Name: 258506-68-2|3-Chloro-6-(trifluoromethyl)pyridazine|98%
Brand: Ambeed
SKU: A241404
Rating: 98 (26 reviews)

1
[ 1514-87-0 ]
[ 135034-10-5 ]
[ 258506-68-2 ]

Reference： [1]Tetrahedron,1999,vol. 55,p. 15067 - 15070

2
[ 628331-02-2 ]
[ 258506-68-2 ]
[ 628331-40-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 3-isopropyl-4-[3-(methoxymethoxy)propyl]-1H-pyrazole; 3-chloro-6-(trifluormethyl)pyridazine With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 3h; Stage #2: With methanol In water for 4h; Heating / reflux;	Reference Example 226 Reference Example 226 To a mixture of 4- [3- (methoxymethoxy) propyl]-3- (l-methylethyl)-lH-pyrazole (1.00 g), 3-chloro-6- (trifluoromethyl) pyridazine (1.03 g) and N, N-dimethylformamide (15 ml) was added sodium hydride (60%, in oil, 0.28 g) at0 C, and, after termination of hydrogen generation, the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and washed with water. A mixture of the obtained residue,conc. hydrochloric acid (3 drops) and methanol (15 ml) was refluxed for 4 hours. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration, washed with water, dried and subjected to silica gel column chromatography, and 3- {3- (l-methylethyl)-l- [6- (trifluoromethyl) pyridazin-3-yl]-lH-pyrazol-4-yl}-1-propanol (1.00 g, yield 68%) was obtained as colorless crystals from a fraction eluted with ethyl acetate- chloroform (1: 3, volume ratio). melting point:113-114 C. H-NMR (CDC13) 8 : 1.33 (6H, d, J= 6. 6Hz), 1.42 (1H, t, J= 5. 1Hz), 1.84-2. 01 (2H, m), 2.63 (2H, t, J= 7.9Hz), 3.05 (1H, septet, J= 6.8Hz), 3.77 (2H, q, J= 5.7Hz), 7.83 (1H, d, J= 9. 0Hz), 8.29 (1H, d, J= 9. 0Hz), 8.50 (1H, s).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2003/99793, 2003, A1 Location in patent: Page 228

3
[ 628331-43-1 ]
[ 258506-68-2 ]
[ 628331-44-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: 3-(1-ethylpropyl)-4-[3-(methoxymethoxy) propyl]-1H-pyrazole; 3-chloro-6-(trifluormethyl)pyridazine With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 2h; Stage #2: With methanol In water for 4h; Heating / reflux;	Reference Example 229 Reference Example 229 To a mixture of3- (1-ethylpropyl)-4- [3- (methoxymethoxy) propyl]-lH-pyrazole (2.20 g), 3-chloro-6- (trifluoromethyl) pyridazine (2.17 g) and N, N-dimethylformamide (30 ml) was added sodium hydride(60%, in oil, 0.48 g) at0 C, and, after termination of hydrogen generation, the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried(MgS04) and concentrated. A mixture of the obtained wet crystals,conc. hydrochloric acid (3 drops) and methanol (50 ml) was refluxed for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and3- {3- (1-ethylpropyl)-1- [6- (trifluoromethyl)pyridazin-3-yl]-lH-pyrazol-4-yl}-1-propanol (1.73 g, yield 55%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1: 2, volume ratio). melting point: 86-87 C. H-NMR (CDC13) $ : 0. 87 (6H, d, J= 7. 3Hz), 1.46 (1H, br s), 1.60- 2.00 (6H, m), 2.53-2. 70 (3H, m), 3.76 (2H, t, J= 6.4Hz), 7.83 (1H, d, J= 9.2Hz), 8.29 (1H, d, J= 9.2Hz), 8.51 (1H, s).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2003/99793, 2003, A1 Location in patent: Page 230

4
[ 628331-87-3 ]
[ 258506-68-2 ]
methyl 3-{3-tert-butyl-1-[6-(trifluoromethyl)pyridazin-3-yl]-1H-pyrazol-4-yl}propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydride In DMF (N,N-dimethyl-formamide) at 20℃; for 1h;	Reference Example 305 Reference Example 305 To a mixture of methyl3- (3-tert-butyl-lH-pyrazol-4- yl) propanoate (0.75 g),3-chloro-6- (trifluoromethyl) pyridazine (0.98 g) andN, N-dimethylformamide (10 ml) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3- {3-tert-butyl-1- [6- (trifluoromethyl)pyridazin-3-yl]-lH-pyrazol-4-yl} propanoate (1.08 g, yield 85%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1: 10, volume ratio). 1H-NMR (CDC13) 8 : 1.41 (9H, s), 2.72 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.5 Hz), 3.73 (3H, s), 7.83 (1H, d, J=9.6 Hz), 8.28 (1H, d, J=9.6 Hz), 8.50 (1H, s).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2003/99793, 2003, A1 Location in patent: Page 268

5
[ 628332-26-3 ]
[ 258506-68-2 ]
methyl 3-{3-isopropyl-1-[6-(trifluoromethyl)pyridazin-3-yl]-1H-pyrazol-4-yl}propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 2h;	Reference Example 327 Reference Example 327 To a mixture of methyl3- (3-isopropyl-lH-pyrazol-4- yl) propanoate (70.0 g),3-chloro-6- (trifluoromethyl) pyridazine (71.6 g) and N, N-dimethylformamide (700 ml) was added sodium hydride (60% in oil, 16.4 g) at0 C, and the mixture was stirred at said temperature for 2 hours. The reaction solution was poured into dilute hydrochloric acid and the organic layer was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and saturated brine, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and methyl3- {3-isopropyl-l- [6- (trifluoromethyl)pyridazin-3-yl]-lH-pyrazol-4-yl} propanoate (92.6 g, yield 76%) was obtained as a pale-yellow solid from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). 1H-NMR (CDC13)$ : 1.33 (6H, d, J=7.2 Hz), 2.64-2. 71 (2H, m), 2.82-2. 89 (2H, m), 3.00-3. 10(1H, m), 3.71 (3H, s), 7.84 (1H, d, J=9.0 Hz), 8.29(1H, d, J=9. 0 Hz), 8.49(1H, s).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2003/99793, 2003, A1 Location in patent: Page 278

