[ CAS No. 933190-51-3 ] {[proInfo.proName]}

Name: 933190-51-3|8-Bromo-6-chloroimidazo[1,2-b]pyridazine|97%
Brand: Ambeed
SKU: A112655
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Quality Control of [ 933190-51-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 933190-51-3 ]

SDS Specification

Alternatived Products of [ 933190-51-3 ]

Product Details of [ 933190-51-3 ]

CAS No. :	933190-51-3	MDL No. :	MFCD11520890
Formula :	C₆H₃BrClN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LZEJQXOCRMRVNP-UHFFFAOYSA-N
M.W :	232.47	Pubchem ID :	46835269
Synonyms :

Calculated chemistry of [ 933190-51-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
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 :	45.7
TPSA :	30.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.31 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.89
Log Po/w (XLOGP3) :	1.98
Log Po/w (WLOGP) :	2.15
Log Po/w (MLOGP) :	1.95
Log Po/w (SILICOS-IT) :	1.8
Consensus Log Po/w :	1.95

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.13
Solubility :	0.171 mg/ml ; 0.000734 mol/l
Class :	Soluble
Log S (Ali) :	-2.24
Solubility :	1.34 mg/ml ; 0.00576 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.19
Solubility :	0.15 mg/ml ; 0.000647 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 933190-51-3 ]

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 [ 933190-51-3 ]

* 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 [ 933190-51-3 ]
Downstream synthetic route of [ 933190-51-3 ]

[ 933190-51-3 ] Synthesis Path-Upstream 1~3

1
[ 446273-59-2 ]
[ 621-62-5 ]
[ 933190-51-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: With toluene-4-sulfonic acid In isopropyl alcohol at 80℃; for 20 h;	A solution of 4-bromo-6-chloropyridazin-3-amine (15.7 g, 75.3 mmol), 2-chloro-1,1-diethoxyethane (13.9 g, 90.3 mmol) and PTSA (17.2 g, 90.3 mmol) in isopropanol (150 mL) was heated to 80° C. for 20 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHCO₃solution (300 mL), extracted with dichloromethane (200 mL×3), dried over Na₂SO₄, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 8-bromo-6-chloroimidazo[1,2-b]pyridazine (17.2 g, 98percent) as an orange solid. LC-MS: [M+H]⁺, 231.9, 233.9, t_R=1.46 min.
98%	With toluene-4-sulfonic acid In isopropyl alcohol at 80℃; for 20 h;	A solution of 4-bromo-6-chloropyridazin-3-amine (15.7 g, 75.3 mmol), 2-chloro- 1,1- diethoxyethane (13.9 g, 90.3 mmol) and PTSA (17.2 g, 90.3 mmol) in isopropanol (150 mL) was heated to 80°C for 20 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHC0₃ solution (300 mL), extracted with dichloromethane (200 mL x 3), dried over Na₂S0₄, filtered and concentrated. The residue was purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 3 : 1) to give 8-bromo-6-chloroimidazo[l,2-b]pyridazine (17.2 g, 98 percent) as an orange solid. LC-MS: [M+H]⁺, 231.9, 233.9, t_R = 1.46min

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10414 - 10423
[2] Patent: US2013/109661, 2013, A1, . Location in patent: Paragraph 0227-0228
[3] Patent: WO2013/64445, 2013, A1, . Location in patent: Page/Page column 51

2
[ 107-20-0 ]
[ 446273-59-2 ]
[ 933190-51-3 ]

Yield	Reaction Conditions	Operation in experiment
89.25%	at 45℃; for 15 h;	3-amino-6-chloropyridazine (1.30 g, 10 mmol) was added to a 100 mL single-ended round bottom flask,(15 mmol), sodium bicarbonate (0.84 g, 10 mmol), and 5 g of chloroform and dichloromethane. The reaction mixture was stirred at 40 ° C for 15 hours with a magnetic stirrer.The reaction was terminated by adding 30percent aqueous solution of chloroacetaldehyde (3 mmol of chloroacetaldehyde), followed by further reaction at 45 ° C for 15 hours.TLC and GC determined that the reaction of 3-amino-4-bromo-6-chloropyridazine was complete. The reaction solution was filtered through suction and the cake was recrystallized from ethyl acetate and ethanol to give the pure product 6-chloro-8-bromoimidazo [1,2-b] pyridazine. The filtrate was extracted with ethyl acetate and the extractant was removed by rotary evaporation The pure product 6-chloro-8-bromoimidazo [1, 2-b] pyridazine was obtained by recrystallization from water and ethanol mixed solvent. After drying, the yield was 89.25percent and the purity was 99.50percent
72%	at 95℃;	Intermediate 1-12To a suspension of Intermediate 1-11 (1.6 g, 7.67 mmol) in water (50 mL) heated to 95 °C was added chloroacetaldehyde (50percent in water, 1.5 mL, 11.5 mmol). The reaction mixture was stirred at 95°C overnight. On cooling, NaHC0₃ was added until pH=7. The suspension was filtered off and washed with cold water to afford Intermediate 1-12 (1.28 g) as an orange solid. The filtrate was extracted withDCM. The organic layer was dried, filtered and evaporated to give Intermediate I-12 (310 mg) as a reddish oil. Total yield: 1.59 g, 72percent.¹H NMR (300 MHz, DMSO) δ 8.45 (s, 1H), 7.90 (d, J = 13.4 Hz, 2H).
71%	for 15 h; Reflux	A solution of 4-bromo-6-chloropyridazin-3-amine (5.0 g, 24 mmol) and 2-chloroacetaldehyde (12 g, 75 mmol) in ethanol (100 mL) was heated at reflux for 15 h. The reaction mixture was concentrated and washed with acetone (75 mL) to give 104a as a yellow solid (6.0 g, 71percent). MS: [M+H]⁺234.

70%	for 24 h; Reflux	3-amino-4-bromo-6-chloropyridazine (0. 5g, 2. 4mmol) was added to a chloroacetaldhyde(12mmol) in ethyl acetate 20ml, heated under reflux for 24h, filtered and dried to give a brown solid, yield 70percent
61%	at 50℃;	To a solution of 4-bromo-6-chloropyridazin-3 -amine (6.0g, 28.8 mmol) was added 2-chloroacetaldehyde (22.60 g, 144 mmol) (50percent water solution). The reaction mixture was heated to 50 °C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with (3/4(3/4. Then, saturated aHC0₃ was added slowly until bubbling ceased. The layers were separated. The aqueous layer was extracted with CH2CI2 (3 x 30 mL). The combined organic layer was washed with water and brine, dried over Na₂S0₄. The crude product was purified by BIOTAGE.(R). (10-40percent EtOAc/ CH₂C1₂, 2.1 L) to give 4.1 g (61percent) product as a brown solid. 3/4 NMR (400 MHz, CDC1₃) δ ppm 8.01 (1 H, s), 7.84 (1 H, s), 7.39 (1 H, s); ¹³C NMR (101 MHz, CDC1₃) δ ppm 145.92 (1 C, s), 136.93 (1 C, s), 134.77 (1 C, s), 124.20 (1 C, s), 121.22 (1 C, s), 118.81 (1 C, s).

Reference： [1] Patent: CN105237541, 2016, A, . Location in patent: Paragraph 0027
[2] Patent: WO2013/5041, 2013, A1, . Location in patent: Page/Page column 71
[3] Patent: US2013/116262, 2013, A1, . Location in patent: Paragraph 0242
[4] Patent: CN103360399, 2016, B, . Location in patent: Paragraph 0026; 0123; 0138; 0139; 0140
[5] Patent: WO2011/137155, 2011, A1, . Location in patent: Page/Page column 30
[6] Patent: US2012/122838, 2012, A1, . Location in patent: Page/Page column 80

3
[ 107-20-0 ]
[ 446273-59-2 ]
[ 933190-51-3 ]
[ 1161847-29-5 ]

Reference： [1] Patent: WO2011/51342, 2011, A1, . Location in patent: Page/Page column 69
[2] Patent: US2011/269752, 2011, A1, . Location in patent: Page/Page column 29

[ 933190-51-3 ] Synthesis Path-Downstream 1~65

1
[ 933190-51-3 ]
[ 18144-47-3 ]
tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 50℃; for 3h;	Example XIV(1) 4-((6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)amino)-N-(2-(4-pyridinyl)ethyl)benzamide (1a) In a 250 ml round bottom flask, under a nitrogen atmosphere, was added <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (5.0 g, 18.6 mmol) from Example I(1), step 1b, tert-butyl 4-aminobenzoate (3.95 g, 20.5 mmol), and DMF (30 ml). The solution was cooled to 0 C. and 1.0M potassium tert-butoxide in THF (46 ml) was added drop-wise via syringe over 30 minutes. The reaction was allowed to stir at room temperature for 30 minutes and then warmed to 50 C. for 2 hrs and the concentrated in vacuo to remove THF. The resulting solution was taken up in ethyl acetate and washed with H2O (3300 ml) and then brine (150 ml). The organic layers were combined and dried over Na2SO4 and filtered. Following solvent evaporation, 6.0 g of crude product was obtained. Further purification was done via triteration with 3:1 diethyl ether/heptane to give 2.2 g of tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoate as a brown solid after filtration.

Reference： [1]Patent: US2007/78136,2007,A1 .Location in patent: Page/Page column 56

2
[ 933190-51-3 ]
[ 156-43-4 ]
[ 933035-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 50℃; for 1h;Product distribution / selectivity;	(1c variation 1) To a mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (257 mg, 0.956 mmol) from 1b in THF (2.0 ml) was added p-phenetidine (131 mg, 0.956 mmol) and a 1.0 M solution of KOt-Bu in THF (2.5 eq, 2.4 ml, 2.39 mmol). The mixture was allowed to heat at 50 C. for 1 hour. The solution was then concentrated in vacuo to provide crude 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine as a solid.

Reference： [1]Patent: US2007/78136,2007,A1 .Location in patent: Page/Page column 27

3
[ 933190-51-3 ]
trans-cyclohexane-1,4-diamine [ No CAS ]
N,N'-bis(4-trans-aminocyclohexyl)imidazo[1,2-b]pyridazine-6,8-diamine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 180℃; for 48h;	Example XII(1) N,N'-bis(4-trans-aminocyclohexyl)imidazo[1,2-b]pyridazine-6,8-diamine To <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (50 mg, 0.19 mmol) from Example 1, step 1b was added trans-1,4-diaminocyclohexane (430 mg, 3.8 mmol). The mixture heated at 180 C. for 48 h. The reaction vessel was cooled to rt. and diluted with water (10 mL) and extracted with DCM (310 mL). The organic extracts were combined, concentrated in vacuo and purified using preparative HPLC to provide the title compound (40 mg, 30%) as a TFA salt. 1H NMR (400 MHz, MeOH) delta ppm 7.90 (1H, d, J=2 Hz), 7.81 (1H, d, J=2 Hz), 6.06 (1H, s), 3.75 (1H, m), 3.05 (1H, m), 3.20 (2H, m), 2.28 (4H, M), 2.16 (4H, mn), 1.70-1.48 (6H.m), 1.42 (2H, m). ). LC/MS, m/e 344 (M+1). HPLC Rt, 1.01 min. Waters Sunfire C18 column (4.650 mm). 0% -100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.

