18087-73-5|3-Bromoimidazo[1,2-b]pyridazine| Ambeed

Structure of 18087-73-5

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 18087-73-5 ] Purity: 98% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 18087-73-5 ]

CAS No. :	18087-73-5
Formula :	C₆H₄BrN₃
M.W :	198.02
SMILES Code :	BrC1=CN=C2C=CC=N[N]12
MDL No. :	MFCD09757672
InChI Key :	KJQVHOFAWISYDO-UHFFFAOYSA-N
Pubchem ID :	12872319

Safety of [ 18087-73-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 18087-73-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	40.69
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	30.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.61
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	1.35
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.49
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.	1.35
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	1.2
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.4

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.58
Solubility	0.516 mg/ml ; 0.0026 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.	-1.59
Solubility	5.14 mg/ml ; 0.0259 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	-2.57
Solubility	0.533 mg/ml ; 0.00269 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.	-6.55 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)	2.12

Application In Synthesis of [ 18087-73-5 ]

* 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 [ 18087-73-5 ]

[ 18087-73-5 ] Synthesis Path-Downstream 1~35

1
[ 766-55-2 ]
[ 18087-73-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); at 40 - 45℃;	2) Add 2g of azobisisobutyronitrile to the reaction solution in the previous step, and add NBS 187g in batches. Pay attention to avoid light reaction. After the addition, control the temperature at 40 ~ 45 C and stir for 5 ~ 6 hours. The prepared 10% sodium bisulfite solution was added to the reaction bottle and stirred for 30 minutes (crack the excess NBS), and the temperature was reduced to -5C with suction to obtain a brown solid.Product II product 176g, yield 89%,The mother liquor can be recovered and applied after being layered.
75%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 2h;Reflux;	The imidazo [1,2-b] pyridazine (6.0g, 50 . 4mmol), NBS (6.0g, 75 . 6mmol) and a catalytic amount of AIBN is added to the 50 ml chloroform, heating to reflux the reaction 2 hours, TLC detection of the reaction process, the raw materials of the reaction after cooling to room temperature stirring under the conditions of the ice bath, a precipitate out, filtered and the filtrate concentrated to get the pure product.The pure product as a pale yellow solid, yield: 75%
75%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 2h;Reflux;	The imidazo [1,2-b] pyridazine (6.0 g, 50.4 mmol), NBS (6.0 g, 75.6 mmol) and a catalytic amount of AIBN were added to 50 mL of chloroform and the reaction was heated to reflux for 2 hours, The reaction solution was cooled to room temperature when the raw material disappeared with the TLC detection of the reaction process, and a precipitate precipitated after the solution stirred in an ice bath. After filtering, the filtrate concentrated under reduced pressure to give the pure product. A pale yellow solid, yield: 75%. 1H NMR (CDCl3, 400 MHz, delta ppm): 8.50 (d, J = 3.6 Hz, 1H), 8.01-7.98 (m, 1H), 7.84 (s, 1H), 7.15-7.12 (m, 1H). ESI-MS m/z : 200.1 [M+H]+.

