[ CAS No. 1121-79-5 ] {[proInfo.proName]}

Name: 1121-79-5|3-Chloro-6-methylpyridazine|98%
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Quality Control of [ 1121-79-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1121-79-5 ]

Product Details of [ 1121-79-5 ]

CAS No. :	1121-79-5	MDL No. :	MFCD00052905
Formula :	C₅H₅ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PRORLQAJNJMGAR-UHFFFAOYSA-N
M.W :	128.56	Pubchem ID :	227254
Synonyms :

Calculated chemistry of [ 1121-79-5 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	32.01
TPSA :	25.78 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) :	-6.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.69
Log Po/w (XLOGP3) :	1.21
Log Po/w (WLOGP) :	1.44
Log Po/w (MLOGP) :	0.94
Log Po/w (SILICOS-IT) :	2.04
Consensus Log Po/w :	1.47

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.95
Solubility :	1.43 mg/ml ; 0.0111 mol/l
Class :	Very soluble
Log S (Ali) :	-1.35
Solubility :	5.77 mg/ml ; 0.0449 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.62
Solubility :	0.311 mg/ml ; 0.00242 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.56

Safety of [ 1121-79-5 ]

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

Application In Synthesis of [ 1121-79-5 ]

* 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 [ 1121-79-5 ]
Downstream synthetic route of [ 1121-79-5 ]

[ 1121-79-5 ] Synthesis Path-Upstream 1~9

1
[ 13327-27-0 ]
[ 1121-79-5 ]

Reference： [1] Patent: US4595521, 1986, A,
[2] Patent: EP1422218, 2004, A1, . Location in patent: Page 174
[3] Patent: EP1555259, 2005, A1, . Location in patent: Page/Page column 40

2
[ 13327-27-0 ]
[ 10025-87-3 ]
[ 1121-79-5 ]

Reference： [1] Chemische Berichte, 1901, vol. 34, p. 3263

3
[ 1121-79-5 ]
[ 13327-27-0 ]

Reference： [1] Journal of the Chemical Society, 1948, p. 2191,2194
[2] Patent: WO2004/72029, 2004, A2, . Location in patent: Page 34; 36

4
[ 1121-79-5 ]
[ 2164-61-6 ]

Reference： [1] Journal of the American Chemical Society, 1953, vol. 75, p. 4086

5
[ 1121-79-5 ]
[ 124-41-4 ]
[ 17644-83-6 ]

Reference： [1] Heterocycles, 1992, vol. 34, # 9, p. 1759 - 1771
[2] Chemische Berichte, 1901, vol. 34, p. 3263

6
[ 1121-79-5 ]
[ 38956-79-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With hydrazine In ethanol for 2.5 h; Heating / reflux	[Reference Example 35] 3-Hydrazino-6-methylpyridazine [Show Image] Hydrazine monohydrate (45 mL) was added to a suspension of 3-chloro-6-methylpyridazine (3.00 g) in ethanol (45 mL), and the resultant mixture was heated to reflux for 2.5 hours. After air cooling, a residue obtained by evaporating the solvent of the reaction solution under reduced pressure was purified by silica gel chromatography (chloroform-methanol-water (a lower layer solvent of 7: 3: 1 (v/v)), to obtain the title compound (2.35 g, 81percent) as a solid. ¹H-NMR(400MHz, DMSO-d₆)δ: 2.39(3H, s), 4.20(2H, br), 6.94(1H, d, J=9.3Hz), 7.18(1H, d, J=9.3Hz), 7.64(1H, br). ESI-MSm/z: 125(M+H)⁺.
80%	With hydrazine In ethanol for 3 h; Heating / reflux	Example 11: 6-Methyl-[l,2,4]triazolo[4,3-b]pyridazine-3-thioI; Step 1: (6-Methyl-pyridazin-3-yl)-hydrazine; [0372J To a suspension of 3-chloro-6-methyl-pyridazine (3 g, 23.3 mmol) in ethanol (45 mL) was added hydrazine hydrate (45 mL) and the resultant mixture was heated to reflux for 3 hrs. Most of the solvent was removed under reduced pressure and the white solid was collected by filtration and washed with ethanol. Upon drying 2.3 g of (6-methyl-pyridazin- 3 -yl) -hydrazine was obtained as a white crystalline solid (80percent yield).

Reference： [1] Patent: EP1785418, 2007, A1, . Location in patent: Page/Page column 53
[2] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 107
[3] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1259 - 1261
[4] Journal of the Chemical Society, 1950, p. 3236,3239
[5] Patent: US2484029, 1946, ,
[6] Yakugaku Zasshi, 1955, vol. 75, p. 773[7] Chem.Abstr., 1956, p. 4976

7
[ 1121-79-5 ]
[ 5096-73-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	at 50℃; for 4 h;	A. To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmol) in 140 mL of concentrated sulfuric acid, finely powdered potassium dichromate (55.40 g) was added slowly, the temperature being kept below 50° C. When the addition was complete, stirring was continued for another 4 hours at 50° C. The viscous, dark green liquid was then cooled and crushed ice was added cautiously. The reaction mixture was extracted with ethyl acetate (6*400 mL). The ethyl acetate extracts were combined, dried over anhydrous Na₂SO₄. The solvent was concentrated in vacuo to yield slightly red colored 6-chloropyridazine-3-carboxylic acid (106.6 mmol). This material was used for next reaction without further purification. Yield 69percent. m.p. 145° C. (dec). ¹H NMR (300 MHz, DMSO-d₆) δ 13.1, 8.20, 8.05.
69%	at 50℃; for 4 h;	A. To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmol) in 140 mL of concentrated sulfuric acid, finely powdered potassium dichromate (55.40 g) was added slowly, the temperature being kept below 50° C. When the addition was complete, stirring was continued for another 4 hours at 50° C. The viscous, dark green liquid was then cooled and crushed ice was added cautiously. The reaction mixture was extracted with ethyl acetate (6*400 mL). The ethyl acetate extracts were combined, dried over anhydrous Na₂SO₄. The solvent was concentrated in vacuo to yield slightly red colored 6-chloropyridazine-3-carboxylic acid (106.6 mmol). This material was used for next reaction without further purification. Yield 69percent. m.p. 145° C. (dec). ¹H NMR (300 MHz, DMSO-d₆) δ 13.1, 8.20, 8.05.
69%	at 50℃; for 4 h;	PREPARATION 2 SYNTHESIS OF 6-CHLOROPYRIDAZINE-3-CARBOXYLIC ACID To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmol) in 140 mL of concentrated sulfuric acid, finely powdered potassium dichromate (55.40 g) was added slowly, the temperature being kept below 50 °C. When the addition was complete, stirring was continued for another 4 hours at 50 °C. The viscous, dark green liquid was then cooled and crushed ice was added cautiously. The reaction mixture was extracted with ethyl acetate (6 x 400 mL). The ethyl acetate extracts were combined, dried over anhydrous Na₂SO₄. The solvent was concentrated in vacuo to yield slightly red colored 6-chloropyridazine-3-carboxylic acid (106.6 mmol). This material was used for next reaction without further purification. Yield 69percent. m.p. 145°C (dec). ¹H NMR (300 MHz, DMSO-d₆) δ 13.1, 8.20, 8.05.

57%	at 50℃;	Potassium dichromate (3.3 g, 11.2 mmol) was added in portions to a solution of 3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in [H2SO4] (10 ml). After addition the mixture is stirred at 50 [°C] on. The reaction was pored on ice and the mixture was extracted three times with diethyl ether. The combined organic phases were dried and concentrated to give the title compound (840 mg, 57percent). [LC-MS] [(M++1)] : 159 and 161 (3: 1).
40%	at 0 - 50℃; for 2 h;	To a stirred solution of 3-chloro-6-methylpyridazine (5.0 g, 39.0 mmol) in concentrated H₂S0₄ (20.0 mL) was added K₂Cr₂0₇ (13.7 g, 46.8 mmol) in portions at 0 °C. After addition the mixture was heated to 50 °C for 2 h, the mixture was poured into ice. The water layer was extracted with EtOAc six times. The organic phase was dried and concentrated to give 6-chloropyridazine-3-carboxylic acid (2.5 g, 40percent). MS (ESI) calcd for C₅H₃C1N₂0₂: 157.99.
34%	at 20 - 50℃; for 61.5 h; Cooling with ice	3-Chloro-6-methylpyridazine (3.00 g, 23.3 mmol) was dissolved in concentrated sulfuric acid (23 mL), and potassium dichromate (8.24 g, 28.0 mmol) was added little by little under ice cooling. The mixture was stirred at room temperature for 1.5 hours, and the mixture was further stirred at 50°C for 60 hours. The reaction mixture was slowly poured into ice water, and the mixture was extracted with diethyl ether (x 3). The organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (1.27 g; yield, 34percent) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.80 (1H, d, J = 7.8 Hz), 8.32 (1H, d, J = 7.8 Hz). MS (ESI) m/z: 159 (M+H) ⁺.
27%	With potassium dichromate; sulfuric acid In water at 60℃; for 24 h;	6-Chloro-pyridazine-3-carboxylic Acid A mixture of 3-chloro-6-methyl-pyridazine (10.0 g, 77.8 mmol) and K₂Cr₂O₇ (38.1 g, 128 mmol) in conc. H₂SO₄ (150 ml) was heated to 60° C. for 24 h. The mixture was poured onto ice/water and extracted with EtOAc. The combined org. layers were then concentrated in vacuo and then taken up in EtOAc. The suspension was filtered and dried in vacuo to give 6-chloro-pyridazine-3-carboxylic acid (80percent pure, 4.1 g, 27percent). UPLC (5-100percent CH₃CN): t_R=0.523 min, MS (ES-): 157 [M-1].
27%	at 60℃; for 24 h;	β-Chloro-pyridazine-S-carboxylic acidA mixture of 3-chloro-6-methyl-pyridazine (10.0 g, 77.8 mmol) and K₂Cr₂O₇ (38.1 g, 128 mmol) in cone. H₂SO₄ (150 ml) was heated to 60 ⁰C for 24 h. The mixture was poured onto ice/water and extracted with EtOAc. The combined org. layers were then concentrated in vacuo and then taken up in EtOAc. The suspension was filtered and dried in vacuo to give 6- chloro-pyridazine-3-carboxylic acid (80percent pure, 4.1 g, 27 percent). UPLC (5-100percent CH₃CN): t_R = 0.523 min, MS (ES-): 157 [M-1].

Reference： [1] Patent: US2008/125434, 2008, A1, . Location in patent: Page/Page column 15
[2] Patent: US2008/207587, 2008, A1, . Location in patent: Page/Page column 14
[3] Patent: EP2316827, 2016, B1, . Location in patent: Paragraph 0103
[4] Patent: WO2004/14881, 2004, A2, . Location in patent: Page 148-149
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 479 - 483
[6] Patent: WO2013/59589, 2013, A1, . Location in patent: Page/Page column 78
[7] Patent: EP2409977, 2012, A1, . Location in patent: Page/Page column 45
[8] Patent: US2009/105266, 2009, A1, . Location in patent: Page/Page column 29
[9] Patent: WO2008/128968, 2008, A1, . Location in patent: Page/Page column 66
[10] Journal of the American Chemical Society, 1953, vol. 75, p. 4086
[11] Journal of the Chemical Society, 1948, p. 2191,2194
[12] Journal of the Chemical Society, 1948, p. 2191,2194
[13] Patent: WO2007/9236, 2007, A1, . Location in patent: Page/Page column 42-43
[14] Patent: WO2007/71023, 2007, A1, . Location in patent: Page/Page column 34
[15] Patent: CN105622519, 2016, A, . Location in patent: Paragraph 0010
[16] Patent: WO2007/143823, 2007, A1, . Location in patent: Page/Page column 36

8
[ 1121-79-5 ]
[ 37972-69-3 ]

Reference： [1] Journal of the Chemical Society, 1948, p. 2191,2194

9
[ 1121-79-5 ]
[ 65202-50-8 ]

Reference： [1] Patent: WO2007/143823, 2007, A1,

[ 1121-79-5 ] Synthesis Path-Downstream 1~88

1
[ 1121-79-5 ]
[ 124-41-4 ]
[ 17644-83-6 ]

Reference： [1]Heterocycles,1992,vol. 34,p. 1759 - 1771
[2]Chemische Berichte,1901,vol. 34,p. 3263

2
[ 1121-79-5 ]
[ 18591-87-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With ammonium hydroxide; copper(ll) sulfate pentahydrate; at 120℃; for 40h;	Step A: A mixture of 3-chloro-6-methylpyridazine (516 mg, 4.0 mmol), NH4OH (30%, 3 mL) and copper(II) sulfate pentahydrate (26 mg, 0.2 mmol) was stirred at 120 C. for 40 h. The mixture was cooled to room temperature and partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc five times. The combined organics were dried over NaSO4, filtered, concentrated and purified by silica gel column chromatography (0-10% MeOH in CH2Cl2) to give 6-methylpyridazin-3-amine (160 mg, 37%) as a white solid. MS m/z 109.9 [M+H]+.
20%	With ammonia; In water; at 170℃; for 24h;	Example 1.; Preparation of 8-(1-ethyl-propyl)-3-(2,4-dim_ethyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2- b]pyridazine.; EPO <DP n="26"/>A. 6-Methyl-pyridizin-3-ylarnine.; 3-Chloro-6-methylpyridazine (25.0g, 0.229 moles) is dissolve in 250 mL of NH4OH and heated to 170 C in a sealed container for 24 hours. The solvents are evaporated. The residue is triturated in methylene chloride, and a solid is filtered. This trituration procedure is repeated with the filtrate four times. The filtered solids are combined and dried in a vacuum oven overnight to obtain the title compound as an off- white solid 4.32 g (0.040 moles, 20%). 1H-NMR (dmso-d6): delta 7.1 (d, J = 8.9 Hz, 1H); 6.67 (d, J = 8.9 Hz, 1H); 6.04 (s, br, 2H); 2.33 (s, 3H) ppm. ES+ = 110 (100%, M + 1).
20.4%	With ammonia; In water; at 170℃; for 24h;	Dissolve 25.Og (0.229 moles) of 3-chloro-6-methylpyridazine in 250 ml of NH4OH and heat to 1700C. in a sealed container for 24 h. Evaporate solvents. Triturate in methylene chloride and filter solid. Repeat with filtrate 4 x. Combine all filtered solids and dry in vacuum oven over night to obtain product as off-white solid 4.32 g (0.040 moles, 20.4 %). H1NMR (DMSO-d6): delta 7.1 (d, J = 8.9 Hz, IH); 6.67 (d, J = 6.67 Hz, IH); 6.04 (s, br, 2H); 2.33 (s, 3H) ppm. ES+ = 110 (100%, M + 1).

Reference： [1]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 386; 387
[2]Patent: WO2006/102194,2006,A1 .Location in patent: Page/Page column 25
[3]Patent: WO2006/107784,2006,A1 .Location in patent: Page/Page column 33
[4]Chemische Berichte,1948,vol. 81,p. 1,10
[5]Journal of the Chemical Society,1947,p. 239,242

3
[ 1121-79-5 ]
[ 13327-27-0 ]

Reference： [1]Journal of the Chemical Society,1948,p. 2191,2194
[2]Patent: WO2004/72029,2004,A2 .Location in patent: Page 34; 36

4
[ 1121-79-5 ]
[ 38956-79-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	With hydrazine; In ethanol; for 2.5h;Heating / reflux;Product distribution / selectivity;	[Reference Example 35] 3-Hydrazino-6-methylpyridazine [Show Image] Hydrazine monohydrate (45 mL) was added to a suspension of 3-chloro-6-methylpyridazine (3.00 g) in ethanol (45 mL), and the resultant mixture was heated to reflux for 2.5 hours. After air cooling, a residue obtained by evaporating the solvent of the reaction solution under reduced pressure was purified by silica gel chromatography (chloroform-methanol-water (a lower layer solvent of 7: 3: 1 (v/v)), to obtain the title compound (2.35 g, 81%) as a solid. 1H-NMR(400MHz, DMSO-d6)delta: 2.39(3H, s), 4.20(2H, br), 6.94(1H, d, J=9.3Hz), 7.18(1H, d, J=9.3Hz), 7.64(1H, br). ESI-MSm/z: 125(M+H)+.
80%	With hydrazine; In ethanol; for 3h;Heating / reflux;	Example 11: 6-Methyl-[l,2,4]triazolo[4,3-b]pyridazine-3-thioI; Step 1: (6-Methyl-pyridazin-3-yl)-hydrazine; [0372J To a suspension of 3-chloro-6-methyl-pyridazine (3 g, 23.3 mmol) in ethanol (45 mL) was added hydrazine hydrate (45 mL) and the resultant mixture was heated to reflux for 3 hrs. Most of the solvent was removed under reduced pressure and the white solid was collected by filtration and washed with ethanol. Upon drying 2.3 g of (6-methyl-pyridazin- 3 -yl) -hydrazine was obtained as a white crystalline solid (80% yield).

Reference： [1]Patent: EP1785418,2007,A1 .Location in patent: Page/Page column 53
[2]Patent: WO2008/51808,2008,A2 .Location in patent: Page/Page column 107
[3]Journal of Heterocyclic Chemistry,1983,vol. 20,p. 1259 - 1261
[4]Journal of the Chemical Society,1950,p. 3236,3239

5
[ 1121-79-5 ]
[ 5096-73-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium dichromate; sulfuric acid; at 50℃; for 4h;	A. To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmol) in 140 mL of concentrated sulfuric acid, finely powdered potassium dichromate (55.40 g) was added slowly, the temperature being kept below 50 C. When the addition was complete, stirring was continued for another 4 hours at 50 C. The viscous, dark green liquid was then cooled and crushed ice was added cautiously. The reaction mixture was extracted with ethyl acetate (6*400 mL). The ethyl acetate extracts were combined, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to yield slightly red colored 6-chloropyridazine-3-carboxylic acid (106.6 mmol). This material was used for next reaction without further purification. Yield 69%. m.p. 145 C. (dec). 1H NMR (300 MHz, DMSO-d6) delta 13.1, 8.20, 8.05.
69%	With potassium dichromate; sulfuric acid; at 50℃; for 4h;Product distribution / selectivity;	A. To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmol) in 140 mL of concentrated sulfuric acid, finely powdered potassium dichromate (55.40 g) was added slowly, the temperature being kept below 50 C. When the addition was complete, stirring was continued for another 4 hours at 50 C. The viscous, dark green liquid was then cooled and crushed ice was added cautiously. The reaction mixture was extracted with ethyl acetate (6*400 mL). The ethyl acetate extracts were combined, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to yield slightly red colored 6-chloropyridazine-3-carboxylic acid (106.6 mmol). This material was used for next reaction without further purification. Yield 69%. m.p. 145 C. (dec). 1H NMR (300 MHz, DMSO-d6) delta 13.1, 8.20, 8.05.
69%	With potassium dichromate; sulfuric acid; at 50℃; for 4h;	PREPARATION 2 SYNTHESIS OF 6-CHLOROPYRIDAZINE-3-CARBOXYLIC ACID To a mechanically stirred solution of 3-chloro-6-methylpyridazine (155.6 mmol) in 140 mL of concentrated sulfuric acid, finely powdered potassium dichromate (55.40 g) was added slowly, the temperature being kept below 50 C. When the addition was complete, stirring was continued for another 4 hours at 50 C. The viscous, dark green liquid was then cooled and crushed ice was added cautiously. The reaction mixture was extracted with ethyl acetate (6 x 400 mL). The ethyl acetate extracts were combined, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to yield slightly red colored 6-chloropyridazine-3-carboxylic acid (106.6 mmol). This material was used for next reaction without further purification. Yield 69%. m.p. 145C (dec). 1H NMR (300 MHz, DMSO-d6) delta 13.1, 8.20, 8.05.

