[ CAS No. 20744-39-2 ] {[proInfo.proName]}

Name: 20744-39-2|Pyridazin-4-amine|97%
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3d Animation Molecule Structure of 20744-39-2

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Quality Control of [ 20744-39-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 20744-39-2 ]

SDS Specification

Alternatived Products of [ 20744-39-2 ]

Product Details of [ 20744-39-2 ]

CAS No. :	20744-39-2	MDL No. :	MFCD00233975
Formula :	C₄H₅N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LUCGBEPEAUHERV-UHFFFAOYSA-N
M.W :	95.10	Pubchem ID :	298492
Synonyms :

Calculated chemistry of [ 20744-39-2 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	26.44
TPSA :	51.8 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.26 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.66
Log Po/w (XLOGP3) :	-0.53
Log Po/w (WLOGP) :	0.07
Log Po/w (MLOGP) :	-0.72
Log Po/w (SILICOS-IT) :	0.38
Consensus Log Po/w :	-0.03

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.73
Solubility :	17.7 mg/ml ; 0.186 mol/l
Class :	Very soluble
Log S (Ali) :	-0.09
Solubility :	77.5 mg/ml ; 0.815 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.21
Solubility :	5.93 mg/ml ; 0.0624 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 20744-39-2 ]

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 [ 20744-39-2 ]

* 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 [ 20744-39-2 ]
Downstream synthetic route of [ 20744-39-2 ]

[ 20744-39-2 ] Synthesis Path-Upstream 1~8

1
[ 20744-39-2 ]
[ 5469-70-5 ]

Reference： [1] Patent: US4735650, 1988, A,

2
[ 823-58-5 ]
[ 20744-39-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; hydrogen In tetrahydrofuran; water at 20℃; for 48 h;	Example 151; 4-(3-Phenyl-1,2,4-thiadiazol-5-yl)-N-pyridazin-4-ylpiperazine-1-carboxamide; (1) Pyridazine-4-amine; A mixture of 3,6-dichloropyridazine-4-amine (5.00 g, 18.2 mmol), tetrahydrofuran (100 ml), sodium hydroxide (8.00 g, 200 mmol), water (32 ml) and 10percent palladium-carbon (500 mg) was stirred under a hydrogen atmosphere at room temperature for 2 days, insolubles were filtered off and the filtrate was concentrated. The residue was dissolved in methanol (100 ml), insolubles were filtered off and the filtrate was concentrated to obtain the desired product quantitatively as a solid. ¹H-NMR (DMSO-d₆) δ; 2.51 (2H, br s), 6.00 (1H, br s), 7.81 - 7.85 (1H, m), 7.98 - 8.00 (1H, m).

Reference： [1] Patent: EP1813606, 2007, A1, . Location in patent: Page/Page column 83-84
[2] Pharmaceutical Bulletin, 1956, vol. 4, p. 137,498
[3] Pharmaceutical Bulletin, 1956, vol. 4, p. 137,498

3
[ 14161-11-6 ]
[ 20744-39-2 ]

Reference： [1] Patent: US4728355, 1988, A,
[2] Patent: US4735650, 1988, A,
[3] Patent: WO2011/38572, 2011, A1, . Location in patent: Page/Page column 52

4
[ 289-80-5 ]
[ 20744-39-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: at -78℃; Stage #2: at -78℃; for 0.166667 h; Stage #3: for 0.166667 h;	50 mL of ammonia was condensed in a 200 mL, 3-NECK flask equipped with dry ice condenser. After the addition of a crystal of Fe (N03) 3, potassium (468 mg, 12.0 mmol) was added in small pieces AT-78 C. The cooling bath was removed and the intense dark blue mixture was brought to a gentle reflux until a light grey slurry was obtained. After cooling TO-78 C, 0.35 mL (4.80 mmol) of pyridazine was added and the mixture was stirred for 10 minutes. Solid KM : NO4 (2. 65 g, 16. 8 mmol) was added in small portions, the cooling bath was removed, and the mixture was stirred for 10 minutes The reaction was carefully quenched with 1.2 g of solid ammonium chloride. 20 mL of methanol was added and the ammonia was left to evaporate in the hood. The black mixture was filtered through CELIEZ filter aid, the filtrate was concentrated in vacuo, and the resulting black solid was purified on SI02 (100percent CH2CL2 to 10percent MeOH in CH2C12, gradient) to yield pyridazin-4-ylamine as a brownish solid (380 mg; 83percent yield). Bromination of pyridazin-4-ylamine was performed in the same manner as for the preparation of 4-amino-3-bromo-2,6-dimethylpyridine. Chromatography on Si02 (20percent ethyl acetate in hexanes to 100percent ethyl acetate, gradient, followed by 2percent methanol in ethyl acetate) yielded 4- amino-3-bromopyridazine (first eluting: 15percent yield) and 4-amino-5-bromopyridazine (second eluting: 5percent yield) as tan solids.

Reference： [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 1285 - 1287
[2] Patent: WO2005/30213, 2005, A1, . Location in patent: Page/Page column 175-176

5
[ 53180-76-0 ]
[ 20744-39-2 ]

Reference： [1] Pharmaceutical Bulletin, 1956, vol. 4, p. 137,498
[2] Pharmaceutical Bulletin, 1956, vol. 4, p. 137,498

6
[ 89180-50-7 ]
[ 20744-39-2 ]

Reference： [1] Pharmaceutical Bulletin, 1956, vol. 4, p. 137,498

7
[ 17114-78-2 ]
[ 20744-39-2 ]
[ 106358-48-9 ]

Reference： [1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14

8
[ 20744-39-2 ]
[ 55928-90-0 ]

Yield	Reaction Conditions	Operation in experiment
5.56%	With bromine In acetic acid at 20℃; for 1 h;	5-Bromopyridazin-4-amine: To a solution of pyridazin-4-amine (1.18 g, 12.41 mmol) in Acetic Acid (2.5 mL) was added dibromine (0.638 mL, 12.41 mmol)dropwise at rt in a water bath. After 1 h, 10 N NaOH was added and then extracted with dichloromethane (3x). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in a small amount of dichloromethane and charged to a 40 g silica gel cartridge which was eluted with 0-15percent dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 3-bromopyridazin-4- amine (0.1 g, 0.575 mmol, 4.63 percent yield)(first eluting) and 5-bromopyridazin-4-amine (0.12 g, 0.690 mmol, 5.56 percent yield)(second eluting). 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.75 (s, 1 H) 8.55 (s, 1 H) 6.72 - 6.79 (m, 2 H).

Reference： [1] Patent: WO2015/69594, 2015, A1, . Location in patent: Page/Page column 196
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1583 - 1598

[ 20744-39-2 ] Synthesis Path-Downstream 1~88

1
[ 20744-39-2 ]
[ 108-24-7 ]
[ 98140-86-4 ]

Reference： [1]Pharmaceutical bulletin,1956,vol. 4,p. 497 - 499

2
[ 823-58-5 ]
[ 20744-39-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; water; at 20℃; for 48h;	Example 151; 4-(3-Phenyl-1,2,4-thiadiazol-5-yl)-N-pyridazin-4-ylpiperazine-1-carboxamide; (1) Pyridazine-4-amine; A mixture of 3,6-dichloropyridazine-4-amine (5.00 g, 18.2 mmol), tetrahydrofuran (100 ml), sodium hydroxide (8.00 g, 200 mmol), water (32 ml) and 10% palladium-carbon (500 mg) was stirred under a hydrogen atmosphere at room temperature for 2 days, insolubles were filtered off and the filtrate was concentrated. The residue was dissolved in methanol (100 ml), insolubles were filtered off and the filtrate was concentrated to obtain the desired product quantitatively as a solid. 1H-NMR (DMSO-d6) delta; 2.51 (2H, br s), 6.00 (1H, br s), 7.81 - 7.85 (1H, m), 7.98 - 8.00 (1H, m).

Reference： [1]Patent: EP1813606,2007,A1 .Location in patent: Page/Page column 83-84
[2]Pharmaceutical Bulletin,1956,vol. 4,p. 137,498
[3]Pharmaceutical Bulletin,1956,vol. 4,p. 137,498

3
[ 89180-50-7 ]
[ 20744-39-2 ]

Reference： [1]Pharmaceutical Bulletin,1956,vol. 4,p. 137,498

4
[ 53180-76-0 ]
[ 20744-39-2 ]

Reference： [1]Pharmaceutical Bulletin,1956,vol. 4,p. 137,498
[2]Pharmaceutical Bulletin,1956,vol. 4,p. 137,498

5
[ 289-80-5 ]
[ 20744-39-2 ]

Yield	Reaction Conditions	Operation in experiment
83%		50 mL of ammonia was condensed in a 200 mL, 3-NECK flask equipped with dry ice condenser. After the addition of a crystal of Fe (N03) 3, potassium (468 mg, 12.0 mmol) was added in small pieces AT-78 C. The cooling bath was removed and the intense dark blue mixture was brought to a gentle reflux until a light grey slurry was obtained. After cooling TO-78 C, 0.35 mL (4.80 mmol) of pyridazine was added and the mixture was stirred for 10 minutes. Solid KM : NO4 (2. 65 g, 16. 8 mmol) was added in small portions, the cooling bath was removed, and the mixture was stirred for 10 minutes The reaction was carefully quenched with 1.2 g of solid ammonium chloride. 20 mL of methanol was added and the ammonia was left to evaporate in the hood. The black mixture was filtered through CELIEZ filter aid, the filtrate was concentrated in vacuo, and the resulting black solid was purified on SI02 (100% CH2CL2 to 10% MeOH in CH2C12, gradient) to yield pyridazin-4-ylamine as a brownish solid (380 mg; 83% yield). Bromination of pyridazin-4-ylamine was performed in the same manner as for the preparation of 4-amino-3-bromo-2,6-dimethylpyridine. Chromatography on Si02 (20% ethyl acetate in hexanes to 100% ethyl acetate, gradient, followed by 2% methanol in ethyl acetate) yielded 4- amino-3-bromopyridazine (first eluting: 15% yield) and 4-amino-5-bromopyridazine (second eluting: 5% yield) as tan solids.

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 1285 - 1287
[2]Patent: WO2005/30213,2005,A1 .Location in patent: Page/Page column 175-176

6
[ 20744-39-2 ]
[ 106358-48-9 ]
[ 17114-78-2 ]
C₄H₄N₃^(1-)*K⁽¹⁺⁾ [ No CAS ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1982,vol. 18,p. 6 - 10
Zhurnal Organicheskoi Khimii,1982,vol. 18,p. 9 - 14

7
[ 17114-78-2 ]
C₄H₄N₃^(1-)*K⁽¹⁺⁾ [ No CAS ]
[ 20744-39-2 ]
[ 106358-48-9 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1982,vol. 18,p. 6 - 10
Zhurnal Organicheskoi Khimii,1982,vol. 18,p. 9 - 14

8
[ 20744-39-2 ]
[ 24424-99-5 ]
[ 169050-21-9 ]

Yield	Reaction Conditions	Operation in experiment
1.5 g	With triethylamine; In dichloromethane; at 0 - 30℃; for 16h;	To a solution of 1.0 g (10.Smmol) of <strong>[20744-39-2]pyridazin-4-amine</strong> (CAS 20744-39-2) in 4.8 mL (36.8 mmol) of TEA and 30 mL of DCM was added 5.74 g of(Boc)20 (26.3 mmol) at 0 C. Then the reaction solution was allowed warming to 25 C with stirring at 30 C for 16 h. LCMS showed that the reaction was complete. The solvent was removed under vacuum and the residue was purified by silica gel columnchromatography (PE/EA = 1/3, Rf= 0.2) to give 1.5 g of the product as a pale white solid.?H NMR (400 MHz, DMSO-d6 + D20) 3 ppm: 9.14 (dd, J1 = 2.8 Hz, J2 = 0.8 Hz, 1H), 8.92 (dd, Ji = 6.0 Hz, J2 = 0.8 Hz, 1H), 7.73 (dd, J1 = 6.0 Hz, J2 = 2.8 Hz, 1H).