Reference： [1]Patent: US2007/78136,2007,A1 .Location in patent: Page/Page column 54

4
[ 98-10-2 ]
[ 933190-51-3 ]
N-(6-chloro-imidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16h;	Example XXIX(1) N-(6-((trans-4-aminocyclohexyl)amino)imidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide (1a) To a 16*100 mm tube was added benzenesulfonamide (58 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (2 mg, 0.0022 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mg 0.0077 mmol) and cesium carbonate (240 mg, 1.25 mmol). The tube was evacuated and back filled with nitrogen. 8-Bromo-6-chloroimidazo[1,2-b]pyridazine (120 mg, 0.4466 mmol) Example I(1), step 1b and 1,4-dioxane (1.0 ml) was then added. The mixture was allowed to heat at 100 C for 16 hours. The solution was then diluted with dichloromethane, filtered and concentrated in vacuo to afford crude N-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide 100 mg (73%).

Reference： [1]Patent: US2007/78136,2007,A1 .Location in patent: Page/Page column 69

5
[ 933190-51-3 ]
[ 5509-65-9 ]
6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example II(1) N6-(trans-4-aminocyclohexyl)-N8-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-6,8-diamine (1a) To 60% NaH (22.5 mg, 0.563 mmol) in DMF (400 mul) was added 2,6-difluoroaniline (24 mg, 0.186 mmol). After stirring at RT for 5 minutes THF (1000 mul) was added followed by <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (50 mg, 0.186 mmol, prepared as described in Example 1, step (1b). The reaction was heated at 50 C. for 3 hours. The reaction was quenched with a few drops of water and methanol. The solution was then concentrated in vacuo to give crude 6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine.

Reference： [1]Patent: US2007/78136,2007,A1 .Location in patent: Page/Page column 44

6
[ 107-20-0 ]
[ 446273-59-2 ]
[ 933190-51-3 ]
[ 1161847-29-5 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of intermediate 5: Mixture of 6,8-dichloro-imidazo[l,2-&]pyridazine and 8- bromo-6-chloro-imidazo[l,2-&]pyridazineA 50% wt. solution of chloroacetaldehyde in water (5.79 ml, 44.5 mmol) was added dropwise to a solution of intermediate 1 (2.34 g, 11.2 mmol) in ethanol (50 ml). The mixture was stirred at reflux temperature for 2 h. After cooling to room temperature, the mixture was poured onto a mixture of ice / water and ethyl acetate was added. The mixture was basified by addition of a saturated solution of sodium carbonate. The organic layer was separated, washed with brine, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude products were purified by open column chromatography (silica; 7M solution of ammonia in methanol in dichloromethane 2/98). The desired fractions were collected and concentrated in vacuo to yieldintermediate 5 (1.5 g, 66%>) as a 68/32 mixture of 6,8-dichloro-imidazo[l,2- ¾]pyridazine and 8-bromo-6-chloro-imidazo[l,2-¾]pyridazine.
		Example A5 Preparation of intermediate 5: Mixture of 6,8-dichloro-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine A 50% wt. solution of chloroacetaldehyde in water (5.79 ml, 44.5 mmol) was added dropwise to a solution of intermediate 1 (2.34 g, 11.2 mmol) in ethanol (50 ml). The mixture was stirred at reflux temperature for 2 h. After cooling to room temperature, the mixture was poured onto a mixture of ice/water and ethyl acetate was added. The mixture was basified by addition of a saturated solution of sodium carbonate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude products were purified by open column chromatography (silica; 7M solution of ammonia in methanol in dichloromethane 2/98). The desired fractions were collected and concentrated in vacuo to yield intermediate 5 (1.5 g, 66%) as a 68/32 mixture of 6,8-dichloro-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine.

Reference： [1]Patent: WO2011/51342,2011,A1 .Location in patent: Page/Page column 69
[2]Patent: US2011/269752,2011,A1 .Location in patent: Page/Page column 29

7
[ 933190-51-3 ]
[ 1256280-15-5 ]
[ 1305350-67-7 ]

Yield	Reaction Conditions	Operation in experiment
38%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 1h;Microwave irradiation;	EXAMPLE 41 1 -(4- { 3 - IY 1 S)- 1 -( 6-Chloroimidazo Gamma 1 ,2-blpyridazin-8-ylamino ethyl1 -7-fluoro-8-methyl- quinolin-2-yl)piperazin-l-yl)ethanoneIntermediate 21 (800 mg, 2.42 mmol) and 8-bromo-6-chloroimidazo[l,2- >]- pyridazine (670 mg, 2.8 mmol) in NMP (8 mL) were treated with DIPEA (1.4 g, 11 mmol) and heated at 120C under microwave irradiation for 1 h. The reaction mixture was partitioned between water (25 mL) and EtOAc (150 mL). The organic layer was washed with water (25 mL) and brine (25 mL), then dried (phase separation cartridge) and concentrated in vacuo. Purification by column chromatography (Si02, 20% EtOAc in isohexane) gave the title compound (400 mg, 38%) as a white solid, delta? (CDC13) 8.13 (IH, s), 7.69 (IH, s), 7.52 (IH, dd, J8.92, 6.04 Hz), 7.46 (IH, s), 7.17 (IH, t, J9.01 Hz), 6.48 (IH, d, J6.64 Hz), 6.28 (IH, s), 5.08-5.00 (IH, m), 4.10-4.02 (IH, m), 3.95-3.70 (3H, m), 3.46-3.18 (4H, m), 2.61 (3H, d, J2.34 Hz), 2.21 (3H, s), 1.83 (3H, d, J6.80 Hz). LCMS (ES+) 482/484 (M+H)+, RT 4.22 minutes {Method 2).

Reference： [1]Patent: WO2011/58109,2011,A1 .Location in patent: Page/Page column 61-62

8
[ 107-20-0 ]
[ 446273-59-2 ]
[ 933190-51-3 ]

Yield	Reaction Conditions	Operation in experiment
89.25%	In water; at 45℃; for 15h;	3-amino-6-chloropyridazine (1.30 g, 10 mmol) was added to a 100 mL single-ended round bottom flask,(15 mmol), sodium bicarbonate (0.84 g, 10 mmol), and 5 g of chloroform and dichloromethane. The reaction mixture was stirred at 40 C for 15 hours with a magnetic stirrer.The reaction was terminated by adding 30% aqueous solution of chloroacetaldehyde (3 mmol of chloroacetaldehyde), followed by further reaction at 45 C for 15 hours.TLC and GC determined that the reaction of 3-amino-4-bromo-6-chloropyridazine was complete. The reaction solution was filtered through suction and the cake was recrystallized from ethyl acetate and ethanol to give the pure product 6-chloro-8-bromoimidazo [1,2-b] pyridazine. The filtrate was extracted with ethyl acetate and the extractant was removed by rotary evaporation The pure product 6-chloro-8-bromoimidazo [1, 2-b] pyridazine was obtained by recrystallization from water and ethanol mixed solvent. After drying, the yield was 89.25% and the purity was 99.50%
72%	In water; at 95℃;	Intermediate 1-12To a suspension of Intermediate 1-11 (1.6 g, 7.67 mmol) in water (50 mL) heated to 95 C was added chloroacetaldehyde (50% in water, 1.5 mL, 11.5 mmol). The reaction mixture was stirred at 95C overnight. On cooling, NaHC03 was added until pH=7. The suspension was filtered off and washed with cold water to afford Intermediate 1-12 (1.28 g) as an orange solid. The filtrate was extracted withDCM. The organic layer was dried, filtered and evaporated to give Intermediate I-12 (310 mg) as a reddish oil. Total yield: 1.59 g, 72%.1H NMR (300 MHz, DMSO) delta 8.45 (s, 1H), 7.90 (d, J = 13.4 Hz, 2H).
71%	In ethanol; for 15h;Reflux;	A solution of 4-bromo-6-chloropyridazin-3-amine (5.0 g, 24 mmol) and 2-chloroacetaldehyde (12 g, 75 mmol) in ethanol (100 mL) was heated at reflux for 15 h. The reaction mixture was concentrated and washed with acetone (75 mL) to give 104a as a yellow solid (6.0 g, 71%). MS: [M+H]+234.

70%	In ethyl acetate; for 24h;Reflux;	3-amino-4-bromo-6-chloropyridazine (0. 5g, 2. 4mmol) was added to a chloroacetaldhyde(12mmol) in ethyl acetate 20ml, heated under reflux for 24h, filtered and dried to give a brown solid, yield 70%
61%	In water; at 50℃;	To a solution of 4-bromo-6-chloropyridazin-3 -amine (6.0g, 28.8 mmol) was added 2-chloroacetaldehyde (22.60 g, 144 mmol) (50% water solution). The reaction mixture was heated to 50 C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with (¾(¾. Then, saturated aHC03 was added slowly until bubbling ceased. The layers were separated. The aqueous layer was extracted with CH2CI2 (3 x 30 mL). The combined organic layer was washed with water and brine, dried over Na2S04. The crude product was purified by BIOTAGE (10-40% EtOAc/ CH2C12, 2.1 L) to give 4.1 g (61%) product as a brown solid. ¾ NMR (400 MHz, CDC13) delta ppm 8.01 (1 H, s), 7.84 (1 H, s), 7.39 (1 H, s); 13C NMR (101 MHz, CDC13) delta ppm 145.92 (1 C, s), 136.93 (1 C, s), 134.77 (1 C, s), 124.20 (1 C, s), 121.22 (1 C, s), 118.81 (1 C, s).
	In ethanol;Reflux;	To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (D-2) (16 g, 77.3 mmol, 1.0 eq) in EtOH (200 mL), 2-chloroacetaldehyde (45% in water, 67.4 g, 386.6 mmol, 5.0 eq) is added and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo to remove EtOH. The residue is slurried in acetone. The solid is collected by filtration and washed with acetone. The solid is suspended in water, neutralized with aqueous ammonia to adjust the pH to 8 at 0-5 C. and then extracted with ethyl acetate (2*150 mL). The combined layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (D-3).
	In ethanol; at 90℃; for 3h;	To the crude 4-bromo-6-chloropyridazin-3-amine (120g, 576mmol) was added EtOH (1.2L). ClCH2CHO (600g, 7.65mol) was added to the mixture over 30min. The reaction mixture was heated to 90C for 3h, cooled to RT, and concentrated. The residue was purified by silica gel column chromatography eluted with 9-50% EtOAc in petroleum ether to give the product.1H-NMR (400MHz, DMSO-d6): delta 8.01 (s, 1H), 7.68 (brs, 1H), 6.03 (s, 1H).

