943541-20-6|3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine| Ambeed

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Quality Control of [ 943541-20-6 ] Purity: 95% SDS Specification

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Product Details of [ 943541-20-6 ]

CAS No. :	943541-20-6
Formula :	C₈H₇ClN₄
M.W :	194.62
SMILES Code :	CN1C=C(C=N1)C1=CC=C(Cl)N=N1
MDL No. :	MFCD16109166
InChI Key :	LIRXMNGKIROHGY-UHFFFAOYSA-N
Pubchem ID :	54595607

Safety of [ 943541-20-6 ]

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

Computational Chemistry of [ 943541-20-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	11
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	49.52
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	43.6 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.82
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	0.78
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.53
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.	0.81
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	1.59
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.1
Solubility	1.55 mg/ml ; 0.00798 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.28
Solubility	10.3 mg/ml ; 0.0529 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	-3.19
Solubility	0.126 mg/ml ; 0.000647 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	Yes
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.	-6.93 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)	2.2

Application In Synthesis of [ 943541-20-6 ]

* 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 [ 943541-20-6 ]

[ 943541-20-6 ] Synthesis Path-Downstream 1~35

1
[ 141-30-0 ]
[ 761446-44-0 ]
[ 943541-20-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 4h;	Example 2 : 6-(l-methyI-li/-pyrazol-4-yl)-[l ,2,4] triazolo [4,3-6] pyridazine-3-thiol; Step 1: 3-Chloro-6-(l-methyl-lHr-pyrazol-4-yl)-pyridazine; [0345] A mixture of 3,6-dichloropyridazine (20. Ig, 135 mmol), l-methyl-4- pyrazoleboronic acid pinacol ester (22.46 g, 108 mmol) and K2CO3 (44.71 g, 324 mmol) in 50OmL of dioxane and 20OmL of H2O was degassed with nitrogen. To this mixture was added dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.28 g, 7.2 mmol) and the resulting mixture was bubbled with nitrogen for another 20 min. The reaction mixture was heated at 8O0C for 4h, then concentrated in vacuo. The residue was purified by flash column chromatography with dichloromethane as eluent to provide 21g of 3-chloro-6-(l-methyl-lH-pyrazol-4-yl)-pyridazine (76% yield): 1H NMR(CDCl3) delta 3.99 (s, 3H), 7.45 (d, IH), 7.56 (d, IH), 7.97 (s, IH), 8.11 (s, IH).
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 5h;	To a solution of 3,6-dichloropyridazine (500 mg, 3.4 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (560 mg, 2.7 mmol), K2CO3 (1.1 g, 8.1 mmol) in 1,4-dioxane/H2O (2.5:1, 5 mL) was added PdCl2(dppf)2. After stirred at 90 C for 5 h, the reaction mixture was was extracted with CH2Cl2 (40 mL), and the organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2) afforded 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (494 mg, 75 %). 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (1a) 1HNMR (300 MHz, CDCl3) delta 8.20 (d, J = 7.4 Hz, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 3.95 (s, 3H).
68%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 80℃;Product distribution / selectivity;	A flask was charged with 3,6-dichloropyridazine (AJdrich, 23.91 g, 160.5 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2idioxaborolan-2-yl)-lH-pyrazole (20 g, 96 mmol), 2.0 M Na2Ctheta3 (96 mL) and dioxane (65 mL). Nitrogen was bubbled through the reaction for 60 seconds followed by the addition of Dichlorobis(triphenylphosphine)palladium (0) (6.75 g, 9.6 mmol). The reaction was heated to 800C overnight followed by aqueous work up using AcOEt and a solution of K2CO3. After filtration over celite, the organic layer was dried (MgSO4) and concentrated in vacuo. A first fraction of compound (10.2g) was obtained by crystallization in the solvent (dichoromethane). The filtrate was purified by column chromatography (CH2Cl2 100% and CH2Cl2ZMeOH : 95/5) . The two fractions were gathered and washed with diisopropylether to give the title compound as a yellow solid (12.7 g, 68 %).