Reference： [1]Journal of Heterocyclic Chemistry,1995,vol. 32,p. 841 - 846
[2]Patent: WO2016/128465,2016,A1 .Location in patent: Page/Page column 108

9
[ 20744-39-2 ]
[ 3282-30-2 ]
[ 169050-20-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1995,vol. 32,p. 841 - 846

10
[ 20744-39-2 ]
[ 7693-46-1 ]
C₁₁H₈N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 5h;	4-Amino-pyridazine, p-nitrophenyl chloroformate and Hunig's base (1: 1: 1) were dissolved in 2ml dry DCM. Reaction in r. t. , under N2 and for 5h. The amine (3aS, 6R, 7aS*)-3a- (3, 4-dimethoxyphenyl)-l-methyloctahydro-IH-indol-6- amine (Comparative Example 7; 6mg, 0,021mmol) and another eq. base were added. Reaction in r. t. , under N2 and overnight. MS (electrospray; [M+H] +) m/z 413. Measured mass: 412.2147 Calc. mass: 411.2270 'H NMR (500 MHz, CDC13) 8 3.68 (m, 1 H) 3.90 (s, 3 H) 3.92 (s, 3 H) 4.34 (dt, J=12.02, 8.39 Hz, 1 H) 4.50 (m, 1 H) 6.48 (dd, J=8.30, 2.93 Hz, 1 H) 6.78 (d, J=1.71 Hz, 1 H) 6.81 (dd, J=8. 55, 1.71 Hz, 1 H) 6. 88 (d, J=8. 30 Hz, 1 H) 7.17 (d, J=6. 84 Hz, 1 H) 7.71 (d, J=2.69 Hz, 1 H) 8.74 (d, J=8.30 Hz, 1 H)
	With pyridine; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 20h;	Step One & Two. 6-Hydroxy-2,4-dioxo-N-(pyridazin-4-yl)- 1,2,3,4- tetrahydropyrimidine-5-carboxamide (M3): To a stirred solution of 4-nitrophenyl chloroforaiate (2.12 g, 10.5 mmol) in anhydrous THF (20 mL) was added a solution of compound Ml (1.00 g, 10.5 mmol) and pyridine (1.08 g, 13.7 mmol) in anhydrous THF (20 mL) and anhydrous DMF (5 mL) drop wise over 10 min at 0 C under nitrogen. After the addition was completed, the reaction mixture was slowly warmed to ambient temperature over 2 h and stirred at ambient temperature for 18 h to provide a solution of compound M2 in THF and DMF which was used directly in the subsequent step.

Reference： [1]Patent: WO2005/51381,2005,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2015/123003,2015,A1 .Location in patent: Paragraph 00179

11
[ 14161-11-6 ]
[ 20744-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide;palladium; In ethanol; ethyl acetate;	Step A: 4-Aminopyridazine A solution of 10.1 grams (0.055 mole) of 3,4,5-trichloropyridazine in 100 ml of absolute ethanol, in a 200 ml pressure bottle, is cooled to 0 C. and saturated with ammonia gas. The bottle is sealed and the reaction mixture stirred at ambient temperature for 4 days. The reaction mixture is purged with nitrogen for 2 hours, then filtered to remove ammonium chloride. The filter cake is washed with anhydrous ethanol. The filtrate and washes are placed in a Parr hydrogenation bottle and 5.2 grams (0.13 mole) of sodium hydroxide and 0.6 gram of 10% palladium on carbon are added. The volume of the mixture is brought to 200 ml with absolute ethanol. The mixture is hydrogenated for 4 hours using a Parr hydrogenator, during which time the theoretical amount of hydrogen is taken up. The hydrogenation bottle is purged with nitrogen and the reaction mixture filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure to a residue. The residue is dried under reduced pressure at ambient temperature for several hours. The residue is triturated with 250 ml of ethyl acetate, and the mixture allowed to stand for 7 days under anhydrous conditions. The mixture is filtered to collect a solid, which is dried under reduced pressure at 40 C. to yield 3.9 grams of 4-aminopyridazine. The nmr spectrum is consistent with the proposed structure.
	With sodium hydroxide;palladium on charcoal; In ethanol; ethyl acetate;	Step A: 4-Aminopyridazine A solution of 10.1 grams (0.055 mole) of 3,4,5-trichloropyridazine in 100 ml of absolute ethanol, in a 200 ml pressure bottle, was cooled to 0 C. and saturated with ammonia gas. The bottle was sealed and the reaction mixture stirred at ambient temperature for 4 days. The reaction mixture was purged with nitrogen for 2 hours then filtered to remove ammonium chloride. The filter cake was washed with anhydrous ethanol. The filtrate and washed were placed in a Parr hydrogenation bottle and 5.2 grams (0.13 mole) of sodium hydroxide and 0.6 gram of 10% palladium on charcoal were added. The volume of the mixture was brought to 200 ml with absolute ethanol. The mixture was hydrogenated for 4 hours using a Parr hydrogenator, during which time the theoretical amount of hydrogen was taken up. The hydrogenation bottle was purged with nitrogen and the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to a residue. The residue was dried under reduced pressure at ambient temperature for several hours. The residue was triturated with 250 ml of ethyl acetate, and the mixture allowed to stand for 7 days under anhydrous conditions. The mixture was filtered to collect a solid. The solid was dried under reduced pressure at 40 C. to give 3.9 grams of 4-aminopyridazine. The nmr spectrum was consistent with the proposed structure.
		A solution of 3,4,5-trichloropyridazine (470 mg, 2.56 mmol) in ethanol (30 ml) was cooled to 0C and saturated with ammonia gas and stirred at room temperature for 4 days. The reaction mixture was then purged with nitrogen for 2 h, and filtered to remove ammonium chloride. The filter cake was washed with anhydrous ethanol, the filtrate and washes were used directly in the next step.MS (electrospray): m/z [M+H]+ = 164, 165, 166, 167, 168, 69 4- Pyridazinamine (D11)A solution of 3,5-dichloro-4-pyridazinamine and 5,6-dichloro-4-pyridazinamine (may be prepared as described in Description 0; 419.8 mg, 2.56 mmol), sodium hydroxide (246 mg, 6.14 mmol) and Pd/C (136 mg, 0.128 mmol) in ethanol (20 ml) was hydrogenated overnight. The reaction mixture was purged with nitrogen and filtered. The filtrate was concentrated to a residue and triturated with ethyl acetate. The mixture was filtered again to collect a solid which was dried to yield the title compound as a yellow solid. 98 mg.MS (electrospray): m/z [M+H]+ = 96

Reference： [1]Patent: US4728355,1988,A
[2]Patent: US4735650,1988,A
[3]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 52

12
[ 280-57-9 ]
[ 20744-39-2 ]
[ 1795-48-8 ]
N-(4-pyridazinyl)-N'-(1-methylethyl)-urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; ethanol;	Step B: N-(4-pyridazinyl)-N'-(1-methylethyl)urea To a stirred solution of 2.3 grams (0.024 mole) of <strong>[20744-39-2]4-aminopyridazine</strong> (prepared as in Example 1, Step A) and 0.5 gram (0.004 mole) of 1,4-diazabicyclo[2.2.2]octane in 20 ml of dimethylformamide is added dropwise 3.3 ml (0.033 mole) of (1-methylethyl) isocyanate. Upon completion of addition the reaction mixture is stirred at ambient temperature for two days. The reaction mixture is concentrated under reduced pressure and the solid residue dried at 60-70 C. The solid is stirred with ethanol and collected by filtration to yield 1.9 grams of N-(4-pyridazinyl)-N'-(1-methylethyl)urea; m.p. 206-209 C. then 266-269 C. The nmr spectrum is cnsistent with the proposed structure.

Reference： [1]Patent: US4728355,1988,A

13
[ 20744-39-2 ]
[ 372-39-4 ]
[ 503-38-8 ]
N-(4-pyridazinyl)-N'-(3,5-difluorophenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; water;	Step B: N-(4-pyridazinyl)-N'-(3,5-difluorophenyl)urea To a stirred solution of 2.7 grams (0.021 mole) of 3,5-difluoroaniline in 100 ml of dioxane was added via syringe 1.5 ml (0.013 mole) of trichloromethyl chloroformate. The reaction mixture was heated under reflux for 18 hours, cooled to ambient temperature, and 2.0 grams (0.021 mole) of <strong>[20744-39-2]4-aminopyridazine</strong> and 7.01 ml (0.05 mole) of triethylamine were added. The reaction mixture was heated at 50 C. for one day, cooled to ambient temperature and filtered. The filter cake was washed with dioxane and dried. The solid was slurried in hot water for one hour. The mixture was filtered and the filter cake dried to give 4.1 grams of N-(4-pyridazinyl)-N'-(3,5-difluorophenyl)urea; m.p. 272-273 C. The nmr spectrum was consistent with the proposed structure.

Reference： [1]Patent: US4735650,1988,A

14
[ 20744-39-2 ]
[ 5469-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	palladium on charcoal; In sodium hydroxide; ethanol;	Step A: 3-Aminopyridazine This compound was prepared in a manner analogous to Example 2, Step A by the hydrogenation of 9.5 grams (0.073 mole) of commercially available 3-amino-6-chloropyridazine, in the presence of 3.7 grams (0.09 mole) of sodium hydroxide and 0.8 gram of 10% palladium on charcoal in ethanol. The yield of 3-aminopyridazine was 7.5 grams as a solid.

Reference： [1]Patent: US4735650,1988,A

Yield	Reaction Conditions	Operation in experiment
		A yield of 6.1 grams of solid product having a melting point of 255-262 C. was obtained. NMR confirmed the product to be 4-amino-5-chloro-1-[3,5-bis(trifluoromethyl)phenyl]-1,6-dihydro-6-oxopyridazine. To produce the desired final productproduct, 0.7 grams of the 4-amino pyridazine prepared above was partially dissolved in 15 milliliters of 1,2-dichloroethane and treated with 0.7 grams of 2-chlorobenzoyl isocyanate under a nitrogen atmosphere. The reaction mixture was stirred for about 16 hours at room temperature. The solvent was removed by evaporation and the residue was recrystallized from ethanol. A yield of 0.56 grams of solid product having a melting point of 187-194 C. was obtained. A nuclear magnetic resonance spectrum confirmed the structure of the product to be 1-(2-chlorobenzoyl)-3-[1-(3,5-bis(trifluoromethyl)-phenyl)-5-chloro-1,6-dihydro-6-oxopyridazin-4-yl]urea. Elemental analysis of the product gave the following results: Calc. for C20 H10 Cl2 F6 N4 O3 (Percent)--Theory: C, 44.55; H, 1.87; N, 10.39. Found: C, 44.32; H, 1.89; N, 10.50.

16
[ 20744-39-2 ]
[ 17341-93-4 ]
[ 887624-79-5 ]

Yield	Reaction Conditions	Operation in experiment
4.4%	With pyridine; In tetrahydrofuran; at 0℃; for 1.5h;	(2) 2,2,2-Trichloroethyl pyridazin-4-ylcarbamate; To a solution of <strong>[20744-39-2]pyridazine-4-amine</strong> (1.73 g, 18.2 mmol) and pyridine (4.41 ml, 54.6 mmol) in tetrahydrofuran (100 ml) was added 2,2,2-trichloroethyl chloroformate (3.76 ml, 27.3 mmol) was added, the mixture was stirred for 1.5 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (218 mg, 4.4%) as a solid. 1H-NMR (DMSO-d6) delta; 5.02 (2H, s), 7.78 - 7.81 (1H, m), 9.03 - 9.05 (1H, m), 9.25 - 9.27 (1H, m), 10.95 (1H, br s).

Reference： [1]Patent: EP1813606,2007,A1 .Location in patent: Page/Page column 84

17
[ 20744-39-2 ]
[ 1885-14-9 ]
[ 115136-48-6 ]

Yield	Reaction Conditions	Operation in experiment
41%	With pyridine; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 2.16667h;	To a suspension of <strong>[20744-39-2]4-aminopyridazine</strong> (1.00 g, 10.51 mmol) in a 1:1 mix of THF (10 mL) and acetonitrile (10 mL) at 0 C. was added pyridine (1.03 mL, 12.62 mmol), followed by the dropwise addition of phenyl chloroformate (1.58 mL, 12.62 mmol) over a period of 10 minutes. The reaction mixture was stirred for 2 h while warming to room temperature. The precipitate was isolated by filtration and dried for 1 h under high vacuum to provide the desired product as an off-white powder (0.923 g, 41%). LC-MS (ES, m/z): 216 [M+H]+; 1H-NMR (400 MHz, CDCl3): delta 11.00 (br. s., 1H), 9.25 (d, J=1.96 Hz, 1H), 9.03 (d, J=5.87 Hz, 1H), 7.76 (dd, J=5.87, 2.74 Hz, 1H), 7.38-7.51 (m, 2H), 7.19-7.35 (m, 3H) ppm.
37%	With pyridine; In tetrahydrofuran; acetonitrile; for 18h;	Example 25; Synthesis of N-(pyridazin-4-yl)-4-(3-[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide; Step 1; Phenyl pyridazin-4-ylcarbamate; A solution of <strong>[20744-39-2]4-aminopyridazine</strong> (2.5 g, 26.3 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (2.18, 27.6 mmol) was treated dropwise with phenylchloroformate (1.3 g, 27.6 mmol) in THF (10 mL). After stirring for 18 h, the resulting solid was collected and dried to provide the title compound (2 g, 37%).
	With triethylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice;	Under ice bath cooling, phenyl chloroformate (1.24 g, 7.89 mmol) was added to a solution of TDI01237-1 (500mg, 5.27 mmol) and triethylamine (1.06 g, 10.54 mmol) in dichloromethane (10 mL), and the reaction was performed atroom temperature for 2 h. LC-MS indicated the reaction was complete. The reaction was quenched by adding water (15mL), extracted with dichloromethane (30 mL), washed with saturated brine (15 mL), dried, and concentrated to affordTDI01237-2 (600 mg, crude product). MS m/z (ESI): 216.1 [M+H].

With triethylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice;

Under ice bath cooling, phenyl chloroformate (1.24 g, 7.89 mmol) was added to a solution of TDI01237-1 (500 mg, 5.27 mmol) and triethylamine (1.06 g, 10.54 mmol) in dichloromethane (10 mL), and the reaction was performed at room temperature for 2 h. LC-MS indicated the reaction was complete. The reaction was quenched by adding water (15 mL), extracted with dichloromethane (30 mL), washed with saturated brine (15 mL), dried, and concentrated to afford TDI01237-2 (600 mg, crude product). MS m/z (ESI): 216.1 [M+H].

Reference： [1]Patent: US2016/243100,2016,A1 .Location in patent: Paragraph 0104-0105
[2]Patent: US2008/261941,2008,A1 .Location in patent: Page/Page column 24-25
[3]Patent: EP3421465,2019,A1 .Location in patent: Paragraph 0258; 0259
[4]Patent: EP3421464,2019,A1 .Location in patent: Paragraph 0200; 0201

18
[ 20744-39-2 ]
[ 945104-02-9 ]
[ 945104-55-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 6h;	EXAMPLE 31R 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[2-(pyridazin-4-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dione To a solution of 0.872 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) of Example 7 in 25 mL of dioxane are successively added, under argon, 430 mg of <strong>[20744-39-2]4-aminopyridazine</strong>, 2.8 g of caesium carbonate, 156 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) [xantphos] and 50 mg of palladium diacetate. The reaction mixture is heated at 90 C. for 6 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluding with a mixture of dichloromethane and methanol (98/2 by volume) to give 55 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[2-(pyridazin-4-ylamino)pyridin-4-yl]-methyl}imidazolidine-2,4-dione, the characteristics of which are as follows: 1H NMR spectrum at 400 MHz: 1.32 (s, 9H); 1.42 (s, 6H); 4.60 (s, 2H); 6.98 (broad s, 1H); 7.01 (broad d, J=5.5 Hz, 1H); 7.36 (d, J=8.5 Hz, 2H); 7.53 (d, J=8.5 Hz, 2H); 8.13 (dd, J=3.0 and 6.5 Hz, 1H); 8.29 (d, J=5.5 Hz, 1H); 8.83 (d, J=6.5 Hz, 1H); 9.26 (d, J=3.0 Hz, 1H); 9.81 (s, 1H). Mass Spectrum (ES): m/z=443 [M-H]-; m/z=445 [M+H]+

Reference： [1]Patent: US2009/82379,2009,A1 .Location in patent: Page/Page column 55

19
[ 20744-39-2 ]
[ 945257-67-0 ]
C₂₂H₁₉F₃N₆O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 5h;Heating / reflux;	EXAMPLE 40J 1-[3-(azetidin-1-ylmethyl)cyclobutyl]-3-{4-[(5,5-dimethyl-2,4-dioxo-3-{4-[(trifluoromethyl)thio]phenyl}imidazolidin-1-yl)methyl]pyridin-2-yl}urea To a solution of 0.6 g of 1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethyl-3-{4-[(trifluoromethyl)thio]phenyl}imidazolidine-2,4-dione obtained in stage d) of Example 1 in 15 mL of dioxane are successively added, under argon, 0.2 g of <strong>[20744-39-2]4-aminopyridazine</strong>, 1.73 g of caesium carbonate, 97 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos) and 62 mg of palladium diacetate. The reaction mixture is refluxed for 5 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluding with a mixture of dichloromethane and methanol (98/2 by volume) to give 50 mg of 1-[3-(azetidin-1-ylmethyl)cyclobutyl]-3-{4-[(5,5-dimethyl-2,4-dioxo-3-{4-[(trifluoromethyl)thio]-phenyl}imidazolidin-1-yl)methyl]pyridin-2-yl}urea, the characteristics of which are as follows: 1H NMR spectrum at 400 MHz: 1.43 (s, 6H); 4.61 (s, 2H); 6.99 (broad s, 1H); 7.03 (dd, J=1.5 and 5.5 Hz, 1H); 7.69 (d, J=8.5 Hz, 2H); 7.88 (d, J=8.5 Hz, 2H); 8.12 (dd, J=2.0 and 6.0 Hz, 1H); 8.28 (d, J=5.5 Hz, 1H); 8.82 (d, J=6.0 Hz, 1H); 9.26 (d, J=2.0 Hz, 1H); 9.80 (s, 1H). Mass Spectrum (ES): m/z=489 [M+H]+ m/z=487 [M-H]-

Reference： [1]Patent: US2009/82329,2009,A1 .Location in patent: Page/Page column 46

20
[ 20744-39-2 ]
[ 1186234-64-9 ]
[ 1186234-44-5 ]

Yield	Reaction Conditions	Operation in experiment
16%		To a solution of <strong>[20744-39-2]Pyridazin-4-ylamin</strong>e (30 mg, 0.31 mmol, [Cas. No. 20744-39-2]) in DMF (3 mL) at 0C was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0C for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]- azetidine-1 -carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2 x 50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (15 mg, 16%) LCMS: {Method A) RT = 1.74 min; m/z = 366 [M+H]+.1H NMR: (400 MHz, CD3OD) delta 4.15-4.18 (m, 2H), 4.56-4.61 (m, 2H), 5.46-5.51 (m, 1H), 6.98 (d, 1 H, J 8.6), 7.19-7.29 (m, 2H), 7.37-7.42 (m, 1 H), 7.46-7.50 (m, 1H), 7.91-7.94 (m, 1H), 7.95-7.98 (m, 1H), 8.31 (bs, 1H), 8.87 (d, 1H, J 6.1 ), 9.26-9.28 (m, 1H).

Reference： [1]Patent: WO2009/109743,2009,A1 .Location in patent: Page/Page column 52

21
[ 20744-39-2 ]
[ 79-04-9 ]
[ 1196093-27-2 ]

Yield	Reaction Conditions	Operation in experiment
52.78%	With triethylamine; In dichloromethane; at 20℃; for 3h;	Compound TDI01238-1 (1 g, 10.526 mmol), chloroacetyl chloride (1.3 g, 11.504 mmol) and triethylamine (1.17g, 11.584 mmol) were dissolved in dichloromethane (10 mL), and the reaction was performed at room temperature for3 hours. LC-MS indicated the reaction was complete. Water (25 mL) and dichloromethane (30 mL) were added to thereaction solution, and precipitation occurred. The filter cake was obtained after filtration, washed with water and nhexane,and dried to afford compound TDI01238-2 (950 mg, brown solid, yield: 52.78%).1H NMR (400 MHz, DMSO-d6) delta 10.97 (s, 1H), 9.30 (dd, 1H), 9.07 (dd, 1H), 7.92 (dd, 1H), 4.37 (s, 2H). MS m/z (ESI):172.1 [M+H].
52.78%	With triethylamine; In dichloromethane; at 20℃; for 3h;	Compound TDI01238-1 (1 g, 10.526 mmol), chloroacetyl chloride (1.3 g, 11.504 mmol) and triethylamine (1.17 g, 11.584 mmol) were dissolved in dichloromethane (10 mL), and the reaction was performed at room temperature for 3 hours. LC-MS indicated the reaction was complete. Water (25 mL) and dichloromethane (30 mL) were added to the reaction solution, and precipitation occurred. The filter cake was obtained after filtration, washed with water and n-hexane, and dried to afford compound TDI01238-2 (950 mg, brown solid, yield: 52.78%). 1H NMR (400 MHz, DMSO-d6) delta 10.97 (s, 1H), 9.30 (dd, 1H), 9.07 (dd, 1H), 7.92 (dd, 1H), 4.37 (s, 2H). MS m/z (ESI): 172.1 [M+H].
48%	With triethylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice; Inert atmosphere;	a) 2-Chloro-N-pyridazin-4-yl-acetamide A solution of <strong>[20744-39-2]pyridazin-4-ylamine</strong> (1.0 g) in dry dichloromethane (10 mL) under nitrogen was cooled to 0 C. in an ice bath. Triethylamine (1.6 mL) was added, followed by slow addition of chloroacetyl chloride (0.92 mL). On completion of the addition the ice bath was removed and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25 mL) and dichloromethane (30 mL) A solid was filtered off and washed with pentane, water and more pentane to give the sub-titled compound (0.87 g, 48%) as a brown solid. 1H NMR (400 MHz, DMSO-D6): delta 11.17 (s, 1H), 9.33 (dd, 1H), 9.07 (dd, 1H), 7.94 (dd, 1H), 4.39 (s, 2H).

48%

With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;

Example 27: (R)-3-(l-phenyl-cycloheptanecarbonyIoxy)-l-(pyridazin-4- ylcarbamoylmethy I)- 1 -azonia-bicyclo[2.2.2]octane formatea) 2-Chloro-yV-pyridazin-4-yl-acetamide <n="76"/>A solution of [20744-39-2]pyridazin-4-ylamine (1.0 g) in dry dichloromethane (10 niL) under nitre was cooled to 00C in an ice bath. Triethylamine (1.6 mL) was added, followed by slo addition of chloroacetyl chloride (0.92 mL). On completion of the addition the ice bat removed and the reaction mixture was allowed to reach room temperature and stirred hours. The reaction mixture was diluted with water (25 mL) and dichloromethane (30 A solid was filtered off and washed with pentane, water and more pentane to give the titled compound (0.87g, 48%) as a brown solid.1H NMR (400 MHz, DMSO-D6): delta 1 1.17 (s, IH), 9.33 (dd, IH), 9.07 (dd, IH), 7.94 IH), 4.39 (s, 2H).

Reference： [1]Patent: EP3421465,2019,A1 .Location in patent: Paragraph 0251; 0252
[2]Patent: EP3421464,2019,A1 .Location in patent: Paragraph 0193; 0194
[3]Patent: US2011/172237,2011,A1 .Location in patent: Page/Page column 28
[4]Patent: WO2009/138707,2009,A1 .Location in patent: Page/Page column 74-75

22
[ 20744-39-2 ]
5-methyl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-4-carbonyl chloride [ No CAS ]
[ 1219837-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	With polymerbound diisopropyl ethyl amine (PL-DIPAM resin); In dichloromethane; at 22℃;	800 mg (3.9 mmol) of 5-methyl-1-(2,2,2-trifluoro-ethyl)-1 H-pyrazole-4-carboxylic acid were suspended in 8 mL of toluene and two drops of dimethylformamide were added to the mixture. 0.42 mL of thionylchloride (5.8 mmol) were added at 65 0C to the reaction mixture and stirring was continued at this temperature for four hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained material was then dissolved in 2 mL of dichloromethane and the solution was added dropwise to a solution containing 309 mg (3.25 mmol) of <strong>[20744-39-2]4-aminopyridazine</strong>, 2.0 g (6.5 mmol) polymerbound diisopropyl ethyl amine (PL-DIPAM resin, Polymer Laboratories) in 16 mL dichloromethane.The mixture was agitated for 16 h at 22C. Then, the polymer was removed by filtration and washed with a mixture of dichloromethane / methanol (1 :1 ). The solution that was obtained after washing contained 662 mg (59 %) 5-methyl-1 -(2,2,2- trifluoro-ethyl)-1 H-pyrazole-4-carboxylic acid pyridazin-4-ylamide as a colorless solid which did not need further purification.

Reference： [1]Patent: WO2010/34737,2010,A1 .Location in patent: Page/Page column 132

23
[ 20744-39-2 ]
C₁₈H₂₀N₆O₃ [ No CAS ]
[ 1197165-79-9 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 2636 - 2645

24
[ 20744-39-2 ]
[ 32315-10-9 ]
C₁₉H₂₄N₆O₂ [ No CAS ]
C₂₄H₂₇N₉O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5869 - 5873

25
[ 20744-39-2 ]
[ 31301-45-8 ]
[ 1261078-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With polymerbound diisopropyl ethyl amine (PL-DIPAM resin); In dichloromethane; at 20℃; for 16h;	600 mg (4.3 mmol) 3,5-dimethyl-isoxazole-4-carboxylic acid were suspended in 5 ml. of toluene and two drops of dimethylformamide were added to the mixture. 0.39 ml. of thionylchloride (5.3 mmol) were added at room temperature and the reaction mixture was stirred at 65 0C for three hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained residue was then dissolved in 5 ml. of dichloromethane and the solution was added dropwise to a solution containing 367 mg pyridazin-4-yl-amine (3.8 mmol) and 1.6 g (5.2 mmol) poly- merbound diisopropyl ethyl amine (PL-DIPAM resin, Polymer Laboratories) in 16 mL dichloromethane. The mixture was stirred for 16 h at room temperature. Then, the polymer was removed by filtration and washed with methanol. The solution that was obtained after washing contained 600 mg (58%, 90% purity) of the title compound which did not need further purification.