74%	With N-Bromosuccinimide; In chloroform; for 0.5h;Reflux;	Example 15 -4 Synthesis of 3-bromo-imidazo[1,2-b]pyridazine To imidazo[1,2-b]pyridazine 1b (10 g) stirring in chloroform (250 ml) was added N-bromosuccinimide (15.7 g) at 5 C. The cooling bath was removed and the reaction was heated to reflux which was maintained for 30 minutes. After leaving to cool overnight the reaction mixture was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (500 ml), washed with potassium carbonate solution (3 x 200 ml) then brine (100 ml). The organic extract was dried with magnesium sulphate and concentrated in vacuo to give 3-bromo-imidazo[1,2-b]pyridazine 2b, 12.3 g (74%). 1H-NMR (400MHz, DMSO-D6) : delta = 8.68 (1 H, d, 4.4 Hz, ArH), 8.20 (1 H, d, 9.2 Hz, ArH), 7.95 (1 H, s, ArH), 7.33 (1 H, q, 3.4 Hz, ArH).
36%	With bromine; acetic acid; at 0 - 20℃; for 1h;	To a stirred solution of imidazo[1,2-bjpyridazine (200 mg, 1.679 mmol) in acetic acid (10 mL) was added bromine (0.2 mL, 3.88 mmol) at 0 C. The reaction mixture was allowed to warm to room temperature and stir for 1 hr. The reaction mixture was neutralized with iN sodium hydroxide, poured into EtOAc (20 mL) and 10% NaHCO3 solution. The layers were separated and the aqueous layer extracted with EtOAC (3x20ml). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give 3-bromoimidazo[1,2-bjpyridazine (120 mg, 36%) as light brown solid. ?H NMR (400 MHz, DMSO-d6) oe 8.68 (dd, J=4.52, 1.51 Hz, 1 H) 8.19 (dd, J=9.54, 1.51 Hz, 1 H) 7.94 (s, 1 H) 7.28-7.39 (m, 1 H).
	With bromine; In acetic acid; at 20℃;	EXAMPLE 1; Lambda/-[(l,6i?)-6-Amino-2,2-difluorocyclohexyl]-4-(imidazo[1,2-b]pyridazin-3-yl)-5- methylthiophene-2-carboxamide; 3 -Bromoimidazo [ 1,2-b]pyridazine; Bromine (0.649 mL, 12,6 mmol) was added dropwise to a stirred mixture of Imidazo[1,2- 6]pyridazine (1.0 g, 839 mmol) in acetic acid (42 ml) and the mixture was stirred at room temperature for 1 h. The mixture was neutralized with 1 N sodium hydroxide (100 mL) and solid sodium hydroxide, poured into ethyl acetate and sodium bicarbonate solution, and extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with brine, dried (MgSO,*), and concentrated to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) delta 8.66 (d, 1H); 8.17 (d, 1H); 7.93 (s, 1H); 7.31 (dd, 1H). LRMS (APCI) calc'd for (C6H5BrN3) [M+H]+, 198.0; found 198.0.
	With N-Bromosuccinimide; In chloroform; for 2h;Reflux;	A mixture of imidazo[1,2-b]pyridazine (2.0 g), N-bromosuccinimide (2.94 g), and chloroform (100 mL) was heated under reflux for 2 hr. Upon cooling, the solution was treated with a saturated aqueous solution of sodium carbonate (200 mL) and shaken. The chloroform layer was separated and concentrated to afford the compound 3-bromoimidazo[1,2-b]pyridazine (IIb).
9.9 g	With N-Bromosuccinimide; In chloroform; for 0.5h;Reflux;	theImidazo [1,2-b] pyridazin(50mmol) dissolved in Chloroform (50 ml), Bromosuccinimide(55 mmoles) was slowly added into the reaction . at reflux System was stirredfor 30 minutes. After cooling to room temperature, the pH was adjusted to 8-9 usingsaturated aqueous sodium carbonatesolution and extracted with ethyl acetate. The extract was washed with water andsaturated brine. After dried overanhydrous sodium sulfate and concentrated to give 9.9 g of the title compound.
9.9 g	With N-Bromosuccinimide; In chloroform; for 0.5h;Reflux;	The imidazo [l, 2_b] pyridazine ¢ .0 g, 50 mmol) was dissolved in chloroform (50 ml), N- bromobutyrate ni imide (NBS) (9.8 g, 55 mmol mol) was slowly added thereto.Was refluxed for 30 minutes.After cooling to room temperature, the PH value was adjusted to 8-9 with saturated sodium carbonate solution, extracted with ethyl acetate.The extract was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 9.9 g.
	With N-Bromosuccinimide; In ethyl acetate; at 95℃; for 2h;	Was added 3-amino-pyridazine in 250 ml single neck round bottom flask (9.51g, 100mmol), 40% aqueous solution of chloroacetaldehyde (chloroacetaldehyde 190mmol) and 81g of ethyl acetate, Start the magnetic stirrer, the mixture of the reaction flask The reaction was stirred at 85 C for 2 hours. TLC, starting material 3-amino-pyridazine completion of the reaction, was added N- bromosuccinimide (17.80g, 100mmol), 95 under stirring for 2 hours,TLC and GC detection to determine the intermediate imidazo [1,2-b] pyridazine was complete. The reaction mixture was suction filtered, the reaction solution was suction filtered, the filter cake with ethyl acetate: n-hexane = 1: 5 to give the pure product recrystallized from 3-bromo-imidazo [1,2-b] pyridazine, the filtrate with ethyl acetate. The pure product was obtained by recrystallization from ethyl acetate: n-hexane = 1: 5 to give the pure product 3-bromoimidazo [1,2-b] pyridazine. After drying, the yield was calculated 88.98%, purity 99% (HPLC).

