[ CAS No. 823-58-5 ] {[proInfo.proName]}

Name: 823-58-5|4-Amino-3,6-dichloropyridazine|97%
Brand: Ambeed
SKU: A144660
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Quality Control of [ 823-58-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 823-58-5 ]

Product Details of [ 823-58-5 ]

CAS No. :	823-58-5	MDL No. :	MFCD01647253
Formula :	C₄H₃Cl₂N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HODYDVHWWMTUEL-UHFFFAOYSA-N
M.W :	163.99	Pubchem ID :	298498
Synonyms :

Calculated chemistry of [ 823-58-5 ]

Physicochemical Properties

Num. heavy atoms :	9
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 :	36.46
TPSA :	51.8 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.32
Log Po/w (XLOGP3) :	1.09
Log Po/w (WLOGP) :	1.37
Log Po/w (MLOGP) :	0.6
Log Po/w (SILICOS-IT) :	1.64
Consensus Log Po/w :	1.2

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.04
Solubility :	1.51 mg/ml ; 0.00919 mol/l
Class :	Soluble
Log S (Ali) :	-1.77
Solubility :	2.78 mg/ml ; 0.017 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.52
Solubility :	0.5 mg/ml ; 0.00305 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.07

Safety of [ 823-58-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 823-58-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 823-58-5 ]
Downstream synthetic route of [ 823-58-5 ]

[ 823-58-5 ] Synthesis Path-Upstream 1~10

1
[ 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

2
[ 6082-66-2 ]
[ 823-58-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With ammonium hydroxide In water at 75℃; for 16 h;	Example 24A 3,6-dichloropyridazin-4-amine 3,4,6-Trichloropyridazine (25 g, 136 mmol) was added to 14. 8 N ammonium hydroxide (200 mL) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 16 hours at 75° C. The mixture was cooled to ambient temperature, and 17 g (76percent) of the title compound was collected by filtration as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.16 (s, 2H), 6.82 (s, 1H); MS (ESI+) m/z 164 (M+H)⁺.
35%	With ammonia In methanol at 100℃; for 0.166667 h;	Step 1. 3,6-dichloropyridazin-4-amine A glass microwave reaction vessel was charged with 3,4,6-trichloropyridazine (732 mg, 3991 μmol), ammonia, (2.0 M solution in methanol, 3991 μl, 7982 μmol). The reaction mixture was stirred and heated in a Smith Synthesizer.(R). microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 100° C. for 10 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (80percent EtOAc/hexanes) to give 6-dichloropyridazin-4-amine (226 mg, 35percent yield). MS (ESI positive ion) m/z: 164 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 6.83 (s, 1H) 7.15 (s, 2H)
32%	With ammonia In methanol at 100℃; for 0.5 h; Microwave irradiation; Sealed tube	Step 112.1: 3,6-dichloropyridazin-4-amine A MW vial was charged with 3,4,6-trichloropyridazine (5 g, 27.3 mmol) and 7N NH₃in MeOH (19.47 mL, 136 mmol). The MW vial was sealed and the resulting mixture was submitted to MW irradiation at 100° C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 35-60percent) to afford the title product (1.49 g, 8.63 mmol, 32percent yield) as yellow solid. t_R: 1.61 min (HPLC 1); t_R: 0.45 min (LC-MS 2); ESI-MS: 163 [M+H]⁺ (LC-MS 2); R_f=0.40 (hexane/EtOAc 1:1).

32%

With ammonia In methanol at 100℃; for 0.5 h; Microwave irradiation; Sealed tube

A MW vial was charged with 3,4,6-trichloropyridazine (5 g, 27.3 mmol) and 7N NH3 in MeOH (19.47 mL, 136 mmol). The MW vial was sealed and the resulting mixture was submitted to MWirradiation at 100 00 for 30 mm. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 35-60percent) to afford the title product (1.49 g, 8.63 mmol, 32percent yield) as yellow solid. tR: 1.61 mm (HPLC 1); tR: 0.45 mm (LC-MS 2); ESI-MS: 163 [M+H] (LC-MS 2); R = 0.40 (hexane/EtOAc 1:1).

