-3 ]

Yield	Reaction Conditions	Operation in experiment
6.60%	With caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane;Reflux;	Step 2. A solution of 4-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (2.8 g, 9.38 mmol), <strong>[1124-16-9]3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine</strong> (1.305 g, 9.38 mmol) and cesium carbonate (9.17 g, 28.1 mmol) in 1,4-dioxane (40 mL) was degassed. DPEPhos (0.404 g, 0.750 mmol) followed by palladium acetate (0.084 g, 0.375 mmol) were added, and the suspension was refluxed overnight. The solid was filtered, the reaction mixture was evaporated. The black oil was purified by flush column chromatography on silica gel (5percent EtOAc:DCM). The combined fractions were evaporated. The resulting oil was dissolved in dioxane (20 mL) and sodium hydroxide (20 mL, 20.00 mmol) was added and the reaction mixture was refluxed overnight. The layers were separated and the organic layer was washed with 20 ml of 1 M NaOH. The aqueous layers were combined and washed with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4 and filtered. The solution was evaporated, suspended in acetonitrile and filtered. 4-Chloro-2-[(5-chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (260 mg, 0.619 mmol, 6.60percent yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.28 (d, J=6.57 Hz, 6H) 1.91 (s, 1H) 2.13 (s, 3H) 4.43 (quin, J=6.57 Hz, 1H) 5.97 (s, 1H) 6.78 (s, 1H) 7.05 (dd, J=8.46, 1.89 Hz, 1H) 7.48 (d, J=1.77 Hz, 1H) 7.96 (d, J=8.34 Hz, 1H) 8.03 (s, 1H) 8.61 (s, 1H); HPLC Rt=2.70 min, MS (ESI): 420.1, 422.0 [M+H]+.

References: [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 39.

10
[ 1224888-05-4 ]
[ 1124-16-9 ]
[ 1224888-06-5 ]

Yield	Reaction Conditions	Operation in experiment
35.1%	With caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane;Reflux;	Step 2. To a solution of 5-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (1.8 g, 6.03 mmol) and <strong>[1124-16-9]3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine</strong> (0.839 g, 6.03 mmol) in 1,4-dioxane (40 mL) was added cesium carbonate (5.89 g, 18.09 mmol) and the reaction mixture was degassed. DPEPhos (0.260 g, 0.482 mmol) was added followed by palladium acetate (0.054 g, 0.241 mmol) and the reaction mixture was heated to reflux overnight. The suspension was then filtered. The dioxane was evaporated. Solid was partitioned between 1 M HCl and ethyl acetate. Layers were separated, and organic layer discarded. The HCl-containing layer was neutralized and extracted with 2*50 mL of ethyl acetate. Organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated. 5-Chloro-2-[(5-chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (850 mg, 2.118 mmol, 35.1percent yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.25 (d, J=6.57 Hz, 6H) 2.09 (s, 3H) 4.35 (quin, J=6.57 Hz, 1H) 5.89 (s, 1H) 6.03 (s, 1H) 7.46 (d, J=8.84 Hz, 1H) 7.81 (dd, J=8.72, 2.65 Hz, 1H) 7.96 (s, 1H) 8.11 (d, J=2.53 Hz, 1H) 8.42 (s, 1H) 8.54 (s, 1H) HPLC Rt=2.60 min, MS (ESI): 400.8, 403.1 [M+H]+.

References: [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 40.

11
[ 1224888-08-7 ]
[ 1124-16-9 ]
[ 1224888-09-8 ]