63.1%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 16.3h;Inert atmosphere;	Preparation 1 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine To a 3000 mL round bottom flask containing a solution of 1-methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (76 g, 365.3 mmol), 3,6-dichloropyridazine (68 g, 456.4 mmol) in 1,4-dioxane (1200 mL) is added a aqueous solution of K2CO3 (127 g, 919 mmol) in water (480 mL). After [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (7.5 g, 9.2 mmol) is added, the mixture is purged with N2 for 20 min and stirred at 80 C. for 16 h. The reaction mixture is poured into water (300 mL) and dichloromethane (2000 mL), and the aqueous layer is extracted with DCM (3*800 mL). The combined organic layers are dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product is purified with silica gel column eluting with DCM/methanol (40:1) to give the title compound as a pale yellow solid (56 g, 63.1%). MS (m/z): 195.1 (M+H).
47%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃;Product distribution / selectivity;	A flask was charged with 3,6-dichloropyridzine (Aldrich, 297 mg, 2.0 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (499 mg, 2.4 mmol), 2 M Na2COs (4 mL) and dioxane (4 mL). Argon was bubbled through the reaction for 60 seconds followed by the addition ofTetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol). The reaction was heated to 80 0C overnight followed by aqueous work up using EtOAc and brine. The organic layer was dried (MgSO4) and concentrated in vacuo followed by column chromatography purification (20 % Ethyl Acetate in Hexanes) resulting in the title compound as a white solid (183 mg, 47 %). 1H-NMR (CD3OD): delta 8.23 (IH, s), 8.08 (IH, s), 7.84 (IH, br s), 7.34 (IH, br s), 4.00 (3H, s).
44%		A solution of 3,6-dichloropyridazine (4.57 g, 0.003 1 mol), (1-methyl-1H-pyrazol-4- yl)boronic acid pinacol ester (3.82 g, 0.0 184 mol) and a solution ofNa2CO3 2M (18.3 mL) in dioxane (18.4 mL) was stirred for 1 minute. PdC12(PPh3)2 (1.29 g, 0.0018 mol) was added and the solution was heated at 80C for 15 hours. The mixture was cooled to room temperature and poured into water. K2C03 was added and the mixture wasfiltered through a short pad of Celite. The organic layer was dried (Mg504), filtered and evaporated to dryness. The Celite was washed with CH2C12, the filtrate was dried (Mg504) and evaporated. The residue was crystallized from CH2C12. The precipitate was filtered and dried to give 1.5 g of a first batch of intermediate 5 (42%). The filtrate was purified by chromatography over silica gel (30 g of SiOHl5-40jim,mobile phase : gradient from CH2C12 100% to CH2C12 95%/CH3OH 5%). The pure fractions were collected and evaporated until dryness to give 1.58 g of a second batch of intermediate 5 (44%)
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere;	STEP 1 : 3-chloro-6-(1 -methyl-1 H-pyrazol-4-yl)pyridazine In a two-neck flask was placed 3,6-dichloropyridazine (1 .49 g, 10 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (1 .04 g, 5 mmol), K2CO3 (1.38 g, 10 mmol), and Pd(PPh3)4 (289 mg, 0.25 mmol). The resulting mixture was degassed and refilled with N2 (3 times). 1 ,4-Dioxane/H20 (9 mL/2 mL) was added and the resulting mixture was heated at 100C for 5 h. The resulting mixture was poured into EtOAc/H20 (30 mL/30 mL). The organic layer was washed with brine (30 mL), dried (Na2S04), and filtered. The solvent was removed and the resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield 3-chloro-6-(1-methyl-1 H-pyrazol-4- yl)pyridazine.

References: [1]Patent: WO2008/51808,2008,A2 .Location in patent: Page/Page column 96.
[2]Archives of Pharmacal Research,2016,vol. 39,p. 453 - 464.
[3]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 119.
[4]Patent: US2012/28984,2012,A1 .Location in patent: Page/Page column 2.
[5]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 69.
[6]Patent: WO2016/87586,2016,A1 .Location in patent: Page/Page column 17; 18.
[7]Patent: WO2013/85957,2013,A1 .Location in patent: Page/Page column 55.

