Name: 3430-10-2|2-Methylpyridin-3-amine|98%
Brand: Ambeed
SKU: A106022
Price: 7.0 USD
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1
[ 3430-10-2 ]
[ 14736-31-3 ]
4-oxo-4<i>H</i>-chromene-2-carboxylic acid-([3]pyridylmethyl-amide) [ No CAS ]

Reference： [1]Chemicke Listy,1953,vol. 47,p. 575,578
Chem.Abstr.,1955,p. 306

2
[ 3430-10-2 ]
[ 18699-87-1 ]

Reference： [1]Journal of the American Chemical Society,1952,vol. 74,p. 3828,3830

3
[ 58539-65-4 ]
[ 3430-10-2 ]

Reference： [1]Chemische Berichte,1940,vol. 73,p. 78

4
[ 22280-60-0 ]
[ 3430-10-2 ]

Reference： [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547
[2]Journal of the American Chemical Society,1939,vol. 61,p. 2562
[3]Journal of the Chemical Society,1953,p. 1313
[4]Journal of the American Chemical Society,1954,vol. 76,p. 596,598

5
[ 3430-10-2 ]
[ 126325-47-1 ]
3-amino-4-bromo-2-methylpyridine [ No CAS ]
3-amino-4,6-dibromo-2-methylpyridine [ No CAS ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1989,vol. 331,p. 369 - 374
[2]Journal fur praktische Chemie (Leipzig 1954),1989,vol. 331,p. 369 - 374

6
[ 18699-87-1 ]
[ 3430-10-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; triethylamine;palladium 10% on activated carbon; In methanol; at 20℃; under 760.051 Torr; for 6h;	Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70C for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate =3:1) to obtain 35.4 g of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> as a colorless oil. Then 35.4 g of <strong>[18699-87-1]2-methyl-3-nitropyridine</strong> was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methyl pyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate :methanol =100:3), to afford 74 g of the title compound as colorless crystals.1H-NMR (400 MHz, CDCl3) delta2.25 (3H, s), 2.53 (3H, s), 7.00 (1H, bs), 7.18 (1H, dd, J = 4.6, 8.0 Hz), 8.23 (1H, d, J = 8.0 Hz), 8.30 (1H, d, J = 4.6 Hz).

Reference： [1]Bulletin de la Societe Chimique de France,1992,p. 79 - 84
[2]Patent: EP1510516,2005,A1 .Location in patent: Page/Page column 134

7
[ 3430-10-2 ]
[ 75315-63-8 ]
[ 177559-93-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	In N,N-dimethyl-formamide for 48h;
68%	In N,N-dimethyl-formamide for 48h;	8.F Preparation of[00765] 3-(N-Benzyloxycarbonyl)-2-methylpyridine 85 [00766] A mixture of 3-aminopicoline (84, 0.60 g, 5.5 m mol), (N-benzyloxycarbonyl)succinimide (2.1 g, 8.3 m mol) and DMF (2 ml) was left for 2 days. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried (Na2SO4). The solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate-hexane to give 85 (0.92 g, 68%), mp, 76-78° C. IR νmax (nujol) 1725, 1551, 1227, 1061 cm-1. 1H NMR (CDCl3) δ 2.49 (3H, s), 5.22 (3H, s), 7.16 (1H, m), J=8.7 Hz), 7.36-7.45 (5H, m), 8.15-8.27 (2H, m). Analyses: Calc'd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.62; H, 5.89; N, 11.31.

Reference： [1]Hagishita, Sanji; Yamada, Masaaki; Shirahase, Kazuhiro; Okada, Toshihiko; Murakami, Yasushi; Ito, Yuji; Matsuura, Takaharu; Wada, Masaaki; Kato, Toshiyuki; Ueno, Masahiko; Chikazawa, Yukiko; Yamada, Katsutoshi; Ono, Takashi; Teshirogi, Isao; Ohtani, Mitsuaki [Journal of Medicinal Chemistry, 1996, vol. 39, # 19, p. 3636 - 3658]
[2]Current Patent Assignee: SHIONOGI & CO., LTD.; ELI LILLY & CO - US6645976, 2003, B1 Location in patent: Page/Page column 84

8
[ 3430-10-2 ]
[ 1004991-70-1 ]
[ 1004991-74-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 2-methyl-3-pyridinamine; (R)-tert-butyl 3-(tert-butoxycarbonylamino)-3-formylpyrrolidine-1-carboxylate With sodium tris(acetoxy)borohydride In acetonitrile Molecular sieve; Stage #2: With trifluoroacetic acid In acetonitrile at 0 - 25℃; Stage #3: With sodium hydrogencarbonate In water; acetonitrile	2.1 Step 1 : A solution of C4 (1.6g, 5.09mmol) in anhydrous acetonitrile (32mL) was treated with 2-methylpyridin-3-amine (0.55g, 5.09mmol) and molecular sieves (1g). The resultant mixture was then treated with sodium triacetoxyborohydride (1.62g, 7.63mmol), cooled to O3C, and treated drop-wise with TFA (1.5mL). The mixture was allowed to warm to 25SC and stirred overnight. The mixture was then quenched with saturated NaHCO3 and extracted with ethyl acetate (3 X 45mL). The combined organic extracts were concentrated, and the resultant residue was purified via lsco Combiflash using MeOH/Chloroform gradient. The fractions containing produce were concentrated to provide (S)-tert-butyl 3-(tert- butoxycarbonyi)-3-((2-methylpyridin-3-ylamino)methyl)pyrrolidine-1 -carboxylate (C8). Yield: 1.31g, 63%. LRMS (M+): 407.5; tR (LCMS standard): 1.46 min.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/12635, 2008, A2 Location in patent: Page/Page column 79

9
[ 3430-10-2 ]
[ 108-24-7 ]
[ 34050-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In dichloromethane at 20℃; for 3h;	407 Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70°C for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate =3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methyl pyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate :methanol =100:3), to afford 74 g of the title compound as colorless crystals.1H-NMR (400 MHz, CDCl3) δ2.25 (3H, s), 2.53 (3H, s), 7.00 (1H, bs), 7.18 (1H, dd, J = 4.6, 8.0 Hz), 8.23 (1H, d, J = 8.0 Hz), 8.30 (1H, d, J = 4.6 Hz).
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; for 0.5h;	29 Intermediate 29; N-(2-Methylpyridin-3-yl)acetamide; Acetic Acid Anhydride (17.9 mmol; 1.7 mL) was added to 3-Amino-2-picoline (17.0 mmol; 1.8 g) in dichloromethane (10 mL) and diisopropylethylamine (17.9 mmol; 3.1 mL) at 250C under argon. The reaction aged 30 min at 25 0C then was diluted with dichloromethane and extracted with water and brine. The aqueous layer was extracted with dichloromethane and ether then the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was purified by chromatography (0% to 66% ethyl acetate in hexane) to afford the title compound. EPO 1H NMRMS (m/e): 151.3 (M+l)
	In chloroform for 1h; Inert atmosphere;

Reference： [1]Current Patent Assignee: EISAI CO LTD - EP1510516, 2005, A1 Location in patent: Page/Page column 134
[2]Current Patent Assignee: ELI LILLY & CO - WO2007/15767, 2007, A1 Location in patent: Page/Page column 62-63
[3]Adamson, Christopher; Kajino, Hidetoshi; Kanai, Motomu; Kawashima, Shigehiro A.; Yamatsugu, Kenzo [Journal of the American Chemical Society, 2021, vol. 143, # 37, p. 14976 - 14980]

10
[ 3430-10-2 ]
[ 832099-55-5 ]
N-(2-Methyl-pyridin-3-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 48h;	61 Example 61; N-(2-Methyl-pyridin-3-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide Example 61 N-(2-Methyl-pyridin-3-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (225 l, 1.61 mmol) was added followed by 3-amino-2-methyl-pyridine (61 mg, 0.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol). The reaction was stirred under nitrogen at room temperature for 48 h and the solvent was removed under reduced pressure. The residue was partitioned between water (10 ml) and dichloromethane (20 ml) and the aqueous phase was extracted with dichloromethane (2*20 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using pentane:ethylacetate (70:30) as eluent to give the title compound (96 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=9.91 (1H, brs), 8.63-8.65 (1H, d), 8.45-8.47 (1H, dd), 8.30-8.31 (1H, d), 8.13-8.14 (1H, d), 7.38-7.42 (1H, t), 7.19-7.25 (2H, m), 7.07 (1H, s), 6.95-6.97 (1H, d), 2.52 (3H, s), 2.50 (3H, s) ppm. LRMS (electrospray): mlz [M+H]+ 370 and [M+Na]+ 392. Anal. Found C, 60.70; H, 4.41; N, 10.91. C19H16FN3O2S. 0.3 mol H2O requires C, 60.88; H, 4.46; N, 11.21%.

Reference： [1]Current Patent Assignee: PFIZER INC - US2005/20587, 2005, A1 Location in patent: Page 50

11
[ 3430-10-2 ]
[ 1934-75-4 ]
[ 861393-55-7 ]

Yield	Reaction Conditions	Operation in experiment
30%	With hydrogenchloride In water at 60℃;
	With hydrogenchloride In water at 60℃;	1C Example 1C; N"-cyano-N-(2-methyl-3-pyridinyl)guanidine Example 1C N"-cyano-N-(2-methyl-3-pyridinyl)guanidine To a solution of 2-methyl-3-pyridinylamine (22.7 g, 0.21 moles) in water was added 6N HCl (42 mL, 0.25 moles), and sodium dicyanamide (22.46 g, 0.25 moles). The reaction was stirred overnight at 60° C. The reaction was continued for an additional 36 hours with one more equivalent of 6N HCl and sodium dicyanamide added at the 12 and 24 hr time points. The reaction mixture was cooled, the precipitate collected, and washed with water. The crude product was purified by Soxhlet extraction method using 5% methanol in methylene chloride, followed by flash chromatography (sequential elution with 2, 5, and 10% of methanol in methylene chloride) to provide the title compound. MS (ESI+) m/z 176 (M+H)+.

Reference： [1]Location in patent: experimental part Perez-Medrano, Arturo; Donnelly-Roberts, Diana L.; Honore, Prisca; Hsieh, Gin C.; Namovic, Marian T.; Peddi, Sridhar; Shuai, Qi; Wang, Ying; Faltynek, Connie R.; Jarvis, Michael F.; Carroll, William A. [Journal of Medicinal Chemistry, 2009, vol. 52, # 10, p. 3366 - 3376]
[2]Current Patent Assignee: ABBOTT LABORATORIES INC - US2005/171195, 2005, A1 Location in patent: Page/Page column 13

12
[ 3430-10-2 ]
[ 899897-86-0 ]
2-Methyl-5-(2-methyl-pyridin-3-ylamino)-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With caesium carbonate In 1,4-dioxane at 100 - 150℃; for 0.5h; Microwave irradiation;	159.C C) A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (0.24 g, 0.76 mmol) and 2-methyl-pyridin-3-ylamine (0.099 g, 0.92 mmol) in dry dioxane (12 ml) was degassed by sonication and argon bubbling. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.149 g, 0.26 mmol) and palladium dibenzylideneacetone chloroform complex (0.081 g, 0.08 mmol) were added and the mixture was stirred until dissolution was complete. Finally, the mixture was treated with cesium carbonate (0.495 g, 1.52 mmol) and irradiated in a microwave oven at 100° C. for 10 min, 130° C. for 10 min and 150° C. for 10 min. The solvent was removed under vacuum and the residue purified by flash chromatography (heptane, ethyl acetate) to yield the title compound (0.178 g, 68%) as a light brown solid

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2006/160857, 2006, A1 Location in patent: Page/Page column 39

13
[ 3430-10-2 ]
5-bromo-2-methyl-thiazole-4-carboxylic acid (6-methyl-pyridin-2-yl)-amide [ No CAS ]
2-Methyl-5-(2-methyl-pyridin-3-ylamino)-thiazole-4-carboxylic acid (6-methyl-pyridin-2-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With caesium carbonate In 1,4-dioxane at 150℃; for 0.216667h; Microwave irradiation;	130.B B) A solution of 2-bromo-5-methyl-thiophene-3-carboxylic acid (6-methyl-pyridin-2-yl)-amide (0.05 g, 0.16 mmol) and 2-methyl-pyridin-3-ylamine in dry dioxane (1.50 ml) was degassed by sonication and argon bubbling. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.016 g, 0.03 mmol) and palladium dibenzylideneacetone chloroform complex (0.008 g, 0.01 mmol) were added and the mixture was stirred until dissolution was complete. Finally, the mixture was treated with cesium carbonate (0.05 g, 0.28 mmol) and irradiated in a microwave oven at 150° C. for 13 min. The solvent was removed under vacuum and the residue purified by flash chromatography (dichloromethane/methanol/ammonia) to yield the title compound (0.015 g, 28%) as a light yellow solid

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2006/160857, 2006, A1 Location in patent: Page/Page column 33

14
[ 1824-81-3 ]
[ 3430-10-2 ]
[ 1122-58-3 ]
2,6-pyridine dicarbonyl dichloride [ No CAS ]
[ 4663-97-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In dichloromethane	11 EXAMPLE 11 A solution of 2,6-pyridine dicarbonyl dichloride (4.34 g, 21.2 mmol) and 4-dimethylamino-pyridine (0.259 g, 2.12 mmol) in methylene chloride (10 ml) is prepared under nitrogen. In a separate flask, a solution of 2-amino-6-picoline (4.58 g, 42.4 mmol) and triethylamine (5.77 ml, 42.4 mmol) in methylene chloride (10 ml) is prepared. The aminopicoline solution is added over 10 minutes to the pyridine dicarbonyl dichloride while stirring and refluxing. After refluxing the reaction for 3 hours, the precipitate is filtered, and washed with cold methanol (35 ml). The brown filtrate is then washed with water (310 ml). After washing the aqueous extract once with methylene chloride (5 ml), the combined organic layer is stripped of solvent and the resulting solid is recrystallized from pyridine as white needles (6.47 g, 88% yield). This material is characterized as follows: 1H NMR (CDCl3, 200 MHz) δ11.15 (s, 2H), 8.50 (d, J=7.6 Hz, 2H), 8.33 (d, J=8.2 Hz, 2H), 8.14 (t, J=7.7 Hz, 1H), 7.70 (t, J=7.9 Hz, 2H), 6.98 (d, J=7.4, 2H), 2.56 (s, 6H); 13C (CDCl3, 50 MHz) δ159.78, 147.56, 137.82, 133.12, 128.08, 123.82, 118.92, 19.27.
88%	With triethylamine In dichloromethane	11 EXAMPLE 11 A solution of 2,6-pyridine dicarbonyl dichloride (4.34 g, 21.2 mmol) and 4-dimethylamino-pyridine (0.259 g, 2.12 mmol) in methylene chloride (10 ml) is prepared under nitrogen. In a separate flask, a solution of 2-amino-6-picoline (4.58 g, 42.4 mmol) and triethylamine (5.77 ml, 42.4 mmol) in methylene chloride (10 ml) is prepared. The aminopicoline solution is added over 10 minutes to the pyridine dicarbonyl dichloride while stirring and refluxing. After refluxing the reaction for 3 hours, the precipitate is filtered, and washed with cold methanol (35 ml). The brown filtrate is then washed with water (310 ml) After washing the aqueous extract once with methylene chloride (5 ml), the combined organic layer is stripped of solvent and the resulting solid is recrystallized from pyridine as white needles (6.47 g, 88% yield). This material is characterized as follows: 1H NMR (CDCl3, 200 MHz) δ 11.15 (s, 2H), 8.50 (d, J=7.6 Hz, 2H), 8.33 (d, J=8.2 Hz, 2H), 8.14 (t, J=7.7 Hz, 1H), 7.70 (t, J=7.9 Hz, 2H), 6.98 (d, J=7.4, 2H), 2.56 (s, 6H); 13C (CDCl3, 50 MHz) δ 159.78, 147.56, 137.82, 133.12, 128.08, 123.82, 118.92, 19.27.