Reference： [1] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10311 - 10322
[2] Patent: US2017/15675, 2017, A1, . Location in patent: Paragraph 1001
[3] Patent: US2009/163489, 2009, A1, . Location in patent: Page/Page column 51
[4] Patent: US2014/349990, 2014, A1, . Location in patent: Paragraph 1051; 1052
[5] Patent: WO2014/191896, 2014, A1, . Location in patent: Page/Page column 217; 218
[6] Pharmaceutical Bulletin, 1956, vol. 4, p. 138[7] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 641,644
[8] Patent: WO2003/87098, 2003, A1, . Location in patent: Page/Page column 111

3
[ 10344-42-0 ]
[ 823-58-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With ammonia In ethanol at 20℃; Autoclave	4-Bromo-3,6-dichloro-pyridazine (15.0 g, 65.8 mmol, prepared as described in WO 20081 16815) was dissolved in EtOH (73.1 mL) and introduced into an autoclave. At rt, gaseous NH3 (4.48 g, 263mmol) was introduced, and the reaction mixture was then stirred over night at reflux. The solution was concentrated in vacuo and the residue was triturated with EtOAc, the insoluble part was filtrated off, and the mother liquor evaporated to give the crude product. This was purified by Flash-Chromatography, eluting with cyclohexan /EtOAc 1/1 +2.5percent Et3N, to give the title compound as a pale brown solid (5.82g, 53percent). LCMS (method ZCQ13): Rt. 0.3min, 164/166/168 (M+H)

Reference： [1] Patent: WO2015/715, 2015, A1, . Location in patent: Page/Page column 123; 124

4
[ 887310-61-4 ]
[ 823-58-5 ]

Reference： [1] MedChemComm, 2014, vol. 5, # 4, p. 540 - 546
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2807 - 2812
[3] Patent: WO2006/51270, 2006, A1, . Location in patent: Page/Page column 152

5
[ 1104202-03-0 ]
[ 823-58-5 ]

Reference： [1] Journal of the American Chemical Society, 2017, vol. 139, # 1, p. 115 - 118

6
[ 17285-22-2 ]
[ 823-58-5 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 641,644

7
[ 6082-66-2 ]
[ 7664-41-7 ]
[ 823-58-5 ]

Reference： [1] Pharmaceutical Bulletin, 1956, vol. 4, p. 138[2] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 641,644

8
[ 823-58-5 ]
[ 934-26-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	With hydrazine hydrate In ethanol at 100℃; for 3 h;	Step 112.2: 6-chloro-3-hydrazinylpyridazin-4-amine To a stirred suspension of 3,6-dichloropyridazin-4-amine (Step 112.1) (1.49 g, 9.09 mmol) in EtOH (15 mL) was added hydrazine hydrate (11.04 mL, 227 mmol) and the resulting mixture was heated up and stirred at 100° C. for 3 hr. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was triturated with water (25 mL) to afford the title product (478 mg, 3 mmol, 33percent yield) as yellow solid. t_R: 0.24 min (LC-MS 2); ESI-MS: 160 [M+H]⁺ (LC-MS 2); ESI-MS: 158 [M−H]⁻ (LC-MS 2).
33%	With hydrazine hydrate In ethanol at 100℃; for 3 h;	To a stirred suspension of 3,6-dichloropyridazin-4-amine (Step 112.1) (1.49 g, 9.09 mmol) in EtOH (15 mL) was added hydrazine hydrate (11.04 mL, 227 mmol) and the resulting mixture was heated up and stirred at 100 00 for 3 hr. The reaction was cooled down to RT andconcentrated under reduced pressure. The crude product was triturated with water (25 mL) to afford the title product (478 mg, 3 mmol, 33percent yield) as yellow solid. tR: 0.24 mm (LC-MS 2); ESIMS: 160 [M+H] (LC-MS 2); ESl-MS: 158 [M-H] (LC-MS 2).