2
[ 943541-20-6 ]
[ 5622-41-3 ]
6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	In butan-1-ol; at 120℃;	Quinolin-6-yl-acetic acid hydrazide (188 mg, 0.93 mmol) and3-Chloro-6-(l -methyl- lH-pyrazol-4-yi)-pyridazine (202 mg, 0.93 mmol, Example 1: step a) were dissolved in butanol (120 mL). The reaction mixture was heated to 120 0C overnight fitted with water cooled refiuxing condenser and argon line. The reaction was concentrated in vacuo followed by HPLC purification (5-65% CH3CN over 40 min) resulting in the title compound as a tan solid (201.6 mg, 65 %). 1H-NMR (CD3OD): delta 9.08-9.04 (2H, m), 8.30-8.29 (2H, m), 8.21-8.06 (4H, m), 7.99-7.95 (IH, q, / = 5.3, 3.0 Hz), 7.68-7.65 (IH, d, J= 9.8), 4.85 (2H, s), 3.89 (3H, s), 4.96 (2H, s). ESI-MS (m/z): Calcd. For Ci9Hi5N7: 341.37; found: 342.3 (M+H).

References: [1]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 69; 70.

3
[ 943541-20-6 ]
[ 943541-39-7 ]
JNJ-38877605 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		Step 6: 6-{difluoror6-(1-methyl-1/-/-pyrazol-4-yl)M ,2,41triazolor4,3-frlpyridazin-3- yllmethyllquinolineTo a reactor under inert atmosphere was added 73,84 g (0,38 mol) 3-chloro-6-(1-methyl- 1H-pyrazol-4-yl)pyridazine, 9Og (0,38 mol) 2,2-difluoro-2-quinolin-6-ylacetohydrazide and 1200 mL 1-methoxy-2-propanol. Then 29,85 mL (0,455 mol) methane sulphonic acid was added and the reaction mixture was heated at 8O0C for 8 hours. After cooling to ambient temperature the mesylate salt of the title compound was filtered off from the reaction mixture. This salt was dissolved in a mixture of 400 mL ethanol and 300 mL water, after alkalisation at 8O0C with 50 mL ammonia (0.65 mol) in 200 mL water the free base of the title compound precipitates and was filtered off. This precipitate was dried at 5O0C and was subsequently re-crystallized from 2-propanol (1 ,8 L/mol) to yield the title compound in 75% yield.1 H NMR (600 MHz, CHLOROFORM-d) delta ppm 4.01 (s, 3 H) 7.40 (d, J=9.44 Hz, 1 H) 7.50 (dd, J=8.31 , 4.15 Hz, 1 H) 7.95 (s, 1 H) 7.98 (s, 1 H) 8.08 (dd, J=8.69, 1.89 Hz, 1 H) 8.14 (d, J=9.82 Hz, 1 H) 8.25 (d, J=9.06 Hz, 1 H) 8.27 (dd, J=8.31 , 1.51 Hz, 1 H) 8.29 (d, J=1.13 Hz, 1 H) 9.02 (dd, J=4.15, 1.89 Hz, 1 H)
62%		A mixture of 3-chIoro-6-(l-methyl-lH-pyrazol-4-yl)-pyridazine (step d) ( 4.57g, 23.6mmol) and difluoro-quinolin-6-yl-acetic acid hydrazide (step c) (5.60 g, 23.6 mmol) in n-butanol (125 mL) was heated to 1300C overnight. The mixture was <n="121"/>cooled to room temperature, followed by aqueous work up using AcOEt and a solution of K2CO3. The organic layer was dried (MgSO4) and concentrated in vacuo . The residue was purified by flash column chromatography (first chromatography : CH2Cl2 100% and CH2CI2/MeOH : 88/12 followed by another column with toluene/iPrOH/ NH4OH : 85/15/2) to give the title compound (5.5g, 62%). M.p = 199.7 0C

References: [1]Patent: WO2008/155378,2008,A1 .Location in patent: Page/Page column 73.
[2]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 117; 119-120.

4
[ 943541-20-6 ]
quinazolin-6-ylacetic acid hydrazide [ No CAS ]
6-[6-(1-methyl-1H-pyrazol-4-yl)triazolo[4,3-b]pyridazin-3-ylmethyl]quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7%	In butan-1-ol; at 165℃; for 5h;	Quinazolin-6-yl-acetic acid hydrazide (0.032 g, 0.158 mmol) and 3-chloro-6-(l- methyl-lH-pyrazol-4-yl)-pyridazine (0.031 g, 0.158 mmol) were heated to 165C in 5 butanol (2 mL) for five hours. The reaction was cooled to room temperature, evaporated in vacuo and purified via silica gel column chromatography eluting with 5% methanol in dichloromethane to give 0.0031g (7%) of 6-[6-( 1 -methyl- IH- pyrazol^-yO-tl^^triazolo^.S-blpyridazin-S-ylmethyll-quinazoline. 1H NMR (400 MHz, CD3OD) 5 8.45 (s, IH), 8.29 (s, IH), 8.06 (d, 2H, J=9.6Hz), 7.60 (d, 2H, <n="132"/>J=9.6Hz), 7.55 (m, IH), 7.17 (d, IH, J==8.0Hz), 6.08 (s, IH), 4.58 (m, 2H), 3.89 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for Ci8H)4N8; found: 343.3 (M+H).