Reference： [1]Current Patent Assignee: SAN DIEGO STATE UNIVERSITY; UNIVERSITY OF CALIFORNIA - US2002/115860, 2002, A1
[2]Current Patent Assignee: SAN DIEGO STATE UNIVERSITY; UNIVERSITY OF CALIFORNIA - US6380393, 2002, B1

15
[ 3430-10-2 ]
[ 113209-81-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 3-chloro-benzenecarboperoxoic acid; sodium nitrite In tetrafluoroboric acid	27.i Preparation of 2-(4-morpholino-3-fluoro-2-pyridylmethylthio)-5-Methoxy-(1H)-benzimidazole (i) Sodium nitrite (15.3 g) was added to a stirred solution of 3-amino-2-picoline (20 g) in 40% fluoroboric acid (215 ml) at -5° to -10°. The mixture was stirred for 2 hours at -10° followed by a further 2 hours at room temperature, after which time, the solution was basified (NaOH) and extracted with dichloromethane. The extracts were back-washed with water (pH 6 HCl) to remove some unreacted amine and, after drying (K2 CO3), m-chloroperbenzoic acid (35.7 g) was added and the mixture allowed to stand for 16 hours. Ammonia gas was passed through the solution and the precipitated benzoate salts filtered off. The filtrate was evaporated to dryness to give 2-methyl-3-fluoropyridine-N-oxide (13.36 g) m.p. softens 55° melts 80°.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US5250527, 1993, A

16
[ 3430-10-2 ]
[ 305830-57-3 ]
[ 1044535-52-5 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 35℃; for 0.5h;	1 Example 1 (4βS,7R,8αR)-4β-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxamide The (4βS,7R,8αR)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (10 g; 23.9 mmol, which may be prepared as described in Preparation 6), and 3-amino-2-picoline (2.71 g; 25.1 mmol) were dissolved in toluene (200 mL). The 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 mL; 74.1 mmol) was added at a rate such that the temperature was maintained below 35° C. There was a mild exotherm and a solid precipitated during the addition. The mixture was held an additional 30 minutes after the addition. Water (250 mL) was added to the mixture. There was a mild exotherm and the solid dissolved. Ethyl acetate (50 mL) was added to the mixture to ensure the product did not precipitate. Stirring was stopped to allow the phases to separate. The aqueous phase was removed. The organic phase was washed with water (250 mL). Solvent (230 mL) was distilled at atmospheric pressure from the organic phase. The mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with toluene (2 times) followed by heptane (2 times). The solid was dried in a vacuum oven at 70° C. The title compound of the present example (10 g) was obtained as a beige solid. 1H NMR (DMSO) δ ppm: 1.32 (m, 1H), 1.82 (m, 4H), 2.10 (m, 4H), 2.41 (s, 3H), 2.68 (d, 1H), 3.08 (m, 3H), 6.00 (s, 1H), 6.43 (d, 1H), 6.59 (m, 2H), 7.12 (m, 3H), 7.25 (dd, 1H), 7.44 (dd, 1H), 7.71 (dd, 1H), 7.75 (d, 1H), 8.31 (dd, 1H), 9.91 (s, 1H).

Reference： [1]Current Patent Assignee: PFIZER INC - US2008/188443, 2008, A1 Location in patent: Page/Page column 13; 18

17
[ 3430-10-2 ]
[ 1044535-54-7 ]
[ 1044535-56-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 10℃; for 0.5h;	8 Preparation 8 dibenzyl (2R,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl phosphate The (4βS,7R,8αR)-methyl 4β-benzyl-7-(bis(benzyloxy)phosphoryloxy)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (7.9 g; 11.6 mmol, which may be prepared as in Preparation 7) and 3-amino-2-picoline (1.3 g; 12.2 mmol) were mixed together in tetrahydrofuran (80 mL) and chilled to 0° C. The 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (24 mL; 24.4 mmol) was added while maintaining the temperature below 10° C. The mixture was stirred for 30 minutes. Water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic extract was washed with water. The organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography with 70% ethyl acetate in hexanes. The purified title compound (6.79 g; 68% yield) was obtained as a yellow gum that contained 6% ethyl acetate by weight. 1H NMR (DMSO): δ 1.33 (t, 1H), 1.66-1.93 (m, 3H), 2.08-2.34 (m, 3H), 2.41 (s, 3H), 2.68 (d, 1H), 2.76-3.19 (m, 4H), 5.14 (m, 4H), 6.47 (d, 1H), 6.56 (m, 2H), 7.07-7.19 (m, 3H), 7.20-7.53 (m, 12H), 7.71 (d, 1H), 7.76 (s, 1H), 8.32 (d, 1H), 9.93 (s, 1H).

Reference： [1]Current Patent Assignee: PFIZER INC - US2008/188443, 2008, A1 Location in patent: Page/Page column 14; 18

18
[ 22280-62-2 ]
[ 3430-10-2 ]

Reference： [1]Russian Journal of Organic Chemistry,2009,vol. 45,p. 115 - 118
[2]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547

19
[ 18699-87-1 ]
[ 4637-24-5 ]
[ 3430-10-2 ]
[ 272-49-1 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 1357 - 1360

20
[ 3430-10-2 ]
[ 791852-35-2 ]
[ 1196484-62-4 ]

Yield	Reaction Conditions	Operation in experiment
24%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 160℃; for 0.166667h;	7 Example 74-[4-(2-Methyl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester; A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 3-amino-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 21 mg, 0.19 mmol), and potassium tert-butoxide (22 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(2-methyl-pyridin-3-ylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 24%) as a white powder. Mass spectrum (ES) MH+=410. HRMS Calcd. for C21H28N7O2 (MH+): 410.2299. Found: 410.2299.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2009/286812, 2009, A1 Location in patent: Page/Page column 34

21
[ 3430-10-2 ]
[ 1206877-03-3 ]
[ 1206877-04-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 1-methyl-1H-imidazole; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate; acetonitrile at 25℃;	G.9 Preparation 9: (4bR,7R,8aR)-4b-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-6-oxo-7-phenyl- 4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide; (4bR,7R,8aR)-4b-benzyl-7-hydroxy-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2- b li id (21 49 2 l) 3 i 2 i li (5 8 52 2 l) d 1 th li id l (20 l

Reference： [1]Current Patent Assignee: KIMBERLY-CLARK CORP; PFIZER INC - WO2010/13158, 2010, A1 Location in patent: Page/Page column 21-22

22
[ 3430-10-2 ]
[ 24424-99-5 ]
[ 1219095-87-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	In tetrahydrofuran; at 20℃; for 336h;	3-Amino-2-methylpyridine (3.11 g, 28.83 mmol) was dissolved in 60 mL of THF and di-tert-butyl dicarbonate (6.3g, 28.83 mmol) were added. The solution was stirred for at room temperature for 2 weeks. The mixture was concentrated under vacuum and the crude purified by flash chromatography (silica) eluting with ethyl acetate in cyclohexane acetate from 50 to 100%. The fractions containing the product were collected and concentrated in vacuum to give the desired compound tert-butyl N-(2-methylpyridin-3-yl)carbamate (5.41 g, 90% yield).
46%	In hexane; ethyl acetate; at 60℃;	EXAMPLES Example 1N-Boc-3-Amino-2-methylpyridine[00145] Referring now to the Scheme 1 as shown in Fig. 1 , A solution of BOC2O(18.624g, 85.35 mmol, 1.6 eq.) in 30 ml. of hexane was placed in a 10O mL three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and heating mantle. A solution of 5.785g (53.49 mmol) of 3-amino-2-methylpyridine in 20 ml_ of ethyl acetate was slowly added via syringe to the solution BOC-anhydride at 60 0C and the resulting brown suspension stirred at this temperature for 1 hour. The reaction was cooled to room temperature and concentrated on rotavap to give 22g of oil. This material was dissolved in 50 ml. of dichloromethane and insoluble white precipitate was removed by filtration. Upon concentration of the filtrate a total of 17 g of yellow oil was isolated. This crude material was purified on CombiFlash (33Og column) using hexane as solvent to give 5.1g (46% yield) of n-boc-3-amino-2-methylpyridine as white solid.
	In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;	A solution of di-teit-butyl dicarbonate (1.01 g, 4.62 mmol) in dry THF (15 ml) was added to 3-amino-2-methylpyridine (500.00 mg, 4.62 mmol) under an atmosphere of nitrogen. The resulting solution was stirred at room temperature, under an atmopshere of nitrogen overnight. After this time, further di-teit-butyl dicarbonate (500.00 mg) was added and the reaction mixture was stirred for a further 24 hours at room temperature. The solvent was removed under reduced pressure and the resulting residue was chromatographed [Si02, Hex:EtOAc 1:1] to give tert-butyl N-(2-methyl-3-pyridyl)carbamate (P58) as a pale yellow coloured solid, LCMS ES 209 [M+H], Rt = 1.02 mins (Generic Basic Method).

Reference： [1]Patent: WO2016/196776,2016,A2 .Location in patent: Paragraph 00750
[2]Patent: WO2010/33980,2010,A2 .Location in patent: Page/Page column 27-28
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5580 - 5590
[4]Patent: WO2019/34890,2019,A1 .Location in patent: Paragraph 00153; 00203

23
[ 3430-10-2 ]
[ 16019-33-3 ]
[ 1001398-59-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 2-methyl-3-pyridinamine With trifluoroacetic acid at -15℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride for 0.5h; Stage #3: 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde With water; sodium hydrogencarbonate more than 3 stages;	70.1 Step 1 : 4-Chloro-7-(2-methyl-3-pyridinyl)-6,7-dihydro-5H-pyrrolo[2,3-c/]pyrimidine (139)A round bottom flask was charged with 2-methyl-3-pyridinamine (5.20 g, 47 mmol) and then cooled to -150C. Trifluoroacetic acid (100 ml.) was added to the above cold pyridinamine while stirring the contents for 0.5 h. Na(OAc)3BH (32.5 g, 48 mmol) was added portion-wise to the above mixture and stirred for additional 0.5 h. The aldehyde 209 (see example 117, step 1 , 7.4 g, 48 mmol) in CH2CI2 (25 ml.) was added to the above mixture. The resultant mixture was allowed to warm up to the ambient temperature and stirred for 18 h. The reaction mixture was concentrated under reduced pressure and the residue was poured into sat. NaHCO3 solution (250 ml.) and then the mixture was extracted with CH2CI2 (3 x 250 ml_). The combined organic layer was washed with brine (1 x 100 ml_), dried over sat. Na2SO4 and then concentrated under reduced pressure to afford ~11.5 g (-100%) the crude material. The required bicyclic product was not obtained, but the uncyclized λ/-[2-(4,6-dichloro-5-pyrimidinyl)ethyl]-2- methyl-3-pyridinamine was isolated as a major product. 1H NMR (400 MHz, DMSO-Ok): δ 8.81 (s, 1 H), 7.95-7.94 (m, 1 H), 7.71-7.66 (m, 2 H), 6.63 (app. t, J = 5.6 Hz, 1 H), 3.59 (app. q, J = 6.0 Hz, 2 H), 3.08 (t, J = 6.4 Hz, 2 H), 2.40 (s, 3 H), LCMS (ESI): m/z 285 (M + H)+.
	With sodium cyanoborohydride; acetic acid In methanol at -15 - 20℃; for 19h;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/8895, 2008, A1 Location in patent: Page/Page column 132; 133
[2]Katamreddy, Subba R.; Carpenter, Andrew J.; Ammala, Carina E.; Boros, Eric E.; Brashear, Ron L.; Briscoe, Celia P.; Bullard, Sarah R.; Caldwell, Richard D.; Conlee, Christopher R.; Croom, Dallas K.; Hart, Shane M.; Heyer, Dennis O.; Johnson, Paul R.; Kashatus, Jennifer A.; Minick, Doug J.; Peckham, Gregory E.; Ross, Sean A.; Roller, Shane G.; Samano, Vicente A.; Sauls, Howard R.; Tadepalli, Sarva M.; Thompson, James B.; Xu, Yun; Way, James M. [Journal of Medicinal Chemistry, 2012, vol. 55, # 24, p. 10972 - 10994]

24
[ 3430-10-2 ]
[ 89711-08-0 ]
[ 1253380-90-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 65h; Molecular sieve;	119.i (i) 3-Amino-2-methylpyridine (0.61 g, 5.65 mmol) was dissolved in dichloromethane (25 ml). 4A molecular sieves (0.2 g), 1 ,1-dimethylethyl(2-oxoethyl)carbamate (1.0 g, 6.28 mmol), acetic acid (0.54 ml, 9.42 mmol) and sodium triacetoxyborohydride (2.0 g, 9.42 mmol) were added and the reaction was stirred at room temperature for approximately 65 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (15 ml) and stirred for 5 minutes. The organic layer was separated using a hydrophobic frit and concentrated in vacuo to give 1 ,1-dimethylethyl {2-[(2-methyl- 3-pyridinyl)amino]ethyl}carbamate (1.56 g) as an orange gum, which was used without purification.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/125103, 2010, A1 Location in patent: Page/Page column 111

25
[ 3430-10-2 ]
[ 1258001-40-9 ]
[ 1258001-54-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 2-methyl-3-pyridinamine; isopropyl 4-(5-cyano-4-formyl-1H-pyrazol-1-yl)piperidine-1-carboxylate With titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine In 1,1-dichloroethane at 20℃; for 19h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In 1,1-dichloroethane at 20℃; for 24h; Stage #3: With water In dichloromethane	6 Example 6: lsopropyl 4-(5-cvano-4-{r(2-methylpyridin-3-yl)aminolmethyl}-1 H-pyrazol-1- yl)piperidine-1 -carboxvlateTo a flask charged with isopropyl 4-(5-cyano-4-formyl-1 H-pyrazol-1-yl)piperidine-1- carboxylate (Example 9, Step A) (50 mg, 0.17 mmol) and 2-methylpyridin-3-amine (19 mg , 0.17 mmol) was added 2 mL of dichloroethane followed by N,N- diisopropylethylamine (0.03 mL, 0.17 mmol). The flask was flushed with nitrogen gas and titanium isopropoxide (97.8 mg, 0.34 mmol) was added at room temperature. The reaction mixture was stirred at this temperature for 19 hours before sodium triacetoxyborohydride (75.2 mg, 0.34 mmol) was added. The mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with dichloromethane and saturated aqueous bicarbonate was added. The mixture was filtered through a pad of Celite . The filtrate layers were separated and the aqueous phase was extracted once with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography, eluting with a gradient mixture of ethyl acetate in heptane (60 to 80% ethyl acetate). Proton NMR showed that the material was the imine. The imine was then dissolved in 2 ml. of methanol and 1 ml. of tetrahydrofuran, and the mixture was cooled to zero degrees Celsius. Sodium borohydride (10 mg, 0.26 mmol) was added and the ice bath was removed. The mixture was stirred for at room temperature for 4 hours before saturated aqueous sodium bicarbonate was added. The mixture was partially concentrated in vacuo and the aqueous mixture was extracted once with ethyl acetate. The organic extracts were concentrated in vacuo and the residue was purified by flash chromatography, eluting with a gradient mixture of ethyl acetate in heptane (80 to 100% ethyl acetate) to give the title compound (24 mg, 63% yield). 1H NMR (400 MHz, deuterochloroform) delta 1.15 - 1.33 (m, 6 H), 1.93 - 2.04 (m, 2 H), 2.11 (qd, J=12.2, 4.6 Hz, 2 H), 2.43 (s, 3 H), 2.84 - 2.99 (m, 2 H), 3.94 (t, J=5.2 Hz, 1 H), 4.31 (br. s., 2 H), 4.37 (d, J=5.5 Hz, 2 H), 4.41 - 4.54 (m, 1 H), 4.86 - 4.98 (m, 1 H), 6.78 - 6.87 (m, 1 H), 6.96 - 7.07 (m, 1 H), 7.52 - 7.62 (m, 1 H), 7.87 - 7.97 (m, 1 H). LCMS (ES+) 383.1 (M+1 ).