57%	With potassium dichromate; sulfuric acid; at 50℃;	Potassium dichromate (3.3 g, 11.2 mmol) was added in portions to a solution of 3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in [H2SO4] (10 ml). After addition the mixture is stirred at 50 [C] on. The reaction was pored on ice and the mixture was extracted three times with diethyl ether. The combined organic phases were dried and concentrated to give the title compound (840 mg, 57%). [LC-MS] [(M++1)] : 159 and 161 (3: 1).
40%	With potassium dichromate; sulfuric acid; at 0 - 50℃; for 2h;	To a stirred solution of 3-chloro-6-methylpyridazine (5.0 g, 39.0 mmol) in concentrated H2S04 (20.0 mL) was added K2Cr207 (13.7 g, 46.8 mmol) in portions at 0 C. After addition the mixture was heated to 50 C for 2 h, the mixture was poured into ice. The water layer was extracted with EtOAc six times. The organic phase was dried and concentrated to give 6-chloropyridazine-3-carboxylic acid (2.5 g, 40%). MS (ESI) calcd for C5H3C1N202: 157.99.
34%	With potassium dichromate; sulfuric acid; at 20 - 50℃; for 61.5h;Cooling with ice;	3-Chloro-6-methylpyridazine (3.00 g, 23.3 mmol) was dissolved in concentrated sulfuric acid (23 mL), and potassium dichromate (8.24 g, 28.0 mmol) was added little by little under ice cooling. The mixture was stirred at room temperature for 1.5 hours, and the mixture was further stirred at 50C for 60 hours. The reaction mixture was slowly poured into ice water, and the mixture was extracted with diethyl ether (x 3). The organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (1.27 g; yield, 34%) as a white solid. 1H NMR (CDCl3, 400 MHz): delta 7.80 (1H, d, J = 7.8 Hz), 8.32 (1H, d, J = 7.8 Hz). MS (ESI) m/z: 159 (M+H) +.
27%	With potassium dichromate; sulfuric acid; In water; at 60℃; for 24h;	6-Chloro-pyridazine-3-carboxylic Acid A mixture of 3-chloro-6-methyl-pyridazine (10.0 g, 77.8 mmol) and K2Cr2O7 (38.1 g, 128 mmol) in conc. H2SO4 (150 ml) was heated to 60 C. for 24 h. The mixture was poured onto ice/water and extracted with EtOAc. The combined org. layers were then concentrated in vacuo and then taken up in EtOAc. The suspension was filtered and dried in vacuo to give 6-chloro-pyridazine-3-carboxylic acid (80% pure, 4.1 g, 27%). UPLC (5-100% CH3CN): tR=0.523 min, MS (ES-): 157 [M-1].
27%	With potassium dichromate; sulfuric acid; at 60℃; for 24h;	beta-Chloro-pyridazine-S-carboxylic acidA mixture of 3-chloro-6-methyl-pyridazine (10.0 g, 77.8 mmol) and K2Cr2O7 (38.1 g, 128 mmol) in cone. H2SO4 (150 ml) was heated to 60 0C for 24 h. The mixture was poured onto ice/water and extracted with EtOAc. The combined org. layers were then concentrated in vacuo and then taken up in EtOAc. The suspension was filtered and dried in vacuo to give 6- chloro-pyridazine-3-carboxylic acid (80% pure, 4.1 g, 27 %). UPLC (5-100% CH3CN): tR = 0.523 min, MS (ES-): 157 [M-1].
	With potassium dichromate; sulfuric acid; at 60 - 65℃; for 3.66667h;	EXAMPLE l; EPO <DP n="44"/>2-(6-(4-[2-(rTrifluoromethyl')benzoyl1piperazin-l-v?pyridazin-3-yl)-l,3-benzothiazole; Step 1; 6-Chloropyridazine-3 -carboxylic acid; To concentrated sulfuric acid (175 mL) in a flask equipped with a mechanical stirrer was added 3-chloro-6-methylpyridazine (25 g, 194 mmol). To the resulting solution was added K2Cr2O7 (69 g, 234 mmol) portionwise over 40 min, using a cold water bath to maintain the internal temperature below 65 0C. The reaction was then maintained at 60 0C for 3 h. The mixture was cooled and quenched by the addition of ice, then poured onto 200 g ice and extracted eight times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give the title compound.
	With potassium dichromate; sulfuric acid; at 60 - 65℃; for 3.66667h;	Step 1: 6-Chloropyridazine-3-carboxylic acidTo concentrated sulfuric acid (175 mL) in a flask equipped with a mechanical stirrer was added 3-chloro-6-methylpyridazine (25 g, 194 mmol). To the resulting solution was added K2Cr2O7 (69 g, 234 mmol) portionwise over 40 min, using a cold water bath to maintain the internal temperature below 65 0C. The reaction was then maintained at 60 0C for 3 h. The mixture was cooled and quenched by the addition of ice, then poured onto 200 g ice and extracted eight times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give the title compound.
	With sulfuric acid; at 50℃; for 5h;	3-Chloro-6-methylpyridazine was added to sulfuric acid under ice-cooling, and the oxidizing agent was added in portions with stirring at a molar ratio of oxidant to 3-chloro-6-methylpyridazine of 4: 1 , Followed by reaction at 50 C for 5h, then cooled by adding ice water, diluted, extracted,The extracts were combined, dried, decompressed to dryness and the residue recrystallized to give the crystalline powder, 6-chloropyridazine-3-carboxylic acid;
	With potassium dichromate; sulfuric acid; at 60 - 65℃; for 3.33h;	EXAMPLE 6; Methyl 6-(3- { [2-(trifluoromethyl)benzylloxy\| azetidin- 1 -yl)pyridazine-3-carboxylate; Step 1 : -Chloropyridazine-S-carboxylic acid; Concentrated sulfuric acid (175 mL) was added into a flask equipped with a mechanical stirrer, and then 3-chloro-6-methylpyridazine (25 g, 194 mmol) was slowly added. To the resulting mixture was added K2Cr2O7 (69 g, 234 mmol) portion wise over 40 min, using a cold water bath to maintain the internal temperature below 65 C. The reaction was then maintained at 60 C for 3 h. The mixture was cooled and quenched by the addition of ice, then poured onto 200 g ice and extracted eight times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give the title compound as a beige solid.

Reference： [1]Patent: US2008/125434,2008,A1 .Location in patent: Page/Page column 15
[2]Patent: US2008/207587,2008,A1 .Location in patent: Page/Page column 14
[3]Patent: EP2316827,2016,B1 .Location in patent: Paragraph 0103
[4]Patent: WO2004/14881,2004,A2 .Location in patent: Page 148-149
[5]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 479 - 483
[6]Patent: WO2013/59589,2013,A1 .Location in patent: Page/Page column 78
[7]Patent: EP2409977,2012,A1 .Location in patent: Page/Page column 45
[8]Patent: US2009/105266,2009,A1 .Location in patent: Page/Page column 29
[9]Patent: WO2008/128968,2008,A1 .Location in patent: Page/Page column 66
[10]Journal of the American Chemical Society,1953,vol. 75,p. 4086
[11]Journal of the Chemical Society,1948,p. 2191,2194
[12]Patent: WO2007/9236,2007,A1 .Location in patent: Page/Page column 42-43
[13]Patent: WO2007/71023,2007,A1 .Location in patent: Page/Page column 34
[14]Patent: CN105622519,2016,A .Location in patent: Paragraph 0010
[15]Patent: WO2007/143823,2007,A1 .Location in patent: Page/Page column 36

6
[ 13327-27-0 ]
[ 10025-87-3 ]
[ 1121-79-5 ]

Reference： [1]Chemische Berichte,1901,vol. 34,p. 3263

7
[ 1121-79-5 ]
[ 201230-82-2 ]
[ 71-36-3 ]
n-Butyl 6-methylpyridazine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With triethylamine at 130℃; for 15h;
83%	With 1,1'-bis-(diphenylphosphino)ferrocene; triethylamine at 130℃; for 15h;

Reference： [1]Beller, Matthias; Maegerlein, Wolfganf; Indolese, Adriano F.; Fischer, Christine [Synthesis, 2001, # 7, p. 1098 - 1109]
[2]Beller, Matthias; Indolese, Adriano F. [Chimia, 2001, vol. 55, # 9, p. 684 - 687]

8
[ 1121-79-5 ]
[ 39800-84-5 ]
3-chloro-6-(3-ethyl-[1,2,4]thiadiazol-5-yl)-pyridazine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 589 - 591

9
[ 1121-79-5 ]
[ 6145-42-2 ]
[ 193955-37-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 589 - 591

10
[ 1121-79-5 ]
[ 120276-59-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With trichloroisocyanuric acid; In chloroform; at 60℃; for 16h;	Step 1. 3-Chloro-6-chloromethyl-pyridazine To a solution of 3-chloro-6-methyl-pyridazine (25 g, 0.2 mol) in chloroform (850 mL) at 60 C. was added trichloroisocyanuric acid (0.4 eqivalent, 18.1 mol) and stirred for 15 hours. An additional charge of trichloroisocyanuric acid (3 g) was added and the mixture heated for an additional hour. The mixture was then cooled in an ice bath and filtered over celite. The organic solution was concentrated to a yellow oil which darkened and solidified upon standing in the freezer (yield 30 g, 95%).
66%	With trichloroisocyanuric acid; In 1,2-dichloro-ethane; at 90℃;	A mixture of 3-chloro-6- methylpyridazine (1.00 g, 7.78 mmol) and 1,3,5-trichloroisocyanuric acid (0.72 g, 3.11 mmol) in DCE (50 mL) was stirred and heated at 90 C. The mixture was cooled and filtered through a Whatman 0.45 muetaiota frit. The collected white solid was washed with DCM. The solid was discarded and the collected filtrate was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide 3-chloro-6- (chloromethyl)pyridazine (0.84 g, 5.12 mmol, 66% yield) as a slightly purple solid. MS (ESI, pos. ion) m/z: 162.9 (M+l).
49.3%	With trichloroisocyanuric acid; In chloroform;Reflux;	A mixture of 3-chloro-6-methyl-pyridazine (4 g, 31.2 mmol) in CHCI3 (80 mL) was added l ,3,5-trichloro-[l ,3,5]triazinane-2,4,6-trione (2.47 g, 10.4 mmol) at room temperature. The mixture was refluxed till the reaction was over. The mixture was concentrated to give the residue, which was purified by column to give 3-chloro-6-chloromethyl-pyridazine (2.5 g, 49.3% yield). 1H NMR(400 MHz, CDC13) delta ppm 7.69 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.86 (s, 2H), ES-LCMS m/z 163 (M+ )+.

46%	With trichloroisocyanuric acid; In chloroform;Reflux;	To a refluxing solution of 3-chloro-6-methylpyridazine (5.0 g, 39 mmol) in chloroform (75 mL) was added trichloroisocyanuric acid (3.6 g, 16 mmol) portionwise. The solution was allowed to reflux overnight, after which the crude reaction mixture was filtered, washed with 1 M sodium hydroxide (NaOH), and the organic phase was dried over magnesium sulfate. The crude product was concentrated under reduced pressure and purified by silica gel chromatography to furnish 3-chloro-6-chloromethyl-pyridazine (D) as a yellow oil which upon sitting became a brown solid=2.9 g (46%).
39%	With trichloroisocyanuric acid; In chloroform; at 20 - 60℃;	Intermediate 4-(6-Chloro-pyridazin-3-yl)-cvclopropanecarbonitrileStep 1 : 3-chloro-6-chloromethyl-pyridazine; Trichloroisocyanuric acid (3.62 g) was added to a solution of 3-chloro-6-methyl-pyridazine (5.00 g) in chloroform (130 mL) heated to 60 C. The mixture was stirred at 60
	With N-chloro-succinimide; dibenzoyl peroxide; In tetrachloromethane;	Preparation 14 6-Chloro-3-chloromethylpyridazine A suspension of 3-chloro-6-methylpyridazine (3 g), benzoyl peroxide (150 mg) and N-chlorosuccinimide (3.12 g) in CCl4 (30 ml) was refluxed 16 hours, cooled, filtered and evaporated. Chromatography (EtOAc/hexane) gave title compound (1.67 g). NMR delta (CDCl3) 4.87 (2H, s), 7.58 (1H, d), 7.71 (1H, d).
	With trichloroisocyanuric acid; In chloroform; at 60℃; for 1.5h;	To a solution of the commercially available starting material (SM) in CHCl3, trichloroisocyanuric acid (TCCA) was added at 60 C. Then the solution was stirred for 1.5 hrs., cooled down and filtered with HiFlo-Celite. The filtrate was concentrated and dried with vacuum. The yield was 5.037 g.
5.037 g	With trichloroisocyanuric acid; In chloroform; at 60℃; for 1.5h;	To a solution of the commercially available starting material 101 in CHCI3, trichloroisocyanuric acid (TCCA) was added at 60C. Then the solution was stirred for 1.5 hrs, cooled, and filtered with HiFlo-Celite. The filtrate was concentrated and dried with vacuum. The yield was 5.037 g of compound 102.
5.037 g	With trichloroisocyanuric acid; In chloroform; at 60℃; for 1.5h;	To a solution of the commercially available starting material 101 in CHCl3, trichloroisocyanuric acid (TCCA) was added at 60 C. Then the solution was stirred for 1.5 hrs, cooled, and filtered with HiFlo-Celite. The filtrate was concentrated and dried with vacuum. The yield was 5.037 g of compound 102.
	With trichloroisocyanuric acid; In 1,2-dichloro-ethane; at 90℃; for 16h;	A mixture of 3-chloro-6-methylpyridazine (3.00 g, 23.3 mmol) and trichloroisocyanuric acid (2.17 g, 9.33 mmol) in DCE (150 mL) was stirred at 90 C for 16 h. After cooling to ambient temperature, the mixture was filtered and washed with 1N NaHCO3 (50 mL), brine (30 mL), and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 0~30% EA/PE gradient 40 mL/min) to give 3-chloro-6- (chloromethyl)pyridazine as a solid. ESI-MS m/z [M+H] +: 162.9/164.9.
0.201 g	With trichloroisocyanuric acid; In chloroform; at 60℃; for 12h;	Add trichloroisocyanuric acid (0.189 g) to a solution of 3-chloro-6-methylpyridazine (0.208 g) in chloroform (10 mL). Heat the oil bath to 60 C, lasts for 12 hours. Cool to room temperature, the filtrate was collected by filtration. Concentrated and purified by column chromatography (PE/EA=10/1). 0.201 g of 3-chloro-6-(chloromethyl)pyridazine was obtained.

Reference： [1]Patent: US2010/29655,2010,A1 .Location in patent: Page/Page column 91
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 1964 - 1975
[3]Patent: WO2012/148775,2012,A1 .Location in patent: Page/Page column 55; 56
[4]Patent: WO2013/166621,2013,A1 .Location in patent: Page/Page column 146
[5]Patent: US2010/56534,2010,A1 .Location in patent: Page/Page column 6
[6]Patent: WO2011/159760,2011,A1 .Location in patent: Page/Page column 62
[7]Journal of Medicinal Chemistry,2005,vol. 48,p. 1367 - 1383
[8]Patent: US2004/58937,2004,A1
[9]Journal of Agricultural and Food Chemistry,2008,vol. 56,p. 204 - 212
[10]Patent: US2008/199427,2008,A1 .Location in patent: Page/Page column 6
[11]Patent: WO2013/40492,2013,A2 .Location in patent: Page/Page column 59
[12]Patent: US2013/273005,2013,A1 .Location in patent: Paragraph 0242; 0243
[13]Patent: WO2017/222951,2017,A1 .Location in patent: Page/Page column 145
[14]Patent: TW2018/29406,2018,A .Location in patent: Page/Page column 37

11
[ 1121-79-5 ]
[ 949922-33-2 ]
[ 949922-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In 1,4-dioxane at 90℃; for 16h;	1.XIII.3 To a mixture of [6-(4A5,5-tetramemyl-[l,3,2]dioxaborolan-2-yl)-3,4^ihydro-lH- isoquinolin-2-yl]-acetic acid tert-butyl ester (1.12 g, 3 mmol), 3-chloro-6-methyl-pyridazine(501 mg, 3.9 mmol, 1.3 eq.), Pd(PPh3)4 (104 mg, 0.009 mmol, 0.03 eq.) under nitrogen, are added dioxane (30.0 ml) and sodium carbonate aqueous solution. (2.0N, 3.0 ml). The resulting mixture is stirred at 900C for 16 hr. The reaction mixture is diluted with EtOAc (80 ml), washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel flash chromatography (hexane/EtOAc 1:1) to give the title compound. MS (+VE) m/z 340.20 (M+ + .).

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2007/106349, 2007, A2 Location in patent: Page/Page column 75

12
[ 1121-79-5 ]
[ 918792-82-2 ]
N-[9-(3-fluoro-benzyl)-6-(6-methyl-pyridazin-3-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation;	139 Example 139; N-[9-(3-Fluoro-benzyl)-6-(6-methyl-pyridazin-3-yl)-2,3,4,9-tetrahydro-lH- carbazol-3-yl]-isobutyramideDissolve N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[l ,3,2]dioxaborolan-2- yl)-2,3,4,9-tetrahydro-lH-carbazol-3-yl]isobutyramide (Preparation 23) (150 mg, 0.31 mmol) and 3-chloro-6-methylpyridazine (39 mg, 0.31 mmol) in dioxane (2.5 mL) and 2M Na2Cθ3 (388 μL). Sparge the solution with nitrogen for 5 min, add dichlorobis(triphenylphosphine)palladium (S) (11 mg, 0.016 mmol) and seal the reaction vessel. Heat to 140 0C in a microwave reactor for 30 min, then dilute with water (20 mL). Extract into EtOAc (3 x 25 mL), dry organics (MgSO4), filter, and concentrate in-vacuo to give the crude product (179 mg) as a brown solid. Purify the crude product on silica gel (12 g), eluting with 25-70% (4% (2M NH3/Me0H)/CH2Cl2)/hexanes to afford 35 mg (25%) of the title compound as a white solid. MS (ES): m/z 457 (M+l), 455 (M-I); HPLC (Method B) Rt = 3.37 min (100%).