6
[ 174607-36-4 ]
[ 258506-68-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With thionyl chloride;N,N-dimethyl-formamide; for 2h;Heating / reflux;	Reference Example 313 A mixture of6- (trifluoromethyl)-3-pyridazinone (1.41 g), thionyl chloride (1.5 ml) and N, N-dimethylformamide (0.3 ml) was refluxed for 2 hours. Excess thionyl chloride was evaporated under reduced pressure and aqueous sodium hydrogen carbonate was added. The mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and 3-chloro-6- (trifluoromethyl) pyridazine (1.45 g, yield92%) was obtained as white crystals from a fraction eluted with ethyl acetate- hexane (1: 3, volume ratio). melting point:51-52 C.lH-NMR (CDC13) 6 : 7.75(1H, dd, J=8.7, 0.6 Hz), 7.82(1H, d, J=9.0Hz).
89%	With trichlorophosphate; at 90℃; for 6h;	Description 87; 3-Chloro-6-trifluoromethvlpvridazine; A mixture of Description 86 (2.00 g, 12.2 mmol) and phosphorous oxychloride (11.4 ml, 122 mmol) was heated at 90C for 6 hours. The excess phosphorous oxychloride was removed by evaporation, and the residue then dissolved in dichloromethane (100 ml) and ice (100 g) added. The mixture was stirred for 30 min, then carefully basified by the addition of saturated aqueous K2CO3, filtered and evaporated to give the title compound as a pale brown solid (2 g, 89%). IH NMR (400 MHz, CDCl3) 7.79 (1 H, d, J9.0), 7.86 (1 H, d, J9.0).
63%		To 380 <strong>[174607-36-4]3-(trifluoromethyl)-1H-pyridazin-6-one</strong> (1.1 g, 6.7 mmol) was added 133 phosphorusoxychloride (10 mL) and the mixture was stirred at 100 C. for 2.5 hr, and concentrated under reducedpressure. To the obtained residue were added 12 dichloromethane and 52 water, and the mixture wasstirred at room temperature for 5 min. The mixture was alkalified by adding 106 potassium carbonate topartition the mixture. The organic layer was washed with saturated brine, dried over sodium sulfate, and thedesiccant was filtered off, and the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the 381 title compound ( 0.77 g , 4.2mmol, 63%).MS (ESI) m/z 182 (M+H)+ 1H NMR (400 MHz, CDCl3) delta 7.82 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H)

63%

With trichlorophosphate; In dichloromethane; water; at 100℃; for 2.5h;

To <strong>[174607-36-4]3-(trifluoromethyl)-1H-pyridazin-6-one</strong> (1.1 g, 6.7 mmol) was added phosphorus oxychloride (10 mL) and the mixture was stirred at 100C for 2.5 hr, and concentrated under reduced pressure. To the obtained residue were added dichloromethane and water, and the mixture was stirred at room temperature for 5 min. After stirring, the mixture was alkalified with potassium carbonate and partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate and the desiccant was filtered off. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (0.77 g, 4.2 mmol, 63%). MS (ESI) m/z 182 (M+H)+ 1H NMR (400 MHz, CDCl3) delta 7.82 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H).

Reference： [1]Patent: WO2003/99793,2003,A1 .Location in patent: Page 272
[2]Patent: WO2005/47279,2005,A1 .Location in patent: Page/Page column 49
[3]Tetrahedron,2009,vol. 65,p. 4212 - 4219
[4]Patent: US2016/332999,2016,A1 .Location in patent: Paragraph 0548; 0549; 0550
[5]Patent: EP3330266,2018,A1 .Location in patent: Paragraph 0143

7
[ 799559-57-2 ]
[ 258506-68-2 ]
(S)-1-isopropyl-4-[1-(6-trifluoromethyl-pyridazin-3-yl)-piperidine-4-carbonyl]-2-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 120℃; for 0.0833333h;	88 Example 88; (S)-1-ISOPROPYL-4- [1- (6-TRIFLUOROMETHYL-PYRIDAZIN-3-YL)-PIPERIDINE-4-CARBONYL]-2- methyl piperazine hydrochloride (E88) (S)-1-LSOPROPYL-4-(PIPERIDINE-4-CARBONYL)-2-METHYLPIPERAZINE (free base compound from D29) (0. 10g), 3-chloro-6-trifluoromethyl-pyridazine (A. J. Goodman, S. P. Stanforth and B. Tarbit, Tetrahedron, 1999,55 (52), 15067-15070) (0. 071G) and potassium carbonate (0. 1G) were stirred in DMSO (1. 5MOI) at 120°C for 5min in a microwave reactor. The reaction was worked up as described for Example 78 and the purified free base was dissolved in MEOH (2ML) and treated with 1 N ETHEREAL HCI solution (2ml) to give the title hydrochloride salt (E88) as a white solid (92mg). LCMS electrospray (+ve) 400 (MH+). 'H NMR 8 [DMSO-d6]: 1.29 (3H, d, J=6.4Hz), 1.34-1. 39 (6H, m), 1.47-1. 85 (4H, m), 2.75-3. 2 (5H, m), 3.30-3. 90 (4H, m), 4.6 (4H, m), 7.47 (1 H, d, J=9.6Hz), 7.80 (1 H, d, J=9.6Hz), 11.15 (1H, bs).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/101546, 2004, A1 Location in patent: Page 50

8
[ 845305-84-2 ]
[ 258506-68-2 ]
3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]-1-piperidinyl}-6-(trifluoromethyl)pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 120℃; for 0.0833333h; Microwave irradiation;	82 Example 82 3- {4- [ (1-Cyclobutyl-4-piperidinyl) oxy]-1-piperidinyl}-6- (trifluoromethyl) pyridazine HYDROCHLORIDE (E82) 3-Chloro-6- (trifluoromethyl) pyridazine (A. J. Goodman, S. P. Stanforth and B. Tarbit, Tetrahedron, 1999,55 (52), 15067-15070) (0.09g), 1-CYCLOBUTYL-4- (4- piperidinyloxy) piperidine (D6) (0. 10G), and potassium carbonate (0. 11G) in DMSO (2ML) were heated in the microwave at 120°C for 5min. The reaction was poured directly onto an SCX COLUMN (10G) and washed with MeOH (60ml) and then eluted with 2M ammonia in MeOH SOLUTION (60ML). After evaporation the residue was purified by chromatography [silica gel (10g cartridge), eluting with 10% NH3 in MeOH/DCM, 0-10%]. Pure fractions were evaporated and the free base was dissolved in DCM and converted into the HCI salt with excess 1 M HCI in diethyl ether. After evaporation of solvent the title compound (E82) was obtained as a pale brown solid (0.16g). MS ELECTROSPRAY (+ve ion) 385 (MH+). H NMR 8 (DMSO-D6) : 11.09 (1H, s), 7.80 (1H, d, J=9.6Hz), 7.48 (1H, d, J=9.6Hz), 4.10 (2H, m), 3.95-3. 38 (5H, m), 3.33-3. 04 (2H, m), 2.90-2. 65 (2H, m), 2.38 (2H, m), 2.10- 1.57 (10H, m), 1.50 (2H, m).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/14571, 2005, A1 Location in patent: Page/Page column 49