Reference： [1]Current Patent Assignee: KIMBERLY-CLARK CORP; PFIZER INC - WO2010/140092, 2010, A1 Location in patent: Page/Page column 73; 74

26
[ 28489-45-4 ]
[ 3430-10-2 ]

Reference： [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 541 - 547

27
[ 3430-10-2 ]
[ 80745-07-9 ]
[ 1215008-92-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 140 - 152

28
[ 3430-10-2 ]
[ 1400926-96-6 ]
[ 1400926-97-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0 - 20℃; for 1.5h; Inert atmosphere;	108.8; 109.8 Step No.8: (4a'S,10a'R)-4a'-Benzyl-N-(2-methylpyridin-3-yl)-3',4',4a',10a'-tetrahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthrene]-7'-carboxamide (99, R2=Benzyl, R6=2-Methylpyridin-3-yl)LiHMDS (1 M solution in THF, 3.50 mL, 3.50 mmol) was added dropwise over about 5 min to a mixture of (4a'S,10a'R)-methyl 4a'-benzyl-3',4',4a',10a'-tetrahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthrene]-7'-carboxylate (98, R2=Benzyl) (0.653 g, 1.62 mmol), 2-methyl-pyridin-3-ylamine (0.228 g, 2.11 mmol), and toluene (16 mL) under a nitrogen atmosphere at about 0° C. After about 30 min, the ice bath was removed and the mixture was stirred at rt for about 1 h. Saturated aqueous NaHCO3 (50 mL) was added. The mixture was extracted with EtOAc (2×25 mL). The combined organics were washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (80 g) using a gradient of 50-100% EtOAc in DCM. The product containing fractions were combined and concentrated under reduced pressure to afford (4a'S,10aR)-4a'-benzyl-N-(2-methylpyridin-3-yl)-3',4',4a',10a'-tetrahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthrene]-7'-carboxamide (99, R2=Benzyl, R6=2-Methylpyridin-3-yl) (0.716 g, 95%) as a light tan foam. LC/MS, method 2, Rt=2.32 min, MS m/z 467 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.34 (dd, J=4.8, 1.6 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.79-7.73 (m, 2H), 7.28 (dd, J=8.0, 4.8 Hz, 1H), 7.24-7.17 (m, 3H), 7.15 (d, J=8.1 Hz, 1H), 6.86-6.80 (m, 2H), 6.70 (d, J=9.6 Hz, 1H), 6.22 (dd, J=9.5, 6.2 Hz, 1H), 3.83-3.71 (m, 4H), 2.74 (d, J=12.8 Hz, 1H), 2.63 (d, J=12.8 Hz, 1H), 2.46 (s, 3H), 2.38-2.31 (m, 1H), 2.31-2.21 (m, 1H), 1.79-1.68 (m, 1H), 1.66-1.54 (m, 2H), 1.47-1.36 (m, 1H), 0.99-0.91 (, m, 1H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 102

29
[ 3430-10-2 ]
[ 1400927-09-4 ]
[ 1400925-72-5 ]

Yield	Reaction Conditions	Operation in experiment
24%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0℃; for 3.25h; Inert atmosphere;	114.4 Step No.4: (7aR,9R,11aS)-11a-Benzyl-9-ethyl-9-hydroxy-6-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (117, R2=Benzyl, R3=Ethyl, R6=2-Methylpyridin-3-yl)LiHMDS (1 M solution in THF, 0.300 mL, 0.300 mmol) was added dropwise to a solution of (7aR,9R,11aS)-11a-benzyl-9-ethyl-9-hydroxy-6-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (116, R2=Benzyl, R3=Ethyl) (0.023 g, 0.058 mmol) in toluene (0.5 mL) under a nitrogen atmosphere at about 0° C. for about 5 min. 2-Methylpyridin-3-amine (0.0080 g, 0.074 mmol) was added and the reaction was stirred for about 15 min at about 0° C. The ice bath was removed and the brown mixture was left to stir for about 3 h. Water (10 mL) and EtOAc (10 mL) were added. The layers were separated and the organic layer was washed with water (5 mL) and then saturated aqueous NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (12 g) using a gradient from 50-100% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure. The residue was purified by HPLC: The gradient was 10% B for 2.5 min then 10-15% B in 1.0 min then 15-70% B in 9 min then 70-95% in 0.3 min then 95% for 0.7 min (22.5 mL/min flow rate). Mobile phase A: 50 mM NH4OAc in water, mobile phase B was HPLC grade MeCN. The column used for chromatography is 19×50 mm Waters Atlantis T3 OBD C18 column (5.0 μm particles). Detection methods are photodiode array (DAD) and Waters ZQ 2000 mass spectrometer. The organic volatiles were removed under reduced pressure. The mixture was frozen then lyophilized to provide a white solid. The material was slurried in water (5 mL) and then lyophilized to yield (7aR,9R,11aS)-11a-benzyl-9-ethyl-9-hydroxy-6-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (117, R2=Benzyl, R3=Ethyl, R6=2-Methylpyridin-3-yl) (0.0066 g, 24%) as a white solid. LC/MS, method 2, Rt=1.87 min, MS m/z 483 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.36-8.30 (m, 1H), 7.82 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.26 (dd, J=8.0, 4.8 Hz, 1H), 7.15-7.06 (m, 3H), 6.94 (d, J=8.5 Hz, 1H), 6.74-6.66 (m, 2H), 4.70 (d, J=13.0 Hz, 1H), 3.98 (s, 1H), 3.74-3.62 (m, 2H), 3.60-3.51 (m, 1H), 2.81 (d, J=13.4 Hz, 1H), 2.68-2.56 (m, 1H), 2.43 (s, 3H), 2.19-2.12 (m, 1H), 2.06-1.97 (m, 1H), 1.93-1.80 (m, 1H), 1.48-1.38 (m, 1H), 1.32-1.21 (m, 2H), 1.13-1.03 (m, 2H), 0.76-0.69 (m, 1H), 0.65 (t, J=7.4 Hz, 3H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 113

30
[ 3430-10-2 ]
(7aSR,11aSR)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid [ No CAS ]
(7aSR,11aSR)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: (7aSR,11aSR)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 2-methyl-3-pyridinamine In tetrahydrofuran at 60℃; for 36h;	43.3 Step 3: (7aS,11aS)-11a-Benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,11aR)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (66, R2=Benzyl, R3=Phenyl)To a round flask was added (7aS,11aS)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid; compound with (7aR,11aR)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (65, R2=Benzyl, R3=Phenyl) (0.150 g, 0.367 mmol) and DIEA (0.064 mL, 0.37 mmol) in THF (6 mL). TFFH (0.097 g, 0.37 mmol) was added and mixture was stirred at rt for about 10 min. 2-Methylpyridin-3-amine (0.079 g, 0.73 mmol) was then added and the mixture was heated to about 60° C. for about 18 h. Additional 2-methylpyridin-3-amine (0.020 g, 0.18 mmol) was added followed by TFFH (0.015 g, 0.055 mmol). The mixture was stirred at about 60° C. for about 18 h. Solvents were removed under reduced pressure and the residue was purified on a silica gel (12 g), eluting with a gradient of 0-100% EtOAc in heptane to give (7aR,11aR)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aS,11aS)-11a-benzyl-9-phenyl-6,7,7a,8,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (66, R2=Benzyl, R3=Phenyl) (0.108 g, 59%). LC/MS, method 2, Rt=3.38 min, MS m/z 499 (M+H)+.

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 67

31
[ 3430-10-2 ]
C₁₈H₂₂O₃ [ No CAS ]
(7aRS,11aSR)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₁₈H₂₂O₃ With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N′,N′-bis(tetramethylene)formamidinium hexafluorophosphate In tetrahydrofuran for 0.0833333h; Stage #2: 2-methyl-3-pyridinamine In tetrahydrofuran at 60℃; for 36h;	44.8; 45.8 Step No.8: (7aR,11aS)-11a-Ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aS,11aR)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (75, R4=Methyl)A solution of (7aR,11aS)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester; compound with (7aS,11aR)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (74, R4=Methyl) (3.10 g, 10.3 mmol) in 1,4-dioxane (25.0 mL) and was treated with lithium hydroxide monohydrate (1.30 g, 31.0 mmol) and the reaction was stirred at about 70° C. for about 15 min. The reaction was cooled and concentrated. The residue was dissolved in water (50 mL), washed with Et2O (30 mL), then acidified with 2 N aqueous HCl. The carboxylic acid was extracted with DCM (2×40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (30.0 mL) and treated with DIEA (1.80 mL, 10.3 mmol) and BTFFH (3.26 g, 10.3 mmol). The mixture was stirred for about 5 min, then 2-methylpyridin-3-amine (1.12 g, 10.3 mmol) was added and the mixture was heated at about 60° C. for about 18 h. The mixture was cooled to rt, then additional DIEA and BTFFH were added (about 0.10 equivalents each). The mixture was re-heated to about 60° C. for about 18 h. The reaction was cooled and concentrated under reduced pressure and the residue was dissolved in DCM (50 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 0-100% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure. The residue was triturated with EtOAc (20 mL). The product was collected by filteration and dried under reduced pressure to yield (7aR,11aS)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aS,11aR)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (75, R4=Methyl) (2.66 g, 68%) as an off-white solid. LC/MS, method 4, Rt=2.17 min, no parent mass. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.30 (dd, J=4.7, 1.5 Hz, 1H), 7.82-7.75 (m, 2H), 7.71 (dd, J=8.0, 1.6 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.25 (dd, J=8.0, 4.8 Hz, 1H), 3.13-3.00 (m, 1H), 2.95-2.84 (m, 1H), 2.77-2.67 (m, 1H), 2.46-2.38 (m, 4H), 2.36-2.27 (m, 1H), 2.27-2.14 (m, 3H), 2.13-2.00 (m, 1H), 1.95-1.87 (m, 1H), 1.81-1.65 (m, 2H), 1.65-1.40 (m, 3H), 0.64 (t, J=7.4 Hz, 3H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 73-74

32
[ 3430-10-2 ]
(7aSR,9RS,11aRS)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester [ No CAS ]
(7aSR,9RS,11aRS)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: 2-methyl-3-pyridinamine; (7aSR,9RS,11aRS)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With ammonium chloride In tetrahydrofuran; water	61.6; 61.7 Step 6: (7aS,9R,11aR)-11a-Ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,9S,11aS)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (83, R4=Methyl, R5=Ethyl, R6=2-Methyl-3-pyridyl)A solution of (7aS,9R,11aR)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester; compound with (7aR,9S,11aS)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (82, R4=Methyl, R5=Ethyl) (116 mg, 0.322 mmol) was dissolved in THF (3 mL), 2-methylpyridin-3-amine (38.3 mg, 0.354 mmol) was added and the mixture was cooled to about 0° C. with stirring. LiHMDS (1 M solution in THF, 1.3 mL, 1.3 mmol) was added dropwise and the reaction was stirred for about 30 min. Saturated aqueous NH4Cl (10 mL) was added and the volatiles were removed under reduced pressure. The mixture was extracted with EtOAc (2×10 mL). The combined organics were washed with saturated aqueous NaHCO3 (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using EtOAc as eluant. Product fractions were combined and concentrated to yield (7aS,9R,11aR)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,9S,11aS)-11a-ethyl-5,9-dihydroxy-9-propyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (83, R4=Methyl, R5=Ethyl, R6=2-Methyl-3-pyridyl) (72 mg, 51%) as a glass. LC/MS, method 4, Rt=1.09 min, MS m/z 437 (M+H)+. The mixture of isomers was taken to the next step without further purification.

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 80

33
[ 3430-10-2 ]
(7aSR,11aSR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid [ No CAS ]
(7aSR,11aSR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: (7aSR,11aSR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N′,N′-bis(tetramethylene)formamidinium hexafluorophosphate In tetrahydrofuran for 0.333333h; Stage #2: 2-methyl-3-pyridinamine In tetrahydrofuran at 20 - 60℃; for 77h;	63.8 Step No.8: (7aS,11aS)-9-Oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,11aR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (75, R4=Trifluoromethyl)To (7aS,11aS)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester; compound with (7aR,11aR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (74, R4=Trifluoromethyl) (0.320 g, 0.903 mmol) was added LiOH (0.108 g, 4.52 mmol) in MeOH (2 mL) and water (2 mL). The mixture was heated to about 60° C. for about 1 h, then stirred at rt for about 18 h. The reaction was concentrated to remove MeOH, then 5 N aqueous HCl was added dropwise to pH 2. The solid was collected by filtration and rinsed with water to provide (7aS,11aS)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid; compound with (7aR,11aR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (0.278 g, 90%) as a white solid. LC/MS, method 3, Rt=1.99 min, MS m/z 339 (M-H)- 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.78-7.71 (m, 2H), 7.56 (d, J=8.2 Hz, 1H), 3.50-3.34 (m, 1H), 3.08 (t, J=13.4 Hz, 1H), 2.99-2.88 (m, 2H), 2.61-2.52 (m, 1H), 2.41-2.19 (m, 4H), 2.06-1.89 (m, 3H), 1.71 (s, 1H), 1.64-1.58 (m, 1H), 1.56-1.45 (m, 1H). To (7aS,11aS)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid; compound with (7aR,11aR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (0.357 g, 1.05 mmol) was added DIEA (0.256 mL, 1.47 mmol) and THF (5 mL) and the mixture was stirred for about 5 min. BTFFH (0.348 g, 1.10 mmol) was added and the mixture stirred about 15 min. 2-Methylpyridin-3-amine (0.170 g, 1.57 mmol) was added and the mixture was heated to about 60° C. for about 5 h. Additional DIEA (0.100 mL, 0.574 mmol) and 2-methylpyridin-3-amine (0.030 g, 0.278 mmol) were added and the mixture was stirred at rt for about 72 h. The mixture was concentrated in vacuo and then purified on silica gel (12 g), eluting with a gradient of 50-100% EtOAc in heptane to provide (7aS,11aS)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,11aR)-9-oxo-11a-(2,2,2-trifluoro-ethyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (75, R4=Trifluoromethyl) (0.452 g, 100%). LC/MS, method 3, Rt=2.06 min, MS m/z 429 (M-H)-.