Reference： [1]Current Patent Assignee: ELI LILLY & CO; CELLECTIS - WO2007/2181, 2007, A2 Location in patent: Page/Page column 128

13
[ 1121-79-5 ]
[ 1618-47-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogen iodide; sodium iodide In water at 40 - 100℃; for 19.5h; Inert atmosphere;
92%	With hydrogen iodide In water at 100℃; for 1.5h;
88%	With hydrogen iodide; sodium iodide at 40 - 70℃;	To a solution of 3-chloro-6-methylpyridazine (500 mg) in HI (3 ml) was added Nal (782 mg). The reaction was heated at 40 °C for 4 hours and at 70 °C overnight. The yellow precipitate was filtered. The mother liquors were basified using solid NaOH, extracted with CH2Cl2, dried over MgSO4, filtered, concentrated, and purified by chromatography on silica gel using EtOAc/hexane as eluent to give 171.7 mg (20%) of the title compound as a white solid almost pure by HPLC. The yellow precipitate was basified using the same aqueous phase, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated, to give 579.1 mg (68%) of the pure title compound as a white solid. 1H-NMR (δ, ppm, CDCl3): 7.74 (1 H, d), 7.02 (1 H, d), 2.66 (3H, s). [ES MS] m/z 221 (MH+).

84%	Stage #1: 3-chloro-6-methylpyridazine With hydrogen iodide In water at 120℃; for 2h; Stage #2: With sodium hydroxide In water at 0℃;	XIV Example XIV; 3-iodo-6-methyl-pyridazine2.5 g 3-chloro-6-nnethyl-pyridazine are dissolved in 10 ml of 57 % hydrogen iodide solution and heated for 2 hours to 1200C. Then the mixture is cooled to 00C and carefully neutralised with 1 N sodium hydroxide solution. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed twice with water and once with saturated sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo.Yield: 3.6 g (84 % of theory)Mass spectrum (ESI+): m/z = 221 [M+H]+
82%	Stage #1: 3-chloro-6-methylpyridazine With hydrogen iodide In water for 1h; Heating / reflux; Stage #2: With water; sodium carbonate at 20℃;	19.a a) 3-Iodo-6-methyl-pyridazine A mixture of 3-chloro-6-methylpyridazine (2.00 g, 15.6 mmol) and hydriodic acid (57% in water, 41.1 mL, 311 mmol) was heated at reflux for 1 h. After cooling to ambient temperature aqueous sodium carbonate (saturated) was added (pH=8) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate and concentrated afforded the title compound (2.80 mg, 82%) as a light yellow solid. MS: m/e=221.1 [M+H]+.
68%	With hydrogen iodide; sodium iodide at 40 - 70℃;	1.a Preparation 1; 3-(Bromomethyl)-6-(trifluoromethyl)pyridazine (Used to prepare Examples 17 and 18) (a) 3-Iodo-6-methylpyridazineTo a solution of 3-chloro-6-methylpyridazine (500 mg) in HI (3 ml) was added NaI (782 mg). The reaction was heated at 40° C. for 4 h and at 70° C. overnight. The yellow precipitate was filtered. The mother liquors were basified using solid NaOH, extracted with DCM, dried over MgSO4, filtered, concentrated, and purified by chromatography on silica gel using EtOAc/hexane as eluent to give 171.7 mg (20%) of the title compound as a white solid almost pure by HPLC. The yellow precipitate was basified using the same aqueous phase, extracted with DCM, dried over MgSO4, filtered and concentrated, to give 579.1 mg (68%) of the pure title compound as a white solid.1H-NMR (δ, ppm, CDCl3): 7.74 (1H, d), 7.02 (1H, d), 2.66 (3H, s). [ES MS] m/z 221 (MH+).
54%	With hydrogen iodide In water at 100℃; for 2h;	1 n a 1-L round bottomed flask, a mixture of 3- chloro-6-methylpyridazine (8.84 g, 68.8 mmol) and HI (57% wt. in H20) (144 mL, 688 mmol) was heated in an oil bath at 100 °C for 2 h. The mixture was cooled in an ice bath and stirred for 15 min. The precipitated solid was filtered through a fritted funnel and the aqueous solution was discarded. The solid was stirred in 400 mL of EtOAc and 100 mL of saturated NaHCC (aq). The basic aqueous layer was separated and extracted with EtOAc (2 X 100 mL). The combined organic layers were dried over anh. Na2S04, filtered and concentrated to give 3-iodo-6-methylpyridazine (8.15 g, 37.0 mmol, 54% yield) as a tan solid. MS (ESI, pos. ion) m/z: 220.9 (M+l). .H NMR (400 MHz, CDC13) δ ppm 7.73 (d, J=8.61 Hz, 1 H), 7.01 (d, J=8.61 Hz, 1 H), 2.66 (s, 3 H).
	With hydrogen iodide; sodium iodide at 120℃; for 16h; Inert atmosphere;	7.A Step A: 3-Iodo-6-methylpyridazine 3-Chloro-6-methylpyridazine (0.500 g, 3.89 mmol, 1.00 equiv), HI (3 mL), and Nal (0.581 g, 3.88 mmol, 1.00 equiv) were placed to a 10-mL round-bottom flask purged and maintained under N2. The resulting mixture was stirred at 120 °C in an oil bath for 16 hours. The reaction mixture was cooled, diluted with water (10 mL), and the pH was adjusted to pH 8 by addition of saturated aqueous NaHC03. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10.0 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with EtO Ac/petroleum ether (30% - 100%) giving 3-iodo-6-methylpyridazine as a light yellow solid: MS (ES, m/z) 220.9 (M + 1).

Reference： [1]Kaleta, Jiří; Kaletová, Eva; Císařová, Ivana; Teat, Simon J.; Michl, Josef [Journal of Organic Chemistry, 2015, vol. 80, # 20, p. 10134 - 10150]
[2]Wurz, Ryan P.; Sastri, Christine; D'Amico, Derin C.; Herberich, Brad; Jackson, Claire L.M.; Pettus, Liping H.; Tasker, Andrew S.; Wu, Bin; Guerrero, Nadia; Lipford, J. Russell; Winston, Jeffrey T.; Yang, Yajing; Wang, Paul; Nguyen, Yen; Andrews, Kristin L.; Huang, Xin; Lee, Matthew R.; Mohr, Christopher; Zhang; Reid, Darren L.; Xu, Yang; Zhou, Yihong; Wang, Hui-Ling [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 22, p. 5580 - 5590]
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - EP2080761, 2009, A1 Location in patent: Page/Page column 34
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/16118, 2009, A1 Location in patent: Page/Page column 45
[5]Current Patent Assignee: ROCHE HOLDING AG - US2007/287739, 2007, A1 Location in patent: Page/Page column 9
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2009/306089, 2009, A1 Location in patent: Page/Page column 25
[7]Current Patent Assignee: AMGEN INC - WO2012/148775, 2012, A1 Location in patent: Page/Page column 50
[8]Current Patent Assignee: MERCK & CO INC - WO2015/123089, 2015, A1 Location in patent: Page/Page column 65

14
[ 1121-79-5 ]
[ 149104-88-1 ]
[ 1010072-60-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate In 1,4-dioxane; water at 95℃;	A1.1 3-Methyl-6-[4-(methylsulfonyl)phenyl]pyridazine Intermediate A1 3-Methyl-6-[4-(methylsulfonyl)phenyl]pyridazineA suspension of 3-chloro-6-methylpyridazine (1.0 g, 7.78 mmol), (4-methylsulfonyl-phenyl)boronic acid (1.71 g, 8.56 mmol), Pd(PPh3)4 (450 mg, 0.39 mmol), potassium carbonate (2.69 g, 19.45 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was heated at 95 C. overnight. Upon evaporation of the solvents, the residue was partitioned between water (150 mL) and chloroform (150 mL). The layers were separated and the water phase was extracted with chloroform (2 100 mL). The combined organic layers were evaporated and purified by flash chromatography (1:1 DCM/EtOAc, then 100% EtOAc). Yield 1.36 g (70%); Analytical HPLC: purity 99% (System A, RT=1.04 min); LRESIMS for C12H12N2O2S m/z 249 (M+H)+.

Reference： [1]Current Patent Assignee: KANCERA AB - US2008/58339, 2008, A1 Location in patent: Page/Page column 16

15
[ 1121-79-5 ]
[ 625-95-6 ]
3-methyl-6-m-tolylpyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With tetrabutylammomium bromide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;

16
[ 1121-79-5 ]
[ 619-42-1 ]
methyl 4-(6-methylpyridazin-3-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With tetrabutylammomium bromide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;
59%	With NiBr₂bpy In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere;

Reference： [1]Sengmany, Stephane; Leonel, Eric; Polissaint, Frantz; Nedelec, Jean-Yves; Pipelier, Muriel; Thobie-Gautier, Christine; Dubreuil, Didier [Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5631 - 5636]
[2]Location in patent: scheme or table Urgin, Karène; Barhdadi, Rachid; Condon, Sylvie; Léonel, Eric; Pipelier, Muriel; Blot, Virginie; Thobie-Gautier, Christine; Dubreuil, Didier [Electrochimica Acta, 2010, vol. 55, # 15, p. 4495 - 4500]

17
[ 1121-79-5 ]
[ 529-28-2 ]
3-(2-methoxyphenyl)-6-methylpyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tetrabutylammomium bromide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;

18
[ 1121-79-5 ]
[ 766-85-8 ]
3-(3-methoxyphenyl)-6-methylpyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With tetrabutylammomium bromide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;

19
[ 1121-79-5 ]
[ 696-62-8 ]
3-(4-methoxyphenyl)-6-methylpyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetrabutylammomium bromide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;

20
[ 1121-79-5 ]
[ 623-00-7 ]
[ 486437-13-2 ]

Yield	Reaction Conditions	Operation in experiment
63%	With NiBr₂bpy In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere;
46%	With tetrabutylammomium bromide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction;

Reference： [1]Location in patent: scheme or table Urgin, Karène; Barhdadi, Rachid; Condon, Sylvie; Léonel, Eric; Pipelier, Muriel; Blot, Virginie; Thobie-Gautier, Christine; Dubreuil, Didier [Electrochimica Acta, 2010, vol. 55, # 15, p. 4495 - 4500]
[2]Sengmany, Stephane; Leonel, Eric; Polissaint, Frantz; Nedelec, Jean-Yves; Pipelier, Muriel; Thobie-Gautier, Christine; Dubreuil, Didier [Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5631 - 5636]

21
[ 1121-79-5 ]
[ 77778-20-2 ]

Reference： [1]Synthesis,1983,p. 312 - 314

22
[ 1121-79-5 ]
[ 2164-61-6 ]

Reference： [1]Journal of the American Chemical Society,1953,vol. 75,p. 4086

23
[ 1121-79-5 ]
[ 37972-69-3 ]

Reference： [1]Journal of the Chemical Society,1948,p. 2191,2194

24
[ 1121-79-5 ]
[ 7428-91-3 ]
2-(6-methylpyridazin-3-ylamino)dibenzothiophene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); In toluene; at 80℃; for 18h;Heating / reflux;	A mixture of <strong>[7428-91-3]2-aminodibenzothiophene</strong> (0.90 g, 4.52 mM), 3-chloro-6-methyl-pyridazine (0.58 g, 4.52 mM), sodium t-butoxide (0.61 g, 6.33 mM), tris(dibenzylidene-acetone)dipalladium(0) (0.083 g, 0.09 mM) and S-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (0.113 g, 0.18 mM) in toluene (23 ml) was heated to 80 C. for 18 hours under an inert atmosphere. On cooling to room temperature the mixture was diluted with DCM, washed with aqueous potassium carbonate, dried over sodium sulphate and concentrated. Chromatography (eluent gradient of DCM to EtOAc then MeOH: EtOAc (1:9)) gave the product as an off white solid (0.456 g). NMR: 9.38 (brs, 1H), 8.81 (brs, 1H), 8.18 (m, 1H), 8.01 (m, 1H), 7.94 (d, 1H), 7.75 (dd, 1H), 7.50 (m, 1H), 7.36 (d, 1H), 7.14 (d, 1H), 2.50 (s, 3H); m/z 292.29.

Reference： [1]Patent: US2003/225097,2003,A1 .Location in patent: Page 34

25
[ 1121-79-5 ]
[ 859161-48-1 ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride at 70℃;	1 Step 1: 3-(bromomethyl)-6-chloropyridazine (41B) 3-(methyl)-6-chloropyridazine (12.8g, 100mmol) was dissolved in carbon tetrachloride (300mL), N-bromosuccinimide (17.8g, 100mmol) was added, azodiisobutyronitrile (3.4g, 20mmol), 70 °C reaction overnight, after filtering and concentrating filtrate, it was purified by silica gel column chromatography (PE:EA(v/v) = 1:10~1:5) to give the title compound (41B), (4g, yield 20%)
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride for 8h; Heating / reflux;	7 1.0 g of 3-chloro-6-methylpyridazine was dissolved in 20 ml of carbontetrachloride and then added with 1.4 g of N-bromosuccinimide and 0.13 g of azobisisobutyronitrile, followed by heating under ref lux for 8 hours. The reaction mixture was cooled down to room temperature and then filtrated, followed by the filtrate being concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to obtain 0.27 g of 3-bromomethyl-6-chloropyridazine represented by above formula.1H-NMR (CDCl3, TMS) , δ (ppm) : 4.56 (2H, s), 7.38 (1H, d) , 7.44 (1H, d)
	With N-Bromosuccinimide In Carbon tetrachloride for 4h; Reflux; under light;	A solution of 3 -Chloro-6-methyl- pyridazine 1OA (5.12 g, 40 mmol) and NBS (8.9Og, 50 mmol) in CCl4 (300 mL) was refluxed under light (200 w) for 4 hours. The reaction mixture was cooled to room temperature and filtered. The solid residue was washed thoroughly with Cl4C and filtered. The filtrates was combined, concentrated to small volume and loaded on to a silica gel column. The column was eluted with 50% hexane/ ethyl acetate to give 2.2g of desired product (10B) which was dried in vacuum and used immediately in next step. ESI-MS :m/z 206.9 (M+H)+.

		2.Z NaH (60% w/w, 0.304 g, 7.60 mmol) was added to a solution of oxazine alcohol 41 (0.893 g, 4.82 mmol) in DMF (20 mL) at 0 °C. The resulting solution was cooled to - 42 0C and a solution of 3-(bromomethyl)-6-chloropyridazine (108) (obtained via free radical bromination of 3-chloro-6-methylpyridazine, as reported in EP 1555259) (1.053 g, 5.08 mmol) in DMF (5 mL) was added. The mixture was stirred at -42 0C for 1 h and then quenched with ice. EtOAc (200 mL) was added and the organic layer was dried (MgSO4) and then concentrated under reduced pressure. The residue was chromatographed on silica gel, initially eluting with hexanes/EtOAc (1 : 1) to remove unreacted 3-(bromomethyl)-6-chloropyridazine and then with EtOAc to give (6£)-6-[(6-chloro-3-pyridazinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,l- 6][l,3]oxazine (109) (0.843 g, 56%) as a white solid: mp 180-184 0C; 1H NMR [(CD3)2SO] δ 8.02 (s, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.74 (d, J= 8.8 Hz, 1 H), 4.97 (d, J= 13.2 Hz, 1 H), 4.94 (d, J= 13.2 Hz, 1 H), 4.69 (dt, J= 12.0, 2.6 Hz, 1 H), 4.50 (d, J= 12.1 Hz, 1 H), 4.30-4.39 (m, 2 H), 4.25 (dd, J= 13.5, 3.3 Hz, 1 H). Anal. (Ci1H1OClN5O4) C, H, N.
1.59 g	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride Reflux;	4.A Step A: Preparation of 3-(bromomethyl)-6-chloro-pyridazine Step A: Preparation of 3-(bromomethyl)-6-chloro-pyridazine A mixture of 3-chloro-6-methylpyridazine (5.14 g, 40 mmol), N-bromosuccinimide (7.19 g, 10.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (657 mg, 4 mmol) in carbon tetrachloride (100 mL) was heated at reflux overnight. The reaction mixture was cooled and filtered, washing with carbon tetrachloride. The combined filtrate and washings were concentrated under reduced pressure. The resulting material was purified by medium pressure liquid chromatography on silica gel (0 to 50% gradient of ethyl acetate in hexanes as eluant) to give the title compound an oil (1.59 g). H NMR ^DC^): δ 7.65-7.67 (m, 1H), 7.55-7.57 (m, 1H), 4.72 (s, 2H).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In Carbon tetrachloride at 90℃;	21.1 Step 1. 3-(Bromomethyl)-6-chloropyridazine: A mixture of 3-chloro-6-methylpyridazine (1 g, 7.78 mmol), NBS (1.384 g, 7.78 mmol) and AIBN (0.128 g, 0.778 mmol) in CCl4(26 ml) was stirred at 90 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexanes) to afford the title compound. MS = 208.9 [M+1]+

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - WO2022/42591, 2022, A1 Location in patent: Page/Page column 94-95
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP1555259, 2005, A1 Location in patent: Page/Page column 40
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/19899, 2010, A1 Location in patent: Page/Page column 136-137
[4]Current Patent Assignee: TB ALLIANCE INC - WO2011/14774, 2011, A1 Location in patent: Page/Page column 51
[5]Current Patent Assignee: DUPONT DE NEMOURS INC - WO2014/179144, 2014, A1 Location in patent: Page/Page column 64
[6]Current Patent Assignee: SHEARN NANCE GALEN PAUL; TAOKA BRANDON M; LOMBARDO MATTHEW J; MERCK & CO INC; SINZ CHRISTOPHER J; HAYES DONNA A A W; LANG SIMON B; CHENG ALAN C; HICKS JACQUELINE D; OGAWA ANTHONY KEN - WO2021/257353, 2021, A1 Location in patent: Page/Page column 108

26
[ 13327-27-0 ]
[ 1121-79-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; In hexane; water;	(c) 34.5 g of phosphorus oxychloride were heated to 70 C. under nitrogen and treated within 1 hour with 16.5 g of 6-methyl-3(2H)-pyridazinone in small portions. After completion of of the addition, the temperature was increased to 90 C. and the mixture was stirred for about a further 2 hours. For the working-up, the dark brown solution was poured into 300 ml of water, stirred well and neutralized with solid sodium hydroxide and sodium hydrogen carbonate. The aqueous phase was subsequently extracted continuously overnight with 500 ml of hexane. The organic phase was separated and freed from solvent. The brown coloured crystals obtained were sublimed from a bath heated at 50-60 C. There were thus obtained 12.8 g (66.4%) of 3-chloro-6-methylpyridazine as white crystals of melting point 59-60 C.
	With trichlorophosphate; for 2.0h;Heating / reflux;	5.0 g of 6-methyl-2H-pyridazine-3-one and 28 g of phosphorus oxychloride were mixed, followed by heating under reflux for 2 hours. The reaction mixture was cooled down to room temperature and then poured into ice water, followed by extraction with ethylacetate. The organic phase was dried with an anhydrous sodium sulfate, followed by concentration under reduced pressure to obtain 1.6 g of 3-chloro-6-methylpyridazine

Reference： [1]Patent: US4595521,1986,A
[2]Patent: EP1422218,2004,A1 .Location in patent: Page 174
[3]Patent: EP1555259,2005,A1 .Location in patent: Page/Page column 40

27
[ 1121-79-5 ]
C₂₅H₃₀BNO₃S [ No CAS ]
(+)-4-(4-methoxy-benzothiophen-5-yl)-2-methyl-7-(6-methyl-pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 3h;	84.A Step A: 3-Chloro-6-methyl-pyridazine (230 mg, 1.78 mmol) was added to a mixture of the crude product from Step A of Example 83 (545 g, 1.19 mmol) and sodium carbonate (2M, 1.8 mL, 3.6 mmol) in dimethyl formamide (10 mL). The reaction mixture was degassed with argon. PdCl2(dppf) (52 mg, 0.071 mmol) was added and the reaction mixture was stirred at 100° C. for 3 hours, cooled, diluted with water and extracted with ethyl acetate twice. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica gel, 3% to 6% MeOH/CH2Cl2 gave the desired product (300 mg, 63% for 3 steps): 1H NMR (CDCl3, 500 MHz) δ 7.90 (d, J=1.3 Hz, 1H), 7.72-7.67 (m, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.48 (d, J=5.5 Hz, 1H), 7.44 (d, J=5.5 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.03-6.98 (m, 2H), 4.96-4.93 (m, 1H), 3.97 (s, 3H), 3.92 (d, J=14.9 Hz, 1H), 3.73 (d, J=14.9 Hz, 1H), 3.14-3.10 (m, 1H), 2.74 (s, 3H), 2.65 (dd, J=11.4, 9.0 Hz, 1H), 2.49 (s, 3H); ESI MS m/z=402 [M+H]+.