Yield	Reaction Conditions	Operation in experiment
12.76%	With caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether;palladium diacetate; In 1,4-dioxane;Reflux;	Step 2. To a solution of 2-[(2,5-dichloro-4-pyridinyl)amino]-5-fluorobenzonitrile (7.09 g, 25.1 mmol) and <strong>[1124-16-9]3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine</strong> (3.5 g, 25.1 mmol) in 1,4-dioxane (100 mL) was added cesium carbonate (24.58 g, 75 mmol) and the reaction mixture was degassed. DPEPhos (1.083 g, 2.012 mmol) was added followed by palladium acetate (0.226 g, 1.006 mmol) and the reaction mixture was heated to reflux overnight. The suspension was then filtered. The dioxane was evaporated off. The solid was purified by flash column chromatography on silica gel (10percent DCM: EtOAC). Fractions were collected and evaporated. The yellow oil was dissolved in diethyl ether, sonicated and filtered. 2-[(5-Chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-5-fluorobenzonitrile (1.3 g, 3.21 mmol, 12.76percent yield) was isolated as a white solid; 1H NMR (400 MHz, METHANOL-d4) delta ppm 1.35 (d, J=6.82 Hz, 6H) 2.20 (s, 3H) 4.43 (quin, J=6.69 Hz, 1H) 5.82 (s, 1H) 5.89 (s, 1H) 7.47-7.57 (m, 2H) 7.61-7.74 (m, 1H) 7.88 (s, 1H); HPLC Rt=2.40 min, MS (ESI): 385.2 [M+H]+.

References: [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 40.

12
[ 80517-22-2 ]
[ 1124-16-9 ]
[ 796851-03-1 ]
[ 1224888-13-4 ]

Yield	Reaction Conditions	Operation in experiment
33.9%		Step 1 To a degassed solution of 2,5-dichloro-4-iodopyridine (5 g, 18.26 mmol), 2-amino-4-fluorobenzonitrile (2.485 g, 18.26 mmol) and potassium triphosphate (11.63 g, 54.8 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (0.787 g, 1.460 mmol) and palladium acetate (0.164 g, 0.730 mmol). The reaction mixture was stirred at the reflux for 18 hr. The reaction mixture was filtered. 3-Methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (2.54 g, 18.26 mmol) and cesium carbonate (17.84 g, 54.8 mmol) were added. The reaction mixture was degassed and palladium acetate (0.164 g, 0.730 mmol) and DPEPhos (0.787 g, 1.460 mmol) were added. The reaction mixture was refluxed overnight. The reaction mixture was filtered. NaOH (60 mL, 60.0 mmol) was added and the reaction mixture refluxed overnight. Ethyl acetate was added and the layers were separated. The combined organics were washed with 1 M NaOH (40 ml). The combined aqueous layers were washed with ethyl acetate, and neutralized with acetic acid. 2-[(5-Chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-4-fluorobenzoic acid (2.5 g, 6.19 mmol, 33.9percent yield) was isolated by filtration as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.29 (d, J=6.57 Hz, 6H) 2.12 (s, 3H) 4.43 (quin, J=6.57 Hz, 1H) 5.99 (s, 1H) 6.86 (s, 1H) 6.87-6.93 (m, 1H) 7.34 (dd, J=11.62, 2.53 Hz, 1H) 8.03-8.10 (m, 2H) 8.62 (s, 1H) 10.65 (br. s., 1H); HPLC Rt=2.57 min, MS (ESI): 404.2 [M+H]+.

References: [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 42.

13
[ 1124-16-9 ]
[ 115661-37-5 ]
[ 796851-03-1 ]
[ 1224888-11-2 ]

Yield	Reaction Conditions	Operation in experiment
53.4%		Step 1 To a degassed solution of 2,5-dichloro-4-iodopyridine (8 g, 29.2 mmol), 2-amino-3-fluorobenzonitrile (3.98 g, 29.2 mmol) and potassium triphosphate (18.60 g, 88 mmol) in 1,4-dioxane (60 ml) stirred under nitrogen at the room temperature was added DPEPhos (1.258 g, 2.337 mmol) and palladium acetate (0.262 g, 1.168 mmol) The reaction mixture was stirred at reflux for 18 hr. The reaction mixture was filtered. 3-Methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (4.07 g, 29.2 mmol) and cesium carbonate (28.6 g, 88 mmol) were added. The reaction mixture was degassed and palladium acetate (0.262 g, 1.168 mmol) and DPEPhos (1.258 g, 2.337 mmol) were added. The reaction mixture was refluxed overnight. The reaction mixture was filtered and the solid was dissolved in water, heated to 50° C. and stirred for 10 minutes, then filtered again. 2-[(5-Chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-3-fluorobenzonitrile (6 g, 15.59 mmol, 53.4percent yield) was isolated as an orange solid. 1H NMR (400 MHz, DMSO-d6) d ppm 1.23 (d, J=6.57 Hz, 6H) 2.07 (s, 3H) 4.32 (quin, J=6.57 Hz, 1H) 5.64 (d, J=2.02 Hz, 1H) 5.83 (s, 1H) 7.39-7.58 (m, 1H) 7.63-7.82 (m, 2H) 7.88 (s, 1H) 8.26 (br. s., 1H) 8.41 (br. s., 1H); HPLC Rt=2.35 min, MS (ESI): 385.0 [M+H]+.