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 84

34
[ 3430-10-2 ]
[ 1400927-02-7 ]
[ 1400927-03-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0 - 20℃; for 0.833333h; Inert atmosphere;	111.3 Step No.3: (4bS,7R,8aR)-4b-Benzyl-7-ethyl-7-hydroxy-N-(2-methylpyridin-3-yl)-4b,5,6,7,8,8 a-hexahydrophenanthrene-2-carboxamide (107, R2=Benzyl, R3=Ethyl, R6=2-Methylpyridin-3-yl)2-Methylpyridin-3-amine (0.113 g, 1.045 mmol) was added in one portion to a solution of (4bS,7R,8aR)-methyl 4b-benzyl-7-ethyl-7-hydroxy-4b,5,6,7,8,8 a-hexahydrophenanthrene-2-carboxylate (106, R2=Benzyl, R3=Ethyl) (0.302 g, 0.682 mmol) and toluene (8 mL) under a nitrogen atmosphere. The mixture was cooled to about 0° C. LiHMDS (1 M solution in THF, 3.0 mL, 3.0 mmol) was added dropwise over about 5 min. After about 30 min, the ice bath was removed. After about 15 min at rt, the mixture was poured into saturated aqueous NaHCO3 (10 mL) and water (10 mL). The mixture was extracted with EtOAc (2×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 50-100% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure to afford (4bS,7R,8aR)-4b-benzyl-7-ethyl-7-hydroxy-N-(2-methylpyridin-3-yl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide (107, R2=Benzyl, R3=Ethyl, R6=2-Methylpyridin-3-yl) (0.252 g, 82%) as a pale yellow solid. LC/MS, method 3, Rt=2.18 min, MS m/z 454 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.34 (dd, J=4.7, 1.6 Hz, 1H), 7.80-7.70 (m, 3H), 7.28 (dd, J=7.8, 4.7 Hz, 1H), 7.22-7.13 (m, 3H), 7.07 (d, J=8.1 Hz, 1H), 6.82-6.76 (m, 2H), 6.65 (d, J=9.5 Hz, 1H), 6.20 (dd, J=9.4, 6.2 Hz, 1H), 3.80 (s, 1H), 2.76 (d, J=12.8 Hz, 1H), 2.61 (d, J=12.9 Hz, 1H), 2.56-2.48 (m, 1H), 2.45 (s, 3H), 2.06-1.85 (m, 2H), 1.50-1.35 (m, 2H), 1.20-1.08 (m, 3H), 0.73-0.61 (m, 4H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 107

35
[ 3430-10-2 ]
(7aRS,9RS,11aSR)-11a-benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester [ No CAS ]
(7aRS,9RS,11aSR)-11a-benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 20℃; for 0.5h; Inert atmosphere;	3.5 Step No.5: (7aR,9R,11aS)-11a-Benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aS,9S,11aR)-11a-benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (12, R2=Benzyl, R3=Trifluoromethyl)A solution of (7aR,9R,11aS)-11a-benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester; compound with (7aS,9S,11aR)-11a-benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (11, R2=Benzyl, R3=Trifluoromethyl) (0.070 g, 0.16 mmol) and 3-amino-2-methylpyridine (0.018 g, 0.17 mmol) in toluene (1.5 mL) was stirred at rt under nitrogen and LiHMDS (0.470 mL, 0.470 mmol) (1M solution in THF) was added dropwise. The mixture was stirred for about 30 min, quenched with water (2 mL) and the crude product was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (12 g) using a gradient from 80 to 100% EtOAc in heptane. Pure product fractions were combined and concentrated to an oil that was precipitated from MeCN with water. The product was filtered off and dried under vacuum to yield (7aR,9R,11aS)-11a-benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aS,9S,11aR)-11a-benzyl-9-hydroxy-9-trifluoromethyl-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (12, R2=Benzyl, R3=Trifluoromethyl) (0.033 g, 41%) as an off-white solid. LC/MS, method 1, Rt=0.74 min, MS m/z 509 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.31 (dd, J=4.8, 1.6 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.72 (dd, J=8.0, 1.5 Hz, 1H), 7.59 (dd, J=8.4, 1.9 Hz, 1H), 7.25 (dd, J=7.9, 4.8 Hz, 1H), 7.12-6.93 (m, 4H), 6.56 (dd, J=6.5, 2.9 Hz, 2H), 5.90 (s, 1H), 3.58 (d, J=13.5 Hz, 1H), 3.54-3.44 (m, 1H), 3.06-2.96 (m, 1H), 2.87 (d, J=13.8 Hz, 1H), 2.42 (s, 3H), 2.11-1.59 (m, 10H), 1.53-1.39 (m, 1H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 33

36
[ 3430-10-2 ]
[ 1400927-12-9 ]
[ 1044589-16-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0 - 20℃; for 1.5h;	115.6 Step No.6: (4bS,7R,8aS)-4b-Benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide (123, R2=Benzyl, R3=Trifluoromethyl, R6=2-Methylpyridin-3-yl)Toluene (3.0 mL) and THF (3.0 mL) were added to (4bS,7R,8aS)-methyl 4b-benzyl-7-hydroxy-7-(trifluoromethyl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxylate (122, R2=Benzyl, R3=Trifluoromethyl) (0.127 g, 0.305 mmol) and the solution was cooled to about 0° C., then 2-methylpyridin-3-amine (0.040 g, 0.366 mmol) was added in one portion. LiHMDS (1 M solution in THF, 0.92 mL, 0.92 mmol) was added dropwise and the reaction was stirred for about 30 min at about 0° C. The ice bath was removed and the reaction mixture was stirred at rt for about 60 min. Saturated aqueous NaHCO3 (10 mL) was added and the biphasic solution was extracted with EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-20% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure to yield (4bS,7R,8aS)-4b-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide (123, R2=Benzyl, R3=Trifluoromethyl, R6=2-Methylpyridin-3-yl) (124 mg, 83%) as a solid. LC/MS, method 3, Rt=2.15 min, MS m/z 493 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.36-8.32 (m, 1H), 7.85-7.79 (m, 1H), 7.78-7.72 (m, 1H), 7.59-7.51 (m, 1H), 7.32-7.23 (m, 1H), 7.15-7.01 (m, 3H), 6.84-6.74 (m, 1H), 6.53-6.46 (m, 1H), 6.46-6.37 (m, 2H), 6.11 (s, 1H), 5.96-5.88 (m, 1H), 2.98 (d, J=13.2 Hz, 1H), 2.88 (d, J=13.2 Hz 1H), 2.73-2.63 (m, 1H), 2.44 (s, 3H), 2.31-2.19 (m, 2H), 2.20-1.98 (m, 3H), 1.62-1.42 (m, 1H).

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37
[ 3430-10-2 ]
[ 1400927-16-3 ]
[ 1400927-17-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0℃; for 1h; Inert atmosphere;	118.4 Step No.4: (4bS,7R,8aS)-4b-Benzyl-10-methyl-N-(2-methylpyridin-3-yl)-7-(triethylsilyloxy)-7-(trifluoromethyl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide (131, R2=Benzyl, R3=Trifluoromethyl, R6=2-Methylpyridin-3-yl)LiHMDS (1.0 M solution in THF, 2.30 mL, 2.30 mmol) was added dropwise to a solution of (4bS,7R,8aS)-methyl 4b-benzyl-10-methyl-7-(triethylsilyloxy)-7-(trifluoromethyl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxylate (130, R2=Benzyl, R3=Trifluoromethyl) (0.364 g, 0.668 mmol), 3-amino-2-methylpyridine (0.108 g, 1.00 mmol), and toluene (6.50 mL) under a nitrogen atmosphere at about 0° C. After about 1 h, saturated aqueous NaHCO3 (5 mL) and water (5 mL) were added. The solution was extracted with EtOAc (2×10 mL). The combined organics were washed with saturated aqueous NaCl (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-50% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure to afford (4bS,7R,8aS)-4b-benzyl-10-methyl-N-(2-methylpyridin-3-yl)-7-(triethylsilyloxy)-7-(trifluoromethyl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide (131, R2=Benzyl, R3=Trifluoromethyl, R6=2-Methylpyridin-3-yl) (0.383 g, 92%) of a pale yellow film/glass. LC/MS, method 3, Rt=3.44 min, MS m/z 622 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.35-8.31 (m, 1H), 7.93 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.58 (d, J=6.3 Hz, 1H), 7.27 (dd, J=7.8, 4.9 Hz, 1H), 7.11-7.03 (m, 3H), 6.49 (d, J=8.2 Hz, 1H), 6.43-6.37 (m, 2H), 5.73 (s, 1H), 2.91 (d, J=13.1 Hz, 1H), 2.81 (d, J=13.1 Hz, 1H), 2.69-2.59 (m, 1H), 2.42 (s, 3H), 2.40-2.26 (m, 2H), 2.19 (s, 3H), 2.15-2.01 (m, 3H), 1.60-1.46 (m, 1H), 0.99 (t, J=7.9 Hz, 9H), 0.72 (q, J=7.8 Hz, 6H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 122-123

38
[ 3430-10-2 ]
(7aSR,11aRS)-methyl 11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1.3]dioxolane]-3-carboxylate [ No CAS ]
(7aSR,11aRS)-11a-ethyl-N-(2-methylpyridin-3-yl)-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1.3]dioxolane]-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0℃; for 0.25h;	119.14 Step No.14: (7aS,11aR)-11a-Ethyl-N-(2-methylpyridin-3-yl)-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolane]-3-carboxamide; compound with (7aR,11aS)-11a-ethyl-N-(2-methylpyridin-3-yl)-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolane]-3-carboxamide (149, R6=2-Methylpyridin-3-yl, R8H, R9=H)A round bottom flask with stir bar and nitrogen line was charged with (7aS,11aR)-methyl 11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolane]-3-carboxylate; compound with (7aR,11aS)-methyl 11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolane]-3-carboxylate (148, R8=H, R9=H) (2.04 g, 5.89 mmol), toluene (60 mL) and 2-methylpyridin-3-amine (0.764 g, 7.07 mmol). The mixture was stirred for about 15 min at rt then cooled to about 0° C. and treated with LiHMDS (1 M solution in THF, 17.7 mL, 17.7 mmol). The mixture was stirred at about 0° C. for about 15 min then treated with saturated aqueous NaHCO3 (50 mL) and water (25 mL). The mixture was warmed to rt with stirring. The layers were separated then the aqueous layer was extracted with EtOAc (2×25 mL). The combined organics were washed with saturated aqueous NaCl (30 mL) then dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified on silica gel (40 g) using a gradient from 0-10% MeOH in DCM. Pure product fractions were combined and concentrated to give (7aS,11aR)-11a-ethyl-N-(2-methylpyridin-3-yl)-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolane]-3-carboxamide; compound with (7aR,11aS)-11a-ethyl-N-(2-methylpyridin-3-yl)-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolane]-3-carboxamide (149, R6=2-Methylpyridin-3-yl, R8=H, R9=H) (2.55 g, 102%) as a foam. LC/MS, method 3, Rt=2.29 min, m/z: 423 (M+H)+; NMR indicates presence of 4 wt % DCM. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=8.2 Hz, 1H), 8.33 (dd, J=4.8, 1.5 Hz, 1H), 7.64 (s, 1H), 7.55 (dd, J=8.2, 2.1 Hz, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.23 (dd, J=8.2, 4.8 Hz, 1H), 4.29-4.24 (m, 1H), 4.03-3.85 (m, 4H), 3.77-3.71 (m, 1H), 2.74-2.65 (m, 1H), 2.62 (s, 3H), 2.42-2.36 (m, 1H), 2.28-2.15 (m, 2H), 1.96-1.75 (m, 2H), 1.75-1.46 (m, 4H), 1.39-1.35 (m, 1H), 0.65 (t, J=7.5 Hz, 3H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 132

39
[ 3430-10-2 ]
C₂₁H₂₆O₄ [ No CAS ]
C₂₆H₃₀N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 20℃; for 0.0833333h;	128.5 Step No.5: (+/-) Compound 161 (R4=Methyl)A suspension of (+/-) Compound 160 (R4=Methyl) (0.171 g, 0.499 mmol) and 3-amino-2-picoline (0.095 g, 0.87 mmol) in toluene (5.0 mL) at rt was treated with LiHMDS (1.50 mL, 1.50 mmol, 1 M solution in THF) and the resulting suspension was stirred at rt for about 5 min. The reaction mixture was quenched at rt by addition of saturated aqueous NH4Cl (15 mL). The mixture was diluted with EtOAc (10 mL), and after separating the layers, the organic phase was washed with saturated aqueous NaCl (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-25% EtOAc in heptane. Collection and concentration of the appropriate fractions gave (+/-) Compound 161 (R4=Methyl) (0.214 g, 100% yield). LC/MS, method 3, Rt=2.22 min, MS m/z 419 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.46-8.40 (m, 1H), 8.34 (dd, J=4.8, 1.6 Hz, 1H), 7.73-7.60 (m, 3H), 7.47 (d, J=8.3 Hz, 1H), 7.30-7.19 (m, 1H), 6.42 (dd, J=12.2, 3.0 Hz, 1H), 5.91-5.82 (m, 1H), 3.98-3.82 (m, 4H), 2.93-2.82 (m, 1H), 2.64 (s, 3H), 2.63-2.46 (m, 1H), 2.30-2.14 (m, 2H), 1.63-1.30 (m, 7H), 0.78 (t, J=7.4 Hz, 3H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 140

40
[ 3430-10-2 ]
(7aSR,9SR,11aRS)-11a-ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester [ No CAS ]
(7aSR,9SR,11aRS)-11a-ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 20℃; for 0.0833333h;	133.3 Step No.3: (7aS,9S,11aR)-11a-Ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,9R,11aS)-11a-ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (167, R3=3,3,3-Trifluoro-propyl, R4=Methyl)A suspension of (7aS,9S,11aR)-11a-ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester; compound with (7aR,9R,11aS)-11a-ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (166, R3=3,3,3-Trifluoro-propyl, R4=Methyl) (0.036 g, 0.090 mmol) and 3-amino-2-picoline (0.017 g, 0.16 mmol) in toluene (1.8 mL) was treated with LiHMDS (0.27 mL, 0.27 mmol, 1 M solution in THF). The resulting suspension was allowed to stir at rt for about 5 min, and then the reaction was quenched by addition of saturated aqueous NH4Cl (2 mL). After separating the layers, the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-5% MeOH in DCM. Collection and concentration of the appropriate fractions gave (7aS,9S,11aR)-11a-ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,9R,11aS)-11a-ethyl-9-hydroxy-9-(3,3,3-trifluoro-propyl)-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (167, R3=3,3,3-Trifluoro-propyl, R4=Methyl) (0.035 g, 82%). LC/MS, method 2, Rt=2.48 min, MS m/z 475 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.33 (dd, J=4.8, 1.6 Hz, 1H), 7.78 (dd, J=8.1, 2.1 Hz, 1H), 7.72 (dd, J=8.0, 1.7 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.27 (dd, J=8.0, 4.7 Hz, 1H), 4.34 (s, 1H), 3.04-2.83 (m, 2H), 2.47-2.40 (m, 4H), 2.35-2.02 (m, 4H), 1.87-1.56 (m, 7H), 1.55-1.13 (m, 5H), 0.60 (t, J=7.3 Hz, 3H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 143-144