References: [1]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 128-129; 130-131.

5
[ 943541-20-6 ]
quinoxalin-6-yl-acetic acid hydrazide [ No CAS ]
6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]quinoxaline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	In butan-1-ol; at 125℃; for 4h;	Quinoxalin-6-yl-acetic acid hydrazide (0.019 g, 0.094 mmol) and 3-chloro-6-(l- methyl-lH-pyrazol-4-yl)-pyridazine (0.018 g, 0.094 mmol) were heated to 125C in butanol (2 mL) for four hours. The reaction was cooled to room temperature, evaporated in vacuo and purified via silica gel column chromatography eluting with 5% methanol in dichloromethane to give 0.0029g (15%) of 6- [6-(l -methyl -IH- pyrazol-4-yl)-[l,2,4]triazolo[4,3b]pyridazin-3-ylmethyl]-quinoxaline. 1H NMR (400 MHz, CD3OD) 5 8.77 (m, 2H), 8.16 (s, IH), 8.09 (m, IH), 8.07 (d, IH, J=10.0Hz), 8.00 (m, 2H), 7.85 (dd, IH, J=8.8, 2.0Hz), 7.56 (d, IH, J=9.6Hz), 4.79 (s, 2H), 3.94 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for Ci8Hi4N8; found: 343.3, 344.3 (M+H).

References: [1]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 131; 132-133.

6
[ 943541-20-6 ]
[ 1022091-74-2 ]

Yield	Reaction Conditions	Operation in experiment
90.4%	With hydrazine hydrate; In ethanol; at 4℃; for 18h;Reflux;	Preparation 2 3-Hydrazinyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine To a 1000 mL round bottom flask containing a solution of hydrazine monohydrate (280 mL, 4.89 mol) in ethanol (300 mL) is added <strong>[943541-20-6]3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine</strong> (60 g, 308.3 mmol) at 4 C. The resulting clear solution is heated to reflux for 18 h, and then cooled to 10 C. The product precipitated is collected by filtration and dried under vacuum to give the title compound as a white solid (53 g, 90.4%) and is used as is.
90%	With hydrazine hydrate; In ethanol; for 18h;Cooling with ice; Reflux;	To 100 ml of ethanol is added to the flask (40 ml) as the solvent, then steps are sequentially added under ice bath 1 (HJ-8) made of (1.90g) and hydrazine hydrate (3.5 ml), stirring 10 minutes evacuation goes to the ice-bath, heated up to reflow. Reaction 18 hours later, cold to 10 C, a white solid precipitated. Buchner filter for filtering, the filter cake is washed with cold ethanol washing 2 times, vacuum drying, to obtain 3-hydrazino-6 - (1-methyl -1H-pyrazol-4-yl) pyridazine (HJ-9) 1.68g, yield 90%
87%	With hydrazine; In ethanol; for 18h;Heating / reflux;	Step 2: [6-(l-Methyl-ljfiT-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine; [0346] To a suspension of 3-chloro-6-(l-methyl-lH-pyrazole-4-yl)-pyridazine (21.0 g, 108 mmol) in ethanol (370 mL) was added hydrazine monohydrate (36 mL). The reaction mixture was stirred at reflux for 18h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide 18 g of [6- (1 -methyl- lH-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine as a beige solid (87% yield): 1HNMR (DMSO-ct°) delta 3.88 (s, 3H), 4.28 (s, 2H), 7.02 (d, IH), 7.59 (d, IH), 7.83 (s, IH), 7.91 (s, IH), 8.19 (s, IH); MS (m/z) 191 [M+H+]+.