9
ethyl chlorodifluoromethyl acetate [ No CAS ]
[ 135034-10-5 ]
[ 258506-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride; copper(l) iodide; In DMF (N,N-dimethyl-formamide); at 120℃; for 5h;	A mixture of <strong>[135034-10-5]6-chloro-3-iodopyridazine</strong> (12.0 g, 50 mmol), ethyl chlorodifluoromethyl acetate (45 g, 280 mmol), KF (168 g, 290 mmol), CuI (14.4 g, 76 mmol) in DMF (600 mL) was stirred at 120 C. for 5 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 (500 mL) and washed with brine. The solution was concentrated in vacuo and the residue was purified by column chromatography to afford 3-chloro-6-trifluoromethylpyridazine, 2.9 g.

Reference： [1]Patent: US2005/234046,2005,A1 .Location in patent: Page/Page column 66

10
[ 754-10-9 ]
[ 258506-68-2 ]
[ 912331-60-3 ]

Yield	Reaction Conditions	Operation in experiment
18%	With caesium carbonate In 1,4-dioxane Heating / reflux;	19.A S-Chloro-δ-trifluoromethyl-pyridazine (4.4 g, 24.18 mmol), prepared according to the lit. procedure (Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron Lett. 1999, 55, 15067), is mixed with 2,2-dimethyl-propionamide (2.93 g, 29.01 mmol) in dioxane (10O mL). The mixture is treated with Cs2CO3 (11.82 g, 36.27 mmol) and BINAP (0.75 g, 1.21 mmol), then degassed with bubbling N2 for 5 min. Pd2(dba)3 (1.11 g, 1.1 mmol) is added under N2. The reaction is refluxed overnight. It is cooled to it, filtered through silical gel; washed with EtOAc, and concentrated. Purification of the crude mixture by chromatography gives the title compound (1.09 g, 4.41 mmol, 18%). 1H NMR (CDCl3): δ 1.39 (s, 9H), 7.09 (d, J = 15.8 Hz, IH), 8.68 (d, J = 9.2 Hz, IH) ppm. ES-MS (m/z): calcd for C10H12F3N3O (M+H)+: 248.2; found: 248.1.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2006/107784, 2006, A1 Location in patent: Page/Page column 58-59

11
[ 926296-77-7 ]
[ 258506-68-2 ]
[ 926297-14-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h;	196 To a solution of ethyl (2E) -3- [2-hydroxy-4- (2- methoxyethoxy) phenyl] acrylate (1.05 g) in N, N- dimethylformamide (10 ml) were added 3-chloro-6- (trifluoromethyl)pyridazine (1.48 g) and potassium carbonate (1.53 g) , and the mixture was stirred at 800C for 3 hr. After cooling, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate EPO layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was, subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (49:1, v/v) . The obtained crude crystals were recrystallized from ethyl acetate-hexane to give ethyl (2E)-3- (4- (2- methoxyethoxy) -2-{ [6- (trifluoromethyl)pyridazin-3- yl]oxy}phenyl) acrylate (2.14 g, yield: 90%) as colorless crystals. 1H-NMR (300 MHz, CDCl3) διl.21 (3 H, t, J = 7.1 Hz), 3.43 (3 H, s), 3.73 - 3.75 (2 H, m) , 4.11 - 4.14 (2 ,H, m) , 4.19 (2 H, q, J = 7.1 Hz), 6.35 (1 H, d, J = 16.2 Hz)/ 6.75 (1 H, d, J = 2.7 Hz), 6.91 (1 H, dd, J = 8.7, 2.7 Hz), 7.40 (1 H, d, J = 9.0 Hz), 7.64 (l.H, d, J = 8.7 Hz), 7.70 (1 H, d, J = 16.2 Hz), 7.84 (1 -H, d, J = 9.0 Hz) .

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/18314, 2007, A2 Location in patent: Page/Page column 189-190

12
[ 87120-72-7 ]
[ 258506-68-2 ]
[ 935777-19-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 150℃; for 0.5h;	1 Description 1; tert-Bntyl 4-[6-(trifluoromethyl)pyridazin-3-yl]amino}piperidine-l-carboxylate; A mixture of S-chloro--trifluoromethyl-pyridazine (4.4 g, 24.1 mmol) (prepared by a procedure similar to that described in Tetrahedron, 1999, 55 (52), 15067-15070), 4-amino-l-tøt-butyloxycarbonylpiperidine (9.63 g, 48.1 mmol) and potassium iodide (cat.) were heated in a melt at 150 0C for 30 min. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was separated, dried and the solvent evaporated in vacuo. The crude product was purified by chromatography (silica; 1 %-4 % ammonia in methanol (7 M) / dichloromethane) to give Dl (7.06 g, 85 %). Ci5H2IF3N4O2 requires 346; Found 347 (MH+)

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/48779, 2007, A1 Location in patent: Page/Page column 13-14