Reference： [1]Patent: WO2011/3793,2011,A1 .Location in patent: Page/Page column 89

26
[ 20744-39-2 ]
C₉H₁₁ClN₂O₃ [ No CAS ]
[ 1261078-95-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 16h;	600 mg (2.8 mmol) of S-tert-Butylcarbamoyl-isoxazole^-carboxylic acid were suspended in 20 ml. of toluene and two drops of dimethylformamide were added to the mixture. 0.26 ml. of thionylchloride (3.5 mmol) were added at room temperature and the reaction mixture was stirred at 65 0C for two hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained resi- due was then dissolved in 10 ml. of dichloromethane and the solution was added dropwise to a solution containing 247 mg <strong>[20744-39-2]pyridazin-4-ylamine</strong> (2.6 mmol) and 0.43 ml triethyl amine (3.1 mmol) in 40 ml dichloromethane. The mixture was stirred at room temperature for 16 h and the solvent was removed under vaccum. The obtained residue was purified by flash column chromatography (silica, gradient elution cyclohexane? ethyl acetate? methanol) to give 275 mg (32%, 95% purity) of the title compound.

Reference： [1]Patent: WO2011/3793,2011,A1 .Location in patent: Page/Page column 88

27
[ 20744-39-2 ]
C₇H₆ClNO₂ [ No CAS ]
[ 1261078-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 16h;	400 mg (2.6 mmol) of 3-cyclopropyl-isoxazole-4-carboxylic acid were suspended in 10 ml. of toluene and one drop of dimethylformamide was added to the mixture. 0.24 ml. of thionylchloride (3.3 mmol) were added at room temperature and the re- action mixture was stirred at 65 0C for two hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained residue was then dissolved in 5 ml. of dichloromethane and the solution was added dropwise to a solution containing 248 mg pyridazin-4-yl-amine (2.6 mmol) and 0.45 ml triethyl amine (3.3 mmol) in 5 ml dichloromethane. The mixture was stirred at room temperature for 16 h and the solvent was removed under vaccum. The obtained brown oil was purified by flash column chromatography (silica, gradient elution cyclohex- ane? ethyl acetate? methanol) and the solvent was removed under vaccum. The residue was dissolved in dichloromethane, wahed with water, dried over sodium sulfate, filtered and the solvent was removed to give 230 mg (29%, 95% purity) of the title compound.

Reference： [1]Patent: WO2011/3793,2011,A1 .Location in patent: Page/Page column 87

28
[ 20744-39-2 ]
[ 62176-31-2 ]
[ 1285513-38-3 ]

Yield	Reaction Conditions	Operation in experiment
38%		To a suspension of CDI (106 mg, 0.651 mmol) in THF (10 mL) under nitrogen at roomtemperature was added 11g (200 mg, 0.651mmol). The reaction was stirred at room temperaturefor 10 min and <strong>[20744-39-2]4-pyridazinamine</strong> (61.9 mg, 0.651 mmol) was added dropwise. After refluxed for14 hrs, the mixture was concentrated and water was added. The mixture was then extracted withEtOAc (50 mL*3). The combined organic phases were washed with brine, dried over Na2SO4 andconcentrated. The crude product was then washed with MeOH to give the title compound 7a (95mg, 38%) as a white solid.
		Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) in THF (10 ml) under nitrogen at 20C. The reaction mixture was stirred at room temperature for 10 min and <strong>[20744-39-2]4-pyridazinamine</strong> (may be prepared as described in Description 11 ; 61.9 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate (3 x 50 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo. The residue was washed with methanol to yield the title compound as a white solid. 95 mg. MS (electrospray): m/z [M+Hf =384H NMR (DMSO-d6): 5.29 (2H, s), 7.32-7.40 (4H, m), 7.52 (1 H, s), 7.53 (1 H, s), 7.76 (1 H, dd, J=2.8 Hz, J=9.2 Hz), 7.83 (1 H, d, J=2.8 Hz), 8.05 ( H, dd, J=2.4 Hz, J=6 Hz), 9.1 1 (1 H, d, J=6 Hz), 9.30 (1 H, d, J=2.4 Hz), 10.90 (1 H, s)
		To a solution of 10b in DCM (20 mL) was added several drops of DMF, then oxalyl dichloride (1.653 mL, 19.54 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hr. Solvent was removed and the residue was re-dissolved in DCM (20 mL), then pyridine (1.580 mL, 19.54 mmol) was added. The mixture was cooled to 0 oC and <strong>[20744-39-2]pyridazin-4-amine</strong> (0.975 g, 10.26 mmol) was added in several portions. The reaction was warmed to room temperature and stirred for further 2 hrs. The mixture was concentrated in vacuum and the crude was purified by flash column chromatography on silica gel (0~6% methanol in DCM) to give the title compound (2.45 g, 65.3 % yield). LCMS: 384, 386 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4034 - 4038
[2]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 88
[3]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 212 - 215

29
[ 20744-39-2 ]
[ 938243-43-7 ]
[ 1285514-69-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;	Diisopropylethylamine (1.61 ml, 9.23 mmol), <strong>[20744-39-2]4-pyridazinamine</strong> (0.53 g, 5.54 mmol) and HATU (2.63 g, 6.92 mmol) were added to a solution of 5-bromo-2-[(4- fluoropheny.)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 1.5 g, 4.61 mmol) in Nu,Nu-dimethylformamide (10 ml). The mixture was stirred for 2 hours and the solid was filtered and washed with ethyl acetate to yield the title compound as a white solid. 658 mg.MS (electrospray): m/z [M+H]+ = 402/404 N R (DMSO-ofe): 5.21 (2 H, s), 7.10 - 7.24 (2 H, m), 7.27 (1 H, d, J=8.99 Hz), 7.53 (2 H, dd, J=8.66, 5.59 Hz), 7.67 - 7.82 (2 H, m), 8.00 (1 H, dd, J=5.92, 2.85 Hz), 9.07 (1 H, d, J=5.92 Hz), 9.25 (1 H, d, J=1.75 Hz), 10.85 (1 H, s)

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 137; 138

30
[ 20744-39-2 ]
[ 1285517-09-0 ]
[ 1285514-70-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	4-Pyridazinamine (0.42 g, 4.37 mmol), HATU (2.22 g, 5.83 mmol) anddiisopropylethylamine (1.53 ml, 8,74 mmol) were added to a solution of 5-bromo-2-[(3,4- difluorophenyl)methyl]oxy}benzoic acid (may be prepared by Description 89; 1g, 2,91 mmol) in Nu,Nu-dimethylformamide (25 ml). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), shaken and allowed to stand for 5 min. The precipitate was filtered, washed with water (25 ml) and ethyl acetate (50 ml), and dried under vacuum to yield the title compound as a white solid. No further purification was carried out. 900 mg.MS (electrospray): m/z [M+H]+ = 421

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 138; 139

31
[ 20744-39-2 ]
[ 1285517-25-0 ]
[ 1285514-73-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethylmorpholine;; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	EDC (0.79 g, 4. 1 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 mL, 6.84 mmol) and <strong>[20744-39-2]4-pyridazinamine</strong> (0.49 g, 5.13 mmol) were added to a solution of 2-[(3,4- difluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 101 ; 1 g, 3.42 mmol) in N, N -d i methy If orm amide (DMF; 25 ml) and the mixture was stirred at room temperature. The DMF was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml) and the organic layer washed with saturated sodium hydrogencarbonate (2 x 50 ml) and water (2 x 50 ml). The organic layer was dried (MgS04), filtered and evaporated under reduced pressure to yield the title compound as a dark yellow solid. 0.98 g.MS (electrospray): m/z [M+Hf = 370

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 139

32
[ 20744-39-2 ]
[ 1285517-32-9 ]
[ 1285514-82-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethylmorpholine;; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4h;	4-Pyridazinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2-[(4- fluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 05; 1 g, 3.65 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hrs. The Nu,Nu-dimethylformamide was evaporated under reduced pressure on a buchi. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 mins. The organics were separated and washed with water (50 ml), dried (MgS04) and evaporated under reduced pressure to yield the title compound as a pale yellow solid. No further purification. No further purification carried out. 0.98 g.MS (electrospray): m/z [M+H]+ = 352

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 142; 143

33
[ 20744-39-2 ]
[ 1285517-46-5 ]
[ 1285515-82-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 3h;	To a solution of 2-[(4-fiuorophenyl)methyl]oxy}-5-{1-[2-(4-rnorpholinyl)ethyl]-1H-pyrazol- 4-yl}benzoic acid {may be prepared as described in Description 114; 220 mg, 0.52 mmol) in N,N-dimethylformamide (10 ml) was added diisopropylethylamine (0.18 ml, 1.03 mmol), 1-hydroxy-7-azabenzotriazole (84 mg, 0.62 mmol), <strong>[20744-39-2]4-pyridazinamine</strong> (59.0 mg, 0.62 mmol) and EDC (149 mg, 0.78 mmol). The solution was stirred for 3 hours, then Nu,Nu-dimethylformamide was removed in vacuo and redissolved in ethyl acetate ( 0ml). The solution was washed with water (3 x 10 ml), dried (MgS04) and the solvent removed in vacuo. Trituration with 1 :1 methanol/dimethyl sulfoxide gave the product as a brown solid (12mg, 5% yield). The filtrate was purified by DAP to give a brown solid which was partitioned between NaHC03 solution (5ml) and ethyl acetate (10 ml). The organic layer was dried (MgS04) and the solvent removed in vacuo to give an oil which was lyophilised to give a white solid. This was combined with the previous crop to to yield the title compound as a white solid. 27 mg.MS (electrospray): m/z [M+H]+ 503H NMR (DMSO-d6): 2.33 - 2.44 (4 H, m), 2.73 (2 H, t, J=6.65 Hz), 3.49 - 3.63 (4 H, m), 4.23 (2 H, t, J=6.53 Hz), 5.23 (2 H, s), 7.12 - 7.26 (2 H, m), 7.30 (1 H, d, .7=8,78 Hz), 7.55 (2 H, dd, J=8.41 , 5.65 Hz), 7.74 (1 H, dd, J=8.66, 2.38 Hz), 7.81 (1 H, d, J=2.26 Hz), 7.88 (1 H, s), 8.02 (1 H, dd, J=5.77, 2.76 Hz), 8.21 (1 H, s), 9.06 (1 H, d, J=5.77 Hz), 9.27 (1 H, d, J=2.01 Hz), 10.80 (1 H, s).

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 189; 190

34
[ 20744-39-2 ]
[ 1285517-55-6 ]
[ 1285515-73-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 70℃;	4-Pyridazinamine (60.5 mg, 0.64 mmol), EDC (122 mg, 0.64 mmol), HOBT (63.4 mg, 0.41 mmol) and diisopropylethylamine (0.11 ml, 0.64 mmol) were added to a solution of 2-[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 119; 100 mg, 0.32 mmol) in N,N-dimethylformamide (20 ml) and the mixture was stirred at room temperature overnight. The mixture was then heated to 70C overnight (NOTE: it would be better to prepare the acid chloride and react this with the amine). The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The organics were combined, evaporated under reduced pressure on a buchi and the residue was purifed using an MDAP to yield the title compound.70 mg. MS (electrospray): m/z [ +H]+ = 392H N R (400 MHz, METHANOL-^) delta ppm 5.34 (2 H, s) 7.15 (2 H, t, J=8.78 Hz) 7.48 (1 H, d, J=8.78 Hz) 7.57 (2 H, dd, J=8.53, 5.52 Hz) 7.80 - 7.93 (1 H, m) 8.08 (1 H, dd, J=5.90, 2.64 Hz) 8.15 (1 H, d, J=2.01 Hz) 8.92 - 9.05 (2 H, m)

Reference： [1]Patent: WO2011/38572,2011,A1 .Location in patent: Page/Page column 185; 186

35
[ 20744-39-2 ]
[ 88-14-2 ]
[ 1335099-49-4 ]

Yield	Reaction Conditions	Operation in experiment
54%		Furan-2-carboxylic acid pyridazin-4-ylamide (example 11.31 )2.00 g (17.8 mmol) of furan-2-carboxylic acid were suspended in 25 ml. of toluene and one drop of dimethylformamide was added to the mixture. 1 .95 ml of thionylchlo- ride (26.8 mmol) were added at room temperature and the reaction mixture was stirred at 80 C for two hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained residue was then dissolved in 5 ml of dichloro- methane and the solution was added dropwise to a solution containing 1 .70 g of pyri- dazin-4-yl-amine (17.8 mmol) and 2.73 ml of triethyl amine (19.6 mmol) in 20 ml of di- chloromethane. The mixture was stirred at room temperature for 2 days and washed twice with water. The organic layer was dried over Na2S04, filtered and the solvent was removed under vaccum to give the title compound as a brown solid (1 .9 g, 54%, 95% purity). HPLC-MS: r.t. 1 .146 minutes, m/z [M+H+]189.9