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 2447 - 2465
[2]Patent: CN105237541,2016,A .Location in patent: Paragraph 0027
[3]Patent: WO2013/5041,2013,A1 .Location in patent: Page/Page column 71
[4]Patent: US2013/116262,2013,A1 .Location in patent: Paragraph 0242
[5]Patent: CN103360399,2016,B .Location in patent: Paragraph 0026; 0123; 0138; 0139; 0140
[6]Patent: WO2011/137155,2011,A1 .Location in patent: Page/Page column 30
[7]Patent: US2012/122838,2012,A1 .Location in patent: Page/Page column 80
[8]Patent: WO2019/125974,2019,A1 .Location in patent: Paragraph 0202-0203

9
[ 933190-51-3 ]
pyridine-3-boronic acid 1,3-propanediol cyclic ester [ No CAS ]
[ 1345843-56-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 100℃; for 8.08333h;Microwave; Inert atmosphere;	A microwave vial was charged with a mixture of 8-bromo-6- chloroimidazo[l,2-b]pyridazine (1.06 g, 4.56 mmol), 3-(l,3,2-dioxaborinan-2-yl)pyridine (0.743 g, 4.56 mmol), dioxane (14 mL), and tetrakis(triphenylphosphine)palladium(0) (0.527 g, 0.456 mmol), and K3P04 (2.90 g, 13.68 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100 C for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE (20-60% EtOAc/hex, 1.5 L) to the product (0.39 g, 37%). LC/MS: Rt = 1.07 min. LC/MS (Condition A): 231.09/233.09.

Reference： [1]Patent: WO2011/137155,2011,A1 .Location in patent: Page/Page column 36

10
[ 933190-51-3 ]
[ 192182-56-2 ]
[ 1345843-59-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 100℃; for 4.08333h;Microwave; Inert atmosphere;	A microwave vial was charged with a mixture of 8-bromo-6- chloroimidazo[l,2-b]pyridazine (0.8 g, 3.44 mmol), <strong>[192182-56-2]isoquinolin-4-ylboronic acid</strong> (0.6 g, 1.734 mmol), dioxane (16 mL), tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.087 mmol), and K3PO4 (2.60 mL, 5.20 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100 C for 4 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE (30-100% EtOAc/ EtOAc/CH2Cl2, 1.2 L, then 50-100%B/ EtOAc/CH2Cl2, B: 10% MeOH/EtOAc/CH2Cl2, 800 mL) to give the product (0.27 g, 55%). XH NMR (400 MHz, CDC13) delta ppm 9.41 (1 H, s), 8.72 (1 H, s), 8.66 (1 H, d, J=4.53 Hz), 8.03-8.17 (1 H, m), 7.90 (1 H, s), 7.71 (3 H, d, J=3.02 Hz), 7.26 (1 H, d, J=4.53 Hz); LC/MS: Rt = 1.35 min. LC/MS (Condition A): 281.13/283.13.

Reference： [1]Patent: WO2011/137155,2011,A1 .Location in patent: Page/Page column 39-40

11
[ 933190-51-3 ]
4-methylpyridin-3-ylboronic acid [ No CAS ]
[ 1345843-53-9 ]

Yield	Reaction Conditions	Operation in experiment
34%	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 100℃; for 8.08333h;Microwave; Inert atmosphere;	A microwave vial was charged with a mixture of 8-bromo-6- chloroimidazo[l,2-b]pyridazine (1.1 g, 4.73 mmol), 4-methylpyridin-3-ylboronic acid (0.648 g, 4.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.547 g, 0.473 mmol), dioxane (14 niL), and K3PO4 (7.10 niL, 14.20 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100 C for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S04, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE (20-80% EtOAc/CH2Cl2, 1.5 L, then 20%-65% B/CH2C12, 0.9 L; B: 10% MeOH/ CH2C12) to give 400 mg (34%) product. 'H NMR (400 MHz, CD3OD) delta ppm 9.00 (1 H, s), 8.80 (1 H, d, J=5.79 Hz), 8.38 (1 H, d, J=1.51 Hz), 8.04 (1 H, d, J=6.04 Hz), 7.96 (1 H, d, J=1.51 Hz), 7.86 (1 H, s), 2.73 (3 H, s); LC/MS: Rt = 0.98 min. LC/MS (Condition A): 245.1 1/247.08.

Reference： [1]Patent: WO2011/137155,2011,A1 .Location in patent: Page/Page column 30-31

12
[ 933190-51-3 ]
[ 1345842-98-9 ]

Reference： [1]Patent: WO2011/137155,2011,A1

13
[ 933190-51-3 ]
[ 1345843-54-0 ]

Reference： [1]Patent: WO2011/137155,2011,A1

14
[ 933190-51-3 ]
[ 1345843-55-1 ]

Reference： [1]Patent: WO2011/137155,2011,A1

15
[ 933190-51-3 ]
[ 1345843-13-1 ]

Reference： [1]Patent: WO2011/137155,2011,A1

16
[ 933190-51-3 ]
[ 1345843-57-3 ]

Reference： [1]Patent: WO2011/137155,2011,A1

17
[ 933190-51-3 ]
[ 1345843-58-4 ]

Reference： [1]Patent: WO2011/137155,2011,A1

18
[ 933190-51-3 ]
[ 1345843-23-3 ]

Reference： [1]Patent: WO2011/137155,2011,A1

19
[ 933190-51-3 ]
[ 1345843-60-8 ]

Reference： [1]Patent: WO2011/137155,2011,A1

20
[ 933190-51-3 ]
[ 1345843-61-9 ]

Reference： [1]Patent: WO2011/137155,2011,A1

21
[ 933190-51-3 ]
[ 1345843-26-6 ]

Reference： [1]Patent: WO2011/137155,2011,A1

22
[ 933190-51-3 ]
[ 1345843-49-3 ]

Reference： [1]Patent: WO2011/137155,2011,A1

23
[ 933190-51-3 ]
[ 1263425-59-7 ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-iodo-succinimide; trifluoroacetic acid; In chloroform; at 20℃; for 2h;	To a solution of 8-bromo-6-chloroimidazo[l,2-b]pyridazine (1.2 g, 5.16 mmol) in chloroform (30 mL) were added MS (1.161 g, 5.16 mmol) and TFA (0.795 mL, 10.32 mmol). The reaction mixture was stirred at room temperature for 2h and quenched with aHC03. The organic layers were washed with brine and dried over a2S04. The crude product was purified by BIOTAGE (100% CH2C12) to give the product (1.4 g, 76%). XH NMR (400 MHz, CDC13) delta ppm 7.91 (1 H, s), 7.46 (1 H, s); LC/MS: Rt = 2.44 min. LC/MS (Condition A): 357.80/359.80/361.80.
43%		Intermediate Example 1 c; -Bromo-6-chloro-3-iodoimidazo[1 ,2-b]pyridazine; A mixture comprising 100 g (430 mmol) 8-bromo-6-chloroimidazo[1 ,2-b]pyridazine which was prepared according to a procedure described in US2007/78136(WO2007/38314), 145 g N-iodosuccinimide, 5 percent per weight cone, hydrochloric acid and 1 L trichloromethane was heated at reflux for 6 hours. 20 gN-iodosuccinimide were added and heating was continued for additional 3 hours. The precipitate was removed and the filtrate was washed with 1 N sodium hydroxide solution, brine and dried over sodium sulfate. After filtration and removal of solvent diisopropyl ether was added and the residue was stirred at 23 C overnight. The precipitate was filtered off and dried to give 66.6 g (43%) of the title compound.
43%	With hydrogenchloride; N-iodo-succinimide; In water; for 9h;Inert atmosphere; Reflux;	A mixture comprising 100 g (430 mmol) 8-bromo-6-chloroimidazo[1 ,2-£>]pyridazine which was prepared according to a procedure described in US2007/78136 (WO2007/38314), 145 g N-iodosuccinimide, 5 percent per weight cone, hydrochloric acid and 1 L trichloromethane was heated at reflux for 6 hours. 20 g N-iodosuccinimide were added and heating was continued for additional 3 hours. The precipitate was removed and the filtrate was washed with 1 N sodium hydroxide solution, brine and dried over sodium sulfate. After filtration and removal of solvent diisopropyl ether was added and the residue was stirred at 23C overnight. The precipitate was filtered off and dried to give 66.6 g (43%) of the title compound.

43%

With hydrogenchloride; N-iodo-succinimide; In chloroform; water; for 9h;Inert atmosphere; Reflux;

Comparative Example 1 e 8-Bromo-6-chloro-3-iodoimidazo 1 ,2-b]pyridazine A mixture comprising 100 g (430 mmol) 8-bromo-6-chloroimidazo[1 ,2- b]pyridazine which was prepared according to a procedure described in US2007/78136 (WO2007/38314), 145 g N-iodosuccinimide, 5 percent per weight cone, hydrochloric acid and 1 L trichloromethane was heated at reflux for 6 hours. 20 g N-iodosuccinimide were added and heating was continued for additional 3 hours. The precipitate was removed and the filtrate was washed with 1 N sodium hydroxide solution, brine and dried over sodium sulfate. After filtration and removal of solvent diisopropyl ether was added and the residue was stirred at 23 C overnight. The precipitate was filtered off and dried to give 66.6 g (43%) of the title compound.