13
[ 258506-68-2 ]
[ 935777-24-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With ammonium hydroxide; In tetrahydrofuran; at 100.0℃; for 1h;Microwave irradiation;	A mixture of 3-chloro-6-trifluoromethylpyridazine (1.6 g, 8.76 mmol) and ammonium hydroxide (12 mL) in THF (4 mL) was heated at 100 C in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was extracted with DCM (with MeOH 10%) and H20. The aqueous layer was extracted 5 times. The combined extracts were dried over with MgSO4, filtered, and evaporated under reduce pressure to afford the amine compound 13 (1.37 g, 96%) as a white solid.
93%	With ammonia; In tetrahydrofuran; water; at 100.0℃; for 1h;Microwave irradiation;	Description 6; 6-Trifluoromethyl-3-pyridazina; A mixture of S-chloro--trifluoromethyl-pyridazine (1.6 g, 8.8 mmol) (prepared by a procedure similar to that described in Tetrahedron, 1999, 55 (52), 15067-15070) and ammonium hydroxide (30 ml) in THF (10 ml) was heated at 100 0C in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 1 h. After this period, the reaction mixture was evaporated and the residue extracted with dichloromethane. The combined extracts were dried (MgSO4), filtered and the solvents evaporated in vacuo to give D6 (1.3 g, 93 %). C5H4F3N3 requires 163; Found 164 (MH+)
93%	With ammonium hydroxide; In tetrahydrofuran; at 100.0℃; for 1h;Microwave irradiation;	Example 301a 6-(Trifluoromethyl)pyridazin-3-amine 301a A mixture of 3-chloro-6-trifluoromethylpyridazine (1.6 g, 8.80 mmol) and ammonium hydroxide (9 mL) in THF (3 mL) was heated at 100 0C in a microwave reactor for 1 h. After this period, the reaction mixture was evaporated and the residue was extracted with dichloromethane. The combined extract was dried over with MgSO4, filtered, and evaporated under reduce pressure to afford 301a (1.3 g, 93%) as a white solid. MS-ESI: [M+H]+ 164.1

73%	With ammonium hydroxide; In tetrahydrofuran; at 100.0℃; for 1h;Microwave irradiation;	[00439] Intermediate 35: 6-(Trifluoromethyl)pyridazin-3-amine [00440] A solution of 3-chloro-6-(trifluoromethyl)pyridazine (250mg, 1 .37mmol) and ammonium hydroxide (7.OmL, 1 .37mmol) in THF (3mL) was heated in the microwave at 100 C for 1 hour. LCMS showed conversion to product. The solvent was removed in vacuo and then extracted twicewith DCM. The combined organic layers were dried over anhydrous Na2504, filtered and the solvent removed in vacuo to afford 6-(trifluoromethyl)pyridazin-3-amine (1 63mg, 0.99mmol, 73% yield). 1H NMR (DMSO-d6, 400MHz) O/ppm: 7.53 (1H, d, J= 9.4Hz), 6.85 (1H, d, J= 9.4Hz), 5.21 (2H, bs).MS Method 2: RT: 1.82 mi mlz 163.7[M+H], 327.0 [2M+H]
	With ammonium hydroxide; In tetrahydrofuran; at 100.0℃; for 2h;Sealed tube;	A mixture of 3-chloro-6-(trifluoromethyl)pyridazine (0.5 g, 2.739 mmol) and NH4OH (3 mL, 77.04 mmol) in THF (1 mL) was heated at 100 C in a sealed tube for 2 hours. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residue was diluted with the minimum of water and extracted with DCM (x 3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title product as an orange solid; 1H NMR (500 MHz, DMSO-d6) delta 7.66 (d, J = 9.3 Hz, 1H), 7.15 (s, 2H), 6.90 (d, J = 9.3 Hz, 1H); 19F NMR (471 MHz, DMSO-d6) delta -64.58; MS m/z: 164.0 (M+H)+.

Reference： [1]Patent: WO2018/211323,2018,A1 .Location in patent: Paragraph 00235
[2]Patent: WO2007/48779,2007,A1 .Location in patent: Page/Page column 16
[3]Patent: EP2773638,2015,B1 .Location in patent: Paragraph 1220; 1221
[4]Patent: WO2016/51193,2016,A1 .Location in patent: Paragraph 00438; 00439; 00440
[5]Patent: WO2019/148132,2019,A1 .Location in patent: Paragraph 00960; 00961; 00962

14
C₁₆H₂₂F₃NO₂ [ No CAS ]
[ 258506-68-2 ]
trans-3-methyl-4-[2-propoxy-4-(trifluoromethyl)phenoxy]-1-[6-(trifluoromethyl)-pyridazin-3-yl]piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 120℃; for 1h; Heating / reflux;

Reference： [1]Current Patent Assignee: NIPPON SODA COMPANY LIMITED - WO2007/40280, 2007, A1 Location in patent: Page/Page column 31-33

15
[ 935777-23-4 ]
[ 258506-68-2 ]
N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-N-methyl-6-(trifluoromethyl)pyridazin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 190℃; for 2h; Microwave irradiation;	12 Example 12; λ/-[l-(3,4-difluorobenzyl)piperidin-4-yl]-λ/-methyl-6-(trifluoromethyl)pyridazine-3- amine (E12); A solution of D5 (480 mg, 2 mmol), S-chloro--trifluoromethylpyridazine (182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in n-butanol (4 ml) was heated at 190 0C in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 2 h. After this period, the reaction mixture was evaporated in vacuo and the residue extracted with dichloromethane. The organic layer was washed with a saturated solution of sodium hydrogen carbonate, dried (MgSO4) and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E12 (210 mg, 54 %). Ci8Hi9F5N4 requires 386; Found 387 (MH+). 1R NMR (CDCl3) δ 1.74 (br.d, J=12.0 Hz, 2 H), 1.88 (qd, J=12.0, 3.9 Hz, 2 H), 2.17 (td, J=I 1.8, 2.5 Hz, 2 H), 2.96 (br.d, J=I 1.6 Hz, 2 H), 3.00 (s, 3 H), 3.47 (s, 2 H), 4.85 (t, J=12.1 Hz, 1 H), 6.78 (d, J=9.6 Hz, 1 H), 6.99 - 7.05 (m, 1 H), 7.10 (dt, J=10.2, 8.1 Hz, 1 H), 7.20 (ddd, J=11.4, 7.8, 2.1 Hz, 1 H), 7.46 (d, J=9.6 Hz, 1 H)

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/48779, 2007, A1 Location in patent: Page/Page column 19

16
C₁₈H₂₂F₃NO₃ [ No CAS ]
[ 258506-68-2 ]
9β-[2-cyclopropylmethoxy-4-(trifluoromethyl)phenoxy]-7-[6-(trifluoromethyl)-3-pyridazyl]-3-oxa-7-azabicyclo[3.3.1]nonane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 120 - 130℃; for 3h;
57%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 120 - 130℃; for 3h;	1.8.3 0.19 g of 3-chloro-6-(trifluoromethyl)pyridazine and 0.15 g of DBU were added to 3 ml of N-methylpyrrolidone solution containing the obtained compound (AB) and the resulting mixture was stirred for 3 hours at 120 to 130°C. After cooling the reaction mixture to room temperature, water was poured thereto and extracted with ethyl acetate. After being washed with saturated saline and dried with anhydrous magnesium sulfate, the organic layer was filtered and vacuum-concentrated. The obtained residue was purified by silica gel column chromatography (eluant: n-hexane: ethyl acetate = 1:1 (v/v)) to obtain 0.24 g of the target compound (AC). Yield 57%, mp. 93 to 95°C