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2807 - 2812
[2] Patent: US2014/349990, 2014, A1, . Location in patent: Paragraph 1053; 1054
[3] Patent: WO2014/191896, 2014, A1, . Location in patent: Page/Page column 218
[4] Patent: US4728355, 1988, A,

9
[ 823-58-5 ]
[ 74-89-5 ]
[ 17645-17-9 ]

Yield	Reaction Conditions	Operation in experiment
57%	at 100℃; for 48 h; Autoclave	In an autoclave, 3,6-dichloropyridazin-4-amine (2.35 g, 14.3 mmol) was treated with Methylamine dissolved in EtOH (20.2 g, 215 mmol, 26.7 mL) and heated to 100°C. After 48h at 100°C LCMS showed no more starting material. The reaction mixture was evaporated to dryness. The crude product was diluted in dichloromethane and 4ml Et₃N was added. The mixture was stirred 5' at rt and evapourated. The residue was diluted with 5ml water and the insoluble material was filtrated and dried to give the title product 1 .35g , 57percent) as a pale brown solid. LCMS (Method ZCQ13): Rt. 0.17 min, 157/159 (M-H).

Reference： [1] Patent: WO2015/715, 2015, A1, . Location in patent: Page/Page column 124

10
[ 823-58-5 ]
[ 28682-68-0 ]

Yield	Reaction Conditions	Operation in experiment
45%	at 0 - 60℃; for 3 h;	The commercially available 3,6-dichloropyridazine-4-amine (15 g, 92 mmol, 1 eq.) was added dropwise to the solution of fuming ΗΝΟ₃ (12 ml, 290 mmol, 3.15 eq.) in cone. H₂SO₄ (60 ml) at 0°C. The mixture was stirred at 60°C for 3 h. The reaction mixture was poured into crushed ice carefully, neutralized to pH=7 with aqueous NaOH solution. The solution was extracted with CH₂CI₂, washed with brine, dried over Na₂S0₄. The solvent was removed under vacuum. The residue was washed with t-butyl methyl ether to give pure intermediate 1 1 (8.5 g, 45percent yield).

Reference： [1] Patent: WO2014/114776, 2014, A1, . Location in patent: Page/Page column 25

[ 823-58-5 ] Synthesis Path-Downstream 1~40

2
[ 823-58-5 ]
[ 98-88-4 ]
[ 111163-93-0 ]

Reference： [1]Chemical and pharmaceutical bulletin,1958,vol. 6,p. 331,333
[2]Chemical and pharmaceutical bulletin,1958,vol. 6,p. 331,333

3
[ 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

4
[ 6082-66-2 ]
[ 823-58-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With ammonium hydroxide; In water; at 75℃; for 16h;	Example 24A 3,6-dichloropyridazin-4-amine <strong>[6082-66-2]3,4,6-Trichloropyridazine</strong> (25 g, 136 mmol) was added to 14. 8 N ammonium hydroxide (200 mL) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 16 hours at 75 C. The mixture was cooled to ambient temperature, and 17 g (76%) of the title compound was collected by filtration as a solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.16 (s, 2H), 6.82 (s, 1H); MS (ESI+) m/z 164 (M+H)+.
35%	With ammonia; In methanol; at 100℃; for 0.166667h;	Step 1. 3,6-dichloropyridazin-4-amine A glass microwave reaction vessel was charged with <strong>[6082-66-2]<strong>[6082-66-2]3,4,6-trichloropyridazin</strong>e</strong> (732 mg, 3991 mumol), ammonia, (2.0 M solution in methanol, 3991 mul, 7982 mumol). The reaction mixture was stirred and heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 100 C. for 10 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (80% EtOAc/hexanes) to give 6-dichloropyridazin-4-amine (226 mg, 35% yield). MS (ESI positive ion) m/z: 164 (M+1). 1H NMR (300 MHz, DMSO-d6) delta ppm 6.83 (s, 1H) 7.15 (s, 2H)
32%	With ammonia; In methanol; at 100℃; for 0.5h;Microwave irradiation; Sealed tube;	Step 112.1: 3,6-dichloropyridazin-4-amine A MW vial was charged with <strong>[6082-66-2]<strong>[6082-66-2]3,4,6-trichloropyridazin</strong>e</strong> (5 g, 27.3 mmol) and 7N NH3 in MeOH (19.47 mL, 136 mmol). The MW vial was sealed and the resulting mixture was submitted to MW irradiation at 100 C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 35-60%) to afford the title product (1.49 g, 8.63 mmol, 32% yield) as yellow solid. tR: 1.61 min (HPLC 1); tR: 0.45 min (LC-MS 2); ESI-MS: 163 [M+H]+ (LC-MS 2); Rf=0.40 (hexane/EtOAc 1:1).