Reference： [1]Patent: WO2011/117198,2011,A2 .Location in patent: Page/Page column 76

36
[ 20744-39-2 ]
[ 1362820-69-6 ]
[ 1362818-47-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 3h;	Example 344-(4-Morpholinylmethyl)-2-[(phenylmethyl)oxy]- V-4-pyridazinyl-5- (trifluoromethyl)benzamide (E34)To a solution of 4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 50; 120 mg, 0.30 mmol) in N,N- dimethylformamide (5 ml) was added diisopropylethylamine (0.11 ml, 0.61 mmol), 4- pyridazinamine (43.3 mg, 0.46 mmol), 1-hydroxy-7-azabenzotriazole (53.7 mg, 0.40 mmol) and EDC (1 16 mg, 0.61 mmol). The reaction was stirred for 3 hours and the solvent was removed in vacuo to give yellow oil. Purification by MDAP gave the title compound as a white solid. 72 mg.MS (electrospray): m/z [M+H]+ 4731 H NMR (DMSO-d6): 2.27 - 2.42 (4 H, m), 3.51 - 3.61 (4 H, m), 3.63 (2 H, s), 5.38 (2 H, s), 7.26 - 7.42 (3 H, m), 7.51 (2 H, d, J=6.78 Hz), 7.62 (1 H, s), 7.94 (1 H, s), 8.03 (1 H, dd, J=5.90, 2.64 Hz), 9.08 (1 H, d, J=5.77 Hz), 9.28 (1 H, d, J=2.01 Hz), 10.85 (1 H, s).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 70-71

37
[ 20744-39-2 ]
[ 1362820-78-7 ]
[ 1362818-53-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 18h;	Example 362-[(Phenylmethyl)oxy]-4-(1 -piperidinylmethyl)- V-4-pyridazinyl-5- (trifluoromethyl)benzamide (E36) To a solution of 2-[(phenylmethyl)oxy]-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 53; 112 mg, 0.29 mmol) in N,N- dimethylformamide (5 ml) was added diisopropylethylamine (0.10 ml, 0.57 mmol), 4- pyridazinamine (40.6 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (50.4 mg, 0.37 mmol) and EDC (109 mg, 0.57 mmol). The reaction was stirred for 18 hours, then the solvent removed in vacuo to give a yellow oil. Purification by MDAP gave the title compound as a white solid. 66 mg.MS (electrospray): m/z [M+H]+ 4711 H NMR (DMSO-d6): 1.29 - 1.60 (6 H, m), 2.23 - 2.41 (5 H, m), 3.50 - 3.70 (2 H, m), 5.36 (2 H, s), 7.18 - 7.44 (3 H, m), 7.46 - 7.57 (2 H, m), 7.64 (1 H, s), 7.93 (1 H, s), 8.02 (1 H, dd, J=5.90, 2.64 Hz), 9.08 (1 H, d, J=5.77 Hz), 9.27 (1 H, d, J=2.51 Hz), 10.84 (1 H, s).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 71-72

38
[ 20744-39-2 ]
[ 1362820-92-5 ]
[ 1362818-65-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 1.5h;	Example 402-[(Phenylmethyl)oxy]-4-(1 -piperidinylcarbonyl)- V-4-pyridazinyl-5- (trifluoromethyl)benzamide (E40)2-[(Phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 58; 70 mg, 0.17 mmol) was dissolved in N,N- dimethylformamide (4 ml). Diisopropylethylamine (0.06 ml, 0.34 mmol) and HATU (131 mg, 0.34 mmol) were added. The mixture was stirred for 5 minutes then <strong>[20744-39-2]4-pyridazinamine</strong> (32.7 mg, 0.34 mmol) was added. The solution was stirred for 90 minutes. The solvent was removed in vacuo and the residue purified by MDAP to give the title compound as a white solid. 30 mg. MS (electrospray): m/z [M+H]+ 4851 H NMR (DMSO-de): 1.20 - 1.72 (6 H, m), 2.97 - 3.10 (2 H, m), 3.45 - 3.73 (2 H, m), 5.36 (2 H, s), 7.23 - 7.43 (5 H, m), 7.48 (2 H, d, J=6.78 Hz), 7.91 - 8.10 (2 H, m), 9.08 (1 H, d, J=5.77 Hz), 9.27 (1 H, d, J=1.76 Hz), 10.94 (1 H, br. s.).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 74-75

39
[ 20744-39-2 ]
[ 1362821-12-2 ]
[ 1362818-70-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 18h;	Example 425-Chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]- V-4- pyridazinylbenzamide (E42)To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2- [(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and <strong>[20744-39-2]4-pyridazinamine</strong> (26.0 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 68 mg.MS (electrospray): m/z [M+H]+ 4731 H NMR (DMSO-d6): 2.40 - 2.60 (2 H, m), 3.37 - 3.43 (1 H, m), 3.52 - 3.67 (1 H, m), 3.75 (1 H, t, J=7.53 Hz), 3.93 (1 H, t, J=13.05 Hz), 5.27 (2 H, s), 7.29 - 7.45 (5 H, m), 7.47 (1 H, s), 7.78 (1 H, d, J=3.01 Hz), 8.01 (1 H, dd, J=5.77, 2.51 Hz), 9.08 (1 H, d, J=5.77 Hz), 9.26 (1 H, d, J=1.51 Hz), 10.92 (1 H, br. s.).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 75-76

40
[ 20744-39-2 ]
[ 1362821-19-9 ]
[ 1362818-83-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;	Example 465-Chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]-W-4-pyridazinylbenzamideTo a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and <strong>[20744-39-2]4-aminopyridazine</strong> (26.8 mg, 0.29 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo. The residue was purified by column chromatography (Si02, Isolute, 1 : 1 ethyl acetate/cyclohexane) to give the title compound as a white solid. 71 mg. MS (electrospray): m/z [M+H]+ 4531 H NMR (DMSO-de): 3.13 (2 H, t, J=4.77 Hz), 3.51 - 3.59 (2 H, m), 3.62 - 3.73 (4 H, m), 5.25 (2 H, d, J=4.02 Hz), 7.27 - 7.41 (4 H, m), 7.42 - 7.52 (2 H, m), 7.74 (1 H, s), 8.00 (1 H, dd, J=5.77, 2.76 Hz), 9.07 (1 H, d, J=5.77 Hz), 9.24 (1 H, d, J=1.76 Hz).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 78

41
[ 20744-39-2 ]
[ 1362820-01-6 ]
[ 1362818-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 2h;	Example 27 2-[(4-Fluorophenyl)methyl]oxy}-5-(1 -methyl-1 H-pyrazol-4-yl)-4-(4- morpholinylcarbonyl)-/V-4-pyridazinylbenzamide (E27)To a solution of 2-[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1 H-pyrazol-4-yl)-4-(4- morpholinylcarbonyl)benzoic acid (may be prepared as described in Description 29; 95 mg, 0.22 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.43 mmol), <strong>[20744-39-2]4-pyridazinamine</strong> (24.67 mg, 0.26 mmol), 1-hydroxy-7-azabenzotriazole (35.3 mg, 0.26 mmol) and EDC (62.2 mg, 0.32 mmol). The mixture was stirred for 2 hours, the solvent removed in vacuo and the residue was purified by MDAP to yield the title compound as a white solid. 50 mg.MS (electrospray): m/z, [M+H]+ = 5171 H NMR (400 MHz, DMSO-d6); 2.73 - 3.11 (3 H, m), 3.46 - 3.76 (5 H, m), 3.90 (3 H, s), 5.14 - 5.35 (2 H, m), 7.1 1 - 7.28 (3 H, m), 7.47 - 7.64 (3 H, m), 7.75 (1 H, s), 7.85 (1 H, s), 8.02 (1 H, dd, J=5.90, 2.64 Hz), 9.07 (1 H, d, J=5.77 Hz), 9.28 (1 H, d, J=2.01 Hz), 10.84 (1 H, s).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 64-65

42
[ 20744-39-2 ]
C₂₃H₂₄FN₃O₄ [ No CAS ]
[ 1362817-99-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 3h;	Example 142-[(4-Fluorophenyl)methyl]oxy}-4-(1 -methyl-1 H-pyrazol-4-yl)-5-(4-morpholinylmethyl)-To a solution of methyl 2-[(4-fluorophenyl)methyl]oxy}-4-(1-methyl-1 H-pyrazol-4-yl)-5-(4- morpholinylmethyl)benzoate (may be prepared as described in Description 18; 144 mg, 0.33 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (23.54 mg, 0.98 mmol) and water (1 ml). The mixture was stirred at room temperature for 18 hours then neutralised with 2M hydrochloric acid (0.79 ml, 1.59 mmol). The solvent was removed in vacuo and the residue redissolved in N,N-dimethylformamide (4 ml). Diisopropylethylamine (0.11 m, 0.66 mmol), <strong>[20744-39-2]4-pyridazinamine</strong> (40.5 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (53.5 mg, 0.39 mmol) and EDC (94 mg, 0.49 mmol) were added and the solution was stirred for 3 hours. The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 57 mg.MS (electrospray): m/z, [M+H]+ = 5031 H NMR (400 MHz, DMSO-d6); 2.34 - 2.46 (4 H, m), 3.43 - 3.49 (2 H, m), 3.59 (4 H, t, J=4.14 Hz), 3.92 (3 H, s), 5.30 (2 H, s), 7.21 (2 H, t, J=8.91 Hz), 7.33 (1 H, s), 7.60 (2 H, dd, J=8.66, 5.65 Hz), 7.70 (1 H, s), 7.87 (1 H, s), 7.99 (1 H, dd, J=5.77, 2.76 Hz), 8.14 (1 H, s), 9.05 (1 H, d, J=5.77 Hz), 9.16 (1 H, d, J=1.76 Hz), 10.61 (1 H, s).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 56

43
[ 20744-39-2 ]
C₂₃H₂₂FN₃O₅ [ No CAS ]
[ 1362818-32-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example 292-[(4-Fluorophenyl)methyl]oxy}-4-(1 -methyl-1 H-pyrazol-4-yl)-5-(4- morpholinylcarbonyl)-/V-4-pyridazinylbenzamide (E29) To a solution of (4-fluorophenyl)methyl 2-[(4-fluorophenyl)methyl]oxy}-4-(1-methyl-1 H- pyrazol-4-yl)-5-(4-morpholinylcarbonyl)benzoate (may be prepared as described inDescription 32; 191 mg, 0.35 mmol) in tetrahydrofuran (6 ml) was added lithium hydroxide (60 mg, 2.51 mmol) and water (1.5 ml). The mixture was stirred for 3 hours then quenched with 2M hydrochloric acid (1.26 ml, 2.51 mmol). The solvent was removed in vacuo and the residue was redissolved in N,N-dimethylformamide (6 ml) and diisopropylethylamine (0.12 ml, 0.70 mmol), <strong>[20744-39-2]4-pyridazinamine</strong> (39.8 mg, 0.42 mmol), 1-hydroxy-7-azabenzotriazole (57.0 mg, 0.42 mmol) and EDC (100 mg, 0.52 mmol) were added. The reaction was stirred for 18 hours then the solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 64 mg.MS (electrospray): m/z, [M+H]+ = 5171 H NMR (400 MHz, DMSO-d6); 2.74 - 3.13 (3 H, m), 3.35 - 3.75 (5 H, m), 3.86 - 3.96 (3 H, m), 5.33 (2 H, s), 7.15 - 7.29 (2 H, m), 7.43 (1 H, s), 7.50 - 7.66 (3 H, m), 7.74 (1 H, s), 7.94 - 8.07 (2 H, m), 8.95 - 9.10 (1 H, m), 9.20 (1 H, d, J=1.76 Hz), 10.69 (1 H, s).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 66-67

44
[ 20744-39-2 ]
C₂₀H₁₈F₃NO₅ [ No CAS ]
[ 1362818-59-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 384- (4-Morpholinylcarbonyl)-2-[(phenylmethyl)oxy]- V-4-pyridazinyl-5- (trifluoromethyl)benzamide (E38)To a solution of phenylmethyl 4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]-5- (trifluoromethyl)benzoate (may be prepared as described in Description 56; 80 mg, 0.16 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (1 1.51 mg, 0.48 mmol) and water (1 ml). The mixture was heated at 45C for one hour, cooled and 2M hydrochloric acid (0.24 ml, 0.48 mmol) was added. The solvent was removed in vacuo to give a residue. The residue was redissolved in N, N-dimethylformamide (4 ml) and diisopropylethylamine (0.06 ml, 0.32 mmol), <strong>[20744-39-2]4-pyridazinamine</strong> (19.80 mg, 0.21 mmol), 1 -hydroxy- 7-azabenzotriazole (28.3 mg, 0.21 mmol) and EDC (55.3 mg, 0.29 mmol) were added. The mixture was stirred for 72 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer separated and washed further with water (10 ml), dried (MgS04) and the solvent removed in vacuo to give a gum. Purification by MDAP gave the title compound as a white solid. 30 mg. MS (electrospray): m/z [M+H]+ 4871 H NMR (DMSO-d6): 2.96 - 3.16 (2 H, m), 3.37 - 3.80 (6 H, m), 5.25 - 5.44 (2 H, m), 7.27 - 7.41 (3 H, m), 7.41 - 7.51 (3 H, m), 7.93 - 8.08 (2 H, m), 9.09 (1 H, d, J=6.02 Hz), 9.27 (1 H, d, J=1.76 Hz), 10.95 (1 H, s).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 73