References: [1]Patent: CN111004240,2020,A .Location in patent: Paragraph 0034; 0036.
[2]Patent: CN105418615,2016,A .Location in patent: Paragraph 0079 ; 0080 ; 0081; 0082; 0083; 0084.
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5830 - 5835.
[4]Patent: EP2818471,2014,A1 .Location in patent: Paragraph 0122; 0123.
[5]Synthesis,1981,p. 987 - 989.
[6]Patent: WO2016/210036,2016,A1 .Location in patent: Page/Page column 107.
[7]Patent: WO2010/83145,2010,A1 .Location in patent: Page/Page column 38-39.
[8]Patent: US2014/343282,2014,A1 .Location in patent: Paragraph 0074; 0086.
[9]Patent: CN103130792,2016,B .Location in patent: Paragraph 0326-0328.
[10]Patent: CN103130791,2016,B .Location in patent: Paragraph 0288-0290.
[11]Patent: CN105218551,2016,A .Location in patent: Paragraph 0024.

3
[ 18087-73-5 ]
[ 1066-54-2 ]
[ 943320-60-3 ]

Yield	Reaction Conditions	Operation in experiment
81.8%	With trans-bis(triphenylphosphine)palladium dichloride; N-cyclohexyl-cyclohexanamine; In acetonitrile; at 80℃; for 1h;Inert atmosphere;	Synthesis of compound 10 (0053) <strong>[18087-73-5]3-bromoimidazo[1,2-b]pyridazine</strong> (compound 9: 10 g, 0.05 mol) was dissolved in acetonitrile (100 ml), under protection of nitrogen, trans-dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol), cuprous iodide (0.3 g, 1.4 mmol), and dicyclohexylamine (11 ml, 0.06 mol) were added, rise the temperature to 80 C, then trimethylsilyl acetylene (8 ml, 0.6 mol) was added slowly into reaction solution, react for 1 hour, detect with TLC, cool down the reaction solution to room temperature, filter the solution, wash the solid with dichloromethane (200 ml), collect the organic phase, evaporate the solvent, add the residue into dichloromethane (100 ml), wash the organic phase with saturated sodium chloride solution (20 ml x2), dry with anhydrous sodium sulfate, evaporate the solvent for the product. Crystallize the product with ethyl acetate/petroleum ether, to give the black powder solid(compound 10:8.9 g, 81.8% yield). (0054) 1HNMR (CDCl3, 400 MHz) delta: 8.47 (dd, J=1.6, 4.4 Hz, 1H), 7.99(s, 1H), 7.96 (dd, J=1.6, 9.2 Hz, 1H), 7.10 (dd, J=4.4, 9.2 Hz, 1H), 0.33 (s, 9H).
71%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	3-bromoimidazo [1,2-b] pyridazine (36.64 g, 0.186 mol), Pd (pph3) 4 (10.73 g, 9.29 mmol),CuI (5.30g, 0.028mmol) and DIPEA (32.4mL, 0.279mol)Add to N, N dimethylformamide (150mL), under nitrogen protection,Trimethylsilylacetylene (21.89g, 0.223mol) was added, and the reaction was carried out at room temperature for 1h.Pour the reaction solution into 200mL of water,Ethyl acetate extraction (100mL × 3), the organic phase was separated and dried over anhydrous sodium sulfate.filter,After concentration, silica gel column chromatography gave 28.22 g of product with a yield of 71%.
71%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	Add 3-bromoimidazo [1,2-b] pyridazine (36.64g, 0.186mol),Tetrakis (triphenylphosphonium) palladium (10.73g, 9.29mmol),cuprous Iodide(5.30g, 0.028mmol) and N, N-diisopropylethylamine (32.4mL, 0.279mol) were added to N, N-dimethylformamide (150mL), under the protection of nitrogen,Trimethylsilyl acetylene (21.89 g, 0.223 mol) was added by injection, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 200 mL of water, and the organic phase was extracted with ethyl acetate (100 mL × 3). After drying with sodium, filtering, and concentrating, the product was isolated by column chromatography on silica gel to obtain 28.22 g, with a yield of 71%.