32%	With ammonia; In methanol; at 100℃; for 0.5h;Microwave irradiation; Sealed tube;	A MW vial was charged with <strong>[6082-66-2]<strong>[6082-66-2]3,4,6-trichloropyridazin</strong>e</strong> (5 g, 27.3 mmol) and 7N NH3 in MeOH (19.47 mL, 136 mmol). The MW vial was sealed and the resulting mixture was submitted to MWirradiation at 100 00 for 30 mm. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 35-60%) to afford the title product (1.49 g, 8.63 mmol, 32% yield) as yellow solid. tR: 1.61 mm (HPLC 1); tR: 0.45 mm (LC-MS 2); ESI-MS: 163 [M+H] (LC-MS 2); R = 0.40 (hexane/EtOAc 1:1).
	With ammonia; water; at 75℃; for 16h;	A suspension of 3,4, 6-trichloropyridazine (prepared by the method of B. Kasnar et al, Nucleosides and Nucleotides, 1994, 13, 459) (lO. Og) in conc. aqueous ammonia (1 L) was heated at 75C for 16h. The mixture was concentrated to a small volume and extracted several times with ethyl acetate. The extracts were washed with brine, dried and evaporated. The crude product was recrystallised from ethyl acetate to give the product (5., 03g).

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 11497 - 11505
[2]Journal of Organic Chemistry,2014,vol. 79,p. 10311 - 10322
[3]Patent: US2017/15675,2017,A1 .Location in patent: Paragraph 1001
[4]Angewandte Chemie - International Edition,2019,vol. 58,p. 1007 - 1012
Angew. Chem.,2019,vol. 131,p. 1019 - 1024,6
[5]Patent: US2009/163489,2009,A1 .Location in patent: Page/Page column 51
[6]Patent: US2014/349990,2014,A1 .Location in patent: Paragraph 1051; 1052
[7]Patent: WO2014/191896,2014,A1 .Location in patent: Page/Page column 217; 218
[8]Pharmaceutical Bulletin,1956,vol. 4,p. 138
Chemical and Pharmaceutical Bulletin,1958,vol. 6,p. 641,644
[9]Patent: WO2003/87098,2003,A1 .Location in patent: Page/Page column 111

5
[ 17285-22-2 ]
[ 823-58-5 ]

Reference： [1]Chemical and pharmaceutical bulletin,1958,vol. 6,p. 641,644

6
[ 823-58-5 ]
[ 4637-24-5 ]
[ 106391-15-5 ]

Reference： [1]Monatshefte fur Chemie,1986,vol. 117,p. 221 - 230

9
[ 6082-66-2 ]
[ 7664-41-7 ]
[ 823-58-5 ]

Reference： [1]Pharmaceutical Bulletin,1956,vol. 4,p. 138
Chemical and Pharmaceutical Bulletin,1958,vol. 6,p. 641,644

10
[ 823-58-5 ]
[ 76-83-5 ]
[ 887310-62-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 0 - 60℃; for 1.58333h;	3,6-Dichloropyridazin-4-amine (683 mg) was added portionwise to a suspension of sodium hydride (60% dispersion in mineral oil; 230 mg) in THF (15 mL) that had been cooled to O0C. The reaction mixture was allowed to warm to room temperature over 45 minutes. The mixture was re-cooled to 0C and trityl chloride (1.25 equivalents) was added. The resultant mixture was heated to 600C for 1 hour. Water (5 mL) was added and mixture was extracted with ethyl acetate. The organic layer was evaporated and the residue was purified by column chromatography on silica using a solvent gradient of 0% to 15% diethyl ether in dichloromethane as eluent. There was thus obtained 3,6-dichloro-N-tritylpyridazin-4-amine as a solid (150 mg); Mass Spectrum: M+H+ 404.