45
[ 20744-39-2 ]
[ 1362819-32-6 ]
[ 1362817-71-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Example 1 5-Bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (E1)Diisopropylethylamine (0.08 ml, 0.47 mmol), HOBT (43.0 mg, 0.28 mmol),<strong>[20744-39-2]4-pyridazinamine</strong> (33.4 mg, 0.35 mmol) and EDC (90 mg, 0.47 mmol) were added to a solution of 5-bromo-4- (4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 7; 95 mg, 0.23 mmol) in N,N-dimethylformamide (5 ml). The mixture was stirred overnight, the solvent removed in vacuo and the solid recrystallised with 1 : 1methanol/DMSO to give the title compound as a white solid. 56.1 mg.MS (electrospray): m/z [M+H]+ 483/4851 H NMR (DMSO-de): 2.29 - 2.43 (4 H, m), 3.50 - 3.63 (6 H, m), 5.30 (2 H, s), 7.24 - 7.40 (4 H, m), 7.49 (2 H, d, J=6.80 Hz), 7.83 (1 H, s), 8.02 (1 H, dd, J=5.92, 2.63 Hz), 9.07 (1 H, dd, J=5.92, 0.88 Hz), 9.19 - 9.30 (1 H, m) 10.82 (1 H, s)

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 48

46
[ 20744-39-2 ]
[ 1362819-39-3 ]
[ 1362817-80-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;	Example 55-Bromo-4-methyl-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (E5)4-Pyridazinamine (207 mg, 2.18 mmol), diisopropylethylamine (0.52 ml, 2.97 mmol) and HATU (904 mg, 2.38 mmol) were added to a solution of 5-bromo-4-methyl-2- [(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 636 mg, 1.98 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours, after 10 minutes a solid had crashed out of solution. The solid was filtered and washed with ethyl acetate (10 ml) to yield the title compound. 475 mg. MS (electrospray): m/z [M+H]+ 398/4001 H NMR (DMSO-d6): 2.42 (3 H, s), 5.25 (2 H, s), 7.28 - 7.43 (4 H, m), 7.51 (2 H, dd, J=7.78, 1.43 Hz), 7.82 (1 H, s), 7.99 (1 H, dd, J=5.92, 2.85 Hz), 9.05 (1 H, dd, J=5.92, 0.88 Hz), 9.13 - 9.23 (1 H, m), 10.72 (1 H, s)

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 50-51

47
[ 20744-39-2 ]
[ 1362819-47-3 ]
[ 1362817-90-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;	Example 104- Bromo-5-methyl-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (E10)4- Aminopyridazine (53.3 mg, 0.56 mmol), diisopropylethylamine (0.16 ml, 0.93 mmol) and HATU (266 mg, 0.70 mmol) were added to a solution of 4-bromo-5-methyl-2- [(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 12; 150 mg, 0.47 mmol) in N,N-dimethylformamide (3 ml). The mixture was stirred overnight. The solid was filtered and washed with water (2 ml) and methanol (3 ml) to give the product as a white solid (80 mg). A 2nd crop was obtained (33 mg). The crops were combined to yield the title compound as a white solid. 113 mg.MS (electrospray): m/z [M+H]+ 398/4001 H NMR (DMSO-de): 2.34 (3 H, s), 5.25 (2 H, s), 7.25 - 7.41 (3 H, m), 7.48 (2 H, dd, J=7.67, 1.53 Hz), 7.57 (1 H, s), 7.64 (1 H, s), 7.99 (1 H, dd, J=5.92, 2.63 Hz), 9.05 (1 H, dd, J=5.92, 1.10 Hz), 9.20 (1 H, dd, J=2.74, 0.99 Hz), 10.73 (1 H, s)

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 53-54

48
[ 20744-39-2 ]
[ 1362819-91-7 ]
[ 1362818-20-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 18h;	Example 245-(1 -Methyl-1 H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]- V-4- pyridazinylbenzamide (E24) To a solution of 5-(1 -methyl- 1 H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2- [(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 26; 150 mg, 0.36 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.12 ml, 0.71 mmol), <strong>[20744-39-2]4-aminopyridazine</strong> (33.8 mg, 0.36 mmol), 1-hydroxy-7-azabenzotriazole (58.1 mg, 0.43 mmol) and EDC (1 16 mg, 0.61 mmol). The reaction was stirred for 18 hours and then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a yellow gum. 1 17 mg.MS (electrospray): m/z, [M+H]+ = 4991 H NMR (400 MHz, DMSO-d6); 2.74 - 3.11 (3 H, m), 3.41 - 3.76 (5 H, m), 3.81 - 3.95 (3 H, m), 5.15 - 5.38 (2 H, m), 7.22 (1 H, s), 7.26 - 7.41 (3 H, m), 7.48 (2 H, d, J=6.78 Hz), 7.59 (1 H, s), 7.75 (1 H, s), 7.85 (1 H, s), 8.03 (1 H, dd, J=5.90, 2.64 Hz), 9.07 (1 H, d, J=5.77 Hz), 9.27 (1 H, d, J=1.76 Hz), 10.87 (1 H, s).

Reference： [1]Patent: WO2012/28629,2012,A1 .Location in patent: Page/Page column 62-63

49
[ 20744-39-2 ]
[ 1001354-44-4 ]
[ 1366452-48-3 ]

Yield	Reaction Conditions	Operation in experiment
23%		General procedure: Isopropylmagnesium chloride (2.0 M solution in THF, 6.23 mL, 12.5 mmol) was added to a solution the amine(13.0 mmol) in THF (90 mL). After stirring for several minutes, the solution was quickly transferred to a flask containing (2S,4S)-methyl 1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-fluoropyrrolidine-2-carboxylate (2.59 mmol). The reaction was stirred overnight at rt, then quenched with sat aq NH4Cl (150 mL). The mixture was extracted with EtOAc (150 mL), and the organics were washed with water (3 × 150 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via a silica gel column (0-35% 90:10:1 [CH2Cl2/MeOH/NH4OH]/CH2Cl2), then by preparative HPLC (Waters Atlantis 30 × 100 mm, 0-70% 9:1 [MeOH/H2O 0.1% TFA]/1:9 [MeOH/H2O 0.1% TFA]). Product-containing fractions were concentrated on a Waters Oasis MCX cartridge, rinsed with MeOH, then eluted with 2 N NH3/MeOH. The eluent was concentrated in vacuo to obtain the desired product.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1961 - 1972

50
[ 20744-39-2 ]
[ 1403618-73-4 ]
[ 1403615-13-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 25℃; for 68h;	Example 1 : Preparation of 5-methyl-1 -(2,2,2-trifluoro-1 -trifluoromethyl-ethyl)-1 H-pyrazole-4- carboxylic acid pyridazin-4-ylamide [I-34]A solution of 398mg 5-methyl-1 -[2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]pyrazole-4-carbonyl chloride in 10ml CH2CI2 was added dropwise to a solution of 185mg <strong>[20744-39-2]pyridazin-4-amine</strong> and 750mg triethylamine in 30ml CH2CI2 at 0C. The mixture was stirred at 20-25C for about 68 h, diluted with 25ml ethylacetate, washed with 3 chi 15ml sat. aq. N H4CI solution, dried over MgS04 and evaporated. Purification by flash chromatography (Ch C /MeOH) gave 160mg of the title compound (90% purity). HPLC-MS (Method 1 ): RT 2.278 min, m/z [MH]+ 354.1 .

Reference： [1]Patent: WO2012/143317,2012,A1 .Location in patent: Page/Page column 34

51
[ 20744-39-2 ]
[ 203436-45-7 ]
[ 1416987-19-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 125 - 131

52
[ 20744-39-2 ]
2-[(3-bromo-4-nitrophenoxy)methyl]quinoline [ No CAS ]
N-[2-nitro-5-(quinolin-2-ylmethoxy)phenyl]pyridazin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With potassium phosphate; copper(l) iodide; N,N-dimethylethylenediamine; In dimethyl sulfoxide; at 110℃; for 0.5h;Inert atmosphere;	To a mixture of 27 (500 mg, 1.39 mmol), <strong>[20744-39-2]4-aminopyridazine</strong> (159 mg, 1.67 mmol) and K3PO4 (355 mg, 1.67 mmol) in DMSO (8 mL) were added CuI (318 mg, 1.67 mmol) and N,N'-dimethylethylenediamine (0.18 mL, 1.67 mmol), and the mixture was stirred at 110 C for 30 min under an argon gas atmosphere. After cooling atroom temperature, the mixture was diluted with water and 28% aqueous ammonia solution, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-5% MeOH in CHCl3) to give 30f (138 mg, 27%) as a yellow solid. 1H NMR (CDCl3) delta 5.47 (s,2H), 6.80 (dd, 1H, J = 9.4, 2.6 Hz), 6.90 (dd, 1H, J = 5.9, 2.9 Hz), 7.07 (d, 1H, J = 2.6 Hz), 7.57-7.64 (m, 2H), 7.78-7.84 (m, 1H), 7.87 (d, 1H, J = 8.1 Hz), 8.05 (d, 1H, J = 8.6 Hz), 8.22-8.27 (m, 2H), 8.59 (br s, 1H), 9.08 (br s, 1H), 9.58 (s, 1H); MS (ESI) m/z 374 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7612 - 7623

53
[ 20744-39-2 ]
[ 1402008-45-0 ]
[ 1402006-40-9 ]

Yield	Reaction Conditions	Operation in experiment
17%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	Trans-4-(1-Methyl-2,5-dioxo-1,2,4,5-tetrahydro-imidazo[4,5-b]pyridin-3-ylmethyl)-cyclohexanecarboxylic acid pyridazin-4-ylamide Trans-4-(1-Methyl-2,5-dioxo-1,2,4,5-tetrahydro-imidazo[4,5-b]pyridin-3-ylmethyl)-cyclohexanecarboxylic acid (100 mg, 0.33 mmol) was dissolved in DMF (1 mL) then TEA (91mu, mL, 0.39 mmol), HATU (149 mg, 0.39 mmol) and 4 aminopyridazine (37.4 mg, 0.39 mmol) were added and the mixture was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure and crude was purified by silica column (AcOEt/MeOH 9:1) then by preparative HPLC (method b) to give 21 mg of the titled compound (yield 17%). 1HNMR (CD3OD) delta: 1.13-1-23 (2H, m), 1.44-1.54 (2H, m), 1.78-1.81 (2H, m), 1.94-2.05 (3H, m), 2.35-2.44 (1H, m), 3.39 (3H, s), 3.76 (2H, d, J=7.2 Hz), 6.39 (1H, d, J=8.0 Hz), 7.36 (1H, d, J=8.0 Hz), 8.05-8.08 (1H, m), 8.93-8.95 (1H, m), 9.23-9.24 (1H, m).

Reference： [1]Patent: US2014/5164,2014,A1 .Location in patent: Paragraph 0363-0366

54
[ 20744-39-2 ]
[ 1566543-96-1 ]
[ 1566543-17-6 ]

Yield	Reaction Conditions	Operation in experiment
21%		2-(2-(2-(5-Chloro-2-(pyridazin-4-ylamino)pyrimidin-4-yl) ethyl)phenyl)propanamide(42)A mixture of 2-(2-(2-(2, 5-Dichloropyrimidin-4-yl) ethyl) phenyl)propanamide (A30) 2-(2-(2-(2, 5-Dichloropyrimidin-4-yl) ethyl) phenyl) propanamide (A30 (0.080 g, 0.25 mmcl),<strong>[20744-39-2]4-aminopyridazine</strong> (0.046 g, 0.49 mmol), Xantphos (0.0057 g, 0.010 mmol) andCs2003 (0.24 g, 0.74 mmol) in 1,4-dioxane (3 mL) was bubbled with nitrogen for 10 minutes. Palladium (II) acetate (0.0011 g, 0.0049 mmol) was added and the mixture was heated at 120 00 under microwave irradiation for 28 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography(Combiflash Rf, 0-15% MeOH in DCM) to give the title compound 42 as a light yellow solid (0.020 g, 21%). LCMS-C: rt 4.23 mm; m/z 383 [M+H].