Reference： [1]Current Patent Assignee: NIPPON SODA COMPANY LIMITED - WO2007/40282, 2007, A1 Location in patent: Page/Page column 43; 66
[2]Current Patent Assignee: NIPPON SODA COMPANY LIMITED - EP1932844, 2015, B1 Location in patent: Paragraph 0124

17
[ 35691-93-1 ]
[ 258506-68-2 ]
[ 946152-66-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;	EXAMPLE 7; 1-Acetyl-azetidine-3-carboxylic acid [(S)-3-{5-[3,5-dimethyl-1-(6-trifluoromethyl-pyridazin-3-yl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-1-(3-fluoro-phenyl)-propyl]-amide (II-17); step 1-; To a solution of <strong>[35691-93-1]3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (0.2 g, 1.19 mmol) in DMF (10 mL) cooled to 0 C. was added sequentially NaH (60% in mineral oil, 72 mg, 1.78 mmol) and 3-chloro-6-trifluoromethyl-pyridazine (0.22 g, 1.21 mmol; Tetrahedron 1999 55:15067-15070). The resulting mixture was stirred at RT for 3 h then partitioned between EtOAc and saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography eluting with hexane/EtOAc to afford 0.228 g (62%) of 55a.
62%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;	EXAMPLE 20; 2-((S)-1-(3-Fluoro-phenyl)-3-{5-[3,5-dimethyl-1-(6-trifluoromethyl-pyridazin-3-yl)-1H-pyrazole-4-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-propylcarbamoyl)-cyclopentanecarboxylic acid (II-1); Step 1-; To a solution of <strong>[35691-93-1]3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (0.2 g, 1.19 mmol) in DMF (10 mL) cooled to 0 C. was added sequentially NaH (60% in mineral oil, 72 mg, 1.78 mmol) and 3-chloro-6-trifluoromethyl-pyridazine (0.22 g, 1.21 mmol; Tetrahedron 1999 55:15067-15070). The resulting mixture was stirred at RT for 3 h then partitioned between EtOAc and saturated aqueous NH4CI. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography eluting with hexane/EtOAc to afford 0.228 g (62%) of 92a.
62%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;	step 1 - To a solution of 3,5-dimethyl-lff-pyrazole-4-carboxylic acid ethyl ester (0.2 g, 1.19 mmol) in DMF (10 mL) cooled to O0C was added sequentially NaH (60% in mineral oil, 72 mg, 1.78 mmol) and S-chloro-?-trifluoromethyl-pyridazine (0.22 g, 1.21 mmol; Tetrahedron 1999 55:15067-15070). The resulting mixture was stirred at RT for 3 h then partitioned between EtOAc and saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified via Si?2 chromatography eluting with hexane/EtOAc to afford 0.228 g (62%) of 118a.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4753 - 4756
[2]Patent: US2007/191335,2007,A1 .Location in patent: Page/Page column 28-29
[3]Patent: US2007/191406,2007,A1 .Location in patent: Page/Page column 33
[4]Patent: WO2008/34731,2008,A1 .Location in patent: Page/Page column 87

18
[ 258506-68-2 ]
[ 57260-71-6 ]
[ 1048685-30-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 180℃; for 0.5h; Irradiation;	9 A mixture of 6-chloro-3-trifuoromethylpyridazine (0.666 g, 5.09 mmol) (prepared by following the procedure described in Goodman, A.J.; Stanforth, S.P; Tarbit B. Tetrahedron 1999, 55, 15067-15070), JV-Boc-piperazine (1.138 g, 6.11 mmol) and diisopropylethylamine (1.95 ml, 1.12 mmol) in acetonitrile (10 ml) was stirred at 180 0C for 30 min., under microwave irradiation. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; hexane / ethyl acetate) to yield D9 (1.67 g, 99%) as a light yellow solid. Ci4Hi9F3N4O2 requires 332; Found 333 (MH+).
99%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 180℃; for 0.5h; Microwave irradiation;	A1.a A mixture of 6-chloro-S-trifluoromethylpyridazine (0.666 g, 5.09 mmol) (prepared by following the procedure described in Goodman, A.J.; Stanforth, S.P; Tarbit B.Tetrahedron 1999, 55, 15067-15070), tert-butyl 1-piperazinecarboxylate (1.138 g, 6.11 mmol) and DIPEA (1.95 ml, 1.12 mmol) in CH3CN (10 ml) was stirred at 180 0C for 30 min. under microwave irradiation. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; hexane/EtOAc) to yield intermediate 1 (1.67 g, 99 %) as a light yellow solid. Ci4H19F3N4O2 requires 332; Found 333 (MH+)
130 mg	In ISOPROPYLAMIDE at 150℃; for 0.166667h; Microwave irradiation;

With N-ethyl-N,N-diisopropylamine In butan-1-ol at 90℃; for 16h;

Intermediate B1.10 was prepared following an analogous procedure to the one described for the synthesis of intermediate B 1.2 using A -tert-butoxy carbonyl piperazine (CAS: 57260-71-6; 0.37 g, 1.93 mmol), 3 -chloro-6-(tri fluoromethyl)pyri dazine (CAS: 258506-68-2; 0.3 g, 1.61 mmol) and DIPEA (0.56 mb, 3.22 mmol) in 1-butanol (4 mL) as starting materials and stirring the mixture at 90 °C for 16h.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2008/98892, 2008, A1 Location in patent: Page/Page column 28
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2010/456, 2010, A1 Location in patent: Page/Page column 18
[3]Pinard, Emmanuel; Alanine, Alexander; Alberati, Daniela; Bender, Markus; Borroni, Edilio; Bourdeaux, Patrick; Brom, Virginie; Burner, Serge; Fischer, Holger; Hainzl, Dominik; Halm, Remy; Hauser, Nicole; Jolidon, Synese; Lengyel, Judith; Marty, Hans-Peter; Meyer, Thierry; Moreau, Jean-Luc; Mory, Roland; Narquizian, Robert; Nettekoven, Mathias; Norcross, Roger D.; Puellmann, Bernd; Schmid, Philipp; Schmitt, Sebastien; Stalder, Henri; Wermuth, Roger; Wettstein, Joseph G.; Zimmerli, Daniel [Journal of Medicinal Chemistry, 2010, vol. 53, # 12, p. 4603 - 4614]
[4]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2021/123291, 2021, A1 Location in patent: Page/Page column 43; 46