Reference： [1]Patent: WO2006/51270,2006,A1 .Location in patent: Page/Page column 152

11
[ 887310-61-4 ]
[ 823-58-5 ]

Yield	Reaction Conditions	Operation in experiment
		A 4M solution of hydrogen chloride in 1,4-dioxane (60 mL) was added to a solution of tert-butyl iV-(3,6-dichloropyridazin-4-yl)carbamate (4.55 g) in dichloromethane (30 mL) and the reaction mixture was stirred at room temperature overnight. The resultant precipitate was isolated and suspended in dichloromethane (20 mL). The mixture was basified by the addition of a 7M methanolic ammonia solution. The resultant mixture was filtered and the filtrate was evaporated to give 3,6-dichloropyridazin-4-amine as a white solid (1.3 g); 1H NMR Spectrum: (DMSOd6) 6.85 (s, IH), 7.15 (br s, 2H).

Reference： [1]MedChemComm,2014,vol. 5,p. 540 - 546
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2807 - 2812
[3]Patent: WO2006/51270,2006,A1 .Location in patent: Page/Page column 152

12
[ 823-58-5 ]
[ 934-26-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	With hydrazine hydrate; In ethanol; at 100℃; for 3.0h;	Step 112.2: 6-chloro-3-hydrazinylpyridazin-4-amine To a stirred suspension of 3,6-dichloropyridazin-4-amine (Step 112.1) (1.49 g, 9.09 mmol) in EtOH (15 mL) was added hydrazine hydrate (11.04 mL, 227 mmol) and the resulting mixture was heated up and stirred at 100 C. for 3 hr. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was triturated with water (25 mL) to afford the title product (478 mg, 3 mmol, 33% yield) as yellow solid. tR: 0.24 min (LC-MS 2); ESI-MS: 160 [M+H]+ (LC-MS 2); ESI-MS: 158 [M-H]- (LC-MS 2).
33%	With hydrazine hydrate; In ethanol; at 100℃; for 3.0h;	To a stirred suspension of 3,6-dichloropyridazin-4-amine (Step 112.1) (1.49 g, 9.09 mmol) in EtOH (15 mL) was added hydrazine hydrate (11.04 mL, 227 mmol) and the resulting mixture was heated up and stirred at 100 00 for 3 hr. The reaction was cooled down to RT andconcentrated under reduced pressure. The crude product was triturated with water (25 mL) to afford the title product (478 mg, 3 mmol, 33% yield) as yellow solid. tR: 0.24 mm (LC-MS 2); ESIMS: 160 [M+H] (LC-MS 2); ESl-MS: 158 [M-H] (LC-MS 2).
	With hydrazine hydrate; In ethanol; water;	Step A: 3-hydrazino-4-amino-6-chloropyridazine A stirred solution of 2.0 grams of 4-amino-3,6-dichloropyridazine and 2.5 ml of hydrazine hydrate in 20 ml of ethanol is heated under reflux for three hours. After this time water is added to the reaction mixture and the resultant precipitate collected by filtration. The filter cake is recrystallized from ethanol to yield 2.3 grams of 3-hydrazino-4-amino-6-chloropyridazine; m.p. 190 C.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2807 - 2812
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 1007 - 1012
Angew. Chem.,2019,vol. 131,p. 1019 - 1024,6
[3]Patent: US2014/349990,2014,A1 .Location in patent: Paragraph 1053; 1054
[4]Patent: WO2014/191896,2014,A1 .Location in patent: Page/Page column 218
[5]Patent: US4728355,1988,A
[6]Journal of the American Chemical Society,2019,vol. 141,p. 11497 - 11505

13
[ 823-58-5 ]
[ 14704-64-4 ]

Yield	Reaction Conditions	Operation in experiment
73%		A mixture of 40 (0.127 g, 0.774 mmol; CASRN 823-58-5) and 4% aqueous NaOH solution (3 mL) was heated at reflux for 21 h, then cooled to RT. The pH was adjusted to 4 with glacial HOAc, then the mixture was partitioned between H2O (20 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 0.082 g (73%) of 42a as a pink solid that was used without further purification.
	With sodium hydroxide; In water; at 100℃; for 24h;	A mixture of <strong>[823-58-5]3,6-dichloropyridazin-4-amine</strong> (6 g, 36.59 mmol, 1 eq) in NaOH aq. (100 mL, 4% aq.) was stirred at 100 C for 24 h. The reaction mixture was quenched by addition HCl 1N until pH ~ 5~6, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (150 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-amino-3-chloro-1H-pyridazin-6-one (I-145) (4.1 g) as a brown solid which was used to do next step without purification.