41
[ 3430-10-2 ]
(4bRS,7RS,8aRS)-methyl 4b-ethyl-7-propyl-7-hydroxy-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxylate [ No CAS ]
(4bRS,7RS,8aRS)-4b-ethyl-7-propyl-7-hydroxy-N-(2-methylpyridin-3-yl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0 - 20℃; for 1.5h; Inert atmosphere;	136.10 Step No.10: (4bR,7R,8 aR)-4b-Ethyl-7-propyl-7-hydroxy-N-(2-methylpyridin-3-yl)-4b,5,6,7,8,8 a-hexahydrophenanthrene-2-carboxamide; compound with (4bS,7S,8aS)-4b-ethyl-7-propyl-7-hydroxy-N-(2-methylpyridin-3-yl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide (107, R2=Ethyl, R3=Propyl, R6=2-Methylpyridin-3-yl)2-Methylpyridin-3-amine (0.183 g, 1.67 mmol) was added in one portion to a solution of (4bR,7R,8aR)-methyl 4b-ethyl-7-propyl-7-hydroxy-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxylate; compound with (4bS,7S,8aS)-methyl 4b-ethyl-7-propyl-7-hydroxy-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxylate (106, R2=Ethyl, R3=Propyl) (0.462 g, 1.41 mmol) and toluene (10 mL) under a nitrogen atmosphere. The mixture was cooled to about 0° C. LiHMDS (1 M solution in THF, 7.0 mL, 7.0 mmol) was added dropwise over about 30 min. After about 30 min, the ice bath was removed and the mixture was allowed to warm to rt. After about 1 h, the mixture was poured into saturated aqueous NaHCO3 (20 mL) and water (20 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with water (40 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 0-85% EtOAc in DCM. The fractions containing product were combined and concentrated under reduced pressure to afford (4bR,7R,8aR)-4b-ethyl-7-propyl-7-hydroxy-N-(2-methylpyridin-3-yl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide; compound with (4bS,7S,8aS)-4b-ethyl-7-propyl-7-hydroxy-N-(2-methylpyridin-3-yl)-4b,5,6,7,8,8a-hexahydrophenanthrene-2-carboxamide (107, R2=Ethyl, R3=Propyl, R6=2-Methylpyridin-3-yl) (0.440 g, 74%) as a foam. LC/MS, method 2, Rt=2.15 min, MS m/z 405 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.0 Hz, 1H), 8.33 (dd, J=4.8, 1.5 Hz, 1H), 7.73-7.66 (m, 2H), 7.55 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.29-7.23 (m, 1H), 6.46 (d, J=9.5 Hz, 1H), 6.03 (dd, J=9.5, 6.3 Hz, 1H), 2.64 (s, 3H), 2.61-2.53 (m, 1H), 2.31-2.22 (m, 1H), 1.89-1.76 (m, 2H), 1.62-1.53 (m, 2H), 1.48-1.25 (m, 6H), 1.06-1.02 (m, 1H), 1.00-0.89 (m, 1H), 0.89-0.80 (m, 3H), 0.67 (t, J=7.5 Hz, 3H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 152

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[ 3430-10-2 ]
C₂₃H₂₃O₃^(1-)*Li⁽¹⁺⁾ [ No CAS ]
(7aRS,11aSR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₂₃H₂₃O₃^(1-)*Li⁽¹⁺⁾ With hydrogenchloride In 1,4-dioxane; water Stage #2: With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In tetrahydrofuran at 20℃; for 0.0833333h; Stage #3: 2-methyl-3-pyridinamine In tetrahydrofuran at 60℃; for 48h;	8.2 Step No.2: (7aR,11aS)-11a-Benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aS,11aR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (18, R2=Benzyl)A solution of (7aR,11aS)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester; compound with (7aS,11aR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (17, R2=Benzyl) (0.750 g, 2.07 mmol) in 1,4-dioxane (12 mL) was treated with LiOH (0.261 g, 6.21 mmol) and water (3 mL). The reaction was warmed briefly to about 50° C., then diluted with water to obtain a homogeneous solution. The conversion to acid was followed to completion by LC/MS (LC/MS method 3, Rt=1.37 min, MS m/z 347 (M-H)-. The mixture was acidified with 2N aqueous HCl (20 mL) and extracted with EtOAc (2×20 mL). The extracts were dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF (25 mL), DIEA (0.367 mL, 2.10 mmol) was added and the mixture was treated with TFFH (0.556 g, 2.10 mmol) at rt for about 5 min, and then with 2-methylpyridin-3-amine (0.455 g, 4.21 mmol). The reaction was stirred for about 48 h at about 60° C. The reaction was cooled and concentrated under reduced pressure. The residue was dissolved in DCM (60 mL) and washed with saturated aqueous NaHCO3 (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (80 g) using a gradient from 80 to 100% EtOAc in heptane. The product fractions were combined, concentrated under reduced pressure and dried under vacuum to yield (7aR,11aS)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aS,11aR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (18, R2=Benzyl) (0.525 g, 57%) as an off-white glass. LC/MS, method 2, Rt=2.15 min, MS m/z 439 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.01-9.95 (m, 1H), 8.36-8.29 (m, 1H), 7.85-7.82 (m, 1H), 7.76-7.70 (m, 1H), 7.64-7.60 (m, 1H), 7.30-7.24 (m, 1H), 7.12-7.00 (m, 4H), 6.68-6.62 (m, 2H), 3.75-3.65 (m, 1H), 3.59-3.47 (m, 1H), 3.23-3.15 (m, 1H), 3.08-2.98 (m, 1H), 2.90-2.71 (m, 2H), 2.44 (s, 3H), 2.23-1.89 (m, 7H), 1.75-1.64 (m, 1H), 1.51-1.36 (m, 1H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 36-37

43
[ 3430-10-2 ]
(7aSR,11aSR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-a]azepine-2-carboxylic acid [ No CAS ]
(7aSR,11aSR)-11a-benzyl-N-(2-methylpyridin-3-yl)-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-a]azepine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In tetrahydrofuran at 20℃; for 72h;	144.10 Step No.10: (7aS,11aS)-11a-Benzyl-N-(2-methylpyridin-3-yl)-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-c]azepine-2-carboxamide; compound with (7aR,11aR)-11a-benzyl-N-(2-methylpyridin-3-yl)-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-c]azepine-2-carboxamide (185, R2=Benzyl, R6=2-Methylpyridin-3-yl)A mixture of 3-amino-2-picoline (0.120 g, 1.11 mmol), (7aS,11aS)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-a]azepine-2-carboxylic acid; compound with (7aR,11aR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-a]azepine-2-carboxylic acid (184, R2=Benzyl) (0.187 g, 0.554 mmol), and TFFH (0.146 g, 0.554 mmol) in THF (2.8 mL) was treated with DIEA (0.10 mL, 0.55 mmol) and the resulting suspension was allowed to stir at rt for about 3 days. The reaction mixture was diluted with DCM (25 mL), and the solution was washed with saturated aqueous NaHCO3 (25 mL). The organic phase was washed with saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-5% MeOH in DCM to yield (7aS,11aS)-11a-benzyl-N-(2-methylpyridin-3-yl)-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-a]azepine-2-carboxamide; compound with (7aR,11aR)-11a-benzyl-N-(2-methylpyridin-3-yl)-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-benzo[c]pyrrolo[1,2-a]azepine-2-carboxamide (185, R2=Benzyl, R6=2-Methylpyridin-3-yl) (0.034 g, 14%). LC/MS, method 2, Rt=1.96 min, MS m/z 428 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.25 (dd, J=4.7, 1.6 Hz, 1H), 7.67 (dd, J=8.0, 1.6 Hz, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.21 (dd, J=7.9, 4.7 Hz, 1H), 7.17-7.08 (m, 3H), 6.68-6.58 (m, 2H), 6.28 (d, J=2.0 Hz, 1H), 4.41-4.26 (m, 2H), 3.53 (d, J=13.2 Hz, 1H), 2.71-2.42 (m, 3H), 2.37 (s, 3H), 2.31-2.14 (m, 3H), 2.06-1.63 (m, 6H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 160

44
[ 3430-10-2 ]
C₂₃H₂₃O₃^(1-)*Li⁽¹⁺⁾ [ No CAS ]
(7aSR,11aSR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₂₃H₂₃O₃^(1-)*Li⁽¹⁺⁾ With hydrogenchloride In 1,4-dioxane; water Stage #2: With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In tetrahydrofuran at 20℃; for 0.0833333h; Stage #3: 2-methyl-3-pyridinamine In tetrahydrofuran at 60℃; for 48h;	11.2 Step No.2: (7aS,11aS)-11a-Benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,11aR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (22, R2=Benzyl)A solution of (7aS,11aS)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester; compound with (7aR,11aR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (21, R2=Benzyl) (1.30 g, 3.59 mmol) in 1,4-dioxane (20 mL) was treated with LiOH (0.452 g, 10.8 mmol) and water (5 mL). The reaction was warmed briefly to about 50° C. to obtain a homogeneous solution. The conversion to acid was followed to completion by LC/MS (method 1, Rt=0.74 min, MS m/z 347 (M-H)-. The mixture was acidified with 2N aqueous HCl (20 mL) and extracted with DCM (2×20 mL). The extracts were dried over Na2SO4, filtered and concentrated. The residue was dissolved in THF (25 mL) and DIEA (0.627 mL, 3.59 mmol) was added. The mixture was treated with TFFH (0.948 g, 3.59 mmol) at rt for about 5 min, and then with 2-methylpyridin-3-amine (0.776 g, 7.18 mmol) was added. The reaction was stirred for about 48 h at about 60° C. The reaction was cooled and concentrated. The residue was dissolved in DCM (60 mL) and washed with saturated aqueous NaHCO3 (30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified on silica gel (80 g) using a gradient from 80% to 100% EtOAc in heptane. The product fractions were combined, concentrated and dried under reduced pressure to yield (7aS,11aS)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide; compound with (7aR,11aR)-11a-benzyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (22, R2=Benzyl) (1.01 g, 64%) as an off-white solid. LC/MS, method 1, Rt=0.77 min, MS m/z 439 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.34 (dd, J=4.7, 1.6 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.74 (dd, J=7.9, 1.6 Hz, 1H), 7.64 (dd, J=8.2, 2.1 Hz, 1H), 7.27 (dd, J=7.9, 4.7 Hz, 1H), 7.15-7.01 (m, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.64-6.58 (m, 2H), 3.73 (d, J=13.0 Hz, 1H), 3.40-3.09 (m, 1H). 3.09-2.99 (m, 1H), 2.66 (d, J=13.1 Hz, 1H), 2.44 (s, 3H), 2.42-2.23 (m, 5H), 2.18-2.05 (m, 1H), 2.03-1.80 (m, 3H), 1.76-1.51 (m, 2H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 39

45
[ 3430-10-2 ]
C₂₃H₂₂O₃ [ No CAS ]
[ 1400926-28-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate In tetrahydrofuran at 20 - 60℃; for 18.25h;	19.3 Step No.3: 11a-Benzyl-9-oxo-6,7,9,10,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (32, R2=Benzyl)To a solution of 11a-benzyl-9-oxo-6,7,9,10,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid methyl ester (31, R2=Benzyl) (102 mg, 0.283 mmol) in 1,4-dioxane (2.0 mL) was added LiOH monohydrate (0.059 g, 1.41 mmol) in water (0.50 mL) and the mixture was stirred at about 50° C. for about 1 h. The reaction was concentrated, 2N aqueous HCl was added to adjust the pH to about 1 and the intermediate was extracted with DCM (2×5 mL). The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in THF (3 mL), and 2-methyl-pyridin-3-ylamine (61.2 mg, 0.566 mmol), DIEA (0.049 mL, 0.28 mmol) and TFFH (74.7 mg, 0.283 mmol) were added. The mixture was stirred at rt for about 15 min then heated at about 60° C. for about 18 h. The reaction was cooled and concentrated under reduced pressure. The residue was dissolved in DCM (5.0 mL) and washed with saturated aqueous NaHCO3 (2×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient from 80-100% EtOAc in heptane. The product fractions were combined, concentrated and dried under vacuum to yield 11a-benzyl-9-oxo-6,7,9,10,11,11a-hexahydro-5H-dibenzo[a,c]cycloheptene-3-carboxylic acid (2-methyl-pyridin-3-yl)-amide (32, R2=Benzyl), LC/MS, method 1, Rt=0.67 min, MS m/z 437 (M+H)+, which was used in the next step without further purification.

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 44

46
[ 3430-10-2 ]
[ 1400926-33-1 ]
[ 1400926-34-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 20℃; for 2h;	21.4; 22.4 Step No.4: (4bS,8aS)-4b-Benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide (41, R2=Benzyl, R3=Trifluoromethyl)A 50 mL round bottom flask equipped with a septa cap outfitted with nitrogen inlet needle was charged with 2-methylpyridin-3-amine (0.465 g, 4.30 mmol) and (4bS,8aS)-methyl 4b-benzyl-7-hydroxy-7-(trifluoromethyl)-4b,5,6,7,8,8 a,9,10-octahydrophenanthrene-2-carboxylate (40, R2=Benzyl, R3=Trifluoromethyl) (1.20 g, 2.87 mmol) in toluene (14.3 mL) to give a colorless solution. LiHMDS (8.60 mL, 8.60 mmol) (1M solution in THF) was added slowly via syringe. The resulting suspension was allowed to stir at rt for about 2 h and then treated with an excess of water (slow addition). The mixture was extracted with EtOAc and the organic phase was separated and washed with water, saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting sample was purified via silica gel chromatography eluting with 2 to 5% MeOH in EtOAc. The fractions containing the desired product were combined and concentrated under reduced pressure to afford (4bS,8aS)-4b-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide (41, R2=Benzyl, R3=Trifluoromethyl) (1.27 g, 90%) as a solid. LC/MS, method 2, Rt=2.41 min, MS m/z 495 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.33 (dd, J=4.7, 1.6 Hz, 1H), 7.81 (dd, J=8.2, 1.9 Hz, 1H), 7.73 (dd, J=8.0, 1.6 Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.0, 4.7 Hz, 1H), 7.17-7.07 (m, 3H), 6.86-6.80 (m, 2H), 3.31 (s, 2H), 3.15 (d, J=13.9 Hz, 1H), 3.04 (d, J=13.9 Hz, 1H), 2.79-2.65 (m, 1H), 2.44 (s, 3H), 2.17-1.78 (m, 7H), 1.62-1.49 (m, 2H).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC; ABBVIE INC - US2012/238549, 2012, A1 Location in patent: Page/Page column 48-49

47
[ 3430-10-2 ]
[ 319923-90-5 ]
[ 1417332-49-0 ]

Yield	Reaction Conditions	Operation in experiment
17%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h;	31 31: 3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-methyl-pyridin-3-yl)-amideA round bottomed flask was charged with 3,6-dimethyl-1-phenyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid IM43 (1.2 g, 4.49 mmol), 3-amino-2-methylpyridine (485 mg, 4.49 mmol) and N-methyl morpholine (907 mg, 8.99 mmol) in DMF (50 mL) at room temperature. To this mixture was added EDC.HCl (947 mg, 4.94 mmol) and HOBt (606 mg, 4.49 mmol). The mixture stirred at for 16 h. The reaction mixture was then poured into water (100 mL). The resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. Flash chromatography (silica, 70% EtOAc in petroleum-ether) gave the title compound as, a solid (277 mg, 17%). mp=208-209° C. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (1H, s), 8.39-8.38 (1H, m), 8.27-8.25 (2H, d), 7.93-7.91 (1H, m), 7.59-7.55 (2H, m), 7.49 (1H, s), 7.35-7.32 (2H, m), 2.74 (3H, s), 2.58 (3H, s), 2.52 (3H, s).LC-MS (m/z) 358.2 (MH+); tR=0.53.
17%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h;	31 General procedure: A round bottomed flask was charged with 3,6-dimethyl-1 -phenyl-1 h-pyrazolo[3,4-b]pyridine-4- carboxylic acid IM43 (1 .2 g, 4.49 mmol), 3-amino-2-methyl pyridine (485 mg, 4.49 mmol) and N-methyl morpholine (907 mg, 8.99 mmol) in DMF (50 ml.) at room temperature. To this mixture was added EDC.HCI (947 mg, 4.94 mmol) and HOBt (606 mg, 4.49 mmol). The mixture stirred at for 16 h. The reaction mixture was then poured into water (100 ml_). The resulting mixture was extracted with ethyl acetate (2x200 ml_). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and evaporated to dryness. Flash chromatography (silica, 70% EtOAc in petroleum-ether) gave the title compound as a solid (277 mg, 17%). mp = 208-209 °C. 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (1 H, s), 8.39-8.38 (1 H, m), 8.27-8.25 (2H, d), 7.93-7.91 (1 H, m),7.59-7.55 (2H, m), 7.49 (1 H, s), 7.35-7.32 (2H, m), 2.74 (3H, s), 2.58 (3H, s), 2.52 (3H, s).LC-MS (m/z) 358.2 (MH+); tR = 0.53.