Reference： [1]Current Patent Assignee: CURIA INC - US2006/52378, 2006, A1 Location in patent: Page/Page column 133-134

28
[ 1121-79-5 ]
[ 178306-51-9 ]
[ 209403-38-3 ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In N,N-dimethyl-formamide;	Example 1 2-(6-Methylpyridazin-3-yloxy)-3-methoxy-3,3-diphenylpropionic acid (I-517) 1.3 g (4.8 mmol) of <strong>[178306-51-9]2-hydroxy-3-methoxy-3,3-diphenylpropionic acid</strong> dissolved in DMF were added dropwise to a suspension of 0.43 g of NaH (14.3 mmol, 80% in white oil) in 10 ml of DMF. After stirring to room temperature for 30 minutes, the mixture was treated with 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine in 10 ml of DMF and stirred overnight at room temperature. To complete the reaction, 0.6 g (4.8 mmol) of 3-chloro-6-methylpyridazine were then added again and the mixture was kept at 60 C. for 5 hours. It was poured onto ice water, extracted three times with ethyl acetate, the aqueous phase was brought to pH 2 with half-concentrated hydrochloric acid and the precipitate which was deposited was extracted with ethyl acetate. These ethyl acetate phases were dried with magnesium sulfate and then filtered and the solvent was stripped off under reduced pressure. 800 mg of the brown residue (1.19 g) were purified by means of MPLC, it being possible to isolate 199 mg of the desired product as a white solid. 1H-NMR (200 MHz, DMSO): 7.5 ppm (1 H, d), 7.2-7.3 (10 H, m), 7.1 (1 H, d), 6.3 (1 H, s), 3.3 (3 H, s), 2.5 (3 H, S). FAB-MS: 365 (M+H+)

Reference： [1]Patent: US6448248,2002,B1

29
[ 1121-79-5 ]
CH₃ [ No CAS ]
[ 1001-53-2 ]
[ 193473-65-3 ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium hydrogencarbonate; In dichloromethane; N,N-dimethyl-formamide;	a N-Acetyl-N'-(6-methyl-3-pyridazinyl)ethylenediamine A mixture of 3-chloro-6-methylpyridazine (1.29 g, 10 mmol), N-(acetyl)ethylenediamine (638 mg, 6.25 mmol) and NaHCO3 (1.6 g) in dry DMF (10 mL) was heated at reflux under argon for 20 h. The mixture was filtered, the filtrate concentrated, and the residue was dissolved in CH2 Cl2 and purified by flash chromatography (silica gel, step gradient, 0-8% CH3 OH/CH2 Cl2) to yield the title compound as a yellow solid (700 mg, 44%): MS (ES) m/e 195.0 [M+H]+.

Reference： [1]Patent: US6159964,2000,A

30
[ 1121-79-5 ]
[ 451-46-7 ]
[ 882974-10-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 3h; Inert atmosphere;
69.6%	With lithium hexamethyldisilazane In tetrahydrofuran at -8 - 6℃; for 1h; Large scale;
	With lithium hexamethyldisilazane In tetrahydrofuran at 15 - 20℃; for 1h;	1 Preparation 1; To a solution of 3-chloro-6-methylpyridazine [51 g) EPO and ethyl 4-fluorobenzoate (66.7 g) in THF (200 ml) was added dropwise lithium bis (trimethylsilyl) amide (793 ml, 1.0 M in THF) over the period of 30 min while maintaining the temperature below 15°C. After stirring for 30 min at room temperature, the mixture was recooled in an ice bath, and neutralized by addition of cold water (250 ml) and 6 N HCl (175 ml) . A solid was separated from the mixture and collected to give 2- (6-chloro-3-pyridazinyl) -1- (4- fluorophenyl) ethanone (36.6 g) as the first crop. The organic layer was separated from the mother liquor and washed with brine (150 ml, twice), dried over Na2SO4, filtered and concentrated to form a suspension. This suspension was dissolved under reflux. To the solution was added hexane (600 ml) and the resulted suspension was aged for 1 hour with stirring at room temperature. The resulted solid was collected and washed with hexane (200 ml) to afford 2- ( 6-chloro-3-pyridazinyl) -1- (4- fluorophenyl) ethanone (51.3 g) as the second crop. Mass ESI (+) 251 (M+1) 1H-NMR (300 MHz, DMSO-d6) δ 4.85 (2H, s) , 7.42 (2H, t, J=9 Hz), 7.78 (IH, d, J=8.7 Hz), 7.93 (IH, d, J=8.7 Hz), 8.13- 8.22 (2H, m)

Stage #1: 3-chloro-6-methylpyridazine; 4-fluorobenzoic acid ethyl ester With lithium hexamethyldisilazane In tetrahydrofuran at 15℃; for 1h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0℃;

1 Preparation 1To a solution of 3-chloro-6-methylpyridazine (5Ig) and. ethyl 4-fluorobenzoate (66.7g) in THF was added dropwise lithium bis(trimethylsilyl)amide (793ml, l.OMinTHF) over the period of 30min maintained below 150C. After stirring for 30min at room temperature, the mixture was recooled on an ice bath and to this was added cold water (250ml) and 6N HCl (175ml) to neutralize. A solid separated from the mixture was collected to give 2-(6-chloro-3-pyridazinyl) - 1-(4-fluorophenyl)ethanone (36.6g) as first crop. The organic layer separated from the mother liquor was washed with brine (150ml, twice), dried and concentrated to form a suspension. This was dissolved under reflux and to this was added hexane (600ml) and the suspension was aged for Ih with stirring at room temperature, collected and washed with hexane (200ml) to afford 2-(6-chloro-3-pyridazinyl)- 1-(4-fluorophenyl)ethanone (51.3g) as second crop. Mass ESI(+) 251(M+l) 1H NMR(300MHz, DMSO-d6)d 4.85 (2H, s) , 7.42 (2H, t, J= 9Hz) , 7.78 (IH, d, J=8.7Hz), 7.93 (IH, d, J=8.7Hz), 8.13-8.22 (2H, m) .

Reference： [1]Asano, Toru; Yamazaki, Hitoshi; Kasahara, Chiyoshi; Kubota, Hirokazu; Kontani, Toru; Harayama, Yu; Ohno, Kazuki; Mizuhara, Hidekazu; Ohta, Mitsuaki; Takeuchi., Makoto; Yokomoto, Masaharu; Misumi, Keiji; Kinoshita, Tomohiko [Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7772 - 7785,14]
[2]Yoshida, Shinya; Hayashi, Yasumasa; Obitsu, Kazuyoshi; Nakamura, Atsushi; Kikuchi, Takashi; Sawada, Tatsuya; Kimura, Takenori; Takahashi, Takumi; Mukuta, Takashi [Organic Process Research and Development, 2012, vol. 16, # 11, p. 1818 - 1826]
[3]Current Patent Assignee: WAKUNAGA PHARMACEUTICAL CO., LTD.; ASTELLAS PHARMA INC. - WO2007/26950, 2007, A1 Location in patent: Page/Page column 44-45
[4]Current Patent Assignee: WAKUNAGA PHARMACEUTICAL CO., LTD.; ASTELLAS PHARMA INC. - WO2006/38734, 2006, A1 Location in patent: Page/Page column 25

31
[ 1121-79-5 ]
[ 754-10-9 ]
[ 910552-56-6 ]

Yield	Reaction Conditions	Operation in experiment
30%	With caesium carbonate In tetrahydrofuran at 100℃;	1.B.2 Method 2: To a dry pressure tube is added 200 mg (1.56 mol) of 3-chloro-5- methylpyridazine, 190 mg (1.87 mmol) of trimethylacetamide, 14.6 mg (0.023 mmol) of rac-2,2'-bis(diphenylphosphine )-l,l'-binaphthyl , tris(dibenzylideneacetone)- dipalladium (0) , 762.4 mg (2.34 mmol) of cesium carbonate and 1.5 ml dry tetrahydrofuran. The pressure tube is purged with nitrogen and sealed. The reaction is heated to 100 °C overnight. The reaction is then cooled, diluted with dichloromethane, and filtered through celite. Solvents are evaporated and the crude product is purified via silica gel chromatography using a ethyl acetate:hexane gradient to obtain 91 mg (0.47 mmol, 30%) as a white solid.
30%	With caesium carbonate In tetrahydrofuran at 100℃;	1.A.B.2 To a dry pressure tube is added 200 mg (1.56 mol) of 3-chloro-5- methylpyridazine, 190 mg (1.87 mmol) of trimethylacetamide, 14.6 mg (0.023 mmol) of rac-2,2'-bis(diphenylphosphine )-l,l'-binaphthyl , tris(dibenzylideneacetone)- dipalladium (0), 762.4 mg (2.34 mmol) of cesium carbonate and 1.5 ml dry tetrahydrofuran. Purged flask with nitrogen and seal then heat to 1000C. overnight. Cooled, diluted with methylene chloride, and filter through celite. Evaporate solvents and chromatograph using 7:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to obtain 91 mg (0.47 mmol), 30% as white solid.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2006/102194, 2006, A1 Location in patent: Page/Page column 25
[2]Current Patent Assignee: ELI LILLY & CO - WO2006/107784, 2006, A1 Location in patent: Page/Page column 34

32
[ 1121-79-5 ]
C₂₃H₃₀BNO₂ [ No CAS ]
C₂₂H₂₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 100℃;	24.G Step G: To a disposable sealed tube were added the product of Step F (200 mg, 0.55 mmol, theoretical) as a solution in anhydrous DMF (4.5 mL), sodium carbonate (175 mg, 1.7 mmol) as a solution in H2O (1 mL), and 3-chloro-6-methylpyridazine (85 mg, 0.66 mmol). The reaction mixture was degassed by a subsurface purge with Ar for one minute. PdCl2(dppf).CH2Cl2 (27 mg, 0.033 mmol) was then added under Ar. The reaction was heated to 100° C. and allowed to stir overnight. TLC analysis showed that the reaction went to completion. After cooling to room temperature, the reaction mixture was diluted with H2O, then extracted with ethyl acetate (3×). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (95:5 CH2Cl2/MeOH) yielded the desired pyridazine (74 mg, 41% over two steps) as a brown oil: [α]25D -2.0° (c 0.05, methanol); 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.40-7.33 (m, 3H), 7.30-7.27 (m, 1H), 7.21 (d, J=7.5 Hz, 2H), 6.85-6.78 (br, 1H), 4.40 (d, J=8.5 Hz, 1H), 4.06-4.04 (m, 1H), 3.89 (d, J=14.5 Hz, 1H), 3.20-3.16 (m, 1H), 3.03 (ddd, J=12.5, 9.8, 2.5 Hz, 1H), 2.75 (s, 3H), 2.41 (s, 3H), 2.40-2.35 (m, 1H), 2.21-2.15 (m, 1H); ESI MS m/z=330 [C22H23N3+H]+.

Reference： [1]Current Patent Assignee: CURIA INC - US2007/21408, 2007, A1 Location in patent: Page/Page column 68-69

33
[ 1121-79-5 ]
C₂₃H₂₉BClNO₂ [ No CAS ]
C₂₂H₂₂ClN₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 100℃;	39.H Step H: To a disposable sealed tube were added the product of Step G (123 mg, 0.31 mmol) as a solution in anhydrous DMF (2.6 mL), sodium carbonate (98 mg, 0.93 mmol) as a solution in H2O (0.6 mL), and 3-chloro-6-methylpyridazine (48 mg, 0.37 mmol). The reaction mixture was degassed by a subsurface purge with Ar for one minute. PdCl2(dppf).CH2Cl2 (15 mg, 0.019 mmol) was then added under Ar. The reaction was heated to 100° C. and allowed to stir overnight. TLC analysis showed that the reaction had gone to completion. After cooling to room temperature, the reaction mixture was diluted with H2O, and then extracted with ethyl acetate (3×). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (95:5 CH2Cl2/MeOH) yielded the desired pyridazine (58 mg, 52% for two steps) as a brown oil: [α]25D -7.14° (c 0.14, methanol); 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.36 (d, J=8.5, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 6.80 (br s, 1H), 4.37 (d, J=8.5 Hz, 1H), 4.03-3.98 (m, 1H), 3.85 (d, J=14.0 Hz, 1H), 3.16-3.11 (m, 1H), 3.00 (ddd, J=12.5, 9.5, 2.0 Hz, 1H), 2.75 (s, 3H), 2.38 (s, 3H), 2.37-2.30 (m, 1H), 2.17-2.11 (m, 1H); ESI MS m/z=364 [C22H22ClN3+H]+.

Reference： [1]Current Patent Assignee: CURIA INC - US2007/21408, 2007, A1 Location in patent: Page/Page column 75

34
[ 1121-79-5 ]
C₂₃H₂₉BFNO₂ [ No CAS ]
5-(3-fluorophenyl)-2-methyl-8-(6-methylpyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 120℃; for 1h;	84.L Step L: A dry flask was loaded with the boronate ester (1.27 mmol) from step K above, 3-chloro-6-methylpyridazine (0.24 g, 1.90 mmol), sodium carbonate (0.33 g, 3.17 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.08 g, 0.10 mmol). The flask was flushed with argon prior to the addition of N,N-dimethylformamide (16 mL) and water (3.2 mL). The reaction mixture was heated to 120° C. under argon for 1 hour. The cooled reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×150 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (first purification 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide; second purification 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford the pyridazinyl benzazepine (150 mg, 34% yield other 4 steps).

Reference： [1]Current Patent Assignee: CURIA INC - US2007/21408, 2007, A1 Location in patent: Page/Page column 109

35
[ 1121-79-5 ]
C₂₄H₂₈BFN₂O₂ [ No CAS ]
2-fluoro-4-(2-methyl-8-(6-methylpyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h;	92.L Step L: A dry flask was loaded with the boronate ester (1.81 mmol) from step K above, 3-chloro-6-methylpyridazine (0.34 g, 2.76 mmol), sodium carbonate (0.48 g, 4.52 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.12 g, 0.14 mmol). The flask was flushed with argon prior to the addition of DMF (16 mL) and water (3.2 mL). The reaction mixture was heated to 90° C. under argon for 2 hours. The cooled reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (95:5 to 85:15 dichloromethane/methanol) to afford the pyridazinyl benzazepine (420 mg, 62% yield over 3 steps).

Reference： [1]Current Patent Assignee: CURIA INC - US2007/21408, 2007, A1 Location in patent: Page/Page column 118

36
[ 1121-79-5 ]
[ 921219-78-5 ]
4-(2-methyl-8-(6-methylpyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: C₁₉H₁₇F₃N₂O₃S; bis(pinacol)diborane With potassium acetate In N,N-dimethyl-formamide at 80℃; for 1h; Stage #2: 3-chloro-6-methylpyridazine With caesium carbonate In water; N,N-dimethyl-formamide at 60℃; for 2h;	101.H Step H: A round bottomed flask was charged with the triflate (0.20 g, 0.44 mmol) from step G above, bis(pinacolato)diboron (0.12 g, 0.48 mmol) and potassium acetate (0.13 g, 1.33 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (36 mg, 0.04 mmol) in DMF (3 mL). The mixture was refilled with nitrogen three times and then stirred at 80° C. for 1 hour. The mixture was cooled to room temperature. Cesium carbonate (0.43 g, 1.33 mmol), 3-chloro-6-methylpyridazine (0.10 g, 0.67 mmol) and water (2 mL) were added. The mixture was refilled with nitrogen three times and then stirred at 60° C. for 2 hours. After cooling, the mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (10:1 methylene chloride/methanol) to yield the desired benzazepine (70 mg, 46%) as an off-white solid.