Reference： [1]Patent: US2009/105209,2009,A1 .Location in patent: Page/Page column 52
[2]Patent: WO2020/33784,2020,A1 .Location in patent: Paragraph 00390

14
[ 823-58-5 ]
[ 2365-48-2 ]
[ 495415-02-6 ]

Yield	Reaction Conditions	Operation in experiment
13%		To a well-stirred suspension of sodium hydride (60% in mineral oil, 0.35 g, 8.5 mmol) in anhydrous dimethylformamide (10 mL) at 0C was added methyl mercaptoacetate (0.70 mL, 7.9 mmol). After stirring at this temperature for 20 min, a solution of amine (312a) (1.29 g, 7. 87 mmol) in dimethylformamide (10 mL) was added. The mixture was stirred at room temperature for 16h, then most of the solvent was removed in vacuo. The residue was diluted with water, the precipitate was filtered off, washed with water and dried. Chromatography on silica gel (0-2% methanol/dichloromethane) gave the product (0. 21g, 13%). MS (+ve ion electrospray) m/z 202/204 (MH+)

Reference： [1]Patent: WO2003/87098,2003,A1 .Location in patent: Page/Page column 111-112

15
[ 823-58-5 ]
[ 141699-55-0 ]
[ 1355345-74-2 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 1,1-dimethylethyl 3 -hydroxy- 1 -azetidinecarboxylate (3.8 g, 22.0 mmol) in DMF (100 mL) was treated with sodium hydride (60% in oil, 805 mg, 18.3 mmol), and the resultant mixture was stirred at ambient temperature for 10 min. 3,6-Dichloro- 4-pyridazinamine (3.0 g, 18.3 mmol) was added, and the mixture was stirred at 90 C overnight. The cooled mixture was diluted with ethyl acetate and washed with water (3x), brine and dried (MgSC^). The residue after concentration was purified by chromatography (silica gel, gradient of 20%? 50% EtOAc in hexanes) followed by trituration with ethyl ether to give the title product as a white solid (1.6 g)..H NMR (acetone-^) delta 6.71 (s, 1H), 6.18 (br s, 2H), 5.46 (m, 1H), 4.32 (br m, 2H), 3.95 (m, 2H), 1.42 (s, 9H).

Reference： [1]Patent: WO2012/12366,2012,A1 .Location in patent: Page/Page column 52

16
[ 823-58-5 ]
[ 75-89-8 ]
[ 1364677-10-0 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide monohydrate; In water; dimethyl sulfoxide; at 20 - 80℃; for 20h;	To a solution of 3.28 g <strong>[823-58-5]3,6-dichloro-pyridazin-4-ylamine</strong> in 30 mL dimethylsulfoxide and 4.0 g trifluoroethanol was added 1.84 g lithium hydroxide hydrate and 3 mL water and the mixture was heated to 80 C. for 18 h. The reaction mixture was diluted with 100 mL water and stirred at ambient temperature for 2 h. The resulting solid was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.84 g of the title compound as off white crystals, MS 228.1 and 230.1 (M+H)+.
	With lithium hydroxide monohydrate; In water; dimethyl sulfoxide; at 80℃; for 18h;	To a solution of 3.28 g <strong>[823-58-5]3,6-dichloro-pyridazin-4-ylamine</strong> in 30 mL dimethyl sulfoxide and 4.0 g trifluoroethanol was added 1.84 g lithium hydroxide hydrate and 3 mL water and the mixture was heated to 80 C for 18 h. The reaction mixture was diluted with 100 mL water and stirred at ambient temperature for 2 h. The resulting solid was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.84 g of the title compound as off white crystals, MS 228.1 and 230.1 (M+H)+
	With lithium hydroxide monohydrate; In water; dimethyl sulfoxide; at 20 - 80℃; for 20h;	Example 16h6-Chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazin-4-ylamineTo a solution of 3.28 g <strong>[823-58-5]3,6-dichloro-pyridazin-4-ylamine</strong> in 30 ml dimethylsulfoxide and 4.0g trifluoroethanol was added 1.84 g lithium hydroxide hydrate and 3 ml water and the mixture was heated to 80 C for 18 h. The reaction mixture was diluted with 100 ml water and stirred at ambient temperature for 2 h. The resulting solid was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.84 g of the title compound as off white crystals. MS (EI): 228.1 and 230.1 (M+H).