	With copper(l) iodide; N-ethyl-N,N-diisopropylamine;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 20℃; for 1h;Sonogashira coupling;	A mixture of 3- bromoimidazo[1 ,2-b]pyridazine (36.78 g, 0.186 mol; prepared according to Stanovnik, B. et a/.Synthesis (1981), 12, 987-989), ethynyltrimethylsilane (21.89 g, 0.223 mol), Pd(PPh3)4 (10.73 g, 9.29 mmol), CuI (5.30 g, 0.028 mol), and diisopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 28.46 g of product.
28.46 g	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	3-((Trimethyisilyl)ethynyl)imidazo[1,2-bJpyridazine: A mixture of 3 -bromoimidazo[ 1,2- b]pyridazine (36.78 g, 0.186 mol; prepared according to Stanovnik, B. eta. Synthesis (1981), 12,987-989), ethynyltrimethylsilane (21.89 g, 0.223 mol), Pd(PPh3)4 (10.73 g, 9.29 mmol), Cu (5.30 g, 0.028 mol), and diisopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for I h. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 28.46 g of product.
28.46 g	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	A mixture of <strong>[18087-73-5]3-bromoimidazo[1,2-b]pyridazine</strong> (IIb) (36.78 g, 0.186 mol), ethynyltrimethylsilane (21.89 g, 0.223 mol), Pd(PPh3)4 (10.73 g, 9.29 mmol), CuI (5.30 g, 0.028 mol), and diisopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 1 hour. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 28.46 g of 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (IIc).

References: [1]Journal of Medicinal Chemistry,2020.
[2]Patent: EP3133069,2017,A1 .Location in patent: Paragraph 0053-0054.
[3]Patent: CN110372705,2019,A .Location in patent: Paragraph 0043; 0048; 0050-0051.
[4]Patent: CN110467620,2019,A .Location in patent: Paragraph 0108; 0122; 0126-0130.
[5]Patent: WO2007/75869,2007,A2 .Location in patent: Page/Page column 65.
[6]Journal of Medicinal Chemistry,2010,vol. 53,p. 4701 - 4719.
[7]Journal of Medicinal Chemistry,2012,vol. 55,p. 10033 - 10046.
[8]Patent: WO2013/162727,2013,A1 .Location in patent: Page/Page column 67.
[9]Patent: US2014/343282,2014,A1 .Location in patent: Paragraph 0074; 0087.

4
[ 97674-02-7 ]
[ 18087-73-5 ]
[ 453548-65-7 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 28; N-[ (1R,6S)-6-Amino-2,2-difluorocyclohexyl]-5-chloro-4-(imidazo[1,2-b]pyridazin-3-yl)-1,3- thiazole-2-carboxamide; Step 1. 1 -(Imidazo[1,2-b]pyridazin-3-yl)ethanone; 3-Bromoimidazo[1,2-b]pyridazine (1.0 g, 5.05 mmol), tributyl(l-ethoxyvinyl)tin (3.41 mL, 10.1 mmol), and PdCb(PPh3)2 (354 mg, 0.505 mmol), were added to a sealed tube. DMF (25.2 mL) was added and the reaction purged with nitrogen for 5 minutes. The reaction was heated at 100 C for 18 h. The reaction was cooled to room temperature and quenched with aqueous saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (x 3) and the combined organic layers were dried with magnesium sulfate, Filtered, and concentrated under reduced pressure. The residue was diluted with methanol (10 mL) and HCl in 1,4-dioxane (1.26 mL, 5.05 mmol, 4M) was added. The solution was stirred at room temperature for 1 h. The reaction was then quenched with aqueous saturated sodium bicarbonate and extracted with ethyl acetate (x 3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) delta 8.76 (d, 1H); 8.55 (s, 1H); 8.31 (d, 1H); 8.49 (dd, 1H); 2.64 (s, 3H). LRMS (APCI) calc'd for (C8H7N3O) [M+H]+, 162.1; found 162.1.