Reference： [1]Patent: WO2014/26243,2014,A1 .Location in patent: Page/Page column 141; 142

55
[ 20744-39-2 ]
[ 1566543-84-7 ]
[ 1566542-97-9 ]

Yield	Reaction Conditions	Operation in experiment
11%		(a) 1-(2-(2-(5-Chloro-2-(pyridazin-4-ylamino)pyrimidin-4-yI) ethyl)phenyl) cyclopropanecarboxamide (22)A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4- yl)ethyl)phenyl)cyclopropanecarboxamide A14 0.080 g, 0.24 mmol), 4- aminopyridazine (0.045 g, 0.48 mmol), Xantphos (0.0055 g, 0.010 mmol) and 0s2003 (0.23 g, 0.71 mmol) in 1,4-dioxane (4 mL) was bubbled with nitrogen for 10 minutes. Palladium(ll) acetate (0.0011 g, 0.0049 mmol) was added and the mixturewas heated in the microwave at 120 00 for 25 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-15% MeOH in DCM) to give the title compound 22 as a light yellow solid (0.010 g, 11%). LCMS-C: rt 4.34 mm; m/z 395 [M+H].

Reference： [1]Patent: WO2014/26243,2014,A1 .Location in patent: Page/Page column 126

56
[ 20744-39-2 ]
[ 55928-84-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1583 - 1598

57
[ 20744-39-2 ]
[ 55928-90-0 ]

Yield	Reaction Conditions	Operation in experiment
5.56%	With bromine; In acetic acid; at 20℃; for 1h;	5-Bromo<strong>[20744-39-2]pyridazin-4-amine</strong>: To a solution of <strong>[20744-39-2]pyridazin-4-amine</strong> (1.18 g, 12.41 mmol) in Acetic Acid (2.5 mL) was added dibromine (0.638 mL, 12.41 mmol)dropwise at rt in a water bath. After 1 h, 10 N NaOH was added and then extracted with dichloromethane (3x). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in a small amount of dichloromethane and charged to a 40 g silica gel cartridge which was eluted with 0-15% dichloromethane / methanol over a period of 40 mins. The desired fractions were combined and dried under vacuo to give 3-bromopyridazin-4- amine (0.1 g, 0.575 mmol, 4.63 % yield)(first eluting) and 5-bromo<strong>[20744-39-2]pyridazin-4-amine</strong> (0.12 g, 0.690 mmol, 5.56 % yield)(second eluting). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.75 (s, 1 H) 8.55 (s, 1 H) 6.72 - 6.79 (m, 2 H).

Reference： [1]Patent: WO2015/69594,2015,A1 .Location in patent: Page/Page column 196
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 1583 - 1598

58
[ 20744-39-2 ]
3-(naphthalen-2-yl)benzoic acid [ No CAS ]
3-(naphthalen-2-yl)-N-(pyridazin-4-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: To a solution of 3-(naphthalen-2-yl)benzoic acid 15 (1 equiv) in CH2Cl2 (0.1 M) were added the appropriate amine (1.5 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.5 equiv) and N,N-dimethyl-4-aminopyridine (1.5 equiv). The reaction mixture was stirred at room temperature until the reaction was completed. Then, H2O was added, and the whole was extracted with AcOEt×2. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by means of silica gel column chromatography (eluent: n-hexane/AcOEt) to obtain the desired heterocyclic product.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 328 - 339

59
[ 20744-39-2 ]
4-(2-(3-ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid [ No CAS ]
[ 1208318-49-3 ]

Yield	Reaction Conditions	Operation in experiment
58%	With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃;	Synthesis of Compound 32C (0294) To a mixture of 32A (200 mg, 0.49 mmol) and <strong>[20744-39-2]pyridazin-4-amine</strong> (56 mg, 0.59 mmol) in THF (3 mL) was added DCC (152 mg, 0.74 mmol) and the mixture was stirred at room temperature overnight. TLC showed the reaction was complete. Water (5 mL) was added and the mixture was extracted with ethyl acetate (5 mL×4). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (DCM:MeOH=15:1) to afford 32C as a yellow solid (137 mg, yield 58%).

Reference： [1]Patent: US9138427,2015,B2 .Location in patent: Page/Page column 259-260

60
[ 20744-39-2 ]
C₁₆H₁₅ClN₆O₂S₂ [ No CAS ]
2-(1-(ethylsulfonyl)-3-(4-(2-(pyridazin-4-ylamino)thieno[3,2-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With toluene-4-sulfonic acid; In butan-1-ol; at 110℃; for 16h;	Compound 5 (50 mg, 0.12 mmol) and <strong>[20744-39-2]4-aminopyridazine</strong> (34 mg, 0.36 mmol) were dissolved in n-butanol (3 mL), p-toluene sulfonic acid monohydrate (45 mg, 0.24 mmol) was added. The mixture was heated to 110 C. and stirred for 16 hours, then concentrated under reduced pressure, the residue was purified by preparation HPLC (mobile phase:acetonitrile, water (0.05% trifluoroacetic acid); gradient: 60%-90%-10%) to give yellow solid T-47 (6 mg, yield: 11%). LC-MS (ESI): m/z=482 [M+H]+. (0328) 1H-NMR (400 MHz, CDCl3) delta: 8.79 (d, J=9 Hz, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.08 (d, J=6 Hz, 1H), 7.92 (d, J=3 Hz, 1H), 7.66 (d, J=6 Hz, 1H), 6.32 (m, 1H), 4.66 (d, J=9 Hz, 2H), 4.26 (d, J=9 Hz, 2H), 3.44 (s, 2H), 3.12 (q, J=7 Hz, 2H), 1.43 (t, J=7 Hz, 3H) ppm

Reference： [1]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0326; 0327; 0328

61
[ 20744-39-2 ]
2-(3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide [ No CAS ]
[ 1885-14-9 ]
2-(3-fluorophenyl)-N⁵-(pyridazin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of primary amine (0.192 mmol) and triethylamine (0.480 mmol) in tetrahydrofuran (3 mE) at 0 C. were added phenyl chloroformate (0.096 mmol) and the reaction mixture stirred for 60 mm. at RT. The reaction mixture was quenched with water and the phenyl carbamate formed was extracted and the Intermediate 4J (25 mg, 0.096 mmol) in THF was added to the extract and the resulting solution was stirred at room temperature for 2 h. Reaction progress wasmonitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate (3x5 mE) The combined organic layer was washed with 10% NaHCO3 (2x5 mE), water, dried over Na2SO4 and concentrated to afford crude product as off-white solid. The crude product wasther purified by preparative HPLC.

Reference： [1]Patent: US9273058,2016,B2 .Location in patent: Page/Page column 77; 78

62
[ 20744-39-2 ]
((1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone [ No CAS ]
cyclopropyl{(1R,5S)-3-[5-fluoro-2-(pyridazin-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos; In tert-Amyl alcohol; at 140℃; for 0.666667h;Inert atmosphere; Microwave irradiation;	General procedure: A 0.2M solution of ((1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 27, 500 mul, 100 mumol) in tert-amyl alcohol was added to amines of formula (R4NH2) (150 mumol) followed by sodium tert-butoxide (200 mumol), Pd2(dba)3 (2 mumol) and XPhos (2 mumol) under nitrogen. The reactions were heated to 140 C. under microwave irradiation for 40 minutes. The reactions were cooled, concentrated in vacuo and purified using preparative HPLC. Preparative HPLC (0398) Purification Method 1 (PM1): Phenomenex Gemini C18, 250×21.2 mm×8 mum; Acetonitrile-ammonium hydroxide; Flow rate 30 mL/min; Gradient time 8 mins. (0399) Purification Method 2 (PM2): DIKMA Diamonsil C18 200 mm×20 mm×5 mum; MeCN-water (0.225% formic acid); Flow rate 35 mL/min; Gradient time 9 mins. LCMS Method: (0400) Column: XBridge C18 2.1 mm×50 mm×5 mum (0401) Mobile Phase A: 0.05% ammonium hydroxide in water (0402) Mobile phase B: 100% MeCN (0403) Gradient: 5% B to 100% B at 3.40 minutes then back to 5% B at 4.21 minutes. (0404) Flow rate: 0.8 mL/min (0405) The compounds of the Examples in the table below were prepared from ((1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 27) and the appropriate amine according to Library Protocol 1.

Reference： [1]Patent: US2016/52930,2016,A1 .Location in patent: Paragraph 0396-0405

63
[ 20744-39-2 ]
[ 1050602-61-3 ]
N4-cyclopropyl-N2-(pyridazin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]
N4-cyclopropyl-N2-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-yl)-N2-(pyridazin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5 mg; 6 mg	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 140℃; for 0.333333h;Microwave irradiation;	Example 221: Preparation of N4-cyclopropyl-N2-(pyridazin-4-yl)-5-(trifluoromethyl) pyrimidine-2,4-diamine and N4-cyclopropyl-N2-(4-(cyclopropylamino)-5-(trifluoromethyl) pyrimidin-2-yl)-N2-(pyridazin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamineFlame dried flask and stir bar. Bubbled nitrogen through reagents and solvents prior to heating. 2-Chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (0.070 g, 0.295 mmol), <strong>[20744-39-2]pyridazin-4-amine</strong> (0.028 g, 0.295 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenyl phosphane) (0.017 g, 0.029 mmol), diacetoxypalladium (3.31 mg, 0.015 mmol) and cesium carbonate (0.1 92 g, 0.589 mmol) were mixed in 1 ,4-Dioxane (1 ml). The mixture was microwaved at 140 C for 20 minutes. Filtered through Celite with methanol and concentrated. 5 mg of N4-cyclopropyl-N2-(pyridazin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine and 6 mg of N4-cyclopropyl-N2-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-yl)-N2-(pyridazin- 4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine were recovered after automated reverse phase chromatography (water-MeCN eluent). MS calcd for 297.1 1, found 296.75. MS calcd for [C2oH17F6N9+H]+: 498.16, found 498.35.

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 197; 198

64
[ 20744-39-2 ]
17-methylmorphinan-3-yl trifluoromethanesulfonate [ No CAS ]
17-methyl-N-(pyridazin-4-yl)morphinan-3-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27.3%		Example 56 Preparation of 17-methyl-N-(pyridazin-4-yl)morphinan-3-amine (56), hydrochloride salt A microwave vial was charged with dicyclohexyl(2',4',6'-triisopropyl-[l,r- biphenyl]-2-yl)phosphine (27.5 mg, 0.058 mmol), cesium carbonate (84 mg, 0.257 mmol), <strong>[20744-39-2]pyridazin-4-amine</strong> (15.8 mg, 0.167 mmol) and tris(dibenzylideneacetone)dipalladium(0) (17.6 mg, 0.019 mmol). The mixture was purged under nitrogen, followed by the addition of a degassed mixture of 17-methylmorphinan-3-yl trifluoromethanesulfonate [Zhang et al. (2004) J Med Chem 47(1): 165-174] (0.128 mmol) in dioxane (1.5 mL). The vial was then irradiated in a microwave oven at 150 C for 30 minutes. The solids were filtered and washed with tetrahydrofuran and the filtrate was concentrated. The residue was first purified by flash chromatography (99: 1 :0.1 to 93:7:0.7 dichloromethane/methanol/aqueous ammonia) and then by reverse phase chromatography (0-30% water/ acetonitrile/0.01% hydrochloric acid). The combined fractions were treated with 1 N hydrochloric acid to afford 17-methyl-N- (pyridazin-4-yl)mophihinan-3-amine (56) hydrochloride salt (14.3 mg, 27.3%) as a light yellow solid. NMR (500 MHz, Methanol-^): delta 8.77 - 8.71 (m, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.35 (d, J = 7.1 Hz, 2H), 3.74 (dd, J = 6.0, 2.9 Hz, 1H), 3.36 - 3.22 (m, 3H), 2.97 (s, 3H), 2.80 - 2.70 (m, 1H), 2.55 (d, J = 14.2 Hz, 1H), 2.18 (dt, J = 12.7, 3.0 Hz, 1H), 2.04 (td, J = 13.6, 4.3 Hz, 1H), 1.80 - 1.69 (m, 2H), 1.69 - 1.60 (m, 2H), 1.60 - 1.43 (m, 2H), 1.30 (ddd, J =16.4, 13.2, 10.1 Hz, 1H), 1.16 (qd, J= 12.9, 4.0 Hz, 1H). MS (EI) for C2iH26N4: 335 (MH+).