With water; lithium hydroxide; In dimethyl sulfoxide; at 80℃; for 18h;

Example 16h6-Chloro-3-(2,2,2-trifluoro-ethoxy)-pyridazin-4-ylamine To a solution of 3.28 g <strong>[823-58-5]3,6-dichloro-pyridazin-4-ylamine</strong> in 30 ml dimethylsulfoxide and 4.0 g trifluoroethanol was added 1.84 g lithium hydroxide hydrate and 3 ml water and the mixture was heated to 80 C. for 18 h. The reaction mixture was diluted with 100 ml water and stirred at ambient temperature for 2 h. The resulting solid was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.84 g of the title compound as off white crystals. MS (EI): 228.1 and 230.1 (M+H).

Reference： [1]Patent: US2012/65212,2012,A1 .Location in patent: Page/Page column 20-21
[2]Patent: WO2012/32018,2012,A1 .Location in patent: Page/Page column 43
[3]Patent: WO2012/80144,2012,A1 .Location in patent: Page/Page column 57
[4]Patent: US2012/157476,2012,A1 .Location in patent: Page/Page column 27

17
[ 823-58-5 ]
C₄H₇Cl₂N₅ [ No CAS ]

Reference： [1]MedChemComm,2014,vol. 5,p. 540 - 546

18
[ 823-58-5 ]
[ 1458-98-6 ]
[ 29049-35-2 ]

Yield	Reaction Conditions	Operation in experiment
52%		General procedure: KOt-Bu (4.56 g, 40.73 mmol) was added to a stirred solution of2-chloro-5-iodopyridin-4-ylamine (8.62 g, 33.94 mmol) inanhydrous THF (140 mL), and the mixture was stirred at r.t. for15 min. 3-Bromo-2-methylpropene (5.51 g, 40.73 mmol) wasadded, and the mixture was stirred at r.t. overnight. The solventwas removed in vacuo and the residues partitioned betweenCH2Cl2 (100 mL) and H2O (100 mL). The organic layer was separated,the solvent removed in vacuo, and the residues subjectedto column chromatography on silica. Elution with 5-20% EtOAcin PE afforded (2-chloro-5-iodopyridin-4-yl)-(2-methylallyl)amine
211.7 g		Preparation 33: (3,6-Dichloro-pyridazin-4-yI)-(2-methyl-aIIyI)-aminePotassium tert-butoxide (157.5 g) was charged portionwise to a stirred solution of 3,6-dichloro- pyridazin-4-ylamine (210 g) in THF (3.36 L). After 15 minutes, 3-bromo-2-methylpropene (141.8mL) was added dropwise over a period of 30 minutes, maintaining the temperature <25 00. The solution was allowed to stir at room temperature for 16 h, after which time the reaction was concentrated and the residue partitioned between DCM (6 L) and water (6 L). The aqueous phase was extracted with DCM (2 x 5 L). The combined organic phases were washed (brine, 5 L), dried with magnesium sulfate, filtered and concentrated. Chromatography (Silica gel, elutingwith 70:30 Heptane:- EtOAc) gave the title compound (211.7 g). 1H NMR (270 MHz, CDCI3):6.49 (1H, 5), 5.48 (1H, brs), 5.00 (1H, 5), 4.91 (1H, 5), 3.81 (2 H, d, J= 6Hz), 1.80 (3H, 5).
211.7 g	With potassium tert-butylate; In tetrahydrofuran; at 20 - 25℃; for 16.5h;	Preparation 49: (3,6-Dichloro-pyridazin-4-yI)-(2-methyl-aIIyI)-amine Potassium teit-butoxide (157.5 g) was charged portionwise to a stirred solution of 3,6- dichloro-pyridazin-4-ylamine (210 g) in THF (3.36 L). After 15 minutes, 3-bromo-2- methylpropene (141.8 mL) was added dropwise over a period of 30 minutes, maintaining the temperature <25 00. The solution was allowed to stir at room temperature for 16 h, after which time the reaction was concentrated and the residue partitioned between DCM (6 L) and water (6 L). The aqueous phase was extracted with DCM (2 x 5 L). The combined organic phases were washed (brine, 5 L), dried with magnesium sulfate, filtered andconcentrated. Chromatography (silica gel, eluting with 70:30 Heptane:- EtOAc) gave the title compound (211.7 g). 1H NMR (270 MHz, CDCI3): 6.49 (1H, 5), 5.48 (1H, br 5), 5.00 (1H, 5),4.91 (1H, 5), 3.81 (2 H, d, J= 6Hz), 1.80 (3H, 5).