References: [1]Patent: WO2010/83145,2010,A1 .Location in patent: Page/Page column 56-57.

5
[ 709648-80-6 ]
[ 18087-73-5 ]
[ 1235545-56-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 1.5h;Inert atmosphere; Sealed tube;	EXAMPLE 18; N- [( 1 R,6R)-6~ Amino-2,2-difluorocyclohexyl] - 5 ~ethyl-4-(imidazo[1,2-b]pyridazin-3 - yl)thiophene-2-carboxamide; Step 1. Methyl 4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate; 3-Bromoimidazo[1,2-b]pyridazine (700 mg, 3.53 mmol), methyl 5-methyl-4-(4,4>;5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.04 g, 3.89 mmol), Pd2(dba)3 (324 mg, 0.353 mmol), tricyclohexylphosphine (248 mg, 0.884 mmol), aqueous tribasic potassium phosphate (2.54 mL, 12.0 mmol, 1.27 M), and 1,4-dioxane (17.7 mL) were placed in a sealed tube and purged with nitrogen for 5 minutes. The solution was heated to 100 C for 1.5 h, after which the reaction was cooled to room temperature. Saturated aqueous sodium bicarbonate was added to the mixture. The aqueous layer was then extracted with ethyl acetate (x 3). The combined organic layers were then dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography affording the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) delta 8.70 (d, 1H); 8.68 (s, 1H); 8.54 (s, 1H); 8.42 (s, 1H); 8.22 (d, 1H); 7.31 (dd, 1H); 3.86 (s, 3H). LRMS (APCI) calc'd for (Ct2H9N3O2S) [M+H]÷, 260.0; found 260.0.

References: [1]Patent: WO2010/83145,2010,A1 .Location in patent: Page/Page column 44-45.

6
[ 1109284-49-2 ]
[ 18087-73-5 ]
[ 1235545-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;	Step 2. Methyl 4-(imidazo[1,2-b]pyrdazin-3-yl)-5-methylthiophene-2-carboxylate; 3 -Bromoimidazo[1,2-b]pyridazine (0.40 g, 2.02 mmol), methyl-5-methyl-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (0.86 g, 3.03 mmol), Pd2(dba)3 (0.19 g, 0.20 mmol), tricyclohexylphosphine (0.14 g, 0.51 mmol), aqueous tribasic potassium phosphate (1.27 M, 1.45 mL, 6.85 mmol), and 1,4-dioxane (10.1 mL) were placed in a flask and purged with nitrogen for five minutes. The solution was heated to 100 C for four hours. The solution was cooled to room temperature, poured into an aqueous solution of saturated sodium bicarbonate, and extracted with ethyl acetate (x 3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated and the residue purified by flash chromatography to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) delta 8.62 (d, 1H); 8.24 (s, 1H); 8.21 (d, 1H); 8.06 (s, 1H); 7.30 (dd, 1H); 3.83 (s, 3H); 2.58 (s, 3H). LRMS (APCI) calc'd for (C13HIiN3O2S) [M+Hf , 274.0; found 274.0.

References: [1]Patent: WO2010/83145,2010,A1 .Location in patent: Page/Page column 39.

7
[ 1235545-65-9 ]
[ 18087-73-5 ]
[ 1235545-66-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 100℃; for 22h;Inert atmosphere; Sealed tube;	Step 3. 9i^Fluoren-9-ylme%l [ (1S,2R)-2-([5-ethyl-4-(imidazo[1,2-b]pyridazin-3 -yl)thiophen-2-yl] carbonyl } amino)-3 , 3 -difluorocyclohexyl] carbamate; 3-Bromoimidazo[1,2-b]pyridazine (53mg, 0.27 mmol), 9H-fluoren-9-ylmethyl [ (1S,2R)-2-([5- ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]carbonyl}amino)-3,3- difluorocyclohexyl] carbamate (187 mg, 0.294 mmol), Pd2(dba)3 (25 mg, 0.03 mmol), tricyclohexylphosphine (19 mg, 0,07 mmol), and aqueous tribasic potassium acetate (0.71 mL, 0.91 mmol, 1.27 M) were placed into a sealed tube and 1 ,4-dioxane (5.4 mL) added. The sealed tube was purged with nitrogen for 5 minutes and heated at at 100 C for 18 h. The solution was cooled to room temperature and additional 9H-fluoren-9-ylmethyl [ (1S,2R)-2-([5-ethyl-4- (4,4,5 ,5-tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)thiophen-2-yl] carbonyl }amino)-3 ,3- difluorocyclohexyl]carbamate (85 mg, 0.13 mmol), Pd2(dba)3 (12 mg, 0.01 mmol), tricyclohexylphosphine (8 mg, 0.03 mmol), and aqueous tribasic potassium acetate (0.42 mL, 0.54 mmol, 1.27 M) were added. The sealed tube was purged with nitrogen for 5 minutes and heat at 100 C for 4 h. The solution was then cooled to room temperature and quenched with aqueous saturated sodium bicarbonate and extracted with dichloromethane (x 3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was taken on to the deprotection step without purification. LRMS (APCI) calc'd for (C34H3IF2N5O3S) [M+H]+, 628.2; found 628.2.