19
[ 258506-68-2 ]
[ 174607-36-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; water for 5h; Heating / reflux;	3 Description 3; 6-Trifluoromethyl-pyridazin-3-ol (D3); A mixture of 6-chloro-3-trifuoromethylpyridazine (10 g, 54. 9 mmol) (prepared by following the procedure described in Goodman, A. J.; Stanforth, S. P.; Tarbit B. Tetrahedron 1999, 55, 15067-15070) and sodium hydroxide (8 g, 0.7 mmol) in water (150 ml) was stirred at reflux for 5 h.. After this period, the solvent was evaporated in vacuo and the crude product dried at 60° C under vacuum for 16h. to yield D3, mixed with sodium chloride, (16.2 g, > 100 %) as a solid. C5H3F3N2O requires 164; Found 165 (MH+).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2008/128995, 2008, A1 Location in patent: Page/Page column 19-20

20
[ 1084743-91-8 ]
[ 258506-68-2 ]
[ 1084742-40-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 7-bromo-1-(4-fluorophenyl)-4-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine With potassium acetate; bis(pinacol)diborane In N,N-dimethyl-formamide at 65℃; Stage #2: 3-chloro-6-(trifluormethyl)pyridazine With caesium carbonate In water; N,N-dimethyl-formamide at 60℃; for 3h;	23.B Step B: A round bottomed flask was charged with 7-bromo-l -(4- fluorophenyl)-4-methyl-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepine (75 mg, 0.22 mmol) from step A above, bis(pinacolato)diboron (62 mg, 0.25 mmol) and potassium acetate (66 mg, 0.67 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (16 mg, 0.02 mmol) in DMF (1 mL). The mixture was refilled with nitrogen three times and then stirred at 65 0C overnight. The mixture was cooled to room temperature. Cesium carbonate (219 mg, 0.67 mmol), S-chloro--trifluoromethylpyridazine (49 mg, 0.67 mmol), and water (0.5 mL) were added. The mixture was refilled with nitrogen three times and then stirred at 60 0C 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 extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (100:0 to 10:1 methylene chloride/methanol) to yield the desired 1- (4-fluorophenyl)-4-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-2,3,4,5-tetrahydro- lH-benzo[e][l,4]diazepine (71 mg, 79%) as a grey solid

Reference： [1]Current Patent Assignee: CURIA INC - WO2008/141081, 2008, A1 Location in patent: Page/Page column 103-104

21
[ 1177269-34-9 ]
[ 258506-68-2 ]
[ 1177267-79-6 ]

Yield	Reaction Conditions	Operation in experiment
16%	With potassium phosphate; (S,S)-1,2-diaminocyclohexane In 1,4-dioxane at 120℃; for 5h;	4.27 (Trans)-8-([6-(3,5-difluorophenyl)-3-pyridazinyl]amino}methyl)-3-[6-(trifluoromethyl)-3-pyridazinyl]-1-oxa-3-azaspiro[4.5]decan-2-one Example 4-27 (Trans)-8-([6-(3,5-difluorophenyl)-3-pyridazinyl]amino}methyl)-3-[6-(trifluoromethyl)-3-pyridazinyl]-1-oxa-3-azaspiro[4.5]decan-2-one (Trans)-8-([6-(3,5-difluorophenyl)-3-pyridazinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]-decan-2-one (Intermediate 63, 20 mg, 0.053 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (9.75 mg, 0.053 mmol), potassium phosphate (56.7 mg, 0.267 mmol), copper(I) iodide (10.17 mg, 0.053 mmol) and trans-1,2-diaminocyclohexane (6.42 μl, 0.053 mmol) in 1,4-dioxane (2.5 ml) were stirred in a closed vial at 120° C. for 5 hours. The mixture was allowed to cool to r.t. and it was dried (vacuo); then the solid was taken up with DCM/MeOH filtering on a filter cartridge. The organic phase was dried (vacuo) to afford a crude that was purified by silica gel chromatography (Biotage SNAP 10 g column) eluding in gradient with 0%-5% MeOHDCM to afford a mixture that was further purified by reverse phase flash-chromatography (Biotage SP1, C18 12+M column), eluding with a gradient of ACN and water made up 0.1% HCOOH. Fractions containing the required compound were collected and passed through an ion exchange SCX cartridge (2g, Varian) eluding with 2M ammonia in MeOH and dried (vacuo) to afford the title compound as a pale yellow solid (4.5 mg, 16%).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2009/203705, 2009, A1 Location in patent: Page/Page column 92

22
[ 258506-68-2 ]
[ 1161005-11-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydrazine hydrate In ethanol at 150℃; for 1h; Sealed tube; Inert atmosphere;	Step 1: 3-hydrazinyl-6-(trifluoromethyl)pyridazine To a solution of 3-chloro-6-(trifluoromethyl)pyridazine (1.0 g, 5.5 mmol) in ethanol (10mL) in a large microwave vial was added hydrazine hydrate (1.25 mL, 22 mmol, 4equiv). The vial was capped and heated in a microwave to 150 °C for 1 h. The reactionmixture was diluted with saturated aqueous sodium bicarbonate (50 mL) and extractedwith isopropyl acetate (3 x 75 mL). The combined organics were dried over sodiumsulfate, filtered, and concentrated to dryness in vacuo to afford 3-hydrazinyl-6-(trifluoromethyl)pyridazine (0.91 g, 93%) as a tan solid, which was used in the next stepwithout further purification. LCMS (2.5 min method) retention time = 0.55 min, m/z =179 [M + H]+.
90%	With potassium carbonate; hydrazine hydrate In tetrahydrofuran at 130℃; for 8h; Inert atmosphere;
36%	With hydrazine hydrate; potassium carbonate In tetrahydrofuran at 25 - 50℃; for 2h;	11.a.1 a) Step-1: 3-hydrazinyl-6-(trifluoromethyl)pyridazine To a stirred solution of 3-chloro-6-(trifluoromethyl)pyridazine (4.6 g, 25.2 mmol) in tetrahydrofuran (40 mL), potassium carbonate was added (0.7 g, 5.04 mmol) followed by drop wise addition of hydrazine hydrate (2.5 mL, 50.4 mmol) at 25 °C. The reaction mixture was heated at 50 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a solid, which was filtered and washed twice with water (100 mL) and hexane (50 mL) to obtain the crude product which was purified by flash column chromatography on silica gel using 50 % ethyl acetate in hexane as an eluent to obtain 3-hydrazinyl-6-(trifluoromethyl)pyridazine (1.6 g, 9.0 mmol, 36 % yield).1H-NMR (400 MHz, DMSO-d6) d 8.80 (d, J = 13.0 Hz, 1H), 7.72 (dd, J = 9.5, 1.7 Hz, 1H), 7.15-7.19 (m, 1H), 4.55 (d, J = 16.9 Hz, 2H) ESI-MS (m/z) 178.90 (MH) +.