Reference： [1]Patent: WO2011/137155,2011,A1 .Location in patent: Page/Page column 46
[2]Patent: WO2012/32031,2012,A1 .Location in patent: Page/Page column 153-154
[3]Patent: WO2014/20041,2014,A1 .Location in patent: Page/Page column 84-85
[4]Patent: WO2014/198776,2014,A1 .Location in patent: Page/Page column 28

24
[ 933190-51-3 ]
[ 1345843-62-0 ]

Reference： [1]Patent: WO2011/137155,2011,A1

25
[ 933190-51-3 ]
[ 1365243-73-7 ]

Reference： [1]Patent: WO2012/32031,2012,A1
[2]Patent: WO2013/135612,2013,A1
[3]Patent: WO2014/20041,2014,A1
[4]Patent: WO2014/198776,2014,A1

26
[ 933190-51-3 ]
[ 1206487-36-6 ]

Reference： [1]Patent: WO2012/32031,2012,A1
[2]Patent: WO2013/135612,2013,A1
[3]Patent: WO2014/20041,2014,A1
[4]Patent: WO2014/198776,2014,A1

27
[ 933190-51-3 ]
[ 100-51-6 ]
[ 1376761-87-3 ]

Yield	Reaction Conditions	Operation in experiment
86.5%		Dissolve benzyl alcohol (1.2 g, 11 mmol) in 20 mL of tetrahydrofuran, and add sodium hydroxide (60%, dispersed in liquid paraffin, 0.44 g, 11 mmol) under an ice bath,Stir for half an hour at room temperature.Slowly add 8-bromo-6-chloroimidazo [1,2-b] pyridazine (2.32 g, 10 mmol) under an ice bath,Remove the ice bath and react at room temperature overnight.TLC showed that the reaction was complete, diluted with 30 mL of water, and the reaction solution was extracted with ethyl acetate (20 mL * 3).The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated.Separated by silica gel column to obtain 2.24 g of pale yellow solid with a yield of 86.5%.
50%		[00350] To a 0C mixture of benzyl alcohol (0.3 mL, 2.98 mmol) in THF (40 mL) was added sodium hydride (0.25 g) in an ice-water bath under a N2 atmosphere. The reaction mixture was stirred for 30 minutes at 0C, and then a solution of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (462 mg, 1.99 mmol) in THF (50 mL) was added in dropwise. The reaction mixture was warmed to rt slowly and stirred for 1 hour, then quenched with saturated aqueous sodium chloride solution (50 mL) and the resulting mixture was extracted with ethyl acetate (500 mL). The organic phase was washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/2) to give the title compound as an oil (0.26 g, 50%). The compound was characterized by the following spectroscopic data:MS-ESI: (ESI, pos.ion)m/z: 260.1 [M+1].
50%		Benzyl alcohol (0.3 mL, 2.98 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen and cooled to 0 C in an ice water bath. Sodium hydride (0.25 g) was added and the solution was stirred at 0 for 30 min. <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (462 mg, 1.99 mmol) in tetrahydrofuran (50 mL) was added dropwise and the mixture was slowly returned to room temperature and stirred for 1 h.The reaction was quenched with saturated sodium chloride solution (50 mL), extracted with ethyl acetate (500 mL), washed with organic phase (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was subjected to column chromatography (V (ethyl acetate) / V (petroleum ether) = 1/2) to give 0.26 g of an oily product in a yield of 50%.

To a stirred solution of phenylmethanol (3.35 g, 31 mmol, 1.2 eq) in THF (80 mL), NaH (60% dispersion in mineral oil, 1.34 g, 33.5 mmol, 1.3 eq) is added in portions. The resulting mixture is stirred at RT for 30 min and then <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (D-3) (6 g, 25.8 mmol, 1.0 eq) is added. The resulting mixture is stirred at RT for an additional 2 h and then poured into water (30 mL). The mixture is extracted with ethyl acetate (2*100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine (D-4).

Reference： [1]Patent: CN110272426,2019,A .Location in patent: Paragraph 0642; 0645-0647
[2]Patent: WO2016/8433,2016,A1 .Location in patent: Paragraph 00350
[3]Patent: TW2017/6256,2017,A .Location in patent: Paragraph 0373; 0374; 0375
[4]Patent: US2012/122838,2012,A1 .Location in patent: Page/Page column 80-81

28
[ 446273-59-2 ]
[ 621-62-5 ]
[ 933190-51-3 ]

Yield	Reaction Conditions	Operation in experiment
98%		A solution of 4-bromo-6-chloropyridazin-3-amine (15.7 g, 75.3 mmol), 2-chloro-1,1-diethoxyethane (13.9 g, 90.3 mmol) and PTSA (17.2 g, 90.3 mmol) in isopropanol (150 mL) was heated to 80 C. for 20 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHCO3 solution (300 mL), extracted with dichloromethane (200 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 8-bromo-6-chloroimidazo[1,2-b]pyridazine (17.2 g, 98%) as an orange solid. LC-MS: [M+H]+, 231.9, 233.9, tR=1.46 min.
98%	With toluene-4-sulfonic acid; In isopropyl alcohol; at 80℃; for 20h;	A solution of 4-bromo-6-chloropyridazin-3-amine (15.7 g, 75.3 mmol), 2-chloro- 1,1- diethoxyethane (13.9 g, 90.3 mmol) and PTSA (17.2 g, 90.3 mmol) in isopropanol (150 mL) was heated to 80C for 20 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHC03 solution (300 mL), extracted with dichloromethane (200 mL x 3), dried over Na2S04, filtered and concentrated. The residue was purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 3 : 1) to give 8-bromo-6-chloroimidazo[l,2-b]pyridazine (17.2 g, 98 %) as an orange solid. LC-MS: [M+H]+, 231.9, 233.9, tR = 1.46min

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10414 - 10423
[2]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0227-0228
[3]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 51

29
[ 4945-46-4 ]
[ 933190-51-3 ]
[ 1415314-17-8 ]

Yield	Reaction Conditions	Operation in experiment
24.1%		To a solution of 6-(piperidin-1-yl)pyridin-2-amine (0.725 g, 4.12 mmol) in DMF (8 mL) was added NaH (0.11 g, 60% dispersion in mineral oil, 4.18 mmol) and the mixture stirred for 0.5 h. To this mixture was added <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (0.384 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h. The resulting mixture was treated with a saturated NH4Cl solution (50 mL), extracted with ether (80 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-chloro-N-(6-(piperidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.13 g, 24.1%) as a yellow solid. LC-MS: [M+H]+, 329.0, 331.0, tR=1.912 min
24.1%		To a solution of 6-(piperidin-l-yl)pyridin-2-amine (0.725 g, 4.12 mmol) in DMF (8 mL) was added NaH (0.11 g, 60 % dispersion in mineral oil, 4.18 mmol) and the mixture stirred for 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[l,2-b]pyridazine (0.384 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h. The resulting mixture was treated with a saturated NH4C1 solution (50 mL), extracted with ether (80 mL), dried over Na2S04, filtered and concentrated. The residue was purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 3 : 1) to give 6-chloro-N-(6-(piperidin-l-yl)pyridin- 2-yl) imidazo[l,2-b]pyridazin-8-amine (0.13 g, 24.1 %) as a yellow solid. LC-MS: [M+H]+, 329.0 > 331.0 , tR = 1.912 min

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10414 - 10423
[2]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0241-0242
[3]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 54-55

30
5,6-dimethoxypyridin-2-amine [ No CAS ]
[ 933190-51-3 ]
[ 1415314-13-4 ]

Yield	Reaction Conditions	Operation in experiment
91.2%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 15.1667h;	A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (2 g, 8.6 mmol) and 5,6-dimethoxypyridin-2-amine (1.39 g, 9.03 mmol) in DMF (72 ml) was cooled to 0 C. To the mixture was added sodium hydride (1.1 g, 27.5 mmol, 60% dispersion in mineral oil). The reaction was stirred for 10 min then warmed to room temperature. After 15 h the reaction was quenched with saturated sodium bicarbonate solution, and then diluted with water and EtOAc. An insoluble solid was filtered off. The filtrate was separated and the aqueous phase was washed with EtOAc. The combined organic extracts were concentrated in vacuo and the residue obtained was crystallized from methanol to give 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (2.4 g, 7.85 mmol, 91.2%) as light brown needles. 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 8.26 (br. s., 1H) 7.95 (s, 1H) 7.81 (s, 1H) 7.55 (s, 1H) 7.15 (d, J=7.93 Hz, 1H) 6.58 (d, J=8.31 Hz, 1H) 4.12 (s, 3H) 3.89 (s, 3H); LC/MS: 305.9 [MH]+.
91.2%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 15.1667h;Inert atmosphere;	A mixture of 8-bromo-6-chloroimidazo[l,2-b]pyridazine (2 g, 8.6 mmol) and 5,6- dimethoxypyridin-2-amine (1.39 g, 9.03 mmol) in DMF (72 ml) was cooled to 0 C. To the mixture was added sodium hydride (1.1 g, 27.5 mmol, 60% dispersion in mineral oil). The reaction was stirred for 10 min then warmed to room temperature. After 15 h the reaction was quenched with saturated sodium bicarbonate solution, and then diluted with water and EtOAc. An insoluble solid was filtered off. The filtrate was separated and the aqueous phase was washed with EtOAc. The combined organic extracts were concentrated in vacuo and the residue obtained was crystalized from methanol to give 6-chloro-N-(5,6-dimethoxypyridin -2- yl)imidazo[l,2-b]pyridazin-8-amine (2.4 g, 7.85 mmo 1, 91.2 %) as light brown needles. 1H NMR (300 MHz, CHLOROFORM- ) delta ppm 8.26 (br. s., 1 H) 7.95 (s, 1 H) 7.81 (s, 1 H) 7.55 (s, 1 H) 7.15 (d, J=7.93 Hz, 1 H) 6.58 (d, J=8.31 Hz, 1 H) 4.12 (s, 3 H) 3.89 (s, 3 H); LC/MS: 305.9 [MH]+.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10414 - 10423
[2]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0629-0630
[3]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 171-172

31
[ 933190-51-3 ]
[ 107-18-6 ]
[ 1417699-02-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate; In acetonitrile; at 20 - 65℃;	Intermediate 1-13To a suspension of Intermediate 1-12 (950 mg, 4.08 mmol) and Cs2C03 (1.6 g, 4.9 mmol) in acetonitrile (20 mL) was added allyl alcohol (0.3 mL, 4.5 mmol). The reaction mixture was heated at 65C for 6 h. More Cs2C03 (1.0 g) and allyl alcohol (0.25 mL) were added and the mixture was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography (cHex:EtOAc 2:1 to 1 :1.5) to give Intermediate 1-13 (690 mg, 80%).HPLC-MS (method 4): Rt =3.32 min, [M+Hf 210.H NMR (300 MHz, CDCI3) delta 7.87 (d, J = 0.9 Hz, 1H), 7.68 (s, 1H), 6.43 (s, 1 H), 6.13 (ddd, J = 22.7, 10.8, 5.5 Hz, 1H), 5.54 (d, J = 16.3 Hz, 1H), 5.44 (d, J = 10.4 Hz, 1H), 4.89 (d, J = 5.5 Hz, 2H).