References: [1]Patent: WO2010/83145,2010,A1 .Location in patent: Page/Page column 51.

8
[ 1232836-11-1 ]
[ 18087-73-5 ]
[ 1232836-30-4 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 4701 - 4719.

9
[ 824-75-9 ]
[ 18087-73-5 ]
[ 1380248-43-0 ]

References: [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 4710 - 4713.

10
[ 18087-73-5 ]
3-ethynyl-imidazo[1,2-b]pyridazine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10033 - 10046.
[2]Patent: WO2013/162727,2013,A1 .
[3]Patent: US2014/343282,2014,A1 .
[4]Patent: EP3133069,2017,A1 .
[5]Patent: CN104250253,2017,B .
[6]Patent: CN110372705,2019,A .
[7]Patent: CN110467620,2019,A .

11
[ 18087-73-5 ]
[ 1407999-83-0 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10033 - 10046.

12
[ 664362-16-7 ]
[ 18087-73-5 ]
[ 1542265-60-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 6h;Inert atmosphere;	Step 3. 1-BOC-3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)piperidine A solution of <strong>[18087-73-5]3-bromoimidazo[1,2-b]pyridazine</strong> (0.40 g, 2 mmol), 1-BOC-3-ethynylpiperidine (0.55 g, 2.6 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (29 mg, 0.15 mmol), and DIPEA (0.39 g, 3 mmol) in DMF (20 mL) was stirred at 80 C. under Are for 6 hrs. The mixture was poured into 100 mL water, extracted with EtOAc (60 mL*3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo. The crude product was purified by chromatography on silica gel (PE/EtOAc 7:3 to 3:2) to give 0.39 g product as yellow oil (60.0%). 1H NMR (300 MHz, CDCl3) delta: 8.50 (1H, d, J=4.2 Hz), 7.98-8.08 (2H, m), 7.13-7.17 (1H, dd, J=4.5 and 8.7 Hz), 4.09 (1H, brs), 3.76-3.82 (1H, m), 3.19 (1H, brs), 3.02-3.09 (1H, m), 2.81-2.88 (1H, m), 2.32 (1H, brs), 2.11-2.15 (1H, m), 1.67-1.81 (2H, m), 1.46 (9H, s). LCMS: m/z [M+H]+ 327.2112.

References: [1]Patent: US2014/31354,2014,A1 .Location in patent: Paragraph 0296; 0425; 0426.

13
[ 18087-73-5 ]
[ 1542265-43-9 ]

References: [1]Patent: US2014/31354,2014,A1 .

14
[ 18087-73-5 ]
[ 1542265-61-1 ]

References: [1]Patent: US2014/31354,2014,A1 .

15
[ 616-45-5 ]
[ 18087-73-5 ]
[ 1572031-48-1 ]

References: [1]Chemical Communications,2014,vol. 50,p. 3163 - 3165.

16
[ 18087-73-5 ]
ponatinib [ No CAS ]

References: [1]Patent: WO2014/93579,2014,A2 .

17
[ 18087-73-5 ]
Ponatinib Hydrochloride [ No CAS ]

References: [1]Patent: WO2014/93579,2014,A2 .

18
[ 90347-66-3 ]
[ 18087-73-5 ]
[ 1066-54-2 ]
C₁₇H₁₃N₃O₂*ClH [ No CAS ]