Reference： [1]Hamilton, Gregory L.; Chen, Huifen; Deshmukh, Gauri; Eigenbrot, Charles; Fong, Rina; Johnson, Adam; Kohli, Pawan Bir; Lupardus, Patrick J.; Liederer, Bianca M.; Ramaswamy, Sreemathy; Wang, Haowei; Wang, Jian; Xu, Zhaowu; Zhu, Yunliang; Vucic, Domagoj; Patel, Snahel [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 12, p. 1497 - 1501]
[2]Location in patent: experimental part Wan, Wen; Hou, Jie; Jiang, Haizhen; Wang, Yangli; Zhu, Shizheng; Deng, Hongmei; Hao, Jian [Tetrahedron, 2009, vol. 65, # 21, p. 4212 - 4219]
[3]Current Patent Assignee: PI INDUSTRIES LTD - WO2020/178789, 2020, A1 Location in patent: Page/Page column 91; 92

23
[ 1201014-11-0 ]
[ 258506-68-2 ]
[ 1201014-16-5 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In tetrahydrofuran at 80℃; for 2h; Inert atmosphere;	10 394 mg 2-lodo-5-methoxypyridine, 144 mg 3-Chloro-6-trifluormethyl-pyhdazine, 323 mg 4-[5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-2,3-dihydro-indole-1 -sulfonyl]- benzonitrile, 2.56 g cesium carbonate and 23 mg fluoroboric acid tri-tert- butylphosphine adduct were dissolved in 65 ml tetrahydrofuran. The reaction mixture was degassed with argon and then 88 mg Tris(dibenzylideneacetone)palladium(0) chloroform adduct were were added and the mixture heated to 800C for two hours. The cooled reaction mixture was diluted with 100 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 160 mg 4-[5-(6-Trifluoromethyl-pyridazin-3-yl)-2,3-dihydro-indole-1- sulfonyl]-benzonitrile. C20H13F3N4O2S (430.41), MS(ESI+): 431.1 (M+H+).

Reference： [1]Current Patent Assignee: SANOFI - WO2009/149819, 2009, A1 Location in patent: Page/Page column 80-81

24
[ 1228430-63-4 ]
[ 258506-68-2 ]
[ 1228430-64-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 4h;	30 1,1-dimethylethyl(1R,4S,6R)-4-(aminomethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D29 (45 mg) was dissolved in DMSO (1 ml) then DIPEA (0.038 ml, 0.219 mmol) and 3-chloro-6-(trifluoromethyl)pyridazine (39.9 mg, 0.219 mmol) were added and the mixture was stirred at 100° C. for 4 hours. NaHCO3 saturated solution was added and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 anhydrous, filtered through a phase separator tube and concentrated under vacuum to give a crude product which was purified by Silica Gel Chromatography (Biotage SP-column size 25 g using Cy:EtOAc=9:1 to 5:5 as eluent). It was recovered the title compound D30 (53 mg). UPLC: (Acid Final_QC): rt=0.77, peak observed: 373 (M+1). C17H23F3N4O2 requires 372. 1H NMR (400 MHz, CDCl3) δ ppm 7.49-7.36 (m, 1H) 6.82-6.66 (m, 1H) 6.19-6.03 (m, 1H) 4.46-4.19 (m, 1H) 4.12-3.80 (m, 1H) 3.74-3.41 (m, 3H) 2.13-1.90 (m, 1H) 1.87-1.75 (m, 1H) 1.51-1.43 (m, 9H) 1.13-0.97 (m, 2H) 0.81-0.65 (m, 1H) 0.27-0.03 (m, 1H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2010/144760, 2010, A1 Location in patent: Page/Page column 23

25
[ 1255924-95-8 ]
[ 258506-68-2 ]
[ 1255924-14-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 1.5h; Inert atmosphere;	10.E S-Trifluoromethyl--chloropyridazine (470 mg, 2.57 mmol) was added to a mixture of the boronate ester from Step D (557 mg, 1.28 mmol), cesium carbonate (1.26 g, 3.87 mmol) in DMF (20 mL), and water (4 mL). The reaction mixture was deoxygenated with argon. Dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (105 mg, 0.128 mmol) was added and the reaction mixture was stirred at 900C for 1.5 hours, cooled, diluted with water, and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 50% 90:9:ldichloromethane/methanol /concentrated ammonium hydroxide solution in dichloromethane) gave the desired tifluoromethylpyridazinyl tetrahydro-isoquinoline product (338 mg, 58% over 2 steps): 1H NMR (CDCl3, 300 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.23 (d, / = 2.0 Hz, IH), 8.01 (d, J = 9.0 Hz, IH), 7.87 (dd, / = 9.0, 2.5 Hz, IH), 7.73 (dd, J = 8.0, 1.5 Hz, IH), 7.39 (dd, / = 8.5, 2.5 Hz, IH), 7.23 (dd, / = 8.5, 2.5 Hz, IH), 7.04 (d, / = 8.0, 2.5 Hz, IH), 6. 94 (d, J = 8.5, 2.0 Hz, IH), 4.13 (t, /= 5.5 Hz, IH), 3.45 (dd, /= 13.5, 5.0 Hz, IH), 3.10 (dd, J= 13.5, 5.5 Hz, IH), 1.66 (s, IH), 1.57 (s, 3H), 1.55 (s, 3H); ESI MS m/z 453 [M + H]+.