Reference： [1]Patent: WO2013/5041,2013,A1 .Location in patent: Page/Page column 72

32
[ 933190-51-3 ]
[ 34486-24-3 ]
[ 1431773-65-7 ]

Yield	Reaction Conditions	Operation in experiment
99%		A solution of 6-(trifluoromethyl)pyridin-2-amine (0.668 g, 4.12 mmol) in DMF (5 mL) was added NaH (0.10 g, 4.18 mmol) and stirred for 0.5 h. To the mixture was added <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (0.38 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h then 100 mL of water was added and the precipitate collected by filtration and washed with water to give 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.513 g, 99%) as a light brown solid. LC-MS: [M+H]+, 314.1, tR=1.738 min.
99%		A solution of 6-(trifluoromethyl)pyridin-2-amine (0.668 g, 4.12 mmol) in DMF (5 mL) was added NaH (0.10 g, 4.18 mmol) and stirred for 0.5 h. To the mixture was added 8-bromo-6- chloroimidazo[l,2-b]pyridazine (0.38 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h then 100 mL of water was added and the precipitate collected by filtration and washed with water to give 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[l,2- b]pyridazin-8-amine (0.513 g, 99 %) as a light brown solid. LC-MS: [M+H]+, 314.1 , tR = 1.738 min.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0229-0230
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 51-52

33
[ 933190-51-3 ]
[ 19842-07-0 ]
[ 1431773-66-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[19842-07-0]5-ethylpyridin-2-amine</strong> (394 mg, 3.23 mmol) in DMF (8 mL) was added NaH (129 mg, 60% dispersion in mineral oil, 3.23 mmol) under N2 atmosphere at room temperature and stirred for another 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.3 g, 1.3 mmol). After 20 h stirring at room temperature, saturated NH4Cl solution was added and the reaction mixture was extracted with ether (200 mL) and washed with water (2×50 mL), then brine (2×50 mL). After drying and filtration, it was concentrated to afford 6-chloro-N-(5-ethylpyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (785 mg, crude) as a yellow solid that was used directly without further purification. LC-MS: [M+1]+=274, tR=1.726 min.
		To a solution of <strong>[19842-07-0]5-ethylpyridin-2-amine</strong> (394 mg, 3.23 mmol) in DMF (8 mL) was added NaH (129 mg,60 % dispersion in mineral oil, 3.23 mmol) under N2 atmosphere at room temperature and stirred for another 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[l,2- b]pyridazine (0.3 g, 1.3 mmol). After 20 h stirring at room temperature, saturated NH4C1 solution was added and the reaction mixture was extracted with ether (200 mL) and washed with water (2 x 50 mL), then brine (2 x 50 mL). After drying and filtration, it was concentrated to afford 6-chloro-N-(5-ethylpyridin-2-yl)imidazo[l,2-b]pyridazin-8-amine (785 mg, crude) as a yellow solid that was used directly without further purification. LC-MS: [M + 1]+ = 274 > tR =1.726 min.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0234-0235
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 53

34
[ 35018-15-6 ]
[ 933190-51-3 ]
[ 1431773-68-0 ]

Yield	Reaction Conditions	Operation in experiment
22%		To a solution of 2,2-dimethylpyrrolidine (0.248 g, 2.5 mmol) in DMF (8 mL) was added NaH (0.060 g, 60% dispersion in mineral oil, 2.5 mmol) and stirred for 0.5 h. To this mixture was added <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (0.233 g, 1 mmol) under N2. The mixture was stirred at room temperature for 16 h. Then it was partitioned between 15 mL of saturated NH4Cl solution and 15 mL of ether. The organic layer was washed with water (10 mL×3) and saturated NaCl solution (10 mL×3), dried over NaSO4, concentrated in vacuo, and purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-chloro-8-(2,2-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine (0.140 g, 22%) as a light brown solid. LC-MS: [M+H]+, 251.1, tR=1.698 min.
22%		To a solution of 2,2-dimethylpyrrolidine (0.248 g, 2.5 mmol) in DMF (8 mL) was added NaH (0.060g, 60 % dispersion in mineral oil, 2.5 mmol) and stirred for 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[l,2-b]pyridazine (0.233g, 1 mmol) under N2. The mixture was stirred at room temperature for 16 h. Then it was partitioned between 15 mL of saturated NH4C1 solution and 15 mL of ether. The organic layer was washed with water (10 mL x 3) and saturated NaCl solution (10 mL x 3), dried over NaS04, concentrated in vacuo, and purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 3 : 1) to give 6- chloro-8-(2,2-dimethylpyrrolidin-l-yl)imidazo[l,2-b]pyridazine (0.140 g, 22 %) as a light brown solid. LC-MS: [M+H]+, 251.1 , tR = 1.698min.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0265-0266
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 61-62

35
[ 933190-51-3 ]
[ 1431774-00-3 ]
[ 1431774-01-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; for 15h;Reflux; Inert atmosphere;	A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (573 mg, 2.47 mmol), 6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-amine (540 mg, 2.47 mmol), Pd2(dba)3 (142 mg, 0.25 mmol), BINAP (307 mg, 0.50 mmol), Cs2CO3 (2.4 g, 7.41 mmol) and dioxane (20 mL) was heated to reflux with stirring for 15 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=50:1) to give N-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazin-8-amine (400 mg, crude) as a brown oil. LC-MS: [M+H]+, 371.1, tR=2.23 min.
	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; for 15h;Inert atmosphere; Reflux;	A mixture of 8-bromo-6-chloroimidazo[l,2-b]pyridazine (573 mg, 2.47 mmol), 6-(3-tert- butylpyrrolidin-l-yl)pyridin-2-amine (540 mg, 2.47 mmol), Pd2(dba)3 (142 mg, 0.25 mmol), BINAP (307 mg, 0.50 mmol), Cs2C03 (2.4 g, 7.41 mmol) and dioxane (20 mL) was heated to reflux with stirring for 15 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200 - 300 mesh, dichloromethane : MeOH = 50 : 1) to give N-(6-(3-tert-butylpyrrolidin-l-yl)pyridin-2-yl)-6-chloroimidazo [l,2-b]pyridazin- 8-amine (400 mg, crude) as a brown oil. LC-MS: [M+H]+, 371.1 , tR = 2.23 min.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0502-0503
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 131

36
[ 933190-51-3 ]
[ 1597-32-6 ]
[ 1415314-23-6 ]

Yield	Reaction Conditions	Operation in experiment
99%		To a solution of 6-fluoropyridin-2-amine (1.12 g, 10 mmol) in DMF (16 mL) was added NaH (0.24 g, 60% dispersion in mineral oil, 10 mmol) and the mixture stirred for 0.5 h. To the mixture was added 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.93 g, 4 mmol) under N2. The mixture was stirred at room temperature for 16 h, then partitioned between 45 mL of saturated NH4Cl solution and 45 mL of ether. The organic layer was washed with water (30 mL×3) and saturated NaCl solution (30 mL×3), dried over Na2SO4, concentrated in vacuo, and purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1.04 g, 99%) as a light brown solid. LC-MS: [M+H]+, 264.1, 266.2, tR=1.601 min.
99%		To a solution of 6-fluoropyridin-2-amine (1.12 g, 10 mmol) in DMF (16 mL) was added NaH (0.24 g, 60 % dispersion in mineral oil, 10 mmol) and the mixture stirred for 0.5 h. To the mixture was added 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[l,2-b]pyridazin-8-amine (0.93 g, 4 mmol) under N2. The mixture was stirred at room temperature for 16 h, then partitioned between 45 mL of saturated NH4C1 solution and 45 mL of ether. The organic layer was washed with water (30 mL x 3) and saturated NaCl solution (30 mL x 3), dried over Na2S04, concentrated in vacuo, and purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 3 : 1) to give 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[l,2-b]pyridazin-8-amine (1.04 g, 99 %) as a light brown solid. LC-MS: [M+H]+, 264.1 > 266.2, tR = 1.601min.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0246-0247
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 56-57

37
[ 933190-51-3 ]
[ 1415695-18-9 ]
[ 1415314-19-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; Sealed tube;	A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (1.0 g, 4.3 mmol), 6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (0.84 g, 4.73 mmol), Pd2(dba)3 (0.247 g, 0.43 mmol), BINAP (0.536 g, 0.86 mmol) and Cs2CO3 (4.21 g, 12.9 mmol) in dioxane (30 mL) was heated to 100 C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200?300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1.2 g, 85%) as a yellow solid. LC-MS: [M+1]+=329, tR=1.930 min.
85%		A mixture of 8-bromo-6-chloroimidazo[l,2-b]pyridazine (1.0 g, 4.3 mmol), 6-(2- methylpyrrolidin-l-yl)pyridin-2-amine (0.84 g, 4.73 mmol), Pd2(dba)3 (0.247 g, 0.43 mmol), BINAP (0.536 g, 0.86 mmol) and Cs2C03 (4.21 g, 12.9 mmol) in dioxane (30 mL) was heated to 100 C for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200 ~ 300 mesh, ethyl acetate : petroleum ether = 1 : 15) to afford 6-chloro-N-(6-(2-methylpyrrolidin-l-yl)pyridin-2-yl)imidazo[l,2-b]pyridazin -8-amine (1.2 g, 85 %) as a yellow solid. LC-MS: [M + l]+ = 329 > tR =1.930 min.
85%		A mixture of 8-bromo-6-chloroimidazo[l ,2-b]pyridazine (1.0 g, 4.3 mmol), 6-(2- methylpyrrolidin-l-yl)pyridin-2-amine (0.84 g, 4.73 mmol), Pd2(dba)3 (0.247 g, 0.43 mmol), BINAP (0.536 g, 0.86 mmol) and Cs2C03 (4.21 g, 12.9 mmol) in dioxane (30 mL) was heated to 100 C for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200 ~ 300 mesh, ethyl acetate : petroleum ether = 1 : 15) to afford 6-chloro-N-(6-(2-methylpyrrolidin-l-yl)pyridin-2-yl)imidazo[l ,2-b]pyridazin- 8- amine (1.2 g, 85 %) as a yellow solid. LC-MS: [M + l]+ = 329 > tR =1.930 min.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0410-0411
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 101
[3]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 108-109

38
[ 933190-51-3 ]
[ 1415695-32-7 ]
[ 1431773-82-8 ]