Reference： [1]Current Patent Assignee: CURIA INC - US2007/21408, 2007, A1 Location in patent: Page/Page column 126-127

37
[ 1121-79-5 ]
tetrakis(triphenlyphosphine)palladium ⁽⁰⁾ [ No CAS ]
[ 80673-00-3 ]
[ 845894-52-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride; triethylamine; In 1,2-dimethoxyethane;	EXAMPLE 44 Synthesis of 3-methyl-6-(pyridin-3-ylethynyl)pyridazine To the solution of <strong>[80673-00-3]3-[(trimethylsilyl)ethynyl]pyridine</strong> (0.175g, 1.0 mmol), 3-chloro-6-methylpyridazine (0.128 g, 1.0 mmol), cupper (I) iodide (0.019 g, 0.1 mmol), triethylamine (0.202 g, 2.1 mmol), in 20 ml Ethylene glycol dimethyl ether was added tetrakis(triphenlyphosphine)palladium (0) (60 mg, 0.052 mmol). The result solution was heated to 80 C. after degasing by argon for 5 minute, and then Tetrabutylammonium fluoride (2.1 ml, 1M/THF) was added dropwise. After stirring at 80 C. for 12 hrour, the reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3*30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc: 9/1 to 1/9) to give 3-methyl-6-(pyridin-3-ylethynyl)pyridazine as brown solid. 1H NMR (CDCl3 300 MHz) delta 8.875-8.87 (m, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (d, 1H), 7.60-7.58 (dd, 1H), 7.39-7.36 (m, 2H), 2.80 (s, 3H). MS (ESI) 196.10 (M++H).
	With tetrabutyl ammonium fluoride; triethylamine; In 1,2-dimethoxyethane;	EXAMPLE 44 Synthesis of 3-methyl-6-(pyridin-3-ylethynyl)pyridazine To the solution of <strong>[80673-00-3]3-[(trimethylsilyl)ethynyl]pyridine</strong> (0. 175g, 1.0 mmol), 3-chloro-6-methylpyridazine (0.128 g, 1.0 mmol), cupper (I) iodide (0.019g, 0.1 mmol), triethylamine (0.202 g, 2.1 mmol), in 20 ml Ethylene glycol dimethyl ether was added tetrakis(triphenlyphosphine)palladium (0) (60 mg, 0.052 mmol). The result solution was heated to 80 C., after degasing by argon for 5 minute, and then Tetrabutylammonium fluoride (2.1 ml, 1M/THF) was added dropwise. After stirring at 80 C., for 12 hrour, the reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3*30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc: 9/1 to 1/9) to give 3-methyl-6-(pyridin-3-ylethynyl)pyridazine as brown solid. 1H NMR (CDCl3 300 MHz) delta8.875-8.87 (m, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (d, 1H), 7.60-7.58 (dd, 1H), 7.39-7.36 (m, 2H), 2.80 (s, 3H). MS (ESI) 196.10 (M++H).

Reference： [1]Patent: US2005/43307,2005,A1
[2]Patent: US2005/245542,2005,A1

38
[ 1121-79-5 ]
[ 1084812-21-4 ]
[ 1084812-54-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In water; N,N-dimethyl-formamide at 100℃; for 2h;	16.G The boronate ester (3.5 g, crude) from Step F above, 3-chloro-6-methylpyridazine (625 mg, 5.1 mmol), and cesium carbonate (4.0 g, 6.8 mmol) were suspended in DMF (20 rnL) and water (5 mL). The mixture was purged with argon. 1 , r-Bis(diphenylphosphino)ferrocenedichloropalladium (240 mg, 0.33 mmol) was added to the mixture. The mixture was heated at 1000C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, and filtered through a pad of Celite. The filtrate was washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (98:1.8:0.2 to 95:4.5:0.5 dichloromethane/methanol/concentrated ammonium hydroxide) to give 2-methyl-8-(6-methylpyridazin-3-yl)-5-phenoxy- 2,3,4,5-tetrahydro-lH-benzo[c]azepine (500 mg, 40% for 3 steps) as an oil.

Reference： [1]Current Patent Assignee: CURIA INC - WO2008/141082, 2008, A1 Location in patent: Page/Page column 78-79

39
[ 1121-79-5 ]
[ 1084743-86-1 ]
[ 1084742-34-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: 7-bromo-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine With potassium acetate; bis(pinacol)diborane In N,N-dimethyl-formamide at 60℃; Stage #2: 3-chloro-6-methylpyridazine With caesium carbonate In water; N,N-dimethyl-formamide at 20 - 60℃; for 3h;	22.B Step B: A round bottomed flask was charged with 7-bromo-4- methyl-l-phenyl-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepine (0.22 g, 0.7 mmol) from step A above, bis(pinacolato)diboron (0.20 g, 0.77 mmol), potassium acetate (0.21 g, 2.1 mmol), dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (57 mg, 0.07 mmol) and DMF (3.5 mL). The mixture was degassed with nitrogen (3χ) and then stirred at 6O0C overnight. The mixture was cooled to room temperature, and cesium carbonate (0.68 g, 2.1 mmol), 3-chloro-6- methylpyridazine (0.14 g, 1.1 mmol) and water (1.8 mL) were added to it. The mixture was degassed with nitrogen (3χ) and then stirred at 6O0C for 3 hours. After cooling, the mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride (3 x 20 mL). The combined organic extract was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride, then 10:1 methylene chloride/methanol) to yield the desired 4-methyl-7-(6-methylpyridazin-3- yl)-l-phenyl-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepine (0.16 g, 67%) as a grey solid.

Reference： [1]Current Patent Assignee: CURIA INC - WO2008/141081, 2008, A1 Location in patent: Page/Page column 102-103

40
[ 1121-79-5 ]
[ 1084744-04-6 ]
[ 1084742-86-8 ]

Yield	Reaction Conditions	Operation in experiment
25%	With caesium carbonate In water; N,N-dimethyl-formamide	31.B To a solution of the boronate ester from Step A above inDMF (2.0 mL) and water (0.5 mL) were added cesium carbonate (266 mg, 0.817 mmol), 3-methyl-6-chloropyridazine (39 mg, 0.299 mmol) and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (23 mg, 0.0272 mmol) and water (0.5 mL). The reaction was then heated for 2 hours and then partitioned between water (50 mL) and ethyl acetate (3 x 50 mL). The combined organic extract was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified twice by flash chromatography (9:1 methylene chloride/methanol) to give the desired benzodiazepine (19 mg, 25%) as a yellow solid.

Reference： [1]Current Patent Assignee: CURIA INC - WO2008/141081, 2008, A1 Location in patent: Page/Page column 110

41
[ 153254-09-2 ]
[ 1121-79-5 ]
[ 1000787-77-8 ]

Yield	Reaction Conditions	Operation in experiment
		3-Chloro-6-methylpyridazine (1.00 eq), 2-(dicyclohexylphosphino)biphenyl (0.05 eq), <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> (1.85 eq), 1,2-dimethoxyethane and aqueous potassium carbonate solution were all charged into a reactor. After degassing three times with nitrogen, palladium acetate (0.025 eq) was charged and the content is heated and agitated under reflux until the reaction was deemed complete.The reaction mixture was cooled to 22 C. Heptane was charged, followed by addition of Celite. After agitating for ca. 30 minutes at 22 C., the mixture was filtered into the first reactor, rinsing forward with a mixture of 1,2-dimethoxyethane and Heptanes. The layers of the filtrate are separated.To the organic layer was charged borane trimethylamine complex (0.03 eq), water, and acetic acid. The resultant mixture with a pH at maximum 4 was agitated for 1-2 h at 22 C. and then refluxed at ca. 80 C. for 2-3 h. After cooling back to 22 C., the mixture was adjusted to pH 10-11 with addition of 5% aq. sodium hydroxide while maintaining the content at 22 C. and then agitated for 1-2 h. The mixture was filtered and the layers were separated. The aq. layer was disposed of and the organic layer was filtered through ZetaCarbon cartridges into the in-process cleaned first reactor, rinsing forward with 1,2-dimethoxyethane through the carbon cartridges.The filtrate was concentrated under vacuum with a maximum jacket setting of 60 C. Heptane was charged and the contents were further concentrated under vacuum with a maximum jacket setting of 60 C. Additional Heptane was charged to the concentrate and the 1,2-dimethoxyethane (DME) content (maximum 0.5%) of the mixture was checked by NMR. After adjusting to 85 C. and agitating for ca. 1 h, the mixture was polished filtered hot through a filter into the second reactor.The filtrate in the second reactor was adjusted to reflux and then agitated for 1 h. With ramp cooling and moderate agitation, the mixture is cooled from reflux to 0 to 6 C. over a period of minimum 4 h and then agitated at 0 to 6 C. for 1 h.The product was filtered, washed with ambient temperature Heptanes and dried under vacuum at a maximum of 40 C. until loss on drying is maximum 1%. w/w Mole v/w Materials M.W. Ratio Ratio Ratio 2,4-Bis(trifluoromethyl)phenyl- 257.92 4.00 1.85 - boronic acid Borane trimethylamine complex 72.92 0.018 0.03 - 3-Chloro-6-methylpyridazine 128.56 1.00 1.00 - Diatomaceous earth (celite) N/A 0.30 - - Di(cyclohexyl)phosphinobiphenyl 350.49 0.14 0.05 - 1,2-Dimethoxyethane 90.12 12.00 - 13.80 Drinking water 18.02 3.75 - 3.75 Glacial acetic acid 60.05 0.05 0.10 - Heptanes 100.21 20.40 - 29.80 Palladium (II) acetate 224.49 0.044 0.025 - Potassium carbonate, 138.21 2.15 2.00 - Sodium hydroxide, 5% solution 40.00 - - -
	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In toluene;	Step 2. 3-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-pyridazine A solution of 3-chloro-6-methyl-pyridazine (2.56 g, 20 mmol), 2,4-bis-trifluoromethyl-phenyl-boronic acid (7.7 g, 30 mmol), tetrakistriphenylphosphine palladium(0) (5 mol %, 1.1 g) in toluene: 2N Na2CO3 (4:1, 100 mL total) was sparged with argon for 3 minutes then heated to 100 C. for 20 hours. The reaction was partitioned, the aqueous phase washed with EtOAc (2*50 mL) and the organics combined, dried (brine, Na2SO4) and purified on silica gel eluding with 10-60% hexanes:EtOAc, yielding the product (1.9 g) as a brown solid.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 20h;Inert atmosphere;	Step 2. 3-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-pyridazine A solution of 3-chloro-6-methyl-pyridazine (2.56 g, 20 mmol), 2,4-bis-trifluoromethyl-phenyl-boronic acid (7.7 g, 30 mmol), tetrakistriphenylphosphine palladium(0) (5 mol %, 1.1 g) in toluene: 2N Na2CO3 (4:1, 100 nIL total) was sparged with argon for 3 minutes then heated to 100 C. for 20 hours. The reaction was partitioned, the aqueous phase washed with EtOAc (2*50 mL) and the organics combined, dried (brine, Na2SO4) and purified on silica gel eluding with 10-60% hexanes:EtOAc, yielding the product (1.9 g) as a brown solid.

Reference： [1]Patent: US2009/36460,2009,A1 .Location in patent: Page/Page column 8
[2]Patent: US2009/226398,2009,A1
[3]Patent: US2010/29655,2010,A1 .Location in patent: Page/Page column 91

42
[ 1121-79-5 ]
[ 1000793-50-9 ]
[ 1000796-30-4 ]

Yield	Reaction Conditions	Operation in experiment
30%	With pyridine at 150℃; for 2h; Microwave irradiation;	26 INTERMEDIATE 266,6-Dimethyl-2-{6-r(6-methylpyridazin-3-yl)amino]-2,3-dihvdro-4H-l,4-benzoxazin-4- vn-6.7-dihvdrori,31thiazolor5.4-c]pyridin-4(5//)-oneA mixture of Intermediate 22 (197 mg, 0.60 mmol) and 3-chloro-6-methyl- pyridazine (39 mg, 0.30 mmol) in pyridine (1 mL) was heated to 1500C under microwave irradiation for 2 h. After cooling to r.t. it was concentrated in vacuo and purified by preparative HPLC {Method 5) to give the title compound (75 mg, 30%) as an off-white solid. δH (CDCl3) 8.00 (IH, d, J2.5 Hz), 7.29-7.25 (2H, m), 7.17-6.91 (3H, m), 5.40 (IH, s), 4.37-4.30 (2H, m), 4.16-4.08 (2H, m), 2.90 (2H, s), 2.60 (3H, s), 1.40 (6H, s). LCMS (ES+) 423.0 (M+H)+, RT 2.73 minutes (Method 2).
	With isopropyl alcohol at 150℃; for 3h;

Reference： [1]Current Patent Assignee: UCB - WO2009/71895, 2009, A1 Location in patent: Page/Page column 105
[2]Location in patent: scheme or table Perry, Benjamin; Beevers, Rebekah; Bennett, Gavin; Buckley, George; Crabbe, Tom; Gowers, Lewis; James, Lynwen; Jenkins, Kerry; Lock, Chris; Sabin, Verity; Wright, Sara [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 19, p. 5299 - 5302]

43
[ 1121-79-5 ]
[ 18718-79-1 ]
[ 1159250-90-4 ]

Yield	Reaction Conditions	Operation in experiment
30%	In tetrahydrofuran; water; mineral oil;	EXAMPLE 4 3-Methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine To a solution of <strong>[18718-79-1](5-methyl-3-phenyl-4-isoxazolyl)methanol</strong> (0.50 g, 2.64 mmol) in THF (8 mL) was added sodium hydride (55% dispersion in mineral oil, 0.16 g, 3.17 mmol) at 0 C. The reaction mixture was stirred for 30 min while it was allowed to warm up to room temperature. 3-Chloro-6-methylpyridazine (0.36 g, 2.77 mmol) was added and stirring was continued for 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (10 mL) and dried over sodium sulfate. Concentration and purification of the residue by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (220 mg, 30%) as a yellow oil. MS: m/e=282.3 [M+H]-.

Reference： [1]Patent: US2009/143385,2009,A1

44
[ 1121-79-5 ]
[ 1155857-04-7 ]
C₂₄H₃₁N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 100℃;	LXIII 2 M Aqueous Na2CO3 solution (1.13 ml.) is added to a mixture of (2R.6R, 11 S)-6, 11 -dimethyl- 8-(4.4.5.5-tetramethyl-[1 .3.2]dioxaborolan-2-yl)-1 .2.5.6-tetrahydro-4H-2,6-methano- benzo[d]azocine-3-carboxylic acid tert-butyl ester (483 mg) and 3-chloro-6-methyl-pyridazine (218 mg) in dimethylformamide (2 ml_). The resulting mixture is flushed with argon and then 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane complex (73 mg) is added. The mixture is heated to 100 0C and stirred at this temperature overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is taken up in CH2CI2 (3 ml.) and treated with F3CCO2H (0.5 ml.) for 1 h. Then, the solution is concentrated and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.Yield: 225 mg (68% of theory) Mass spectrum (ESI+): m/z = 294 [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/63061, 2009, A2 Location in patent: Page/Page column 133

45
[ 1121-79-5 ]
[ 1177269-24-7 ]
[ 1177267-73-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane at 120℃;	4.22 Example 4-22 (Trans)-8-([6-(2-fluorophenyl)-3-pyridazinyl]amino}methyl)-3-(6-methyl-3-pyridazinyl)-1-oxa-3-azaspiro[4.5]decan-2-one Hydrochloride (Trans)-8-([6-(2-fluorophenyl)-3-pyridazinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (Intermediate 47, 40 mg, 0.112 mmol), 3-chloro-6-methylpyridazine (14.43 mg, 0.112 mmol), potassium phosphate (119 mg, 0.561 mmol), copper(I) iodide (21.38 mg, 0.112 mmol) and trans-1,2-diaminocyclohexane (0.013 ml, 0.112 mmol) in 1,4-dioxane (2 ml) in a closed vial were stirred at 120° C. overnight (ca 16 hours). 3-Chloro-6-methylpyridazine (5 mg, 0.039 mmol), trans-1,2-diaminocyclohexane (0.005 ml) and copper(I) iodide (5 mg, 0.026 mmol) were further added and the mixture was stirred at 120° C. for additional 5 hours. The mixture was dried (vacuo) and the solid was taken up with DCM filtering on a filter cartridge. The organic was dried (vacuo) to afford a crude which was purified by KP-NH chromatography (Biotage SP1 12+M) eluding in gradient with 0%-50% EtOAccyclohexane (in 5 cv) then 50% EtOAccyclohexane (5 cv), 50%-100% EtOAccyclohexane (in 5 cv) and 100% EtOAc (5 cv) to afford a white solid (17.4 mg). 1H NMR (400 MHz, CDCl3): δ 1.17-1.35 (m, 2H), 1.83-2.00 (m, 3H), 2.00-2.13 (m, 4H), 2.69 (s, 3H), 3.46 (t, 2H), 4.19 (s, 2H), 4.91-5.02 (m, 1H), 6.73 (d, 1H), 7.11-7.22 (m, 1H), 7.24-7.31 (m, 1H), 7.36 (d, 2H), 7.71 (dd, 1H), 8.12 (d, 1H), 8.45 (d, 1H); UPLC-MS: 0.54 min, 449 [M+H]+

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2009/203705, 2009, A1 Location in patent: Page/Page column 91

46
[ 1121-79-5 ]
[ 87-90-1 ]
[ 120276-59-7 ]

Yield	Reaction Conditions	Operation in experiment
	In chloroform;	Step 1. 3-Chloro-6-chloromethyl-pyridazine To a solution of 3-chloro-6-methyl-pyridazine (25 g, 0.2 mol) in chloroform (850 mL) at 60 C. was added trichloroisocyanuric acid (0.4 equivalent, 18.1 mol) and stirred for 15 hours. An additional charge of trichloroisocyanuric acid (3 g) was added and the mixture heated for an additional hour. The mixture was then cooled in an ice bath and filtered over celite. The organic solution was concentrated to a yellow oil which darkened and solidified upon standing in the freezer (yield 30 g, 95%).