References: [1]Patent: US2012/28984,2012,A1 .Location in patent: Page/Page column 2.
[2]Patent: CN105272995,2016,A .Location in patent: Paragraph 0084; 0087; 0088.
[3]Patent: WO2008/51808,2008,A2 .Location in patent: Page/Page column 96.

7
[ 943541-20-6 ]
[ 870-46-2 ]
[ 1093204-33-1 ]

Yield	Reaction Conditions	Operation in experiment
33%		Example 13: A route to prepare compound (I)6-{difluoror6-(1-methvl-1 H-pvrazol-4-vl)? ,2,41triazolor4,3-lpvridazin-3-vnmethvl>quinolineStep 1 : tert-butyl 2-f6-(1-methyl-1 H-pyrazol-4-yl)pyridazin-3-vnhvdrazinecarboxylatetert-butyl carbazate, 8,98g (67,3 mmol) and 3-chloro-6-(1-methyl-1 /-/-pyrazol-4- yl)pyridazine (11 ,9 g, 61 ,1 mmol) were mixed in 1-butanol (245 ml_). This mixture was heated till 900C and stirred at that temperature for 16h. The reaction mixture was cooled and water (250 ml_) and ethylacetate (250 mL) were added. The biphasic mixture was neutralised with sodium hydrogencarbonate till the pH is 7. Then the organic layer was separated and the water layer was extracted with ethylacetate (250 mL). The combined organic layers were washed once with water (250 mL) and evaporated. The residue was stirred in isopropylether, filtered off and dried under vacuum. Yield: 5,9 g (20,3 mmol; 33%) of the title compound.

References: [1]Patent: WO2008/155378,2008,A1 .Location in patent: Page/Page column 74.

8
[ 135034-10-5 ]
[ 761446-44-0 ]
[ 943541-20-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium phosphate; N-benzyl-N,N,N-triethylammonium chloride; triphenylphosphine;palladium diacetate; In tetrahydrofuran; water; at 65℃; for 16h;	Step 5: 3-chloro-6-(1-methyl-1/-/-pyrazol-4-yl)pyridazineWater (253 mL) and THF (842 mL) were put in the reaction balloon. The reagents were added one by one to the stirred reaction mixture: potassium phosphate monohydrate 86,2 g (374 mmol) and BTEAC 2,25g (9,88 mmol). Then 3-chloro-6-iodopyhdazine, 45 g (187,2 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole, 46,73g(224,6 mmol) were added and finally triphenylphosphine, 1 ,96g (7,49 mmol) and palladiumdiacetate, 420 mg (1 ,87 mmol) were added. The reaction mixture was heated at 65C for 16h . The reaction mixture was allowed to cool to 600C. Then 935 mL water and301 , 5g sodium chloride were added. The mixture was stirred for 15 minutes and allowed <n="74"/>to cool to 450C. The phases were separated and the organic layer was washed with a solution of 45 g sodium chloride in 374 mL water. The organic layer was separated and stirred with magnesium sulphate (225 g) and charcoal (4,5 g). The mixture was filtered and evaporated. The evaporation residue was co-evaporated with toluene twice and evaporated further till a final volume of 200 ml. This residue was stirred for 16 h at room temperature. The resulting solids were collected by filtration. The solids were dried at reduced pressure affording 29,7 g of the title compound (152,6 mmol, yield 82%).1 H NMR (600 MHz, CHLOROFORM-c/) delta ppm 4.00 (s, 3 H) 7.46 (d, J=8.69 Hz, 1 H) 7.56 (d, J=9.06 Hz, 1 H) 7.98 (s, 1 H) 8.11 (s, 1 H)
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 3h;Inert atmosphere; Industry scale;	1.2 705 g (3.39 mol) of pinacolyl 1-methyl-1H-pyrazole-4-boronate and 1.44 kg of tripotassium phosphate trihydrate are added to a solution of 815 g (3.39 mol) of 3-chloro-6-iodopyridazine in 3.8 l of 1,2-dimethoxy-ethane. The resultant suspension is heated to 80 C. under nitrogen and with stirring, and 59.5 g (85 mmol) of bis(triphenylphosphine)palladium(II)-chloride are added. The reaction mixture is stirred at 80 C. for 3 hours. The mixture is allowed to cool to room temperature, and 9 l of water are added. The resultant precipitate is filtered off with suction, washed with water and dried in vacuo: 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine as brown crystals; ESI 195.
	With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 3h;Inert atmosphere;	705 g (3.39 mol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 1.44 kg of tripotassium phosphate trihydrate are added to a solution of 815 g (3.39 mol) of 3-chloro-6-iodopyridazine in 3.8 l of 1,2-dimethoxy-ethane. The resultant suspension is heated to 80 C. under nitrogen and with stirring, and 59.5 g (85 mmol) of bis(triphenylphosphine)palladium(II) chloride are added. The reaction mixture is stirred at 80 C. for 3 hours. The mixture is allowed to cool to room temperature, and 9 l of water are added. The resultant precipitate is filtered off with suction, washed with water and dried in vacuo: 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine as brown crystals; ESI 195.