Yield	Reaction Conditions	Operation in experiment
29%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (300 mg, 1.3 mmol), (S)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (252 mg, 1.42 mmol), Pd2(dba)3 (75 mg, 0.13 mmol), BINAP (324 mg, 0.52 mmol), Cs2CO3 (1272 mg, 3.9 mmol) and dioxane (20 mL) was heated to 100 C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (124 mg, 29%) as a yellow solid. LC-MS: [M+H]+, 329.0, tR=1.951 min.
29%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;	A mixture of 8-bromo-6-chloroimidazo[l,2-b]pyridazine (300 mg, 1.3 mmol), (S)-6-(2- methylpyrrolidin-l-yl)pyridin-2-amine (252 mg, 1.42 mmol), Pd2(dba)3 (75 mg, 0.13 mmol), BINAP (324 mg, 0.52 mmol), Cs2C03 (1272 mg, 3.9 mmol) and dioxane (20 mL) was heated to 100 C with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 3 : 1) to give (S)-6-chloro-N-(6-(2-methylpyrrolidin-l-yl)pyridin-2-yl)imidazo [1,2- b]pyridazin-8-amine (124 mg, 29 %) as a yellow solid. LC-MS: [M+H]+, 329.0, tR = 1.95 lmin.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0350-0351
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 84

39
[ 933190-51-3 ]
[ 1431773-84-0 ]
[ 1431773-85-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;	A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (300 mg, 1.3 mmol), 6-(3-methylcyclopentyl)pyridin-2-amine (277 mg, 1.56 mmol), Pd2(dba)3 (75 mg, 0.13 mmol), BINAP (324 mg, 0.52 mmol), Cs2CO3 (1272 mg, 3.9 mmol) and dioxane (20 mL) was heated to 100 C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=5:1) to give 6-chloro-N-(6-(3-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (301 mg, 70%) as a yellow solid. LC-MS: [M+H]+, 329.1, tR=1.949 min.
70%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;	A mixture of 8-bromo-6-chloroimidazo[l ,2-b]pyridazine (300 mg, 1.3 mmol), 6-(3- methylcyclopentyl)pyridin-2-amine (277 mg, 1.56 mmol), Pd2(dba)3 (75 mg, 0.13 mmol), BINAP (324 mg, 0.52 mmol), Cs2C03 (1272 mg, 3.9 mmol) and dioxane (20 mL) was heated to 100 C with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 5 : 1) to give 6-chloro-N-(6-(3-methylpyrrolidin-l-yl)pyridin-2-yl)imidazo[l ,2-b] pyridazin-8-amine (301 mg, 70 %) as a yellow solid. LC-MS : [M+H]+, 329.1 , tR = 1.949min.

Reference： [1]Patent: US2013/109661,2013,A1 .Location in patent: Paragraph 0359-0360
[2]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 87

40
[ 933190-51-3 ]
C₁₂H₁₆N₄ [ No CAS ]
N-(6-(1-tert-butyl-1H-pyrazol-3-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazin-8-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%		To a solution of 1-tert-Butyl-lH-pyrazo 1-3 -amine (0.348 g, 2.5 mmol) in DMF (8 mL) was added NaH (0.060g, 60 % dispersion in mineral oil, 2.5mmol) and the mixture stirred for 0.5 h. To this mixture was added 8-bromo-6-chloroimidazo[l,2-b]pyridazine (0.233 g, 1 mmol) under N2. The mixture was stirred at room temperature for 16 h then partitioned between 15 mL of saturated aq. MH4CI and 15 mL of ether. The organic layer was washed with water(10 mL x 3) and saturated aq. NaCl (10 mL x 3), dried over NaS04, concentrated in vacuo, purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether : ethyl acetate = 3 : 1) to give N-(6- (l-tert-butyl-lH-pyrazol-3-yl)pyridin-2-yl)-6-chloroimidazo[l,2-b]pyridazin-8-amine (0.168 g, 23 %) as a light brown solid. LC-MS: [M+H]+, 291.1 , tR = 1.648min.

Reference： [1]Patent: WO2013/64445,2013,A1 .Location in patent: Page/Page column 60

41
[ 866620-36-2 ]
[ 933190-51-3 ]
[ 1443042-59-8 ]

Yield	Reaction Conditions	Operation in experiment
23%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 18h;	Step 1. Preparation of (6-Chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-yl]-amine A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (200 mg, 862 mumol, Eq: 0.95) and 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (200 mg, 908 mumol, Eq: 1.00) in DMF (10.0 ml) was cooled to 0 C. To this reaction mixture was added sodium hydride (116 mg, (60% in mineral oil), 2.9 mmol, Eq: 3.2). The reaction was allowed to stir at 0 C. for 10 min then allowed to warm to room temperature and stir 18 h. The reaction mixture was quenched with sat. NaHCO3 (aq) and diluted with water and EtOAc. The organic layer was separated and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 20% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a residue that was placed under high vacuum for 18 h to afford (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-yl]-amine (78 mg, 23%). LC/MS-ESI observed [M+H]+ 372.

Reference： [1]Patent: US2013/150360,2013,A1 .Location in patent: Paragraph 0165; 0166

42
[ 933190-51-3 ]
[ 1197333-44-0 ]
[ 1443042-61-2 ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 72h;	Step 3a. Preparation of (6-Chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amine A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (214 mg, 921 mumol, Eq: 0.95) and 5-((4-methylpiperazin-1-yl)methyl)pyridin-2-amine (200 mg, 970 mumol, Eq: 1.00) in DMF (10.0 ml) was cooled to 0 C. To this was added sodium hydride (60% in mineral oil, 124 mg, 3.1 mmol, Eq: 3.2). The reaction was allowed to stir at 0 C. for 10 min and then allowed to warm to room temperature and stirred for 72 h. The reaction was quenched with saturated NaHCO3 (aq) and then diluted with water and EtOAc. The organic layer was separated and the aqueous phase was washed with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in Et2O. The organic layer was washed with water and dried over MgSO4. The drying agent was removed by filtration. The resulting solution was concentrated in vacuo to give (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amine (170 mg, 49%) as a solid. LC/MS-ESI observed [M+H]+ 358.

Reference： [1]Patent: US2013/150360,2013,A1 .Location in patent: Paragraph 0176; 0177

43
[ 933190-51-3 ]
[ 827587-90-6 ]
[ 1161847-30-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 18h;	Step 1. Preparation of [6-(6-Chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone A mixture of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (272 mg, 1.17 mmol, Eq: 1.00) and (6-aminopyridin-3-yl)(morpholino)methanone (255 mg, 1.23 mmol, Eq: 1.05) in DMF (10.0 ml) was cooled to 0 C. To this reaction mixture was added sodium hydride (150 mg, (60% in mineral oil), 3.74 mmol, Eq: 3.2). The reaction was allowed to stir at 0 C. for 10 minutes and then allowed to warm to room temperature and stir 18 h. The reaction mixture was quenched with sat. NaHCO3 (aq) and diluted with water and EtOAc. An insoluble solid was collected by filtration to give [6-(6-chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (420 mg, 99%). LC/MS-ESI observed [M+H]+ 358.

Reference： [1]Patent: US2013/150360,2013,A1 .Location in patent: Paragraph 0161; 0162

44
[ 933190-51-3 ]
[ 67-66-3 ]
[ 1263425-59-7 ]

Yield	Reaction Conditions	Operation in experiment
43%	With hydrogenchloride; N-iodo-succinimide; In water; for 9h;Reflux; Inert atmosphere;	Comparative Example 1 e -Bromo-6-chloro-3-iodoimidazo[1 ,2-b]pyridazine A mixture comprising 100 g (430 mmoi) 8-bromo-6-chloroimidazo[1 ,2-b]pyridazine which was prepared according to a procedure described in US2007/78136 (WO2007/38314) , 145 g N-iodosuccinimide, 5 percent per weight cone, hydrochloric acid and 1 L trichloromethane was heated at reflux for 6 hours. 20 g N- iodosuccinimide were added and heating was continued for additional 3 hours. The precipitate was removed and the filtrate was washed with 1 N sodium hydroxide solution, brine and dried over sodium sulfate. After filtration and removal of solvent diisopropyl ether was added and the residue was stirred at 23 C overnight. The precipitate was filtered off and dried to give 66.6 g (43%) of the title compound

Reference： [1]Patent: WO2013/135612,2013,A1 .Location in patent: Page/Page column 84; 85

45
[ 571189-49-6 ]
[ 933190-51-3 ]
[ 1433821-73-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 15h;Reflux;	A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 104a (2.0 g, 4 mmol), 5-(4-methylpiperazin-1-yl)pyridin-2-amine (920 mg, 4.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (366 mg, 0.4 mmol), XantPhos (688 mg, 1.2 mmol), Cs2CO3 (2.6 g, 8.0 mmol), and 1,4-dioxane (60 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (20:1) to afford 104b as yellow solid (1.4 g, 70%). MS: [M+H]+344.

Reference： [1]Patent: US2013/116262,2013,A1 .Location in patent: Paragraph 0243

46
[ 933190-51-3 ]
[ 1554458-53-5 ]

Reference： [1]Patent: WO2014/20041,2014,A1
[2]Patent: WO2014/20041,2014,A1
[3]Patent: WO2014/198776,2014,A1

47
[ 933190-51-3 ]
[ 1610035-40-9 ]
[ 1610035-41-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;	[003891 86C. Methyl 2-((2R,4R)- 1 -(4-(( 1 -(6-chloroimidazo[ 1 ,2-b]pyridazin-8- yl)piperidin-4-yl)oxy)phenyl)-4-methoxypyrrolidin-2-yl)acetate: To a solution of 86B (0.150 g, 0.430 mmol) in DMF (5 mL) was added to 8-bromo-6-chloroimidazo[1,2- b]pyridazine (0.150 g, 0.646 mmol) and K2C03 (0.178 g, 1.29 mmol). The reaction mixture was heated to 100 C for 4 h. The reaction mixture was concentrated, dilutedwith water, and extracted with EtOAc (3x). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by silica chromatography to afford 86C (0.060 g, 0.120 mmol, 28% yield) as a light brown gummy oil. LC-MS Anal. Calc?d for C25H30C1N504: 499.99, found [M+H] 500. 1H NMR (400 MHz, CDC13) oe 7.76 (d, J=1.2 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 6.57 (d, J9.1 Hz, 2H),6.11 (s, 1H), 4.48-4.41 (m, 1H), 4.32-4.22 (m, 2H), 4.22-4.14 (m, 1H), 4.14-4.06 (m,3H), 3.73 (s, 3H), 3.54 - 3.48 (m, 1H), 3.41- 3.39 (m, 1H), 3.39 (s, 3H), 2.90 - 2.82 (m,1H), 2.69 (d, J=10.4 Hz, 1H), 2.21 - 2.11 (m, 4H), 2.03- 1.95 (m, 2H).