Reference： [1]Patent: US2009/226398,2009,A1

47
[ 1121-79-5 ]
[ 1155857-04-7 ]
[ 1155857-09-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 3-chloro-6-methylpyridazine; (2R,6R,11S)-6,11-dimethyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester With sodium carbonate at 100℃; Inert atmosphere; Stage #2: With trifluoroacetic acid In dichloromethane for 1h;	LXVII ExampleLXVII(2R6R.11 SV-6.11-Dimethyl-8-(6-methyl-pyridazin-3-yl)-1.2,3,4,5,6-hexahvdro-2,6- methano-benzofdlazocine; 2 M Aqueous Na2CO3 solution (1.13 ml_) is added to a mixture of (2R,6R,11 S)-6,11- dimethyl-8-(4>4I5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 ,2,5,6-tetrahydro-4H-2,6- methano-benzoIdlazocine-S-carboxylic acid tert-butyl ester (483 mg) and 3-chloro-6- methyl-pyridazine (218 mg) in dimethylformamide (2 imL). The resulting mixture is flushed with argon and then 1 ,1'-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane complex (73 mg) is added. The mixture is heated to 100 0C and stirred at this temperature overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is taken up in CH2CI2 (3 ml_) and treated with F3CCO2H (0.5 ml_) for 1 h. Then, the solution is concentrated and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.Yield: 225 mg (68% of theory)Mass spectrum (ESI+): m/z = 294 [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/100872, 2009, A1 Location in patent: Page/Page column 148

48
[ 1121-79-5 ]
[ 862364-67-8 ]
[ 1226771-48-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 180℃; for 0.0833333h;	17.B Step B: Step B: Methyl(3S,4R)-4-(4-chlorophenyl)-1-(6-methylpyridazin-3-yl)pyrrolidine-3-carboxylate The product of Step A, methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.92 mmol) was dissolved in dioxane (2 ml). DIPEA (1.34 ml, 7.67 mmol) and 3-chloro-6-methylpyridazine (0.74 g, 5.76 mmol) were added. The reaction was conducted at 180° C. for 5 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. EtOAc was added to the obtained residue. The mixture was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/2) to give the title compound (0.48 g, 75%). MS[M+H]=332 (M+1)
75%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 180℃; for 0.0833333h; Microwave;	17.B Step B: Methyl G 5 .4 /gV4-(4-chlorophenylVl-(6-methylpyridazin-3-yls)pyrrolidine-3-carboxylate[399] The product of Step A, methyl (35,4R)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate (0.46 g, 1.92 mmol) was dissolved in dioxane (2 ml). DIPEA (1.34 ml, 7.67 mmol) and 3-chloro-6-methylpyridazine (0.74 g, 5.76 mmol) were added. The reaction was conducted at 18O0C for 5 minutes with microwave. Then, the reaction mixture was concentrated in vacuo. EtOAc was added to the obtained residue. The mixture was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (0.48 g, 75 %).[400] MS [M+H] = 332 (M+ 1 )

Reference： [1]Current Patent Assignee: LG CHEM CO.,LTD. - US2010/120783, 2010, A1 Location in patent: Page/Page column 12
[2]Current Patent Assignee: LG CHEM CO.,LTD. - WO2010/56022, 2010, A2 Location in patent: Page/Page column 28

49
[ 1121-79-5 ]
[ 1313595-43-5 ]
C₂₇H₂₈N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 85℃; for 4h; Inert atmosphere;	53 Representative procedure for the synthesis of 22b (Method A): A mixture of 8 (200 mg, 0.48 mmol), 22 (0.060 mL, 0.48 mmol), diacetoxy-palladium (6 mg, 0.02 mmol), cesium carbonate (316 mg, 0.97 mmol), and Xantphos (28 mg, 0.05 mmol) in degassed dioxane (4.0 mL) was heated at 85 °C in a sealed vessel under inert atmosphere for 4 h. The resulting mixture was diluted with dichloromethane and ethanol, extracted with a saturated aqueous solution of NaHCO3. The organics were dried over MgSO4 and concentrated in vacuo. TFA (5 mL) and anisole (0.32 mL, 2.9 mmol) were added to a solution of the crude product in dichloromethane (7 mL). The mixture was stirred at 25-40 °C for 24 h and slowly quenched with a saturated aqueous solution of Na2CO3. Extractive workup (at pH 8-9) with ethyl acetate and then dichloromethane afforded a residue which was adsorbed on silica gel and purified by flash chromatography (2/100 to 5/100 EtOH/DCM + 0.5% NH4OH) to yield 22b (108 mg, 80%) as a pale yellow solid.1H NMR (500 MHz, DMSO) δ 8.56 (NH), 7.87 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.17 (SO2NH2), 2.49 (s, 3H), 2.36 (s, 3H). ESIMS (m/z): 279.3 (MH+).

Reference： [1]Location in patent: experimental part Lach, Franck; Pasquet, Marie-Jeanne; Chabanne, Mylène [Tetrahedron Letters, 2011, vol. 52, # 16, p. 1882 - 1887]

50
[ 1121-79-5 ]
[ 1313595-44-6 ]
C₂₇H₂₈N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 85℃; for 4h; Inert atmosphere;	53 Representative procedure for the synthesis of 22b (Method A): A mixture of 8 (200 mg, 0.48 mmol), 22 (0.060 mL, 0.48 mmol), diacetoxy-palladium (6 mg, 0.02 mmol), cesium carbonate (316 mg, 0.97 mmol), and Xantphos (28 mg, 0.05 mmol) in degassed dioxane (4.0 mL) was heated at 85 °C in a sealed vessel under inert atmosphere for 4 h. The resulting mixture was diluted with dichloromethane and ethanol, extracted with a saturated aqueous solution of NaHCO3. The organics were dried over MgSO4 and concentrated in vacuo. TFA (5 mL) and anisole (0.32 mL, 2.9 mmol) were added to a solution of the crude product in dichloromethane (7 mL). The mixture was stirred at 25-40 °C for 24 h and slowly quenched with a saturated aqueous solution of Na2CO3. Extractive workup (at pH 8-9) with ethyl acetate and then dichloromethane afforded a residue which was adsorbed on silica gel and purified by flash chromatography (2/100 to 5/100 EtOH/DCM + 0.5% NH4OH) to yield 22b (108 mg, 80%) as a pale yellow solid.1H NMR (500 MHz, DMSO) δ 8.56 (NH), 7.87 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.17 (SO2NH2), 2.49 (s, 3H), 2.36 (s, 3H). ESIMS (m/z): 279.3 (MH+).

Reference： [1]Location in patent: experimental part Lach, Franck; Pasquet, Marie-Jeanne; Chabanne, Mylène [Tetrahedron Letters, 2011, vol. 52, # 16, p. 1882 - 1887]

51
[ 1121-79-5 ]
[ 928038-44-2 ]
[ 1341223-03-7 ]

Yield	Reaction Conditions	Operation in experiment
1.3 g	With potassium carbonate; In N,N-dimethyl-formamide; at 130℃;	A mixture of 3-chloro-6-methylpyridazine (4.0 g, 0.03 mol), azetidin-3-ylmethanol (Step 6, 2.5 g, 0.02 mmol) and potassium carbonate (5.5 g, 0.04 mmol) in DMF (20 mL) was heated at 130 C overnight. The reaction mixture was evaporated under reduced pressure and the residue was purified by flash silica chromatography, and product eluted with 10% ethanol in ethyl acetate, to afford [1-(6-methylpyridazin-3-yl)azetidin-3-yl]methanol (1.3 g, 36%) as a yellow oil. m/z (M + H)+ = 180.0 (cal=180) (ES)+1H NMR (300 MHz, CDCl3, 25 C) delta 7.05 (d, J = 9.3 Hz, 1H), 6.49 (d, J = 9.3 Hz, 1H), 4.15 (m, 2H), 3.94 (m, 2H), 3.91 (m, 2H), 2.98 (m, 1H), 2.50 (s, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6031 - 6035

52
[ 1121-79-5 ]
[ 1207557-48-9 ]
[ 1383675-73-7 ]

Yield	Reaction Conditions	Operation in experiment
42%	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 4.0h;Inert atmosphere;	General procedure: Reactions were carried out in a Bohdan XT 24 position block using the appropriate halide indicated.2M Sodium carbonate (0.680 mL, 1.36 mmol) was added to a stirred mixture of <strong>[1207557-48-9]3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine</strong> (10, 151 mg, 0.62 mmol), the appropriate halide (0.74 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(Amphos)Cl2) (26.3 mg, 0.04 mmol) in DME (4 mL) under nitrogen. The resulting mixture was stirred at 80 C for 4 h, allowed to cool, diluted with water (10 mL), extracted with EtOAc (2×25 mL) and the organic layer was evaporated to afford crude products. Unless otherwise stated the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 mu silica, 19 mm diameter, 100 mm length, 5-95% MeCN/1% NH3 in H2O).

Reference： [1]Tetrahedron,2012,vol. 68,p. 5434 - 5444

53
[ 1121-79-5 ]
[ 381248-04-0 ]
[ 1405127-71-0 ]

Yield	Reaction Conditions	Operation in experiment
29%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 105℃; for 0.75h;microwave irradiation;	A mixture of 3-chloro-6- methylpyridazine (1.20 g, 9.33 mmol), <strong>[381248-04-0]2-chloro-3-pyridinylboronic acid</strong> (1.62 g, 10.27 mmol, Frontier Scientific, Logan, UT), Na2C03 (1.98 g, 18.67 mmol), Pd(PPh3)4 (0.54 g, 0.46 mmol) in 12 mL of dioxane and 4 mL of H20 was heated in a microwave at 105 C for 45 min. The reaction was diluted with 100 mL of EtOAc, washed with 5 mL of 0.5 N NaOH (aq.), followed by 5 mL of brine. The organic extract was concentrated and the residue was purified by silica gel chromatography (50-100%o EtOAc in hexanes) to give 3-(2-chloro-3-pyridinyl)-6-methylpyridazine (571 mg, 29 %> yield) as an off white crystalline solid. MS (ESI, pos. ion) m/z: 190.1 (M+l).

Reference： [1]Patent: WO2012/148775,2012,A1 .Location in patent: Page/Page column 54

54
[ 1121-79-5 ]
[ 3900-89-8 ]
[ 1405127-68-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 0.583333h;Inert atmosphere; microwave irradiation;	A mixture of 3-chloro-6- methylpyridazine (1.00 g, 7.78 mmol, Aldrich), <strong>[3900-89-8]2-chlorophenylboronic acid</strong> (1.46 g, 9.33 mmol), and Pd(PPh3)4 (0.449 g, 0.389 mmol) was purged with argon and treated with dioxane (10 mL) and 1 M Na2C03 (aq., 11.7 mL, 11.7 mmol) and heated in the microwave at 110 °C for 35 min. The mixture was diluted with EtOAc (50 mL), washed with 1 N NaOH (10 mL), followed by brine (25 mL). The organic extracts were concentrated under reduced pressure (rotary evaporator) and dried over MgS04 and concentrated. The residue was purified by silica gel chromatography (40-100 percent> EtOAc in hexanes) to afford 3-(2-chlorophenyl)-6-methylpyridazine (1.51 g, 95percent yield) as a light yellow crystalline solid. MS (ESI, pos. ion) m/z: 205.1 (M+l). .H NMR (400 MHz, CDCI3) delta ppm 7.69 - 7.79 (2 H, m), 7.46 - 7.54 (1 H, m), 7.35 - 7.45 (3 H, m), 2.79 (3 H, s).

Reference： [1]Patent: WO2012/148775,2012,A1 .Location in patent: Page/Page column 53

55
[ 1121-79-5 ]
[ 874289-46-0 ]
[ 1405128-21-3 ]

Yield	Reaction Conditions	Operation in experiment
47.6%	With sodium carbonate In 1,4-dioxane at 120℃; for 0.5h; microwave irradiation;	1 A mixture of 3- chloro-6-methylpyridazine (500 mg, 3.89 mmol), (5-(dimethylcarbamoyl)-2- fluorophenyl)boronic acid (1.03 g, 4.86 mmol, Combi-Blocks Inc., San Diego, CA),Pd(PPh3)4 (225 mg, 0.19 mmol, Strem Chemicals) in dioxane (12 mL) and 2M aqueous Na2C03 (5.83 mL, 11.67 mmol) was heated in a microwave reactor at 120 °C for 30 min. The reaction mixture was partitioned between 10 mL of IN NaOH and 50 mL EtOAc. The organic layer was washed with brine and concentrated. The brown residue was purified by silica gel chromatography (40-100% EtOAc in hexanes) to afford 4-fluoro- A,A -dimethyl-3-(6-methylpyridazin-3-yl)benzamide (480 mg, 1.85 mmol, 47.6 % yield) as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 260.1 (M+l). .H NMR (400 MHz, CDCl3) δ ppm 8.26 (1 H, dd, J=7.4, 2.2 Hz), 7.86 (1 H, dd, J=8.7, 1.9 Hz), 7.58 (1 H, ddd, J=8.3, 4.8, 2.2 Hz), 7.40 (1 H, d, J=8.6 Hz), 7.17 - 7.25 (1 H, m), 3.08 (3 H, s), 3.13 (4 H, s), 2.78 (3 H, s). 19F NMR (376 MHz, CDCh) δ ppm -1 15.61 (1 F, s).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/148775, 2012, A1 Location in patent: Page/Page column 82; 83

56
[ 1121-79-5 ]
[ 874289-54-0 ]
[ 1405128-16-6 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium carbonate In 1,4-dioxane at 120℃; for 0.5h; Sealed tube; microwave irradiation;	1 A mixture of 5-(cyclopropylcarbamoyl)-2-fluorophenylboronic acid (672 mg, 3.01 mmol, Combi- Blocks Inc, BB3348), Pd(PPh3)4 (139 mg, 0.12 mmol, Strem Chemicals Inc) and 3- chloro-6-methylpyridazine (310 mg, 2.41 mmol), in dioxane (6 mL) and 2 M Na2C03 (aq., 3.6 mL, 7.23 mmol) in a sealed glass tube was heated in a microwave at 120 °C for 30 min. It was partitioned between 5 mL of 0.5 N NaOH and 50 mL of EtOAc. The organic layer was separated, washed with brine and concentrated. The brown residue was purified by silica gel chromatography (55-100% EtOAc in hexanes) to give N- cyclopropyl-4-fluoro-3-(6-methylpyridazin-3-yl)benzamide (475 mg, 72 % yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 272 (M+l). .H NMR (400 MHz, DMSO-de) δ ppm 8.63 (1 H, d, J=3.5 Hz), 8.41 (1 H, dd, J=7.3, 2.1 Hz), 7.98 (2 H, m), 7.72 (1 H, d, J=8.8 Hz), 7.49 (1 H, dd, J=10.6, 9.0 Hz), 2.88 (1 H, m), 2.70 (3 H, s), 0.72 (2 H, m), 0.59 (2 H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm -114.67.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/148775, 2012, A1 Location in patent: Page/Page column 79; 80

57
[ 1121-79-5 ]
[ 206357-78-0 ]
[ 1405128-18-8 ]

Yield	Reaction Conditions	Operation in experiment
39%	In N,N-dimethyl-formamide at 90℃; for 5h;	1 3-Chloro-2-(tributylstannyl)pyridine (3.26 g, 8.10 mmol, Synthonix, No.C3118G5, Wake Forest, NC,), 3-iodo-6-methylpyridazine (1.62 g, 7.36 mmol), Cul (140 mg, 0.74 mmol) and Pd(PPh3)4 (511 mg, 0.44 mmol, Strem Chemicals) in DMF (12 mL) was heated at 90 °C for 5 h. The reaction mixture was treated with water and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine and dried over Na2S04, filtered and concentrated. The crude compound was purified by silica gel chromatography (50-100% EtOAc in hexanes) to afford 3-(3-chloropyridin-2-yl)-6-methylpyridazine (594 mg, 2.89 mmol, 39 % yield) as a viscous orange oil. MS (ESI, pos. ion) m/z: 206.1 (M+l). .H NMR (400 MHz, CDCl3) δ ppm 8.65 (1 H, d, J=3.7 Hz), 7.87 - 7.92 (1 H, m), 7.85 (1 H, d, J=8.6 Hz), 7.46 (1 H, d, J=8.6 Hz), 7.35 (1 H, dd, J=8.2, 4.7 Hz), 2.82 (3 H, s).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/148775, 2012, A1 Location in patent: Page/Page column 81

58
[ 1121-79-5 ]
[ 1380918-98-8 ]
[ 1405127-65-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	In tetrahydrofuran at 70℃; for 0.5h; Inert atmosphere; microwave irradiation;	1 In a 20 mL glass microwave tube, 3-chloro- 6-methylpyridazine (508 mg, 3.95 mmol) and Pd(dppf)Cl2 (161 mg, 0.20 mmol) were treated with thiazol-2-ylzinc(II) bromide (11.9 mL of 0.5 M solution in THF, 5.95 mmol, Aldrich) via syringe under an atmosphere of argon. The solution was heated in the microwave at 70 °C for 30 min. The reaction was treated with 0.34 M EDTA (pH = 7.4 with LiOH) (3.5 mL) and stirred for 10 min. It was extracted with EtOAc (50 mL), washed with brine (2 x 25 mL) and dried over MgS04, filtered through a plug of Celite and concentrated. Purification by silica gel chromatography (0-20% MeOH in ¾(¾) afforded 2-(6-methylpyridazin-3-yl)thiazole (665 mg, 95% yield) as a rust-colored solid after drying under high vacuum overnight. MS (ESI, pos. ion) m/z: 178.1 (M+l). .H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (1 H, d, J=8.8 Hz), 8.09 (1 H, d, J=3.3 Hz), 7.93 - 8.02 (1 H, m), 7.76 (1 H, d, J=8.6 Hz), 2.71 (3 H, s).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2012/148775, 2012, A1 Location in patent: Page/Page column 52

59
[ 1121-79-5 ]
[ 1403396-21-3 ]
[ 1403396-78-0 ]

Yield	Reaction Conditions	Operation in experiment
29%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,2-dimethoxyethane; water at 130℃; for 1.5h; Microwave irradiation;	64.1 8-([Tert-butyl(dimethyl)silyl]oxy}methyl)-8-methyl-3-{1-[4-(6-methylpyridazin-3-yl)phenyl]cyclopropyl}-5,6,8,9-tetrahydro[1,2,4]triazolo[4,3-d][1,4]thiazepine A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-chloro-6-methylpyridazine (192 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130°C for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate = 0:100 to 20:80, gradient) to obtain the title compound (153 mg, 29%) as a brown solid. 1H-NMR (400 MHz, CDCl3) δ: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.47-1.53 (1H, m), 1.59-1.64 (2H, m), 1.66-1.70 (1H, m), 2.55 (1H, ddd, J = 15.5, 7.9, 2.2 Hz), 2.69 (1H, ddd, J = 15.5, 7.9, 2.1 Hz), 2.76 (3H, s), 3.40 (2H, s), 3.51 (1H, d, J = 9.8 Hz), 3.55 (1H, d, J = 9.8 Hz), 4.08 (1H, ddd, J = 14.3, 7.9, 2.1 Hz), 4.32 (1H, ddd, J = 14.3, 7. 9, 2.2 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.6 Hz), 7.72 (1H, d, J = 8.6 Hz), 8.00 (2H, d, J = 8.6 Hz)

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2700643, 2014, A1 Location in patent: Paragraph 0350

60
[ 1121-79-5 ]
[ 1403396-99-5 ]
[ 1403397-00-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; tricyclohexylphosphine In 1,4-dioxane; water at 140℃; for 2h; Microwave irradiation;	89.2 (8R)-8-([Tert-butyl(dimethyl)silyl]oxy}methyl)-3-{1-[2-fluoro-4-(6-methylpyridazin-3-yl)phenyl]cyclopropyl}-8-methyl-5,6,8,9-tetrahydro[1,2,4]triazolo[4,3-d][1,4]thiazepine The compound (600 mg, 1.05 mmol) obtained in Example 89-1), 3-chloro-6-methylpyridazine (161 mg, 1.26 mmol), tris(dibenzylideneacetone)dipalladium (96 mg, 0.10 mmol), tricyclohexylphosphine (29 mg, 0.10 mmol), and tripotassium phosphate (458 mg, 2.09 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at 140°C for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (200 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol:ethyl acetate = 0:100 to 20:80) to obtain the title compound (366 mg, 65%) as a brown solid. 1H-NMR (CDCl3) δ: 0.02 (3H, s), 0.04 (3H, s), 0.89 (9H, s), 1.15 (3H, s), 1.49-1.75 (4H, m), 2.58 (1H, ddd, J = 15.6, 8.0, 2.2 Hz), 2.71-2.80 (1H, m), 2.77 (3H, s), 3.36 (2H, s), 3.49 (3H, dd, J = 15.1, 10.0 Hz), 4.22 (1H, ddd, J = 14.5, 8.2, 1.6 Hz), 4.52 (1H, ddd, J = 14.5, 7.8, 1.6 Hz), 7.41 (1H, d, J = 9.0 Hz), 7.53 (1H, t, J = 8.2 Hz), 7.72 (1H, d, J = 8.6 Hz), 7.77 (1H, dd, J = 8.2, 1.6 Hz), 7.82 (1H, dd, J = 12.5, 1.6 Hz)