Reference： [1]Current Patent Assignee: CURIA INC - WO2010/132437, 2010, A1 Location in patent: Page/Page column 73-74

26
[ 1255925-33-7 ]
[ 258506-68-2 ]
[ 1255925-36-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 1.5h; Inert atmosphere;	35.A 4-(4-CMorophenyl)-l,l-dimeihyl-7-(4,4,5,5-tBtramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline was prepared following similar methods described in Step A to Step E of Example 9 starting from 2-(3- bromophenyl)propan-2-amine and 2-bromo-l-(4-chlorophenyl)ethanone. 3-Trifluoromethyl-6-chloropyridazine (95 mg, 0.52 mmol) was added to a mixture of the aforementioned boronate ester (285 mg, 0.43 mmol) and cesium carbonate (423 mg, 1.30 mmol) in DMF (5 mL) and water (0.65 mL). The reaction mixture was degassed with argon. Dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (35 mg, 0.043 mmol) was added and the reaction mixture was stirred at 900C for 1.5 hours, cooled, diluted with water, and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography [3% methanol (containing 10% concentrated ammonium hydroxide)/ dichloromethane] gave 4-(4- cUorophenyl)-l,l-dimemyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-l,2,3,4- tetrahydroisoquinoline (140 mg, 78% over 2 steps): 1H NMR (CDCl3, 300 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.23 (d, /= 1.7 Hz, IH), 8.01 (d, /= 8.9 Hz, IH), 7.87 (d, /= 8.9 Hz, IH), 7.73 (dd, /= 8.1, 1.8 Hz, IH), 7.317.26 (m, 2H), 7.077.02 (m, 3H), 4.13 (t, J = 5.3 Hz, IH), 3.45 (dd, J= 13.5, 5.0 Hz, IH), 3.12 (dd, J= 13.5, 5.8 Hz, IH), 1.62 (s, 3H), 1.58 (s, 3H); ESI MS m/z 418 [M + H]+.

Reference： [1]Current Patent Assignee: CURIA INC - WO2010/132437, 2010, A1 Location in patent: Page/Page column 101

27
[ 1255925-45-1 ]
[ 258506-68-2 ]
C₂₅H₂₂Cl₂F₃N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With caesium carbonate In water; N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; Sonication;	11.K A dry flask was loaded with the product from Step J above (0.3 g,0.59 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (0.17 g, 0.97 mmol), cesium carbonate (0.48 g, 1.47 mmol) and dichloro[l,l- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (43 mg, 0.058 mmol). The flask was blanketed with argon then, DMF (10 mL) and water (2 mL) were added followed by a short sonication. The reaction mixture was heated to 800C for 2 hours. The cold reaction mixture was diluted with water (40 mL) and the aqueous layer was extracted with dichloromethane (3x). The combined organic phases were concentrated in vacuo. Purification by flash column chromatography (eluent, 47.5:47.5:5 to 45:45:10 dichloromethane/hexanes/ethyl acetate) gave the Boc-protected 4-(3,4- dicMoropheny^^-ζ-ζtrifluoromethyl^yridazin-S-yO-l^.S^-tetrahydroisoquinoline (0.30 g, 97%) as a tan solid.

Reference： [1]Current Patent Assignee: CURIA INC - WO2010/132437, 2010, A1 Location in patent: Page/Page column 77-78

28
[ 1255925-38-2 ]
[ 258506-68-2 ]
(+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2.5h; Inert atmosphere;	29.A A mixture of (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4-tetrahydroisoquinoline (350 mg, 0.80 mmol, prepared in Step F in Example 26), 3-chloro-6-(trifluoromethyl)pyridazine (176 mg, 0.96 mmol) and cesium carbonate (786 mg, 2.41 mmol), in water (0.8 mL) and N^V-dimethylformamide (4 mL) was degassed with argon and then [1,1- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.04 mmol) was added. The mixture was degassed again and then heated to 900C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) to give (+)-4-(3,4- dicMoropheny^--fluoro^-methyl-V-ζ-ζtrifluoromethylJpyridazin-S-yl)- 1 ,2,3,4- tetrahydroisoquinoline (373 mg, 28%) as a brown oil: ESI MS m/z 456 [M + H]+.

Reference： [1]Current Patent Assignee: CURIA INC - WO2010/132437, 2010, A1 Location in patent: Page/Page column 95-96

29
[ 258506-68-2 ]
[ 408502-23-8 ]
[ 1173155-65-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;	3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol), <strong>[408502-23-8]2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (176 mg, 0.749 mmol), K2CO3 (310 mg, 2.25 mmol) and PdCl2(dppf) (61 mg, 0.075 mmol) were stirred in DMSO (4 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80 C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (115 mg, 60%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).
60%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;	3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol), 2-methoxy-4 -(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749 mmol), K2CO3 (310 mg, 2.25 mmol) and PdCl2(dppf) (61 mg, 0.075 mmol) were stirred in DMSO (4 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80 C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (115 mg, 60%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).
60%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;	3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol), <strong>[408502-23-8]2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (176 mg, 0.749 mmol), K2CO3 (310 mg, 2.25 mmol) and PdCl2(dppf) (61 mg, 0.075 mmol) were stirred in DMSO (4 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80 C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl solution, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (115 mg, 60%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03 (s, 3H).

Reference： [1]Patent: US2011/3739,2011,A1 .Location in patent: Page/Page column 21
[2]Patent: US2011/3793,2011,A1 .Location in patent: Page/Page column 31
[3]Patent: US2012/157460,2012,A1 .Location in patent: Page/Page column 26

30
[ 258506-68-2 ]
[ 1173155-66-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 2 h / 80 °C / Inert atmosphere 2.1: hydrogenchloride / water / 18 h / 120 °C 2.2: pH 8

Reference： [1]Current Patent Assignee: HARMONY BIOSCIENCES - US2011/3793, 2011, A1 Current Patent Assignee: CURIA INC - US2012/157460, 2012, A1

31
[ 258506-68-2 ]
[ 1260493-81-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 2 h / 80 °C / Inert atmosphere 2.1: hydrogenchloride / water / 18 h / 120 °C 2.2: pH 8 3.1: caesium carbonate; 8-quinolinol / copper(l) iodide / dimethyl sulfoxide / 135 °C / Inert atmosphere