References: [1]Patent: WO2008/155378,2008,A1 .Location in patent: Page/Page column 72-73.
[2]Patent: US2011/92498,2011,A1 .Location in patent: Page/Page column 19.
[3]Patent: US2011/257181,2011,A1 .Location in patent: Page/Page column 21.

9
[ 943541-20-6 ]
[ 1201929-62-5 ]

References: [1]Patent: US2011/92498,2011,A1 .

10
[ 943541-20-6 ]
[ 1201930-18-8 ]

References: [1]Patent: US2011/92498,2011,A1 .

11
[ 943541-20-6 ]
[ 1201929-64-7 ]

References: [1]Patent: US2011/92498,2011,A1 .

12
[ 943541-20-6 ]
[ 1201929-66-9 ]

References: [1]Patent: US2011/92498,2011,A1 .

13
[ 943541-20-6 ]
[ 1201929-80-7 ]

References: [1]Patent: US2011/92498,2011,A1 .

14
[ 943541-20-6 ]
[ 1201929-84-1 ]
[ 1201929-98-7 ]

References: [1]Patent: US2011/92498,2011,A1 .

15
[ 943541-20-6 ]
[ 1201930-24-6 ]

References: [1]Patent: US2011/92498,2011,A1 .

16
[ 943541-20-6 ]
[ 1201930-21-3 ]

References: [1]Patent: US2011/92498,2011,A1 .

17
[ 943541-20-6 ]
[ 1201930-23-5 ]

References: [1]Patent: US2011/92498,2011,A1 .

18
[ 943541-20-6 ]
[ 1201929-82-9 ]

References: [1]Patent: US2011/92498,2011,A1 .

19
[ 943541-20-6 ]
[ 863317-29-7 ]
[ 1201930-17-7 ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol; at 130℃; for 18h;	1.4 A suspension of 3.89 g (20.0 mmol) of <strong>[943541-20-6]3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine</strong> and 4.58 g (20.0 mmol) of (3-bromophenyl)acetohydrazide in 40 ml of 1-butanol is heated at 130 C. for 18 hours. The reaction mixture is cooled and partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane /tert-butyl methyl ether /methanol as eluent: 3-(3-bromobenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo-[4,3-b]pyridazine as beige crystals; ESI 369, 371.

References: [1]Patent: US2011/92498,2011,A1 .Location in patent: Page/Page column 19-20.

20
[ 943541-20-6 ]
[ 1201930-19-9 ]
[ 1201930-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol; at 20 - 30℃; for 114h;	3.2 A suspension of 4.18 g (20.0 mmol) of <strong>[943541-20-6]3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine</strong> and 5.46 g (20.0 mmol) of (3-bromophenyl)difluoro-acetohydrazide in 87 ml of 1-butanol is heated at 30 C. for 18 hours. The reaction mixture is cooled and stirred at room temperature for 4 days. The resultant precipitate is filtered off with suction, and the residue is chromatographed on a silica-gel column with dichloromethane /methanol as eluent: 3-[(3-bromophenyl)difluoromethyl]-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazine as colourless solid; ESI 405/407.1H-NMR (d6-DMSO): delta [ppm]=3.95 (s, 3H), 7.55 (t, J=7.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.86 (d, J=9.5 Hz, 1H), 7.97 (s, 1H), 8.09 (s, 1H), 8.49 (d, J=9.5 Hz, 1H), 8.51 (s, 1H).

References: [1]Patent: US2011/92498,2011,A1 .Location in patent: Page/Page column 21.

21
[ 943541-20-6 ]
[ 1100598-42-2 ]