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2700643, 2014, A1 Location in patent: Paragraph 0422

61
[ 1121-79-5 ]
3-amino-5-fluoropyridin-2(1H)-one [ No CAS ]
3-amino-5-fluoro-1-(6-methylpyridazin-3-yl)pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.72%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine In 1,4-dioxane at 110℃; for 40h;	A54.2 Step 2: 3-Amino-S -fluoro- 1 -(6-methylpyridazin-3 -yl)pyridin-2( 1 H)-one (A54) A mixture of 3-amino-5-fluoropyridin-2-ol (0.660 g, 5.15 mmol), 3-chloro-6-methylpyridazine (1.325 g, 10.30 mmol), N1,N2-dimethylethane-1,2-diamine (0.165 mL,1.546 mmol), copper(I) iodide (0.294 g, 1.546 mmol), and potassium carbonate (1.424 g,10.30 mmol) in 1,4-dioxane (25 mL) in a pressure tube was heated at 110 oC for 20 h.Additional 3-chloro-6-methylpyridazine (0.662 g, 5.15 mmol), copper(I) iodide (0.197 g,0.773 mmol), and potassium carbonate (0.7 12 g, 5.15 mmol) were added. The mixturewas heated at 110 oC for another 20 h. The reaction mixture was diluted with ethyl acetate (15 mL) and filtered through Celite. The filtrate was concentrated under vacuum. The residue was subjected to ISCO (80 g silica gel, solid loading, 1-5% MeOH/CH2C12)to provide the desire product, 3 -amino-5 -fluoro- 1 -(6-methylpyridazin-3 -yl)pyridin-2( 1 H)one (0.167 g, 0.758 mmol, 14.72 % yield), as a white solid.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/89143, 2015, A1 Location in patent: Page/Page column 93; 94

62
[ 1121-79-5 ]
[ 147269-67-8 ]
C₁₈H₁₆N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.76%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine In 1,4-dioxane at 110℃; for 56h;	A33.1 Step 1: Benzyl (1 -(6-methylpyridazin-3 -yl)-2-oxo- 1 ,2-dihydropyridin-3 -yl)carbamate A mixture of benzyl (2-hydroxypyridin-3-yl)carbamate (2.45 g, 10.03 mmol), 3-chloro-6-methylpyridazine (2.58 g, 20.06 mmol), Ni ,N2-dimethylethane- 1 ,2-diamine(0.320 mL, 3.01 mmol), copper(I) iodide (0.573 g, 3.01 mmol), and potassium carbonate(2.77 g, 20.06 mmol) in i,4-dioxane (50 mL) in a pressure tube was heated at 110 °C for20 h. Additional 3-chloro-6-methylpyridazine (i.29 g, 10.03 mmol), Ni,N2-dimethylethane-i,2-diamine (0.16 mL, 1.50 mmol), copper(I) iodide (0.282 g, 1.50 mmol), and potassium carbonate (i.38 g, 10.03 mmol) were added. The mixture was heated at 1 10 °C for another 36 h. The reaction was complete, giving the desired product as the major. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was further diluted with ethyl acetate (300 mL), washed withwater (3 x 60 mL) and brine (60 mL), and dried over anhydrous Mg504. An impure product was obtained by ISCO (220 g silica gel, solid loading, i-6% MeOH/dichloromethane). This impure product was further purified by another ISCO run (80 g silica gel, solid loading, 20-50% ethyl acetate/dichloromethane) to provide the desired product, benzyl (i -(6-methylpyridazin-3 -yl)-2-oxo- i ,2-dihydropyridin-3 -yl)carbamate (0.734 g, 2.i82 mmol, 2i.76 % yield), as a white solid.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/89143, 2015, A1 Location in patent: Page/Page column 88; 89

63
[ 1121-79-5 ]
4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazole [ No CAS ]
3-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-6-methylpyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With caesium carbonate In acetonitrile at 140℃; for 2h; Microwave irradiation;
29%	With caesium carbonate In acetonitrile at 140℃; for 2h; Microwave irradiation;	1 Examples of N-arylation of 3-alkoxypyrazoles with halogenoheteroaryl without copper catalyst, general method. General procedure: In a reaction vial designed for microwave heating, the considered alkoxypyrazole (2 mmol), the considered halogenated heteroaryl (2.2 mmol) and cesium carbonate (2.8 mmol) were stirred in dimethylformamide or acetonitrile (3 mL) as specified in the examples. This was heated using a microwave at a temperature between 120 °C and 180 °C for the individually specified duration. The resulting suspension was diluted in water, extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and concentrated to dryness. The residue was further purified as described below.

Reference： [1]Lucas-Hourani, Marianne; Munier-Lehmann, Hélène; El Mazouni, Farah; Malmquist, Nicholas A.; Harpon, Jane; Coutant, Eloi P.; Guillou, Sandrine; Helynck, Olivier; Noel, Anne; Scherf, Artur; Phillips, Margaret A.; Tangy, Frédéric; Vidalain, Pierre-Olivier; Janin, Yves L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5579 - 5598]
[2]Current Patent Assignee: INSTITUT PASTEUR; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - WO2015/155680, 2015, A2 Location in patent: Page/Page column 28

64
[ 557-21-1 ]
[ 1121-79-5 ]
[ 49840-90-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; zinc In N,N-dimethyl acetamide at 120℃; Inert atmosphere;	XII 6-Methylpyridazine-3-carbonitrile A solution of 3-chloro-6-methylpyridazine (50 g, 389 mmol) in DMA (1250 mL) wasdegassed under nitrogen for 10 minutes then zinc (II) cyanide (27.4 g, 233 mmol),zinc dust (1017 mg, 15.6 mmol) and Pd(dppf)C12.DCM (12.7 g, 15.6 mmol) wereadded. The mixture was heated at 120°C overnight. The reaction mixture wascooled to RT, diluted with DCM (1 L) and filtered through celite, washing with further DCM. The fi[trate was concentrated under reduced pressure. The residue was purified by dry f[ash si[ica chormatography (e[uting with TBME) to give 34.9 g (75 % yie[d) of the tit[e compound as an off-white so[id.1H NMR (500 MHz, Ch[oroform-d): 6 [ppm] 7.72 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.6Hz, 1H), 2.85 (5, 3H).

Reference： [1]Current Patent Assignee: BAYER AG; EVOTEC AG - WO2016/91776, 2016, A1 Location in patent: Page/Page column 368; 369

65
[ 1121-79-5 ]
C₄₃H₃₅N₉S₂ [ No CAS ]
C₄₈H₃₉N₁₁S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With tetrabutylammomium bromide; sodium hydroxide In water; toluene at 5 - 20℃; for 1h;	The resulting compound 5 (3.7 g) was dissolved in toluene(100 mL) & cooled to below 5 , 8% aqueous sodium hydroxide solution (100 mL) was added. Here,3-chloro-6-methyl pyridazine (4.0 g, Aldrich Co. manufactured) was added portionwise while maintaining below 5 and further stirred at room temperature for 1 hour.The aqueous phase was removed from the reaction mixture with a liquid separation operation, the remaining ethyl acetate phase was washed with aqueous sodium bicarbonate solution and brine, and after dried over magnesium sulfate, the solvent was distilled off. the resulting oily matter was dissolved in heated methanol and cooled to obtain crystals, and it was recovered by filtration to obtain compound 6 (5.9g, 67% yield).

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - JP5827842, 2015, B2 Location in patent: Paragraph 0120; 0123

66
[ 1121-79-5 ]
C₁₉H₁₇N₃S [ No CAS ]
C₂₄H₂₁N₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium hydroxide In water; toluene at 5 - 20℃; for 1h;	Then, the obtained compound 2 was dissolved in toluene(100ml) & cooled to below 5 , and 8% aqueous sodium hydroxide solution(100 mL) was added. Here, 3-chloro-6-methyl-pyridazine (7.2 g, Aldrich Co.manufactured) was added portionwise while keeping at below 5 and further stirred at room temperature for 1 hour.the aqueous phase was removed from the reaction mixture with a liquid separation operation, the remaining ethyl acetate phase was washed with aqueous sodium bicarbonate solution and brine, and after dried overmagnesium sulfate, the solvent was distilled off. the resulting oily matter wasdissolved in heated methanol and cooled to obtain crystals, and it wasrecovered by filtration to obtain compound 3 (8.3g, 47% yield).

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - JP5827842, 2015, B2 Location in patent: Paragraph 0120; 0122

67
[ 1121-79-5 ]
[ 136466-94-9 ]
C₁₀H₇F₂N₃ [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 81869 - 81876

68
[ 1121-79-5 ]
2-amino-2-iminoethyl benzoate acetic acid salt [ No CAS ]
(5-(6-chloropyridazin-3-yl)-1,2,4-thiadiazol-3-yl)methyl benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: 3-chloro-6-methylpyridazine With thionyl chloride Reflux; Stage #2: 2-amino-2-iminoethyl benzoate acetic acid salt With sodium hydroxide In water at -5 - 0℃; for 1h;	6 5.1.6. (5-(6-Chloropyridazin-3-yl)-1,2,4-thiadiazol-3-yl)methylbenzoate (2c) A mixture of 3-chloro-6-methylpyridazine (20.0 g, 0.156 mol) and thionyl chloride (114 mL) was refluxed overnight. The mixture was cooled to room temperature, concentrated in vacuo and evaporated twice with toluene azeoptropically. The residue was suspended in THF (300 mL). To the suspension was added 2-amino-2-iminoethyl benzoate acetic acid salt 10 (18.6 g, 78.1 mmol) and stirred at -5 °C. Then sodium hydroxide (50% in water, 42 mL) was added drop wise to the mixture at -5 °C. After being stirred at 0 °C for 1 h, the reaction mixture was extracted with EtOAc and concentrated in vacuo. The residue was purified by column chromatography to give (5-(6-chloropyridazin-3-yl)-1,2,4-thiadiazol-3-yl)methyl benzoate 2c (18.4 g, 71%) as a white solid; MS(ESI+) m/z: 333.0 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 5.74 (2H, s), 7.51-7.64 (2H, m), 7.66-7.78 (1H, m), 8.00-8.12 (2H, m), 8.15-8.25 (1H, m), 8.35-8.46 (1H, m). 13C NMR (76 MHz, DMSO-d6) δ 62.2, 127.1, 128.8, 129.0, 129.4, 130.7, 133.7, 151.7, 158.1, 165.2, 172.0, 185.2. Anal. Calcd for C14H9ClN4O2S·0.1H2O: C, 50.26; H, 2.77; N, 16.75. Found: C, 50.43; H, 2.97; N, 16.74.
3.8 g	Stage #1: 3-chloro-6-methylpyridazine With thionyl chloride Reflux; Stage #2: 2-amino-2-iminoethyl benzoate acetic acid salt In tetrahydrofuran at 0℃; Stage #3: With water; sodium hydroxide In tetrahydrofuran at 0℃; for 1h;	108.A A) (5-(6-Chloropyridazin-3-yl)-1,2,4-thiadiazol-3-yl)methyl benzoate A solution of 3-chloro-6-methylpyridazine (17.35 g) in thionyl chloride (98 mL) was heated to reflux overnight.The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was suspendedin THF (250 mL). 2-Amino-2-iminoethyl benzoate acetate (32 g) was added to the mixture, and the resulting mixturewas stirred at 0°C. Sodium hydroxide (50% aqueous solution, 60.6 mL) was added dropwise to the mixture at 0°C, andthe resulting mixture was stirred at 0°C for 1 hour. The reaction was terminated by the addition of cold water to themixture, followed by extraction with ethyl acetate. The organic layer was filtered, washed with water and saturated brine,dried over magnesium sulfate and then concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to obtain the title compound (3.8 g). 1H NMR (300 MHz, DMSO-d6) δ5.74 (2H, s), 7.54-7.65 (2H, m),7.66-7.75 (1H, m), 7.97-8.08 (2H, m), 8.20 (1H, d, J = 8.85 Hz), 8.41 (1H, d, J = 8.85 Hz).

Reference： [1]Imamura, Keisuke; Tomita, Naoki; Kawakita, Youichi; Ito, Yoshiteru; Ono, Kouji; Nii, Noriyuki; Miyazaki, Tohru; Yonemori, Kazuko; Tawada, Michiko; Sumi, Hiroyuki; Satoh, Yoshihiko; Yamamoto, Yukiko; Miyahisa, Ikuo; Sasaki, Masako; Satomi, Yoshinori; Hirayama, Megumi; Nishigaki, Ryuichi; Maezaki, Hironobu [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3768 - 3779]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP3118200, 2017, A1 Location in patent: Paragraph 0480

69
[ 1121-79-5 ]
[ 122536-77-0 ]
tert-butyl N-[(3R)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.8%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 130℃; for 12h; Inert atmosphere;	Intermediate 3 A mixture of DIPEA (8.49 mL, 48.62 mmol), tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (3.62 g, 19.45 mmol), 3-chloro-6-methylpyridazine (2.5 g, 19.45 mmol) and n-butanol (30 mL) was stirred at 130° C. for 12 h then left to cool over the weekend. The reaction mixture was evaporated and the crude product was purified by FCC ( SiO2, 0 to 10% 1M NH3 in MeOH in EtOAc). Pure fractions were evaporated to dryness to afford tert-butyl N-[(3R)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]carbamate (2.1 g, 38.8%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 27° C.) δ 1.39 (9H, s), 1.88 (1H, m), 2.14 (1H, m), 2.40 (3H, s), 3.23 (1H, m), 3.37-3.45 (1H, m), 3.47-3.58 (1H, m), 3.61 (1H, m), 3.99-4.2 (1H, m), 6.77 (1H, d), 7.20 (2H, m); m/z: ES+ [M+H]+ 279.
38.8%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 130℃; for 12h;	8 Intermediate 8 tert-Butyl N-[(3R)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]carbamate Intermediate 8 tert-Butyl N-[(3R)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]carbamateA mixture of DIPEA (8.49 mL, 48.62 mmol), tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (3.62 g, 19.45 mmol), 3-chloro-6-methylpyridazine (2.5 g, 19.45 mmol) and n-butanol (30 mL) was stirred at 130° C. for 12 h then left to cool over the weekend. The reaction mixture was evaporated and the crude product was purified by FCC (SiO2, 0 to 10% 1M NH3 in MeOH in EtOAc). Pure fractions were evaporated to dryness to afford tert-butyl N-[(3R)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl]carbamate (2.1 g, 38.8%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 27° C.) δ1.39 (9H, s), 1.88 (1H, m), 2.14 (1H, m), 2.40 (3H, s), 3.23 (1H, m), 3.37-3.45 (1H, m), 3.47-3.58 (1H, m), 3.61 (1H, m), 3.99-4.2 (1H, m), 6.77 (1H, d), 7.20 (2H, m). m/z: ES+ [M+H]+ 279.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; ASTRAZENECA PLC - US2017/152254, 2017, A1 Location in patent: Paragraph 0191-0192
[2]Current Patent Assignee: CANCER RESEARCH UK - US2017/152255, 2017, A1 Location in patent: Paragraph 0280; 0281

70
[ 1121-79-5 ]
[ 616-38-6 ]
[ 71971-82-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium <i>tert</i>-butylate; palladium diacetate; triphenylphosphine; potassium thioacetate In dimethyl sulfoxide at 120℃; Inert atmosphere;	23 Example 23 Under a nitrogen atmosphere,The substrate 3-chloro-6-methylpyridazine 1n (0.2 mmol, 25.6 mg) was added to a 25 mL test tube reactor, (0.2mmol,25.6mg),KSAc(0.6mmol,68.4mg),DMC(1.0mmol,90mg),Pd(OAc)2(0.01mmol,2.3mg),PPh3 (0.02mmol,5.9mg),tBuOK(0.6mmol,69.2mg),and DMSO(2.0mL). The reaction was heated to 120 ° C to carry out the reaction.After the TLC detection reaction was completed,The system was cooled to room temperature.The reaction was quenched with saturated aqueous ammonium chloride,And extracted with ethyl acetate (3 * 10 mL)The product was purified by column chromatography to give 2n 23.8mg (85%).
85%	With potassium <i>tert</i>-butylate; palladium diacetate; triphenylphosphine; potassium thioacetate In dimethyl sulfoxide at 120℃; Schlenk technique; Inert atmosphere;

Reference： [1]Current Patent Assignee: EAST CHINA NORMAL UNIVERSITY - CN106866327, 2017, A Location in patent: Paragraph 0107; 0108; 0109
[2]Wang, Ming; Qiao, Zongjun; Zhao, Jiaoyan; Jiang, Xuefeng [Organic Letters, 2018, vol. 20, # 19, p. 6193 - 6197]

71
[ 1121-79-5 ]
[ 24152-95-2 ]
2-((6-methylpyridazin-3-yl)amino)-1-(pyrrolidin-1-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 120℃; for 14h;Inert atmosphere; Sealed tube;	3-chloro-6-methylpyridazine (120 mg, 0.93 mmol), 2-amino-1-(pyrrolidin-1-yl)ethanone (150 mg, 1.17 mmol) and DIPEA (245 μL, 1.40 mmol) were dissolved in ethanol (0.23 mL), sealed into a microwave vial and the reaction was heated to 120 C for 14 hr in a Biotage Initiator microwave reactor. The reaction mixture was filtered, diluted with methanol and purified by Open Access Mass Directed AutoPrep on Xbridge column using acetonitrile/water with an ammonium carbonate modifier. The solvent was evaporated in vacuo to give 2-((6-methylpyridazin-3-yl)amino)-1-(pyrrolidin-1-yl)ethanone (25 mg, 0.113 mmol, 12 % yield) as an off-white solid. LCMS (High pH, ES+): tR = 0.54 min, [M+H]+ 221.0. 1H NMR (600 MHz, DMSO-d6) δ 1.79 (quin, J = 6.9 Hz, 2 H), 1.92 (quin, J = 6.9 Hz, 2 H), 2.37 (s, 3 H), 3.33 (t, J = 7.0 Hz, 2 H), 3.48 (t, J = 6.8 Hz, 2 H), 4.08 (d, J = 5.1 Hz, 2 H), 6.64 (t, J = 5.3 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H). 13C NMR (151 MHz, DMSO-d6) δ 21.4, 24.2, 26.1, 43.8, 45.4, 46.0, 115.8, 128.1, 150.5, 157.7, 167.8. νmax (neat): 3317, 2878, 1634, 1606, 1556, 1470, 1436, 1332, 1169, 1106, 1036, 991, 843, 801 cm-1. HRMS: (C11H16N4O) [M+H]+ requires 221.1397, found [M+H]+ 221.1397.