Reference： [1]Synlett,2015,vol. 26,p. 2570 - 2574
[2]Patent: WO2014/60767,2014,A1 .Location in patent: Page/Page column 123
[3]Patent: WO2014/60770,2014,A1 .Location in patent: Page/Page column 150; 151

19
[ 823-58-5 ]
[ 28682-68-0 ]

Yield	Reaction Conditions	Operation in experiment
45%	With sulfuric acid; nitric acid; at 0 - 60℃; for 3.0h;	The commercially available 3,6-dichloropyridazine-4-amine (15 g, 92 mmol, 1 eq.) was added dropwise to the solution of fuming EtaNuOmicron3 (12 ml, 290 mmol, 3.15 eq.) in cone. H2SO4 (60 ml) at 0C. The mixture was stirred at 60C for 3 h. The reaction mixture was poured into crushed ice carefully, neutralized to pH=7 with aqueous NaOH solution. The solution was extracted with CH2CI2, washed with brine, dried over Na2S04. The solvent was removed under vacuum. The residue was washed with t-butyl methyl ether to give pure intermediate 1 1 (8.5 g, 45% yield).

Reference： [1]Chemical Communications,2020,vol. 56,p. 1493 - 1496
[2]Patent: WO2014/114776,2014,A1 .Location in patent: Page/Page column 25
[3]Journal of the American Chemical Society,2020,vol. 142,p. 3652 - 3657

20
[ 823-58-5 ]
[ 74-89-5 ]
[ 17645-17-9 ]

Yield	Reaction Conditions	Operation in experiment
57%	In ethanol; at 100℃; for 48h;Autoclave;	In an autoclave, <strong>[823-58-5]3,6-dichloropyridazin-4-amine</strong> (2.35 g, 14.3 mmol) was treated with Methylamine dissolved in EtOH (20.2 g, 215 mmol, 26.7 mL) and heated to 100C. After 48h at 100C LCMS showed no more starting material. The reaction mixture was evaporated to dryness. The crude product was diluted in dichloromethane and 4ml Et3N was added. The mixture was stirred 5' at rt and evapourated. The residue was diluted with 5ml water and the insoluble material was filtrated and dried to give the title product 1 .35g , 57%) as a pale brown solid. LCMS (Method ZCQ13): Rt. 0.17 min, 157/159 (M-H).

Reference： [1]Patent: WO2015/715,2015,A1 .Location in patent: Page/Page column 124

21
[ 10344-42-0 ]
[ 823-58-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With ammonia; In ethanol; at 20℃;Autoclave;	4-Bromo-3,6-dichloro-pyridazine (15.0 g, 65.8 mmol, prepared as described in WO 20081 16815) was dissolved in EtOH (73.1 mL) and introduced into an autoclave. At rt, gaseous NH3 (4.48 g, 263mmol) was introduced, and the reaction mixture was then stirred over night at reflux. The solution was concentrated in vacuo and the residue was triturated with EtOAc, the insoluble part was filtrated off, and the mother liquor evaporated to give the crude product. This was purified by Flash-Chromatography, eluting with cyclohexan /EtOAc 1/1 +2.5% Et3N, to give the title compound as a pale brown solid (5.82g, 53%). LCMS (method ZCQ13): Rt. 0.3min, 164/166/168 (M+H)

Reference： [1]Patent: WO2015/715,2015,A1 .Location in patent: Page/Page column 123; 124

22
[ 823-58-5 ]
[ 5720-07-0 ]
6-chloro-3-(4-methoxyphenyl)pyridazin-4-amine [ No CAS ]