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S - US2013/5743, 2013, A1 Location in patent: Page/Page column 33
[2]Current Patent Assignee: H. LUNDBECK A/S - WO2013/4617, 2013, A1 Location in patent: Page/Page column 70

48
[ 3430-10-2 ]
[ 108-24-7 ]
[ 52090-62-7 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 2-methyl-3-pyridinamine; acetic anhydride In chloroform at 0 - 20℃; Stage #2: With potassium acetate; isopentyl nitrite In chloroform Reflux;	98.1 Step 11 -Pyrazo lo [4 ,3 -b ]pyridin- 1 -yl-ethanone Example 98.2-(l -Methyl- 1 H-pyrazolo [4,3 -b]pyridin-3 -yl)-5H-pyrrolo [2,3 -b]pyrazine-7-carboxylic acid [(R)- 2-(3 -cyano-azetidin- 1 -yl)- 1 -methyl-2-oxo-ethyl]-amideStep 11 -Pyrazo lo [4 ,3 -b ]pyridin- 1 -yl-ethanoneTo a solution of 3-amino-2-methylpyridine (1.0 g, 9.25 mmol) in CHCI3 (24 ml) at 0°C was slowly added acetic anhydride (2.0 ml, 21.3 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Potassium acetate (272 mg, 2.77 mmol) was added followed by slow addition of isoamyl nitrite (2.7 ml, 19.9 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc and washed with water, sat'd NaHC03 and brine then dried over MgSC^ and concentrated. The residue was purified by silica gel chromatography with 20% to 100% EtO Ac/heptane to give 973 mg (65%) of l-pyrazolo[4,3-b]pyridin-l -yl-ethanone as a light yellow solid.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/30138, 2013, A1 Location in patent: Page/Page column 253

49
[ 3430-10-2 ]
[ 1889-71-0 ]
[ 1501945-32-9 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 220 - 223

50
[ 3430-10-2 ]
[ 1345955-99-8 ]
[ 1345956-37-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 140℃; for 1h; Microwave irradiation;	6.1.9 General procedure A for preparation of compounds IIb-c General procedure: In a degassed solution of dioxane containing 24 (1.0 mmol), primary amines (for IIb) or amides for IIc (1.2 eq.), K2CO3 (2.0 eq.) and xantphos (0.2 eq; for IIb or 0.1 eq. for IIc) was added Pd(OAc)2 (0.1 eq; for IIb or 0.05 eq. for IIc) and the suspension immediately placed in the microwave cavity. After irradiation (60 min for IIb or 70 min for IIc) at 140 °C, the solution was cooled and volatiles were removed under reduced pressure and the crude material was purified by recrystallization or by flash chromatography on silica gel.

Reference： [1]Dehbi, Oussama; Tikad, Abdellatif; Bourg, Stephane; Bonnet, Pascal; Lozach, Olivier; Meijer, Laurent; Aadil, Mina; Akssira, Mohammed; Guillaumet, Gérald; Routier, Sylvain [European Journal of Medicinal Chemistry, 2014, vol. 80, p. 352 - 363]

51
[ 3430-10-2 ]
[ 1616363-73-5 ]
[ 1616363-69-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	With lithium hexamethyldisilazane In tetrahydrofuran at -60 - 0℃; for 0.5h;	4.F Step F: 3-methyl-4-(1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-N-(2-methylpyridin-3-yl)benzamide To a mixture of methyl 3-methyl-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.20 g, 0.51 mmol) and 3-amino-2-methylpyridine (0.066 g, 0.61 mmol) in anhydrous THF (20 mL), was added lithium bis(trimethylsilyl)amide solution (1.01 mL, 1 M in THF, 1.01 mmol), at about -60° C. The resulting mixture was stirred for about 30 min, during which time the temperature was allowed to rise from about -60° C. to about 0° C., and then quenched by the addition of water (20 mL), while keeping the temperature below 0° C. The resulting mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate) to afford 3-methyl-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.10 g, 0.21 mmol, 42%) as a beige foam: LC-MS (Table 1, Method a) Rt=1.85 min, m/z 471 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.56 (3H, s) 2.72 (3H, s) 2.67-2.75 (1H, m) 2.87 (1H, ddd, J=15.0, 9.3, 2.6 Hz) 3.29 (1H, ddd, J=13.3, 9.3, 2.5 Hz) 3.65 (1H, ddd, J=13.3, 6.2, 2.3 Hz) 3.85 (3H, s) 3.87 (1H, br s) 6.76 (1H, s) 7.08 (1H, ddd, J=7.4, 4.9, 1.1 Hz) 7.20 (1H, dd, J=8.1, 4.7 Hz) 7.35 (1H, t, J=8.0 Hz) 7.55 (1H, dd, J=8.0, 2.0 Hz) 7.60 (1H, td, J=7.8, 1.8 Hz) 7.62 (1H, d, J=1.8 Hz) 7.69 (1H, br s) 7.84 (1H, dt, J=8.0, 1.0 Hz) 8.30 (1H, dd, J=4.8, 1.6 Hz) 8.35 (1H, dd, J=8.1, 1.4 Hz) 8.47 (1H, ddd, J=4.8, 1.7, 0.8 Hz).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 0934

52
[ 3430-10-2 ]
[ 1616359-65-9 ]
[ 1616361-50-2 ]

Yield	Reaction Conditions	Operation in experiment
9%	With lithium hexamethyldisilazane In tetrahydrofuran at -40℃; for 0.5h;	F.1 Example No.F.1 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide To a mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.34 mmol, Example No.E.1) and 3-amino-2-methylpyridine (0.04 g, 0.37 mmol) in anhydrous THF (10 mL), was added lithium bis(trimethylsilyl)amide solution (1.3 mL, 1 M in THF, 1.3 mmol), at about -40° C. The resulting mixture was stirred for about 30 min, at about -40° C., and then quenched by the addition of water (10 mL) and ethyl acetate (130 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol 100:0 to 0:100) and preparative HPLC (Table 2, Method a) to afford 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydro-pyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.0162 g, 0.03 mmol, 9%): LC-MS (Table 1, Method b) Rt=3.70 min, m/z 491 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.56 (3H, s), 2.70-2.90 (2H, m), 3.26-3.35 (1H, m), 3.63-3.71 (1H, m) 3.60-4.00 (1H, br s) 3.84 (3H, s) 6.91 (1H, s) 7.09 (1H, ddd, J=1.2, 4.8, 7.9 Hz) 7.21 (1H, dd, J=4.8, 8.2 Hz) 7.44 (1H, d, J=8.0 Hz) 7.58-7.64 (3H, m) 7.80 (1H, d, J=8.0 Hz) 7.92 (1H, d, J=2.0 Hz) 8.28-8.34 (2H, m) 8.48-8.51 (1H, m).
9%	With lithium hexamethyldisilazane In tetrahydrofuran at 40℃; for 0.5h;	3.F Step F: 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydro-pyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide To a mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.34 mmol) and 3-amino-2-methylpyridine (0.04 g, 0.37 mmol) in anhydrous THF (10 mL), was added lithium bis(trimethylsilyl)amide solution (1.3 mL, 1 M in THF, 1.3 mmol), at about -40° C. The resulting mixture was stirred for about 30 min, at about -40° C., and then quenched by the addition of water (10 mL) and ethyl acetate (130 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol 100:0 to 0:100) and prep-HPLC (Table 2, Method a) to afford 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.0162 g, 0.03 mmol, 9%). LC-MS (Table 1, Method b) Rt=3.70 min, m/z 491 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.56 (3H, s), 2.70-2.90 (2H, m), 3.26-3.35 (1H, m), 3.63-3.71 (1H, m) 3.60-4.00 (1H, br s) 3.84 (3H, s) 6.91 (1H, s) 7.09 (1H, ddd, J=1.2, 4.8, 7.9 Hz) 7.21 (1H, dd, J=4.8, 8.2 Hz) 7.44 (1H, d, J=8.0 Hz) 7.58-7.64 (3H, m) 7.80 (1H, d, J=8.0 Hz) 7.92 (1H, d, J=2.0 Hz) 8.28-8.34 (2H, m) 8.48-8.51 (1H, m).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 0820
[2]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 0919

53
[ 3430-10-2 ]
[ 32315-10-9 ]
1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride [ No CAS ]
[ 1616359-71-7 ]

Yield	Reaction Conditions	Operation in experiment
26%	Stage #1: 2-methyl-3-pyridinamine; bis(trichloromethyl) carbonate With triethylamine In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride In tetrahydrofuran at 0℃; for 1h;	6 Preparation No.6: N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]piperidine-1-carboxamide To a mixture of triphosgene (0.017 g, 0.056 mmol) and 3-amino-2-methylpyridine (0.018 g, 0.17 mmol) in anhydrous THF (5 mL) was added dropwise triethylamine (0.14 mL, 1 mmol), at about 0° C. After stirring for about 5 min at about 0° C., 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride (0.07 g, 0.17 mmol, Preparation 4) was added at about 0° C. Subsequently, the mixture was stirred for about 1 h and allowed to come to rt. Then the mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/methanol/ammonium hydroxide 92:7.5:0.5) to give N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]piperidine-1-carboxamide (0.03 g, 0.065 mmol, 26%) as an off white solid: LC-MS (Table 1, Method b) Rt=2.00 min; m/z 464 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 0697

54
[ 3430-10-2 ]
[ 1616363-04-2 ]
[ 1616363-03-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 4-(1,3-dimethyl-7-oxo-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepin-4-yl)-3-methylbenzoic acid With BTFFH; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.0833333h; Stage #2: 2-methyl-3-pyridinamine In tetrahydrofuran at 60℃; for 24h;	O.1 Example No.O.1 4-(1,3-Dimethyl-7-oxo-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepin-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide To a solution of 4-(1,3-dimethyl-7-oxo-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepin-4-yl)-3-methylbenzoic acid (0.047 g, 0.15 mmol, prepared using W from 4-bromo-2-methylbenzaldehyde (Ark Pharm, Inc), X from 1,3-dimethyl-1H-pyrazol-5-amine, Y, Z, AA, then N) and DIEA (0.026 mL, 0.15 mmol) in THF (1 mL) was added BTFFH (0.047 g, 0.15 mmol) and the reaction was stirred for about 5 min at rt. 2-Methylpyridin-3-amine (0.032 g, 0.30 mmol) was added and the mixture was heated to 60° C. for about 24 h. The reaction was cooled to rt and concentrated in vacuo. The residue was purified on silica gel using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated. The residue was triturated with EtOAc (about 2 mL) and the product was filtered off and dried under vacuum at about 50° C. to yield 4-(1,3-dimethyl-7-oxo-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepin-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.021 g, 0.052 mmol, 35%) as an off-white solid; LC-MS (Table 1, Method g) Rt=1.44 min, m/z 404 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 2H), 8.31 (d, J=3.9 Hz, 1H), 7.82-7.75 (m, 1H), 7.73-7.65 (m, 2H), 7.28-7.22 (m, 1H), 7.00-6.95 (m, 1H), 4.31 (dd, J=9.5, 6.7 Hz, 1H), 3.63 (s, 3H), 2.47-2.42 (m, 5H), 2.41 (s, 3H), 2.34-2.21 (m, 1H), 1.74-2.61 (m, 1H), 1.50 (s, 3H).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 0848

55
[ 3430-10-2 ]
rac-methyl (4S,7R)-7-((((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-4-yl)-3-methylbenzoate [ No CAS ]
rac-4-((4S,7R)-(7-((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With lithium hexamethyldisilazane In tetrahydrofuran; hexane at 0 - 20℃; for 2h; Cooling;	13.C Step C: rac-4-((4R,7S)(7-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide To a solution of rac-methyl 4-((4R,7S)-(7-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoate (0.300 g, 0.56 mmol) and 2-methylpyridin-3-amine (0.181 g, 1.67 mmol, Appollo) in THF (6 ml) at about 0° C. was added 1 M lithium bis(trimethylsilyl)amide in hexane (2.78 ml, 2.78 mmol). About 5 min after the complete addition, the cold bath was removed and the reaction was stirred for about 2 h at rt. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 50-100% EtOAc/heptane) to give rac-4-((4R,7S)(7-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.29 g, 0.47 mmol, 85%) as a pale yellow film: LC-MS (Table 1, Method g) Rt=2.83 min, m/z 615 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 9.84 (s, 1H), 8.48-8.44 (m, 1H), 8.30 (d, J=4.6 Hz, 1H), 7.81-7.78 (m, 1H), 7.73-7.66 (m, 2H), 7.64-7.60 (m, 1H), 7.39-7.36 (m, 1H), 7.28-7.16 (m, 2H), 6.87 (d, J=3.1 Hz, 1H), 6.80 (s, 1H), 5.86 (d, J=5.2 Hz, 1H), 4.96 (s, 1H), 3.78-3.61 (m, 4H), 3.52 (s, 1H), 2.87-2.74 (m, 2H), 2.57 (s, 3H), 2.40 (s, 3H), 0.83 (s, 9H), 0.12--0.15 (m, 6H).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 0989