Reference： [1]Patent: WO2016/182840,2016,A1 .Location in patent: Paragraph 00348

65
[ 20744-39-2 ]
17-[2-(2-methoxyethoxy)ethyl]morphinan-3-yl trifluoromethanesulfonate [ No CAS ]
(4bR,8aR,9R)-11-(2-(2-methoxyethoxy)ethyl)-N-(pyridazin-4-yl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.4%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; Microwave irradiation;	Example 99 Preparation of (4bR,8a ?,9R)-l l-(2-(2-methoxyethoxy)ethyl)-N-(pyridazin-4-yl)- 6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-amine (99) A suspension of (4bi?,8ai?,9i?)-l l-(2-(2-methoxyethoxy)ethyl)-6,7,8,8a,9,10- hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-yl trifluoromethanesulfonate (97.5 mg, 0.204 mmol), <strong>[20744-39-2]pyridazin-4-amine</strong> (29.1 mg, 0.306 mmol), XPhos (19.47 mg, 0.041 mmol), and CS2CO3 (100 mg, 0.306 mmol) in dioxane (2 ml) was degassed under nitrogen for ten minutes before tris(dibenzylideneacetone)dipalladium(0) (18.70 mg, 0.020 mmol) was added. The mixture was irradiated in a microwave at 100 C for two hours. LCMS showed the desired product formation with a small amount of starting material remaining. Upon removal of the solvent, the residue was taken up in dichloromethane (30 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate, was filtered and was concentrated. The crude product was purified by chromatography using a Biotage instrument using a KP- NH column and dichloromethane/methanol as the mobile phase. Pure fractions were combined and concentrated. After drying under high vacuum, (4bi?,8aR,9i?)-l l-(2-(2- methoxyethoxy)ethyl)-N-(pyridazin-4-yl)-6,7,8,8a,9,10-hexahydro-5H-9,4b- (epiminoethano)phenanthren-3-amine (99) (46.1 mg, 0.109 mmol, 53.4 % yield) was obtained as an oil. MS (EI) for C25H34N402: 423.2 (MH+).1H NMR (500 MHz, Methanol- d4) delta 8.72 (d, J = 3.0 Hz, 1H), 8.57 (dd, J = 6.3, 1.0 Hz, 1H), 7.25 - 7.14 (m, 2H), 7.07 (ddd, J = 19.3, 7.2, 2.6 Hz, 2H), 3.69 - 3.53 (m, 6H), 3.38 (s, 3H), 3.13 - 3.00 (m, 2H), 2.85 (dt, J = 13.1, 5.9 Hz, 1H), 2.80 - 2.69 (m, 2H), 2.63 (dq, J = 12.4, 2.0 Hz, 1H), 2.44 - 2.36 (m, 1H), 2.17 (td, J = 12.5, 3.2 Hz, 1H), 1.94 - 1.68 (m, 3H), 1.59 (dd, J = 12.8, 4.4 Hz, 1H), 1.52 - 1.24 (m, 6H), 1.16 (qd, J = 13.5, 13.1, 4.2 Hz, 1H).

Reference： [1]Patent: WO2016/182840,2016,A1 .Location in patent: Paragraph 00476

66
[ 20744-39-2 ]
4-((4-(4-chloroquinolin-6-yl)phenyl)sulfonyl)morpholine [ No CAS ]
6-(4-(morpholinosulfonyl)phenyl)-N-(pyridazin-4-yl)quinolin-4-amine [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 350 - 354

67
[ 20744-39-2 ]
[ 89-55-4 ]
C₁₁H₈BrN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	General procedure: To a solution of 5-bromo-2-hydroxybenzoic acid (2 g, 9.22 mmol) in DMF (15 mL) was addedDIPEA (3.22 mL, 18.43 mmol), 3-aminopyridine (1.128 g, 11.98 mmol), HOBT (1.694 g, 11.06mmol) and EDC (3.53 g, 18.43mmol). The reaction was stirred overnight, water was added andthe solid was filtered to give the title compound 12 (346 mg, 12% yield).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4034 - 4038

68
[ 20744-39-2 ]
4-(3-(4-chloroquinazolin-6-yl)phenyl)morpholine [ No CAS ]
6-(3-morpholinophenyl)-N-(pyridazin-4-yl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 105℃; for 12h;Inert atmosphere;	General procedure: To a flame-dried flask was added 8 (0.046g, 0.142mmol), xantphos (0.016g, 0.028mmol), potassium carbonate (0.392g, 2.83mmol), palladium(II) acetate (0.003g, 0.014mmol), and the respective amine (0.170mmol). The flask was purged with nitrogen three times and then anhydrous dioxane (1.5mL) was added under nitrogen. The reaction was refluxed at 105C for 12h while under nitrogen, maintaining a positive pressure. The mixture was concentrated under reduced pressure, separated by silica column chromatography (dichloromethane/isopropanol), and purified by reverse phase chromatography (water/acetonitrile).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 446 - 459

69
[ 20744-39-2 ]
(2S,3S)-2-(fluoromethyl)-7-(methylcarbamoyl)-3-phenyl-2,3-dihydrobenzofuran-5-carboxylic acid [ No CAS ]
(2S,3S)-2-(fluoromethyl)-N₇-methyl-3-phenyl-N₅-(pyridazin-4-yl)-2,3-dihydrobenzofuran-5,7-dicarboxaminde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		A solution of (2S,3S)-2-(fluoromethyl)-7-(methylcarbamoyl)-3-phenyl-2,3-d ihydrobenzofuran5-carboxylic acid (80 mg, 0.24 minol) and HATU (111 mg, 0.292 minol) in DMSO (0.85 mL) was treated at rt with DIPEA (0.127 mL, 0.729 minol) and the reaction minxture was stirred at this temperature for 5 min Pyridazin-4-amine (23.1 mg, 0.243 minol) was then added and the reactionwas stirred 1 h at rt. Further HATU (111 mg, 0.292 minol) and DIPEA (0.127 mL, 0.729 minol) were then added to the reaction and the resulting minxture was left to stir at rt for 5 min Pyridazin-4-amine (23.1 mg, 0.243 minol) was then added and the reaction minxture was stirred 1 h at rt. The minxture was then purified by MDAP (method high pH) to give (2S,3S)-2-(fluoromethyl)-N7-methyl-3-phenyl- N5-(pyridazin-4-yl)-2,3-d ihydrobenzofuran-5,7-d icarboxaminde (6S.2 mg, 66%) as an orange gumLCMS (method forminc): Retention time 0.83 min [M+H] = 407

Reference： [1]Patent: WO2017/174620,2017,A1 .Location in patent: Page/Page column 191; 192

70
[ 20744-39-2 ]
C₁₅H₂₁N₃O₆S [ No CAS ]
(4bS,6R)-1-(1-methanesulfonyl-1-methylethyl)-5-methyl-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triazaphenanthrene-3-carboxylic acidpyridazin-4-ylamide [ No CAS ]

Reference： [1]Patent: WO2017/202748,2017,A1 .Location in patent: Page/Page column 136

71
[ 20744-39-2 ]
C₁₅H₂₁N₃O₆S [ No CAS ]
(4bS,6R)-1-(1-methanesulfonyl-1-methylethyl)-5-methyl-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triazaphenanthrene-3-carboxylic acidpyrimidin-2-ylamide [ No CAS ]

Reference： [1]Patent: WO2017/202748,2017,A1 .Location in patent: Page/Page column 136

72
[ 20744-39-2 ]
(R)-(4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7 8-dihydro-[1,4]dioxino[2',3':3,4]benzo[1,2-d]thiazol-7-yl)methyl carbonochloridate [ No CAS ]
(R)-(4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7, 8-dihydro-[1,4]dioxino[2’,3’:3,4]benzo[1,2-d]thiazol-7-yl)methyl pyridazin-4-ylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.64%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 20℃;	To a solution of Intermediate 25L (20 mg, 0.041 mmol) in DCM (1 mL) and THF (0.5 mL) was added <strong>[20744-39-2]pyridazin-4-amine</strong> (13.52 mg, 0.142 mmol) followed by DIEA (0.07 1 mL, 0.406 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by addition of a small amount of MeOH/water/0. 1% TFA (HPLC solvent). Solvent was removed under vacuum. The residual was dissolved in DMSO andpurified via preparative LC/MS (method C, 30-70% B over 12 mm., then a 5-mm hold at100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to give Example 34 (3.8 mg, 6.76 imol, 16.64 % yield). ?H NMR (500MHz, DMSO-d6) 10.67 (br. s., 1H), 9.21 (br. s., 1H), 9.01 (d, J5.5 Hz, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 7.84 (s, 1H), 7.77 (br. s., 1H), 7.31 (s, 1H), 4.72 (br. s., 1H), 4.66 (d,J11.6Hz, 1H), 4.60-4.37 (m, 2H), 4.35 (d, J=9.1 Hz, 1H), 4.08 (s, 3H), 2.64(s, 3H). LC-MS: method C, RT = 2.13 mm, MS (ESI) m/z: 551.15 (M+H). Analytical HPLC purity (method B): 98%.

Reference： [1]Patent: WO2018/13776,2018,A1 .Location in patent: Page/Page column 234

73
[ 20744-39-2 ]
(R)-(5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydrobenzofuro[5,4-d]thiazol-7-yl)methyl carbonochloridate [ No CAS ]
(R)-(5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7,8-dihydrobenzofuro[5,4-d]thiazol-7-yl)methyl pyridazin-4-ylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18.01%	With pyridine; In dichloromethane; at 20℃; for 0.5h;	Pyridazin-4-amine (13.24 mg, 0.139 mmol) was dissolved in DCM (1.0 mL) along with pyridine (0.045 mL, 0.55 7 mmol). Intermediate 14SF (32 mg, 0.070 mmol) in DCM (2.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then quenched by addition of 1.0 N HC1 (0.6 mL).Dichloromethane was removed under vacuum. The mixture was dissolved in THF/DMSO (1:1, 7 mL), and purified using a preparative preparative HPLC (method A, 35-100% B in 8 mm. Then 100%B in 4 mm.). The desired fractions were placed in a SpeedVac overnight to remove solvent, then lyophilized to give Example 158 (6.7 mg,0.013 mmol, 18.01 % yield) as a yellow solid. ?H NMR (500MHz, THF) 9.70 (br. s.,1H), 9.09 (br. s., 1H), 8.92 (br. s., 1H), 8.72 (s, 1H), 8.56 (s, 1H), 7.82 (br. s., 1H), 7.78(s, 1H), 7.72(d, J= 11.0 Hz, 1H), 5.39 (d, J=6.9 Hz, 1H), 4.60 (d, J9.1 Hz, 1H), 4.48(dd, J11.7, 6.2 Hz, 1H), 4.11 (s, 3H), 3.65 (dd, J14.9, 9.9 Hz, 1H), 3.45-3.35 (m, 1H),2.65 (s, 3H); ?9F NMR (471MHz, THF) -142.43 (s, iF); LC-MS: method H, 2 to 98%B. RT = 0.87 mm, MS (ESI) m/z: 519.15(M+H)t Analytical HPLC purity (method A):97% purity.

Reference： [1]Patent: WO2018/13776,2018,A1 .Location in patent: Page/Page column 359; 360

74
[ 20744-39-2 ]
[ 10511-51-0 ]
C₂₀H₁₆N₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9575 - 9584

75
[ 20744-39-2 ]
4-chloro-7-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)quinoline [ No CAS ]
7-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-N-(pyridazin-4-yl)quinolin-4-amine [ No CAS ]

Reference： [1]ACS Infectious Diseases,2018,vol. 4,p. 577 - 591

76
[ 20744-39-2 ]
C₁₄H₁₉NO₄ [ No CAS ]
N-isopropyl-N-(2-oxo-2-(pyridazin-4-ylamino)ethyl)-2-(p-tolyloxy)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66 mg		General procedure: To a solution of 17c (100mg, 0.34mmol) in 5mL anhydrous THF was added 4-methylmorpholine (35mg, 0.34mmol) and isobutyl carbonochloridate (49mg, 0.36mmol) under nitrogen atmosphere at-10. The reaction mixture was stirred for 30minat-10, then pyrimidin-5-amine (32mg, 0.34mmol) was added. After reacting for another 30minat-10, the reaction mixture was warmed to room temperature and stirred for 6h. The solvent was evaporated and the residues was dissolved in ethyl acetate (10mL), washed with water (10mL×3) and brine (10mL×3). The organic layer was dried over Na2SO4, concentrated under vacuum and purified on silica gel to afford the compound 18g as a white solid (56mg, 43%). Mp: 150.0-153.0C. HPLC purity=99.33%, HPLC tR=15.10min (Method B). The 1H NMR showed 12:1 ratio of atropisomers. 1H NMR (500MHz, CDCl3) delta 9.34 (s, 1H), 8.89 (s, 1H), 8.81 (s, 2H), 7.07 (d, J=8.5Hz, 2H, [6.97 minor isomer]), 6.83 (d, J=8.5Hz, 2H, [6.70 minor isomer]), 4.78 (s, 2H, [4.67 minor isomer]), 4.30-4.21 (m, 1H), 4.02 (s, 2H, [4.16 minor isomer]), 2.49 (t, J=7.5Hz,2H), 1.62-1.51 (m, 2H), 1.27 (d, J=6.5Hz, 6H, [1.16 minor isomer]), 0.89 (t, J=7.5Hz, 3H). 13C NMR (125MHz, CDCl3) delta 168.86, 167.39, 154.63, 152.97, 146.63, 135.37, 132.46, 128.59, 113.26, 66.17, 48.37, 45.19, 36.05, 23.59, 19.95, 12.73. HRMS (ESI) m/z: calcd for C20H27N4O3 [M+ H]+, 371.2078; found 371.2088.