Reference： [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00389

48
[ 933190-51-3 ]
[ 765-30-0 ]
6-chloro-N-cyclopropylimidazo[1,2-b]pyridazin-8-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With toluene-4-sulfonic acid; In dimethyl sulfoxide; at 100℃; for 24h;	Preparation of 6-chloro-N-cyclopropylimidazo[1,2-b]pyridazin-8-amine To a solution of <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (1.00 g, 3.21 mmol, 1.0 equiv) and p-TSA (611 mg, 3.21 mmol, 1.0 equiv) in DMSO (10.0 mL) was added cyclopropylamine (1.13 mL, 16.1 mmol, 5.0 equiv) and heated to 100 C. for 24 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 536 mg of the white solid, 80%.

Reference： [1]Patent: US2014/256733,2014,A1 .Location in patent: Page/Page column 0300-302

49
[ 933190-51-3 ]
[ 933035-31-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; In dichloromethane; at 70℃;Sealed tube;	A solution of 8-bromo-6-chloroimidazo[l,2-£]pyridazine (5.00 g, 21.51 mmol) (prepared as described by Vaccaro W. et al. United States Patent Appl. US 2008/0045536 Al, 2008) and NBS (4.21 g, 23.7 mmol) in CH2C12 (40 mL) was heated to 70 C in a sealed tube. The solvent was evaporated and water was added to the residue resulting in a brown ppt which was filtered and dried to afford 3,8- dibromo-6-chloroimidazo[l,2-]pyridazine (6.7 g, 100% yield) as a brown solid: 1H NMR (400 MHz, CDC13) delta 7.82 (s, 1 H), 7.42 (s, 1 H); LRMS (ESI) mle 313.8 [(M + H)+, calcd for C6H3N3Br2Cl 312.4].

Reference： [1]Patent: WO2015/26574,2015,A1 .Location in patent: Page/Page column 50
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 2447 - 2465

50
[ 933190-51-3 ]
[ 3526-43-0 ]
6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 5h;	To a solution of 8-bromo-6-chloroimidazo[l,2-]pyridazine (340 mg, 1.463 mmol) (prepared as described by Vaccaro W. et al. United States Patent Appl. US 2008/0045536 Al, 2008) and N-(4-methoxybenzyl)aniline (312 mg, 1.46 mmol) in THF (5 mL) at 0 C was added LiHMDS (4.39 mL, 4.39 mmol, 1 M in THF). The reaction mixture was stirred at 0 C for 3 h. The starting material was still present. Additional LiHMDS (4.39 mL, 4.39 mmol, 1 M in THF) was added and the reaction was stirred at room temperature for 2 h. LCMS indicated complete consumption of the starting material. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHC03 solution (25 mL) and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (10%? 30% ethyl acetate in hexanes) to afford 6-chloro-N-(4-methoxybenzyl)-N- phenylimidazo[l,2-£]pyridazin-8-amine (280 mg, 53%> yield) as a yellow solid: LRMS (ESI) mle 365.2 [(M + H)+, calcd for C2oHi8N4OCl 365.2].

Reference： [1]Patent: WO2015/26574,2015,A1 .Location in patent: Page/Page column 34

51
[ 933190-51-3 ]
[ 609-08-5 ]
diethyl 2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-methylmalonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 0.166667h;	0O150] Step 1: To a solution of 8..bromo.-6chioroirnidazo[i,2bjpyridazine (1.0 equiv.) and diethyl 2-methylmalonate (1.0 equiv.) in DMF (0.15 M) was added sodium hydride (2.5 equiv.) at it The reaction was stined for 10 mm, then quenched with saturated ammoniurn chloride and extracted twice with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered and concentrated. The residue was purified via reverse phase prep-1-IPLC to give cliethyl 2-(6-chloroimidazo[i ,2-bpyridazin-8.yI)-2-rnethylmalonate in 21% yield. LCMS (m/z) (M±H) 326.0, Rt 0.84 miii.

Reference： [1]Patent: WO2016/38582,2016,A1 .Location in patent: Paragraph 00150

52
[ 110-91-8 ]
[ 933190-51-3 ]
[ 1298031-99-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In tetrahydrofuran; for 12h;Reflux;	Compound 3-1 (0 · 27g, lmmol), morpholine 0 · 12g (l. 2mmol) and triethylamine (0 · 3ml, 2. 2mmol) Was added to 5ml of tetrahydrofuran was refluxed for 12h, after completion of the reaction, washed with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate. Petroleum ether: ethyl acetate 6: 1 column chromatography to obtain a solid, yield 80%
	With triethylamine; In tetrahydrofuran; for 12h;Reflux;	General procedure: To a solution of 6a-6c (1 mmol) in THF (5 mL) was addedmorpholine (or (S)-3-methylmorpholine, or 8-oxa-3-azabicyclo[3.2.1]octane) (1.2 mmol) and Et3N (2.2 mmol). The mixture washeated under reflux for 12 h. The crude product was extracted with CH2Cl2, dried over Na2SO4, purified over silica gel chromatographyeluting with PE and EtOAc to give 7a-7g [43].

Reference： [1]Patent: CN103360399,2016,B .Location in patent: Paragraph 0016; 0123; 0144; 0145; 0146
[2]European Journal of Medicinal Chemistry,2017,vol. 129,p. 135 - 150

53
[ 350595-57-2 ]
[ 933190-51-3 ]
(S)-8-(3-methyl morpholin-4-yl)-6-chloro-imidazo[1,2-b]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; for 12h;Reflux;	General procedure: To a solution of 6a-6c (1 mmol) in THF (5 mL) was addedmorpholine (or (S)-3-methylmorpholine, or 8-oxa-3-azabicyclo[3.2.1]octane) (1.2 mmol) and Et3N (2.2 mmol). The mixture washeated under reflux for 12 h. The crude product was extracted with CH2Cl2, dried over Na2SO4, purified over silica gel chromatographyeluting with PE and EtOAc to give 7a-7g [43].

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 129,p. 135 - 150

54
[ 280-13-7 ]
[ 933190-51-3 ]
8-(8-oxa-3-aza-bicyclo[3.2.1]octyl-3-yl)-6-chloro-imidazo[1,2-b]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; for 12h;Reflux;	General procedure: To a solution of 6a-6c (1 mmol) in THF (5 mL) was addedmorpholine (or (S)-3-methylmorpholine, or 8-oxa-3-azabicyclo[3.2.1]octane) (1.2 mmol) and Et3N (2.2 mmol). The mixture washeated under reflux for 12 h. The crude product was extracted with CH2Cl2, dried over Na2SO4, purified over silica gel chromatographyeluting with PE and EtOAc to give 7a-7g [43].

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 129,p. 135 - 150

55
[ 446273-59-2 ]
2-haloacetaldehyde [ No CAS ]
[ 933190-51-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;Reflux;	General procedure: 4-Bromo-6-chloropyridazin-3-amine (2.4 mmol)was added to asolution of alpha-haloaldehydes (7.4e12.0 mmol) in EtOH (10 mL) andthe mixture was heated under reflux for 24-48 h. After cooling,saturated sodium carbonate was added to the mixture. The crudeproduct was extracted with CH2Cl2, dried over Na2SO4, purifiedover silica gel chromatography to give 6a-6c [43].

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 129,p. 135 - 150

56
[ 933190-51-3 ]
(S)-benzyl (2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pent-4-en-2-yl)carbamate [ No CAS ]
(S)-benzyl (1-(4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)phenoxy)-2,4-dimethylpent-4-en-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere;	A solution of 8-bromo-6-chloroimidazo[1,2- bjpyridazine (0.05 g, 0.215 mmol), (S)-benzyl (2,4-dimethyl- 1 -(4-(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)phenoxy)pent-4-en-2-yl)carbamate (0.110 g, 0.237 mmol), and potassium phosphate tribasic (2M in water) (0.323 mL, 0.645 mmol) in 1,4-dioxane (1.075 mL) was purged with argon for 5 mi Tetrakis(triphenylphosphine)palladium (0)(triphenylphosphine)palladium(0) (0.0 12 g, 10.75 imol) was added to the reaction mixture under argon and the mixture was heated to 100 C overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2x30 mL). The ethyl acetate layer was washed with water (20 mL), brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silicagel chromatography (0-60% of ethyl acetate/hexane) to afford (5)-benzyl (l-(4-(6- chloroimidazo[ 1 ,2-bj pyridazin-8-yl)phenoxy)-2,4-dimethylpent-4-en-2-yl)carbamate (0.05 g, 0.092 mmol, 43% yield) as a gummy liquid. LCMS (ESI) m/e 491.2 [(M+H), calcd for C27H28C1N403 491.21; LC/MS retention time (method Al): tR = 2.88 mm.

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 90; 91

57
[ 933190-51-3 ]
(S)-tert-butyl (1-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]
(S)-tert-butyl (1-(4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-cyanophenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.055 g	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere;	A solution of 8-bromo-6-chloroimidazo[1,2-bjpyridazine (0.04 g, 0.172 mmol), (S)-tert-bulyl (1 -(2-cyano-4-(4,4,5 ,5-tetramethyl- 1,3,2- dioxaborolan-2- yl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (prepared as described in Example285) (0.079 g, 0.172 mmol), and potassium phosphate tribasic (2M in water) (0.258 mL, 0.5 16 mmol) in 1,4-dioxane (0.860 mL) was purged with argon for 5mm. Tetrakis(triphenylphosphine)palladium(0) (9.94 mg, 8.60 imol) was added to the reaction mixture under argon and the mixture was heated to 100 C overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate(2x30 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-20% of ethyl acetate/hexane) to give (S)-tert-butyl (1- (4-(6-chloroimidazo [1 ,2-bj pyridazin-8-yl)-2-cyanophenoxy)-2,4-dimethylpentan-2- yl)carbamate (0.055 g, 0.091 mmol, 53% yield) as a yellow solid. LCMS (ESI) m/e 484.2 [(M+H), calcd for C25H31C1N503 484.21; LC/MS retention time (method B):tR= 1.18 mm.

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 98; 99

58
[ 933190-51-3 ]
(S)-tert-butyl (2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate [ No CAS ]
(S)-tert-butyl (1-(4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere;	A solution of 8-bromo-6-chloroimidazo[1,2-bjpyridazine (0.03 g, 0.129mmol), (5)-tert-butyl (2,4-dimethyl- 1 -(4-(4,4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (prepared as described in Example 255, Parts A and B) (0.065 g, 0. i29 mmol), and potassium phosphate tribasic (2m in water) (0.194 mL, 0.387 mmol) in 1,4-dioxane (0.645 mL) was purged with argon for 10 mm. Tetrakis(triphenylphosphine)palladium (0) (7.46 mg,6.45 imol) was added to the reaction mixture under argon and the mixture was heated to 100 C overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2x 30 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The cmde product was purified by silica gel chromatography (0-20% of ethylacetate/hexane) to give (S)-tert-butyl (1 -(4-(6-chloroimidazo[ 1 ,2-bj pyridazin-8-yl)-2- (trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-yl)carbamate (0.042 g, 0.073 mmol, 57% yield).LCMS (ESI) m/e 527.2 [(M+H), calcd for C25H31C1F3N403 527.21; LC/MS retention time (method A2): tR = 1.28 mm.