56
[ 3430-10-2 ]
rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate [ No CAS ]
rac-4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0 - 20℃; for 7h;	15.Q Step Q: rac-4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide 1 M lithium bis(trimethylsilyl)amide in toluene (0.13 mL, 0.13 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 0.04 mmol) and 2-methylpyridin-3-amine (6.4 mg, 0.06 mmol, Appollo) in THF (1 mL) at 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (4.2 mg, 0.04 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.04 mL, 0.04 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2*20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM) to give rac-4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.001 g, 5%): LC-MS (Table 1, Method g) Rt=1.94 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.81 (s, 1H), 8.37-8.34 (m, 1H), 8.31-8.27 (m, 1H), 7.79-7.75 (m, 1H), 7.71-7.62 (m, 3H), 7.56-7.51 (m, 1H), 7.26-7.22 (m, 1H), 7.13-7.08 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.32 (s, 1H), 5.28-5.21 (m, 1H), 3.86 (s, 3H), 3.36-3.32 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.22-2.12 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.76 (m, 2H).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 1039

57
[ 3430-10-2 ]
rac-methyl 4-((4S,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate [ No CAS ]
rac-4-((4S,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With lithium hexamethyldisilazane In tetrahydrofuran; toluene at 0 - 20℃; for 7h;	15.P Step P: rac-4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide 1 M lithium bis(trimethylsilyl)amide in toluene (0.24 mL, 0.24 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 0.07 mmol) and 2-methylpyridin-3-amine (0.012 g, 0.11 mmol, Appollo) in THF (2 mL) at about 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (0.008 g, 0.07 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.07 mL, 0.07 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2*20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM). The appropriate fractions were concentrated in vacuo. The product was recrystallized from Et2O to give rac-4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.005 g, 12%): LC-MS (Table 1, Method g) Rt=1.86 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.85 (s, 1H), 8.44-8.41 (m, 1H), 8.32-8.29 (m, 1H), 7.82-7.78 (m, 1H), 7.75-7.67 (m, 3H), 7.60-7.56 (m, 1H), 7.26-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 5.61-5.55 (m, 1H), 3.93 (s, 3H), 3.40-3.32 (m, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.36-2.26 (m, 1H), 1.93-1.83 (m, 1H), 1.80-1.71 (m, 2H).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/179676, 2014, A1 Location in patent: Paragraph 1037

58
[ 3430-10-2 ]
(4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone [ No CAS ]
(4-(3-((2-((2-methylpyridin-3-yl)amino)pyridin-4-yl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In 1,4-dioxane; N,N-dimethyl-formamide at 90℃; for 24h; Microwave irradiation;	47 (4-(3-((2-((2-methylpyridin-3-yl)amino)pyridin-4-yl)ethynyl)imidazo[l,2- b]pyridazin-6-yl)phenyl) (morpholino)methanone To a solution of (4-(3-((2-chloropyridin-4-yl)ethynyl)imidazo[l,2-b]pyridazin- 6-yl)phenyl)(morpholino)methanone (20 mg, 0.045 mmol), 2-methylpyridin-3 -amine (9.7 mg, 0.090 mmol)) in a mixture of 1,4 dioxane and DMF (9:1, 1 mL) was added BINAP (5.6 mg, 0.0090 mmol)), t-BuONa (13 mg, 0.135 mmol)) and then Pd2(dba)3 (4.2 mg, 0.0045 mmol)). The resulting mixture was microwave at 90 °C for 24 hand was filtered. The filtrate was purified by column chromatography (silica gel, eluent EtOAc /CH3OH 90:10) to afford (4-(3-((2-((2-methylpyridin-3-yl)amino)pyridin-4-yl)ethynyl)imidazo[l,2- b]pyridazin-6-yl)phenyl) (morpholino)methanone (5.3 mg, 23%), AUC HPLC 98.7%) as a light yellow solid. 1H NMR (600 MHz, DMSO-i δ (ppm): 8.53 (s, 1H), 8.38 (d, J= 9.5 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J= 8.4 Hz, 2H), 8.16 (t, J= 4.9 Hz, 2H), 8.07 (dd, J= 8.1, 1.4 Hz, 1H), 8.03 (d, J= 9.5 Hz, 1H), 7.64 (d, J= 8.4 Hz, 2H), 7.21 (dd, J= 8.0, 4.7 Hz, 1H), 7.05 (s, 1H), 6.93 (dd, J= 5.2, 1.3 Hz, 1H), 3.63 (m, 8H), 2.46 (s, 3H); 13C NMR (150 MHz, DMSO-i δ (ppm): 168.4, 156.5, 151.6, 150.9, 148.1, 143.3, 139.7, 137.3, 135.6, 134.8, 130.5, 129.7, 127.9, 127.2, 126.6, 124.3, 121.3, 118.2, 115.3, 111.1, 96.6, 91.8, 79.6, 66.1, 63.0, 21.3; MS (ESI) m/z 516 [C30H25N7O2+ H]+.

Reference： [1]Current Patent Assignee: AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH - WO2015/50505, 2015, A1 Location in patent: Paragraph 000291

59
[ 3430-10-2 ]
4-chloro-7-nitroisobenzofuran-1,3-dione [ No CAS ]
4-chloro-2-(2-methylpyridin-3-yl)-7-nitroisoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid at 120℃; for 4h;	28 Synthesis of XC IV: Synthesis of XC IV:To a stirred solution of compound XXV (230 g, 1.01 mol) in acetic acid (4 L) was added 2-methylpyridin-3-amine (XCIII, 118.15 g, 1.09 mol) and the reaction mixture heated at 120°Cfor 4 h. The reaction mixture was cooled to room temperature and the acetic acid removedunder reduced pressure. The residual material was washed with hexane to obtain a crude product 4-chloro-2-(2-methylpyridin-3 -yl)-7-nitroisoindoline- 1,3 -dione as a yellow solid (XCIV; 300 g,). MS (M+1): 318.09. The crude material was carried forward to next step without purification.
	In acetic acid for 18h; Reflux;

Reference： [1]Current Patent Assignee: NORGINE BV - WO2015/97121, 2015, A1 Location in patent: Page/Page column 149
[2]Kalindjian, S. Barret; Kadnur, Sanjay V.; Hewson, Christopher A.; Venkateshappa, Chandregowda; Juluri, Suresh; Kristam, Rajendra; Kulkarni, Bheemashankar; Mohammed, Zainuddin; Saxena, Rohit; Viswanadhan, Vellarkad N.; Aiyar, Jayashree; McVey, Donna [Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3098 - 3111]

60
[ 3430-10-2 ]
[ 63725-87-1 ]
C₁₈H₁₉N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With boron trifluoride diethyl etherate In toluene at 120℃; for 48h;	II.A.G General procedure: Novel aza-ellipticine compounds were prepared using a protic acid in an organic solvent in the presence of microwave irradiation and heating resulted in a mixture of aza20 ellipticines and imine cores. Reaction conditions are described in Table 1. Acidconcentration and time were first explored as methods to reduce the formation of the imine product. The greatest increases in yield were obtained when moving to a polar solvent system. Various strength acids as well as Lewis acids were used and trifluoromethanesulfonic acid (TfOH) was selected as TfOH required only sub39 stoichiometric amounts of acid without reducing the reaction time. Reasonable conversion was also seen with hydrochloric acid.

Reference： [1]Current Patent Assignee: MEDICAL UNIVERSITY OF SOUTH CAROLINA - WO2015/179218, 2015, A1 Location in patent: Page/Page column 39; 40; 41

61
[ 3430-10-2 ]
[ 63725-87-1 ]
C₁₈H₁₉N₃O [ No CAS ]
C₁₈H₂₁N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluorormethanesulfonic acid In 1,4-dioxane; water at 130℃; for 1h;	II.A.D General procedure: Novel aza-ellipticine compounds were prepared using a protic acid in an organic solvent in the presence of microwave irradiation and heating resulted in a mixture of aza20 ellipticines and imine cores. Reaction conditions are described in Table 1. Acidconcentration and time were first explored as methods to reduce the formation of the imine product. The greatest increases in yield were obtained when moving to a polar solvent system. Various strength acids as well as Lewis acids were used and trifluoromethanesulfonic acid (TfOH) was selected as TfOH required only sub39 stoichiometric amounts of acid without reducing the reaction time. Reasonable conversion was also seen with hydrochloric acid.

Reference： [1]Current Patent Assignee: MEDICAL UNIVERSITY OF SOUTH CAROLINA - WO2015/179218, 2015, A1 Location in patent: Page/Page column 39; 40; 41

62
[ 3430-10-2 ]
[ 63725-87-1 ]
C₁₈H₁₉N₃O [ No CAS ]
9-methyl-6-propyl-6H-indolo[2,3-b][1,5]naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid In 1,4-dioxane at 110℃; for 48h;	II.A.A General procedure: Novel aza-ellipticine compounds were prepared using a protic acid in an organic solvent in the presence of microwave irradiation and heating resulted in a mixture of aza20 ellipticines and imine cores. Reaction conditions are described in Table 1. Acidconcentration and time were first explored as methods to reduce the formation of the imine product. The greatest increases in yield were obtained when moving to a polar solvent system. Various strength acids as well as Lewis acids were used and trifluoromethanesulfonic acid (TfOH) was selected as TfOH required only sub39 stoichiometric amounts of acid without reducing the reaction time. Reasonable conversion was also seen with hydrochloric acid.

Reference： [1]Current Patent Assignee: MEDICAL UNIVERSITY OF SOUTH CAROLINA - WO2015/179218, 2015, A1 Location in patent: Page/Page column 39; 40; 41

63
[ 3430-10-2 ]
[ 63725-87-1 ]
9-methyl-6-propyl-6H-indolo[2,3-b][1,5]naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluorormethanesulfonic acid In water at 150℃; for 12h;	II.A.F General procedure: Novel aza-ellipticine compounds were prepared using a protic acid in an organic solvent in the presence of microwave irradiation and heating resulted in a mixture of aza20 ellipticines and imine cores. Reaction conditions are described in Table 1. Acidconcentration and time were first explored as methods to reduce the formation of the imine product. The greatest increases in yield were obtained when moving to a polar solvent system. Various strength acids as well as Lewis acids were used and trifluoromethanesulfonic acid (TfOH) was selected as TfOH required only sub39 stoichiometric amounts of acid without reducing the reaction time. Reasonable conversion was also seen with hydrochloric acid.

Reference： [1]Current Patent Assignee: MEDICAL UNIVERSITY OF SOUTH CAROLINA - WO2015/179218, 2015, A1 Location in patent: Page/Page column 39; 40; 41

64
[ 3430-10-2 ]
[ 41042-12-0 ]
6H-indolo[2,3-b][1,5]naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	In water; at 150℃; for 12h;Sealed tube; Microwave irradiation;	General procedure: The aza-ellipticine analogs were produced using the following general reactionmethod. To a clean microwave safe reaction vial equipped with a stir bar was added theappropriate isatin analog (1.0 equiv., 0.2M in H20) and amino-picoline (3.0 equiv.). A concentrated acid like trifluoromethanesulfonic acid, or concentrated hydrochloric acid (0.2 equiv.) was then added. The vial was sealed and heated in a microwave at 150 C for 12 hours. The solvent was then removed using a rotary evaporator and the residuepurified on a Teledyne ISCO chromatography system using a Cl 8 reverse phase support(H20 with 0.1% Formic acid/MeCN gradient) to afford the desired aza-ellipticine analog. A summary of the compounds synthesized can be found in Table 2.The compound was synthesized as shown in Preparative Example B above. Purificationdone using a Teledyne ISCO Combiflash on a silica support using Dichloromethane:Acetonitrile (9:1). HPLC run on Agilent 1100 using water w/ 0.1% Formic acid:Acetonitrile 95:5 to 100% MeCN over a ten minute gradient on phenomenex 75x4.6mm C18 column. Rt: 4.8 minutes.1H-NMR (400 MHz, CD3OD) d 9.01 (s, 1H),8.87 (dd, IH), 8.45 (d, 1H), 8.30 (d, 1H), 7.77 (dd, 1H), 7.58 (m, 2H), 7.35 (dd, 1H). MSChemical Formula: C14H9N3, calculated mass, 219.08, observed 220.1 (M+1).

Reference： [1]Patent: WO2015/179218,2015,A1 .Location in patent: Page/Page column 42; 43; 45

65
[ 3430-10-2 ]
[ 62803-30-9 ]
4-chloro-N-(2-methylpyridin-3-yl)-5-(trimethylsilyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With t-BuBrettPhos; [(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1‘-biphenyl)]palladium(II) methanesulfonate; caesium carbonate In 2-methyltetrahydrofuran at 100℃; for 16h; Inert atmosphere; regioselective reaction;

Reference： [1]Smith, Sean M.; Buchwald, Stephen L. [Organic Letters, 2016, vol. 18, # 9, p. 2180 - 2183]

66
[ 3430-10-2 ]
[ 79-04-9 ]
2-chloro-N-(2-methylpyridin-3-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine In dichloromethane at 20℃; for 5h;
	With triethylamine In dichloromethane at 20℃; for 5h;	General procedure: choloro acetylcholoride (24mmol) and Et3N (24mmol) was added to a solution of 2-chloro-3-aminopyridine 7e (20mmol) in CH2Cl2 (20mL) at room temperature. The mixture was stirred for 5 hrs, and the solvent was evaporated under vacuum. The residue was purified by column chromatography (CH2Cl2:CH3OH: 30:1) on silica gel to obtain pure compound 8e as a white powder in 72% yield. To a solution of amide derivative 8e (5mmol) and potassium carbonate (7.5mmol) in acetonitrile (20ml) was added isothiocyanate (6mmol) during about 5min. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum. The residue was extracted with ethyl acetate (20mL×3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The obtained residue was purified by silica gel flash chromatography column (CH2Cl2:CH3OH: 30:1) to afford 5l as a white solid in 82% yield. To a solution of 5l (1mmol) in glacial acetic acid (5mL) were added aldehyde 6b (1mmol) and β-alanine (1mmol). The resulting mixture was stirred under reflux for 2h. Upon completion of the reaction, the mixture was cooled, the reaction was quenched with water, and the precipitate was filtered off, then the residue was purified by column chromatography (CH2Cl2:CH3OH: 15:1) on silica gel to obtain pure compound 2r as a faint yellow powder in 80% yield.