References: [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 41.

14
[ 1224887-80-2 ]
[ 1124-16-9 ]
[ 1224887-82-4 ]

Yield	Reaction Conditions	Operation in experiment
52.4%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane;Reflux;	2-[(5-Chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile The solution of 2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (110 g, 396 mmol), <strong>[1124-16-9]3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine</strong> (55.1 g, 396 mmol), and cesium carbonate (387 g, 1187 mmol) in 1,4-dioxane (2.5 L) was degassed by N2 stream, and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (19.71 g, 31.7 mmol) followed by palladium acetate (3.55 g, 15.83 mmol) were added. The reaction mixture was heated to reflux for overnight under N2. The reaction mixture was filtered and the liquid was concentrated. Ethyl acetate (1500 mL), followed by 1 M HCl (1000 mL) were added. Layers were separated. Ethyl acetate was washed with 1 M HCl until no product was observed by HPLC (1000 mL total, 1). HCl phases were combined, and backwashed with ethyl acetate (31000 mL), until the product peak was relativity pure in the HCL layer. The HCl layer was then basified with NaOH (50 w/w followed by 1 M) to ph~4 resulting in a cloudy solution. Ethyl acetate (2000 mL) was added and layers were separated. The ethyl acetate was washed with brine and evaporated. After neutralization-after addition of ethyl acetate-the reaction mixture was filtered to get some product. Also isolation of product during evaporation can be done by filtration of white solid, which comes from the mother liquor. All solids and evaporated products were combined. 2-[(5-Chloro-2-[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (80 g, 207 mmol, 52.4percent yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.24 (d, J=6.57 Hz, 6H) 2.08 (s, 3H) 4.34 (quin, J=6.57 Hz, 1H) 5.87 (s, 1H) 5.97 (s, 1H) 7.41 (td, J=7.58, 1.01 Hz, 1H) 7.47 (d, J=8.08 Hz, 1H) 7.75 (td, J=7.83, 1.52 Hz, 1H) 7.90 (dd, J=7.83, 1.52 Hz, 1H) 7.94 (s, 1H) 8.42 (d, J=17.43 Hz, 2H); HPLC Rt=2.36 min, MS (ESI): [M+H]+=367.1, 368.1.
52.4%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane;Inert atmosphere; Reflux;	Intermediate 22-[(5-Ch loro-2-[3-methyl-1 -(1 -methylethyl)-1 H-yrazol-5-yl1amino)-4-yri di nyl )a m in ol benzon itri I eThe solution of 2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (110 g, 396 mmol), <strong>[1124-16-9]3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine</strong> (55.1 g, 396 mmol), and cesium carbonate (387 g, 1187 mmol) in 1,4-dioxane (2.5 L) was degassed by N2 stream, and 2,2?- bis(diphenylphosphino)-1,1?-binaphthyl (BINAP) (19.71 g, 31.7 mmol) followed bypalladium acetate (3.55 g, 15.83 mmol) were added. The reaction mixture was heated to reflux for overnight under N2. The reaction mixture was filtered and the liquid wasconcentrated. Ethyl acetate (1500 mL), followed by 1 M HCI (1000 mL) were added. Layers were separated. Ethyl acetate was washed with 1 M HCI until no product was observed by HPLC (1000 mL total, 1 x ). HCI phases were combined, and backwashedwith ethyl acetate (3 x 1000 mL), until the product peak was relativity pure in the HCL layer. The HCI layer was then basified with NaOH (50 ww followed by 1 M) to ph?4 resulting in a cloudy solution. Ethyl acetate (2000 mL) was added and layers were separated. The ethyl acetate was washed with brine and evaporated. After neutralizationafter addition of ethyl acetate - the reaction mixture was filtered to get some product.Also isolation of product during evaporation can be done by filtration of white solid, whichcomes from the mother liquor. All solids and evaporated products were combined. 2-[(5- Ch loro-2-[3-methyl- 1 -(1 -methylethyl)-1 H-pyrazol-5-yl]am ino}-4-pyridinyl)amino]benzonitrile (80 g, 207 mmol, 52.4 percent yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.24 (d, J=6.57 Hz, 6 H) 2.08 (s, 3 H) 4.34 (quin,J=6.57 Hz, 1 H) 5.87 (s, 1 H) 5.97 (s, 1 H) 7.41 (td, J=7.58, 1.01 Hz, 1 H) 7.47 (d, J=8.08 Hz, 1 H) 7.75 (td, J=7.83, 1.52 Hz, 1 H) 7.90 (dd, J=7.83, 1.52 Hz, 1 H) 7.94 (s, 1 H) 8.42N(d, J=17.43 Hz, 2 H); HPLC Rt= 2.36 mm, MS (ESI): [M+H]= 367.1, 368.1.