Reference： [1]Synthesis,2017,vol. 49,p. 3775 - 3793

72
[ 1121-79-5 ]
[ 24152-95-2 ]
6-methyl-3-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine [ No CAS ]

Reference： [1]Synthesis,2017,vol. 49,p. 3775 - 3793

73
[ 1121-79-5 ]
[ 17762-03-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With dihydrogen peroxide; acetic acid at 70℃;	27.AAAE Procedure AAAE: Preparation of 3-chloro-6-methylpyridazine 1-oxide To a stirring solution of 3-chloro-6-methylpyridazine ( 15.4 g, 0.12 mol) in AcOH (80 mL) was added H202 (60 mL) in portions at rt. The resulting mixture was stirred at 70 "C overnight. The reaction mixture was partitioned between 20 w% aq. Na2S03 and dichloromethane ( 100 mL), and the aqueous layer was extracted with further dichloromethane (100 mL x 2). The combined organics were dried over Na2S04, and concentrated in vacuo to afford 3-chloro-6- methylpyridazine 1 -oxide ( 1 1.5 g, 66% yield) as a white solid. 'H-NMR (300 MHz, CDC13): δ ppm: 7.55-7.52 (m, 1 H), 7.07-7.05 (m, 1H), 2.46 (s, 3H).

Reference： [1]Current Patent Assignee: PHARMAXIS LTD - WO2017/136871, 2017, A1 Location in patent: Paragraph 0327

74
[ 1121-79-5 ]
C₁₇H₁₅ClN₈OS [ No CAS ]
5-(5-chlorothiazol-2-yl)-N₄-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)-N₂-(6-methylpyridazin-3-yl)pyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.46%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 0.5h; Inert atmosphere;	214 Synthesis of VIII-16 To a solution of compound 213.1. (0.08g, 0.19mmol, l .Oeq) in 1,4-dioxane (lmL) was added methylchloropyridazine (0.04g, 0.231mmol, 1.2eq), cesium carbonate (0.187g, 0.57mmol, 3.0eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.017g, 0.019mmol, O. leq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.027g, 0.037mmol, 0.2eq) were added, again degassed for 5 min. The reaction was stirred at 100°C for 30min. After completion of reaction, reaction mixture was cooled to room temperature, transferred in water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 2% methanol in dichloromethane as eluant to obtain pure VIII-16 (0.020g, 20.46%). MS(ES): m/z 507.31 [M+H]+, LCMS purity : 97.53%, HPLC purity : 97.31%, MR (DMSO-i 400MHZ): 10.84 (s, IH), 10.18 (s, IH), 8.56 (s, IH), 8.03-7.98 (m, 2H), 7.83-7.81 (d, J=7.6Hz, 2H), 7.69-7.67 (d, J=6.8Hz, IH), 7.46-7.43 (d, J=9.2Hz, IH), 7.40-7.36 (t, J=13.2Hz, IH), 4.47 (s, 3H), 3.77 (s, 3H), 2.49 (s, 3H).

Reference： [1]Current Patent Assignee: NIMBUS THERAPEUTICS INC - WO2018/71794, 2018, A1 Location in patent: Paragraph 00981; 00982

75
[ 1121-79-5 ]
[ 406235-30-1 ]
tert-butyl 4-((6-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of tert-butyl 4-((6-methylpyridazin-3-yl)oxy)piperidine-l- carboxylate. To a solution of tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (313 mg, 1.56 mmol) in DMF (1.94 mL) was added sodium hydride (60% w/w, 68.4 mg, 1.71mmol). The reaction was stirred for 5 min at ambient temperature. Then 3-chloro-6-methylpyridazine (100 mg, 0.778 mmol) was added and reaction stirred overnight at 95C. The reaction was cooled to ambient temperature and diluted with saturated NaHC03(aq) and extracted with EtOAc. Combined organics were washed with water and brine. The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo to afford the title compound (assumed quantative yield, 228 mg) in sufficient purity for step 2. MS (apci) m/z = 294.20 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 002064; 002066

76
[ 1121-79-5 ]
[ 109384-19-2 ]
tert-butyl 4-((6-methylpyridazin-3-yl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: 1-(tert-Butyloxycarbonyl)-4-piperidinol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: 3-(methyl)-6-chloropyridazine In N,N-dimethyl-formamide	16.1 Step 1: tert-butyl 4-((6-methylpyridazin-3-yl)oxo)piperidine-1-carboxylate Tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.95 mmol) was added to anhydrous N,N-dimethylformamide (20 mL) at 0 °C, then sodium hydrogen (796 mg.19.9 mmol) was added at 0 °C and the mixture was stirred at room temperature for 30 min, then 3-chloro-6-methylpyridazine (1.9 g, 14.93 mmol) was added; after the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (50 mL FontWeight="Bold" FontSize="10" 3), and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to dryness and separated by column chromatography to obtain white solid tert-butyl 4-((6-methylpyridazin-3-yl)oxo)piperidine-1-carboxylate (1.2 g, yield: 41%). MS m/z (ESI): 294.1 [M+H]+.
14%	Stage #1: 1-(tert-Butyloxycarbonyl)-4-piperidinol With sodium tertiary butoxide In dimethyl sulfoxide at 20℃; for 1h; Stage #2: 3-(methyl)-6-chloropyridazine In dimethyl sulfoxide at 50℃; for 16h;	PREPARATION OF INTERMEDIATE 204 NaOtBu (2.24 g, 23.3 mmol) was added to a solution of 1 -/e/t-butoxycarbonyl-4- hydroxypiperidine (CAS: 109384-19-2; 1.56 g, 7.78 mmol) in DMSO (3 mL), The reaction mixture was stirred at room temperature for 1 h. Then, 3-chloro-6- methylpyridazine (CAS: 1121 79-5; 1.00 g, 7.78 mmol) was added and the reaction mixture was stirred at 50 °C for 16 h. The mixture was cooled to roomtemperature and water was added. The mixture was extracted with EtOAc (3 times). The combined organic layers were washed with NaHCCh and brine, dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 0/100 to 10/90). A second purification was performed by reverse phase chromatography ([25mM NH4HC03]/[MeCN:Me0H 1 : 1], gradient from 70/30 to 27/73). The desired fractions were collected and concentrated in vacuo to afford intermediate 204 (318 mg, 14%) as a white solid.
	Stage #1: 1-(tert-Butyloxycarbonyl)-4-piperidinol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3-(methyl)-6-chloropyridazine In N,N-dimethyl-formamide at 90℃; for 48h;	1 Step 1 : Preparation of tert-butyl 4-((6-methylpyridazin-3-yl)oxy)piperidine-l- carboxylate. A solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (10.22 g, 50.75 mmol) in DMF (56.39 mL) was treated with 60% w/wNaH (2.165 g, 54.14 mmol) at ambient temperature and allowed to stir for 10 min. The reaction mixture was treated with 3-chloro-6-methylpyridazine (4.350 g, 33.84 mmol). The reaction mixture was stirred for 10 min at ambient temperature and then at 90 °C for 48 h. The reaction mixture was cooled to ambient temperature and quenched with saturated NaHCCb(aq) (20 mL) and water (20 mL). The quenched mixture was extracted with DCM (3 x 40 mL), and the combined organic extracts were washed with water (3 x 100 mL) and brine (3 x 100 mL). The combined organic extracts were dried over anhydrous Na2S04(S), filtered, and concentrated in vacuo to afford the title compound (quantitative yield assumed). MS (apci) m/z = 294.20 (M+H).

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - EP3971187, 2022, A1 Location in patent: Paragraph 0260-0263
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/243530, 2019, A1 Location in patent: Page/Page column 81-82
[3]Current Patent Assignee: PFIZER INC - WO2018/136661, 2018, A1 Location in patent: Paragraph 00862

77
[ 1121-79-5 ]
[ 65202-50-8 ]

Reference： [1]Patent: WO2007/143823,2007,A1

78
[ 1121-79-5 ]
[ 908268-52-0 ]
8-methoxy-6-[7-(6-methylpyridazin-3-yl)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one [ No CAS ]

Reference： [1]Patent: WO2019/105886,2019,A1

79
[ 1121-79-5 ]
[ 908268-52-0 ]
[ 1201657-85-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 1h;Sealed tube; Inert atmosphere;	In a sealed tube is charged with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2- ajpyridine (CAS 908268-52-0; 0.5 g, 2.05 mmol, 1 eq.), 3-chloro 6 -methyl pyridazine (CAS 1121-79- 5; 316 mg, 2.46 mmol, 1.2 eq.), CS2CO3 (1.34 g, 4.10 mmol, 2 eq.), Pd(dppf)Cl2-DCM (167 mg, 0.20 mmol, 0.1 eq.) and degassed with N2 dioxane/water solvent mixture: 4/1 (10 mL). The system is purged with N2 then the mixture is stirred to 90 C for 1 h. The reaction mixture is cooled down to RT, diluted in EtOAc, filtered over Celite. The filtrate is concentrated in vacuo and used in the next step without further purification. 1.2.3.3.4 El.l: Saponification of ester

Reference： [1]Patent: WO2019/105886,2019,A1 .Location in patent: Paragraph 0397; 0484

80
[ 1121-79-5 ]
[ 110-82-7 ]
[ 135216-72-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; Selectfluor In water; acetone at 20℃; for 16h; Inert atmosphere; Irradiation;
82%	With hydrogenchloride; dihydrogen peroxide In water; acetonitrile at 20℃; for 18h; Inert atmosphere; Irradiation; Green chemistry;
65%	With hydrogenchloride; tetraethylammonium chloride In water; acetonitrile at 34 - 42℃; Electrochemical reaction; Irradiation; Inert atmosphere;

Reference： [1]Zhao, Hong; Jin, Jian [Organic Letters, 2019, vol. 21, # 16, p. 6179 - 6184]
[2]Zhao, Hong; Li, Zhenlong; Jin, Jian [New Journal of Chemistry, 2019, vol. 43, # 32, p. 12533 - 12537]
[3]Chen, Peng-Yu; Xu, Hai-Chao; Xu, Pin [Angewandte Chemie - International Edition, 2020, vol. 59, # 34, p. 14275 - 14280][Angew. Chem., 2020, vol. 132, # 34, p. 14381 - 14386,6]

81
[ 5049-61-6 ]
[ 1121-79-5 ]
C₉H₉N₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 40h; Inert atmosphere;	DF 6-Methyl-/V-(pyrazin-2-yl)-/V-({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3- yl]thiophen-2-yl}methyl)pyridazin-3-amine Under Ar(g), to a mixture of pyrazin-2-amine (1) (209mg, 2.2mmol), 3- chloro-6-methylpyridazine (2) (257mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90°C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10mL) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (45mg, 12%).

Reference： [1]Current Patent Assignee: KARUS THERAPEUTICS LIMITED - WO2019/166824, 2019, A1 Location in patent: Page/Page column 105

82
[ 1121-79-5 ]
tert-butyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)acetate [ No CAS ]
tert-butyl 2-(3-acetyl-5-(6-methylpyridazin-3-yl)-1H-indazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.6%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 0 - 90℃; for 2h; Inert atmosphere;	1.2 Step 2: tert-Butyl 2-(3-acetyl-5-(6-methylpyridazin-3-yl)-1H-indazol-1-yl)acetate (35- 3): To a mixture of compound 35-2 (200 mg, 0.50 mmol) and 3-chloro-6-methylpyridazine (70 mg, 0.55 mmol) in 1,4-dioxane (7 mL) and water (1 mL) was added potassium carbonate (172 mg,1.25 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) at 0 °C and the mixture was stirred at 90 °C under N2 atmosphere for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (eluted with PE: EtOAc= 50: 1 to 1: 1) to afford compound 35-3 (100 mg, yield 54.6%) as a yellow solid. LC/MS (ESI) m/z: 367 (M+H)+.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2020/41301, 2020, A1 Location in patent: Page/Page column 289; 335-336

83
[ 1121-79-5 ]
[ 290305-47-4 ]
methyl (E)-3-(6-methylpyridazin-3-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With bis-triphenylphosphine-palladium(II) chloride; disodium hydrogenphosphate; triethylamine In 1,4-dioxane; water at 95℃; for 15h; Inert atmosphere;	General procedure for Suzuki couplings General procedure: To the stirred solution of the halogenated compound (0.39 mmol) in dioxane (10 mL), PdCl2(PPh3)2 (0.04 mmol), saturated solution of NaHPO4 (2 mL, 1.2 mmol) were addedand degassed using argon for 15 min. To this mixture, boronic acid (0.42 mmol) wasadded and degassing was continued for 15 more minutes following this TEA (4.0 equiv)was added to the turbid solution and degassed for additional 15 min. The reaction mixturewas heated at 95 °C for 15 h. TLC revealed complete consumption of starting material.The reaction mixture was filtered using Hyflo bed and the bed was washed thoroughlyby ethyl acetate. The solvent mixture was evaporated under reduced pressure, and crudecompound was loaded on a column and eluted using the mixture of ethyl acetate andhexanes. The products were characterized by NMR.

Reference： [1]Balasubramaniam, Sivaraman; Vijayan, Sajith; Goldman, Liam V.; May, Xavier A.; Dodson, Kyra; Adhikari, Sweta; Rivas, Fatima; Watkins, Davita L.; Stoddard, Shana V. [Beilstein Journal of Organic Chemistry, 2020, vol. 16, p. 628 - 637]

84
[ 1121-79-5 ]
1-phenylisoquinolin-3-amine [ No CAS ]
C₂₀H₁₆N₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 12h; Reflux;	5 [Scheme 1-1] Synthesis of [Intermediate 1-a] General procedure: 2-bromo-6-methylpyrazine (17.3 g, 0.1 mol), 1-amino-4-methylbenzene (10.7 g, 0.1 mol), palladium acetate (0.08 g, 0.32 mmol),2,2'-bis(diphenylphosphino)-1-1'-binaphthyl (0.26 g, 0.42 mmol),Sodium tert-butoxide (15.2 g, 0.16 mol) were dissolved in 200 mL toluene was refluxed for 12 hours. After cooling to room temperature, it was washed with methanol, and recrystallized with dichloromethane and methanol to give [Intermediate 1-a] 15.5 g (yield 78%).

Reference： [1]Current Patent Assignee: HODOGAYA CHEMICAL CO LTD - KR102162249, 2020, B1 Location in patent: Paragraph 0279-0283; 0379; 0388-0391

85
[ 1121-79-5 ]
[ 2439-85-2 ]
[ 948996-03-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	With copper(l) iodide; 2,2'-azobis(isobutyronitrile); potassium carbonate; triphenylphosphine In 1,4-dioxane at 120℃; for 24h; Inert atmosphere;	20 Under the protection of nitrogen, N-bromophthalimide B2 (1.0 mmol), CuI (0.025 mmol), PPh3 (0.05 mmol), AIBN (0.05 mmol), potassium carbonate (1.0 mmol), 3- Chloro-6-methylpyridazine A19 (0.5 mmol) and 1,4-dioxane (2 mL) were added to the reaction tube. Stir at 120°C for 24 hours. After stopping the reaction, cool to room temperature, evaporate the solvent, and separate by column chromatography. The volume ratio of eluent used (mL/mL) is ethyl acetate: petroleum ether = 1:10 ~ 1:1 , Obtain 2-(6-chloropyridine-3-methyl)isoindole-1,3-dione 20 with a yield of 50%.

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES - CN112047925, 2020, A Location in patent: Paragraph 0036-0037

86
[ 1121-79-5 ]
[ 134-32-7 ]
C₁₅H₁₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 12h; Reflux;	1 [Scheme 1-1] [Intermediate 1-a] synthesis 6-chloro-3-methylpyridazine (12.8 g, 0.1 mol), 1-naphthalenamine (14.3 g, 0.1 mol), palladium acetate (0.08 g, 0.32 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene(0.26 g, 0.42 mmol) and sodium tert-butoxide (15.2 g, 0.16 mol) were added to 150 mL of toluene and refluxed for 12 hours. After cooling to room temperature, washed with methanol, and recrystallized with dichloromethane and methanol to give [Intermediate 1-a] 18.1 g (77% yield).

Reference： [1]Current Patent Assignee: HODOGAYA CHEMICAL CO LTD - KR102193832, 2020, B1 Location in patent: Paragraph 0198-0202

87
[ 1121-79-5 ]
[ 611-73-4 ]
(3-chloro-6-methylpyridazin-4-yl)(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With sodium persulfate; silver nitrate; trifluoroacetic acid In water at 60℃; for 6h; regioselective reaction;	General experimental procedures General procedure: To an 10 mL vial reaction vessel equipped with a magnetic stirring bar was added pyridazines (0.6 mmol, 1.0 equiv.), α-keto acids (0.6-0.9 mmol, 1.0-1.5 equiv.), AgNO3 (0.12 mmol, 0.2 equiv.), Na2S2O8 (0.6-0.9 mmol, 1.0-1.5 equiv.), TFA (0.6 mmol, 1.0 equiv.) and H2O (6.0 mL). The mixture was stirred at 60 °C for 6 h. After the reaction was complete, the mixture was neutralized with Na2CO3 and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and evaporated in vacuum. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate / petroleum ether = 1/5 - 1/2).

Reference： [1]Wang, Shengqiang; Xu, Xiaobo; Zou, Dapeng; Xu, Qijie [Tetrahedron Letters, 2021, vol. 62]

88
[ 1121-79-5 ]
(1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]
tert-butyl 8-(6-methylpyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; sodium t-butanolate In toluene at 100℃; for 16.1667h; Sealed tube; Inert atmosphere;	Intermediate amine 46: Preparation of 8-(6-methylpyridazin-3-yl)-3,8- diazabicyclo[3.2.1]octane bis hydrochloride Step 1: In a sealable reaction vessel equipped with a magnetic stirrer and a Teflon screwcap was combined tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.2 equiv, PharmaBlock, Inc.), 3-chloro-6-methylpyridazine (1 equiv, Combi-Blocks), sodium tert- butoxide (1.2 equiv, Sigma-Aldrich), Pd2(dba)3 (0.02 equiv, Sigma-Aldrich), and BINAP (0.04 equiv, Ark Pharm) in toluene (0.68 M). The reaction suspension was then deoxygenated via sub-surface purging with N2 for 10 min. Finally, the reaction vessel was tightly sealed and heated at 100oC for 16 h. The reaction mixture was allowed to cool to RT, diluted with water and extracted with EtOAc. The combined organic extracts were washed further with water (2x) and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, gradient elution: Hex → EtOAc → 10:1 (v/v) EtOAc: MeOH) afforded tert-butyl 8-(6-methylpyridazin-3-yl)- 3,8-diazabicyclo[3.2.1]octane-3-carboxylate as an off-white solid (69% yield).

Reference： [1]Current Patent Assignee: PIPELINE THERAPEUTICS INC - WO2021/71843, 2021, A1 Location in patent: Paragraph 0361-0362

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