Reference： [1]Patent: WO2017/59080,2017,A1 .Location in patent: Page/Page column 94

59
[ 288-13-1 ]
[ 933190-51-3 ]
8-bromo-6-chloro-3-(1H-pyrazol-1-yl)imidazo[1,2-b]pyridazine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 11288 - 11299

60
[ 933190-51-3 ]
6-chloroimidazo[1,2-b]pyridazin-8(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; at 100℃; for 16h;	To <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (70g, 301mmol) were added H2O (700mL) and NaOH (26g, 647mmol). The reaction mixture was heated to 100C for 16h, cooled to RT, and neutralized to pH 6-7 with HCl. The product was collected by filtration.

Reference： [1]Patent: WO2019/125974,2019,A1 .Location in patent: Paragraph 0204-0205

61
[ 933190-51-3 ]
(3-((4-fluorophenyl)carbamoyl)-4-methylphenyl)boronic acid [ No CAS ]
5-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-N-(4-fluorophenyl)-2-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide;Microwave irradiation;	Example 33 was synthesized according to the above disclosed synthesis scheme. 8-Bromo-6-chloroimidazo[l,2-b]pyridazine (160 mg, 0.688 mmol), (3-((4- fluorophenyl)carbamoyl)-4-methylphenyl)boronic acid (225.5 mg, 0.826 mmol), Pd(dppf)Cl2 (56.2 mg, 0.069 mmol), and K2CO3 (285.4 mg, 2.065 mmol) were dissolved in degassed DMF (3.0 mL) and water (0.5 mL) and heated in microwave at l20C for 20 minutes. The reaction mixture was filtered through ceilite and washed with EtOAc. The filtrate was concentrated and purified by prep-TLC with 1: 1 ratio of EtOAc and Hexanes to give 5-(6-chloroimidazo[l,2- b]pyridazin-8-yl)-N-(4-fluorophenyl)-2-methylbenzamide.

Reference： [1]Patent: WO2020/10223,2020,A1 .Location in patent: Paragraph 0341

62
[ 933190-51-3 ]
[ 17061-62-0 ]
6-chloro-N,N-bis(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 90℃;	A Step A: 6-chloro-N, N-bis (4-methoxybenzyl) imidazo [1, 2-b] pyridazin-8-amine To a stirred solution of 8-bromo-6-chloroimidazo [1, 2-b] pyridazine (2 g, 8.7 mmol) in DMF (20 mL) , bis (4-methoxybenzyl) amine (2.7 g, 10.44 mmol) and DIEA (2.3 g, 17.4 mmol) were added. The reaction mixture was stirred at 90 overnight. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 ml x 3) . The combined organic phase was washed with brine, dried over Na2SO4and concentrated in vacuo. The crude product was purified by column chromatography to give the product (2.8 mg, 80%) as white solids. MS: M/e 308 (M+1)+.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2020/160711, 2020, A1 Location in patent: Paragraph 1076-1077

63
[ 933190-51-3 ]
[ 792915-20-9 ]
6-chloro-8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 85℃; for 24h;	Intermediate 55. 6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine To a mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (150 mg, 0.645 mmol) and 3-phenylazetidine hydrochloride (109 mg, 0.645 mmol) in MeCN (2 mL) was added N,N- diisopropylethylamine (0.337 mL, 1.94 mmol). The mixture was heated to 100oC and stirred for 4 h. The mixture was then concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford 6-chloro-8-(3-phenylazetidin-1- yl)imidazo[1,2-b]pyridazine. ES/MS m/z: 285.1 [M+1].
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 85℃; for 24h;	Intermediate 55. 6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine To a mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (150 mg, 0.645 mmol) and 3-phenylazetidine hydrochloride (109 mg, 0.645 mmol) in MeCN (2 mL) was added N,N- diisopropylethylamine (0.337 mL, 1.94 mmol). The mixture was heated to 100oC and stirred for 4 h. The mixture was then concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford 6-chloro-8-(3-phenylazetidin-1- yl)imidazo[1,2-b]pyridazine. ES/MS m/z: 285.1 [M+1].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 0808
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 0808

64
[ 933190-51-3 ]
[ 1810-13-5 ]
6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In ethanol at 90℃;	6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine was prepared as follows: To a mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (0.2g, 0.86 mmol) and potassium carbonate (0.24g, 1.72 mmol) in EtOH (2 mL) was added 3,3,4,4- tetrafluoropyrrolidine hydrochloride (154mg, 0.86 mmol). The reaction mixture was heated at 90oC overnight. The solvent was then evaporated and the residue was purified with Prep HPLC to afford 6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine. ES/MS m/z: 392.20 [M+H].
	With potassium carbonate In ethanol at 90℃;	6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine was prepared as follows: To a mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (0.2g, 0.86 mmol) and potassium carbonate (0.24g, 1.72 mmol) in EtOH (2 mL) was added 3,3,4,4- tetrafluoropyrrolidine hydrochloride (154mg, 0.86 mmol). The reaction mixture was heated at 90oC overnight. The solvent was then evaporated and the residue was purified with Prep HPLC to afford 6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine. ES/MS m/z: 392.20 [M+H].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 0818; 1277
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 0818; 1277

65
[ 933190-51-3 ]
[ 1895296-01-1 ]
[ 2735698-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3,3,3-trifluoro-2,2-dimethylpropan-1-ol With sodium hydride In 2-methyltetrahydrofuran; mineral oil for 0.166667h; Stage #2: 8-bromo-6-chloroimidazo[1,2-b]pyridazine In 2-methyltetrahydrofuran; mineral oil at 70℃; for 2h;	6-chloro-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazine was prepared as follows: To a vial add 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (153 mg, 1.1 mmol) and Me-THF (2 ml) then carefully add sodium hydride 60 % dispersion in mineral oil (16.5 mg, 0.43 mmol) allowing to stir for 10 minutes then add 8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.22 mmol) then cap and heat to 70oC for 2 hr. The reaction was cooled quenched with water, extracted 2X EtOAc, the organic layer was dried over sodium sulfate, concentrated, and used crude in the next reaction. ES/MS m/z: 294.21 [M+H].
	Stage #1: 3,3,3-trifluoro-2,2-dimethylpropan-1-ol With sodium hydride In 2-methyltetrahydrofuran; mineral oil for 0.166667h; Stage #2: 8-bromo-6-chloroimidazo[1,2-b]pyridazine In 2-methyltetrahydrofuran; mineral oil at 70℃; for 2h;	6-chloro-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazine was prepared as follows: To a vial add 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (153 mg, 1.1 mmol) and Me-THF (2 ml) then carefully add sodium hydride 60 % dispersion in mineral oil (16.5 mg, 0.43 mmol) allowing to stir for 10 minutes then add 8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.22 mmol) then cap and heat to 70oC for 2 hr. The reaction was cooled quenched with water, extracted 2X EtOAc, the organic layer was dried over sodium sulfate, concentrated, and used crude in the next reaction. ES/MS m/z: 294.21 [M+H].

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 1737
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2021/222522, 2021, A1 Location in patent: Paragraph 1737

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Isomers

Technical Information

• Acid-Catalyzed α -Halogenation of Ketones • Addition of a Hydrogen Halide to an Internal Alkyne • Alcohols from Haloalkanes by Acetate Substitution-Hydrolysis • Alcohols React with PX3 • Alkyl Halide Occurrence • Alkylation of an Alkynyl Anion • An Alkane are Prepared from an Haloalkane • Chloroalkane Synthesis with SOCI2 • Convert Haloalkanes into Alcohols by SN2 • Friedel-Crafts Alkylation of Benzene with Haloalkanes • General Reactivity • Grignard Reaction • Halogenation of Alkenes • Hiyama Cross-Coupling Reaction • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Methylation of Ammonia • Methylation of Ammonia • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Dihalides • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling • Williamson Ether Syntheses

Historical Records

Related Functional Groups of
[ 933190-51-3 ]

Bromides

[ 1298031-94-3 ]

8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine

Similarity: 0.91

[ 13526-66-4 ]

3-Bromo-6-chloroimidazo[1,2-b]pyridazine

Similarity: 0.77

[ 18112-31-7 ]

3-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine

Similarity: 0.71

[ 1159977-65-7 ]

6-Bromoimidazo[1,2-b]pyridazine

Similarity: 0.69

[ 18087-73-5 ]

3-Bromoimidazo[1,2-b]pyridazine

Similarity: 0.67

Chlorides

[ 1298031-94-3 ]

8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine

Similarity: 0.91

[ 6775-78-6 ]

6-Chloroimidazo[1,2-b]pyridazine

Similarity: 0.84

[ 137384-48-6 ]

6-Chloro-3-methylimidazo[1,2-b]pyridazine

Similarity: 0.80

[ 13526-66-4 ]

3-Bromo-6-chloroimidazo[1,2-b]pyridazine

Similarity: 0.77

[ 40972-42-7 ]

3,6-Dichloroimidazo[1,2-b]pyridazine

Similarity: 0.77

Related Parent Nucleus of
[ 933190-51-3 ]

Other Aromatic Heterocycles

[ 1298031-94-3 ]

8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine

Similarity: 0.91

[ 6775-78-6 ]

6-Chloroimidazo[1,2-b]pyridazine

Similarity: 0.84

[ 137384-48-6 ]

6-Chloro-3-methylimidazo[1,2-b]pyridazine

Similarity: 0.80

[ 13526-66-4 ]

3-Bromo-6-chloroimidazo[1,2-b]pyridazine

Similarity: 0.77

[ 40972-42-7 ]

3,6-Dichloroimidazo[1,2-b]pyridazine

Similarity: 0.77

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 933190-51-3 ] {[proInfo.proName]}

Quality Control of [ 933190-51-3 ]

Related Doc. of [ 933190-51-3 ]

Product Details of [ 933190-51-3 ]

Calculated chemistry of [ 933190-51-3 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 933190-51-3 ]

Application In Synthesis of [ 933190-51-3 ]

[ 933190-51-3 ] Synthesis Path-Upstream 1~3

[ 933190-51-3 ] Synthesis Path-Downstream 1~65

Technical Information

Related Functional Groups of [ 933190-51-3 ]

Bromides

Chlorides

Related Parent Nucleus of [ 933190-51-3 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 933190-51-3 ]

Related Parent Nucleus of
[ 933190-51-3 ]