References: [1]Patent: US2010/113475,2010,A1 .Location in patent: Page/Page column 24.
[2]Patent: WO2013/3575,2013,A1 .Location in patent: Page/Page column 54.

15
[ 2257-52-5 ]
[ 2469-99-0 ]
[ 1124-16-9 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In ethanol;Reflux;	General procedure: In a 250 mL RBF, 3-aminobut-2-enenitrile (2.0 g, 0.24 mole) was added to a stirred solution of cyclohexyl hydrazine hydrochloride (4.0 g, 0.026 mole) and acetic acid (0.1 mL) in ethanol (60 mL). The reaction was refluxed for 6 h. Crude was evaporated and loaded on column to elute out product at 40percent ethyl acetate in hexane. (1.74 g, 40percent)

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2340 - 2343.
[2]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 791 - 796.

16
[ 1124-16-9 ]
[ 87-13-8 ]
[ 19735-96-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 2340 - 2343.

17
[ 1124-16-9 ]
[ 609-09-6 ]
[ 1174844-27-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2:To a solution of diethyl 2-oxobutanedione (176 g, 0.94 mol) in toluene (2 L) was added 3 -methyl- l-(l-methylethyl)-lH-pyrazol-5 -amine (82.5 g, 0.59 mol), and the mixture stirred at 62 °C, overnight. After cooling to room temperature, the mixture was concentrated in vacuo and the crude residue dissolved into acetic acid (1.5 L). The mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo to afford a solid residue, which was recrystallized from DCM to afford the desired product as a yellow colored solid. The collected solid was suspended in ethanol (1510 niL) and THF (216 mL) followed by addition of 3N NaOH (334 mL) and the reaction mixture was stirred at 40 °C for 40 min. The mixture was concentrated in vacuo to remove the volatiles and the aqueous phase acidified using IN HC1. The resulting precipitate was collected by filtration and dried under high vacuum to give the title compound, 3-methyl-l-(l-methylethyl)-6-oxo-6,7-dihydro-lH-pyrazolo[3,4-?]pyridine-4- carboxylic acid, as 51.38 g. LCMS E-S (?+?) = 236.1. 1H NMR (400 MHz, DMSO-d6) ? ppm 1.35 (d, J=6.8 Hz, 6 H), 2.41 (s, 3H), 4.84-4.91 (m, 1H), 6.64 (s, 1H). Carboxylic acid proton not observed.

References: [1]Patent: WO2013/39988,2013,A1 .Location in patent: Page/Page column 46-47.

18
[ 2257-52-5 ]
[ 1118-61-2 ]
[ 1124-16-9 ]