Reference： [1]Carrasco, Kendall; Casassa, Justine; Collette, Yves; Derviaux, Carine; Hoffer, Laurent; Montersino, Camille; Morelli, Xavier; Pasquier, Eddy; Restouin, Audrey; Roche, Philippe; Saez-Ayala, Magali; Betzi, Stéphane; Castellano, Rémy; Combes, Sébastien [Journal of Medicinal Chemistry, 2022, vol. 65, # 7, p. 5660 - 5674]
[2]Cai, Ming-Guang; Wu, Yang; Chang, Jun [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2517 - 2520]

67
[ 3430-10-2 ]
4-(((4-(tert-butyl)phenyl)sulfonamido)methyl)benzoic acid [ No CAS ]
4-([(4-tert-Butylphenyl)sulfonyl]amino}methyl)-N-(2-methyl-3-pyridinyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 4-(((4-(tert-butyl)phenyl)sulfonamido)methyl)benzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20 - 66℃; for 3h; Stage #2: 2-methyl-3-pyridinamine With pyridine at 20℃; for 16h;	108 Preparation of 4-([(4-tert-butylphenyl)sulfonyl]amino}methyl)-N-(2-methyl-3-pyridinyl)benzamide Oxalylchloride (132 μL, 1.5 mmol) was added dropwise to a stirred suspension ofbenzoic acid 124 (350 mg, 1.0 mmol) and DMF (1 drop) in dry THF (20 mL) and thesolution was stirred at 20° C. for 2 h, then at 66° C. for 1 h. The solutionwas cooled to 20° C., then the solvent was evaporated and the residue dissolvedin dry pyridine (10 mL). 2-Methyl-3-pyridinylamine was added and the solutionstirred at 20° C. for 16 h. The solvent was evaporated and the residuesuspended in ice/water (50 mL) for 1 h. The precipitate was filtered, washedwith water (5 mL) and dried. The crude solid was purified by columnchromatography, eluting with EtOAc, to give benzamide 126 (266 mg, 60%)

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND; STANFORD UNIVERSITY - JP5789603, 2015, B2 Location in patent: Paragraph 0301

68
[ 3430-10-2 ]
5-{(benzyloxy)methyl}isoxazol-3-carboxylic acid [ No CAS ]
N-(2-methylpyridin-3-yl)-5-benzyloxymethylisoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.17 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 3h;	23 5-benzyloxymethyl-- isoxazole-3-carboxylic acid (0.24g, 1.0mmol), 3- amino-2-methylpyridine (0.13g, 1.2mmol), 1- hydroxybenzotriazole (0.01 g, 0.1mmol) was added to the chloroform (amylene addition of goods) (2.5mL). To the mixture, it was added at room temperature 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g, 1.2 mmol), and stirred at room temperature for 3 hours. Then, water was added to the reaction mixture, and the mixture was extracted twice with chloroform. After removing impurities through the organic layer to a short column which was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, represented by the following formula N-(2-methylpyridin-3-yl) -5-benzyloxymethyl - isoxazole-3-carboxamide (hereinafter, the present invention compound (24) referred to.) was obtained 0.17g.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - JP2016/30727, 2016, A Location in patent: Paragraph 0170

69
[ 3430-10-2 ]
5-[(naphthalen-2-yl)methoxy]methyl}isoxazole-3-carboxylic acid [ No CAS ]
N-(2-methylpyridin-3-yl)-5-(2-naphthylmethoxymethyl)isoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.19 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 3h;	48 5- (2-naphthyl methoxymethyl) isoxazole-3-carboxylic acid (0.29g, 1.0mmol), 3- amino-2-methylpyridine (0.13g, 1.2mmol), 1- hydroxybenzotriazole (0 .01g, 0.1mmol) was added to the chloroform (amylene addition of goods) (3.0mL). To the mixture, it was added at room temperature 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g, 1.2 mmol), and stirred at room temperature for 3 hours. Then, water was added to the reaction mixture, and the mixture was extracted twice with chloroform. After removing impurities through the organic layer to a short column which was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, represented by the following formula N-(2-methylpyridin-3-yl) -5- (2-naphthyl methoxymethyl) - isoxazole-3-carboxamide (hereinafter, the present invention compound referred to as (49).) was obtained 0.19g.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - JP2016/30727, 2016, A Location in patent: Paragraph 0195

70
[ 3430-10-2 ]
5-[6-(2-fluorophenyl)pyridin-3-yl]carbamoyl}-2-methoxybenzoic acid [ No CAS ]
N’-[6-(2-fluorophenyl)pyridin-3-yl]-4-methoxy-N3-(2-methylpyridin-3-yl)isophthalamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	25 Example 25N’-[6-(2-fluorophenyl)pyridin-3-yl]-4-methoxy-N3-(2-methylpyridin-3-yl)isophthalamide Under an atmosphere of argon, 50.0 mg (0.14 mmol) of 5-[6-(2-fluorophenyl)pyridin-3- yl]carbamoyl}-2-methoxybenzoic acid (intermediate 23) and 17.7 mg (0.16 mmol) of 2-methylpyridin- 3-amine were dissolved in 3.0 mL of anh DMF. 0.07 mL (0.41 mmol) of N-ethyl-N-isopropylpropan-2-amine and 85.2 mg (0.16 mmol) of PYBOP were added and it was stirred at rt over night. The reactionmixture was concentrated on a rotavap and the residue was purified py HPLC (method 5) affording34 mg of impure material which was further purified by HPLC (Waters XBrigde C18 5ji 100x30mm;water + 0.1% vol. formic acid (99%) / acetonitril gradient; temperature: room temperature; injection:1000 ilL; DAD scan: 210-400 nm) to give 20.8 mg (33% of theory) of the title compound.‘H-NMR (300 MHz, DMSO-d6) 6 [ppm]: 2.263 (0.47), 2.270 (0.61), 2.276 (0.45), 2.539 (2.84), 2.550 (16.00), 2.720 (0.45), 2.726 (0.61), 4.086 (12.26), 7.276 (1.15), 7.292 (1.34), 7.304 (2.32), 7.309 (1.68), 7.314 (1.62), 7.320 (1.67), 7.329 (2.10), 7.334 (2.90), 7.339 (2.96), 7.363 (2.18), 7.417 (2.12), 7.434 (0.99), 7.441 (1.41), 7.447 (2.64), 7.459 (1.43), 7.468 (0.99), 7.480 (0.98), 7.486 (0.87), 7.493 (0.48),7.503 (0.40), 7.814 (1.38), 7.822 (1.45), 7.843 (1.68), 7.851 (1.44), 7.940 (0.93), 7.947 (0.85), 7.966(1.67), 7.973 (1.48), 7.993 (0.91), 8.000 (0.73), 8.160 (1.97), 8.166 (1.78), 8.187 (1.54), 8.193 (1.55),8.223 (1.38), 8.231 (1.48), 8.252 (1.34), 8.260 (1.40), 8.281 (1.77), 8.287 (1.81), 8.297 (1.84), 8.302(1.70), 8.316 (1.87), 8.325 (1.83), 8.345 (1.51), 8.354 (1.55), 8.548 (2.77), 8.557 (2.77), 9.093 (2.87),9.101 (2.87), 9.985 (3.41), 10.663 (3.14).LC-MS (Method 3): R = 1.15 mm; MS (ESIpos): m/z =457 [M+H].

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/131794, 2016, A1 Location in patent: Page/Page column 84

71
[ 3430-10-2 ]
7-(2-chloro-5-methylpyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one [ No CAS ]
7-(5-methyl-2-((2-methylpyridin-3-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo [1,2-a]pyrazin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; caesium carbonate In <i>tert</i>-butyl alcohol at 100℃; for 1h; Inert atmosphere;	14 7-(5-Methyl-2-((2-methylpyridin-3-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2- yl)methyl)-3 ,4-dihydropyrrolo [1 ,2-alpyrazin- 1 (2H)-one 7-(2-Chloro-5 -methylpyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3 ,4- dihydropyrrolo [1 ,2-a]pyrazin- 1 (2H)-one (309 mg, 0.84 mmol), 2-methylpyridin-3 -amine (100 mg, 0.92 mmol) and cesium carbonate (602 mg, 1.85 mmol) were suspended in tBuOH (15 mL) and de-gassed for 5 minutes. BrettPhos 3rd generation pre-catalyst (38.1mg, 0.04 mmol) was added and the reaction was heated to 100 °C for 1 hour. The reactionmixture was filtered through a layer of celite, and washed through with MeOH and DCM.The organic solution was evaporated to dryness and the crude product purified by preparative HPLC (Waters XBridge Prep C18 OBD column, Sji silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to drynessto afford 7-(5 -methyl-2-((2-methylpyridin-3 -yl)amino)pyrimidin-4-yl)-2-((6- methylpyridin-2-yl)methyl)-3 ,4-dihydropyrrolo [1 ,2-a]pyrazin- 1 (2H)-one (73 mg, 20 %) as a solid. ‘H NMR (400 MHz, DMSO, 30 °C) 2.33 (3H, s), 2.46 (3H, s), 2.47 (3H, s), 3.61 -3.91 (3H, m), 4.27 - 4.35 (2H, m), 4.72 (2H, s), 7.13 (2H, dd), 7.17 - 7.26 (2H, m), 7.62 -7.68 (2H, m), 8.03 (1H, dd), 8.17 (1H, dd), 8.22 (1H, s), 8.52 (1H, s). mlz: ES+ [M+H]+440.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2016/162325, 2016, A1 Location in patent: Page/Page column 148; 149

72
[ 3430-10-2 ]
4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2-oxo-1,2-dihydropyrimido[1,2-b]indazole-10-carboxylic acid [ No CAS ]
tert-butyl 4-{10-[(2-methylpyridin-3-yl)carbamoyl]-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl}piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16h;	83A tert-butyl 4-{10-[(2-methylpyridin-3-yl)carbamoyl]-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4- yljpiperidine- 1 -carboxylate To a solution of 4-[l-(tert-butoxycarbonyl)piperidin-4-yl]-2-oxo-l,2-dihydropyrimido[l,2-b]indazole- 10-carboxylic acid (150 mg, 364 μιηο) and 2-methylpyridin-3-amine (59.0 mg, 546 μιηο) in N,N- Dimethylformamide (4.6 ml, 60 mmol) was added N,N-Diisopropylethylamine (190 μ, 1.1 mmol). After addition of l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (166 mg, 436 μιηο) the reaction mixture was stirred at RT for 16 h. Water was added and the resulting precipitate was filtered off. The filtrate was dried in vacuo and the resulting residue filtered and washed with water. Drying in vacuo afforded the product. The obtained amout was 114 mg (97 % purity, 60 % of theory). LC-MS (Method 1): Rt = 0.81 min; MS (ESIpos): m/z = 503 [M+H]+

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/173948, 2016, A1 Location in patent: Page/Page column 119

73
[ 3430-10-2 ]
tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate [ No CAS ]
tert-butyl 4-{10-[(2-methylpyridin-3-yl)amino]-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl}piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; t-BuBrettPhos; [(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1‘-biphenyl)]palladium(II) methanesulfonate In <i>tert</i>-butyl alcohol at 95℃; for 16h; Inert atmosphere;	131A tert-butyl 4-{10 (2-methylpyridin-3-yl)amino]-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4- yljpiperidine- 1 -carboxylate Under argon, tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate (160 mg, 358 μιηο), 2-methylpyridin-3-amine (96.7 mg, 894 μιηο), Tripotassium phosphate (106 mg, 501 μιηο), tBuBrettPhos (10.4 mg, 21.5 μιηο), and tBuBrettPhos Pd G3 (18.3 mg, 21.5 μιηο) were dissolved in tert-Butanol (3.0 ml, 31 mmol). The mixture was stirred at 95 °C for 16 h and then purified via reverse phase chromatography (Method: Reprosil C18; 10 μιη; 125x30 mm / flow: 50 ml/min / solvents: A = water (0,01% formic acid), B = Acetonitrile / gradient 0.00-4.25 min = 20%B, 4.50min = 30%B, 19.00-22.50min = 100%B, 22.75-25.00min = 20%B) which afforded the product after drying in vacuo. The obtained amout was 74.9 mg (66 % purity, 29 % of theory). LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 475 [M+H]+

Reference： [1]Current Patent Assignee: BAYER AG - WO2016/173948, 2016, A1 Location in patent: Page/Page column 150-151

74
[ 3430-10-2 ]
[ 110-15-6 ]
1-(2-methylpyridin-3-yl)pyrrolidine-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	In water at 100℃; for 2h; Green chemistry;	General experimental procedure (1a-1r) General procedure: A solution of succinic acid (10 mmol) and primary amine (10 mmol) were dissolved in water (5.0 mL) in a flask, stirred, and maintained at boiling for the appropriate time. The reaction progress was monitored by TLC (1:1 n-hexane/acetone). After the reaction mixture was cooled to room temperature, the product was filtered and washed with water. It was recrystallized from methanol. The resulting product was identified using FT-IR, NMR spectroscopy, and GC-MS. Compounds of 1a, 1c, 1f, and 1j were reported in literature and fully characterized by spectral analysis.[23-26]

Reference： [1]Bozdoğan, Burcu; Erşatır, Mehmet; Demirkol, Onur; Akbaşlar, Dilek; Giray, E. Sultan [Synthetic Communications, 2017, vol. 47, # 3, p. 217 - 223]

75
[ 3430-10-2 ]
[ 180995-12-4 ]
2-chloro-4-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 50 - 150℃; for 0.583333h;Microwave irradiation; Sealed tube; Inert atmosphere;	To a 10-20 mL microwave vial were added sequentially <strong>[180995-12-4]2,4-dichloropyridine-3-carbonitrile</strong> (429 mg, 1.62 mmol), 2-methylpyridin-3-amine (175 mg, 1.62 mmol), palladium(II) acetate (7.3 mg, 0.032 mmol), bis(2-diphenylphosphinophenyl)ether (26 mg, 0.049 mmol), and CS2CO3(740 mg, 2.27 mmol). The vial was sealed and was evacuated and refilled with argon three times and dioxane (3.2 mL) was added. The vial was evacuated and refilled with argon once. The suspension was heated for 5 minutes in a 50 C oil bath under argon and then the sealed vial was heated for 30 minutes in a 150 C oil bath. The suspension was removed from the heating bath and stored at room temperature overnight. The crude reaction mixture was used directly in the next step
	With palladium diacetate; caesium carbonate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane;Sealed tube; Inert atmosphere; Heating;	To a 10-20 mL microwave vial were added sequentially 2, 4-dichloropyridine-3-carbonitrile (429 mg, 1.62 mmol) , 2-methylpyridin-3-amine (175 mg, 1.62 mmol) , palladium (II) acetate (7.3 mg, 0.032 mmol) , bis (2-diphenylphosphinophenyl) ether (26 mg, 0.049 mmol) , and Cs2CO3(740 mg, 2.27 mmol) . The vial was sealed and was evacuated and refilled with argon three times and dioxane (3.2 mL) was added. The vial was evacuated and refilled with argon once. The suspension was heated for 5 minutes in a 50 oil bath under argon and then the sealed vial was heated for 30 minutes in a 150 oil bath. The suspension was removed from the heating bath and stored at room temperature overnight. The crude reaction mixture was used directly in the next step.

Reference： [1]Patent: WO2017/100668,2017,A1 .Location in patent: Page/Page column 425; 426
[2]Patent: WO2018/103058,2018,A1 .Location in patent: Page/Page column 425-426

76
[ 3430-10-2 ]
[ 51766-21-3 ]
phenyl N-(2-methylpyridin-3-yl)-N'-phenylphosphorodiamidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With N,N'-dimethylpiperazine In tetrahydrofuran at 30 - 50℃; for 4h;	General procedure for the synthesis of title compounds(3a-j) General procedure: Phenyl phenylphosphoramidochloridate (1) (0.001 mol) and 2-amino-benzothiazole (2a) (0.001 mol) were taken in a bottomed flask (50 mL) and THF (20 mL) was added. To thismixture, dimethylpiperazine (DMP) (0.001 mol) was added andthe reaction mixture was stirred vigorously at 30-50 °C for 4 h.The progress of the reaction was monitored by TLC. After completionof the reaction, DMP. HCl was removed by filtration andthe filtrate was concentrated under vacuum and the resultantsolidwas purified by passing through a columnof silica gel usinghexane:ethyl acetate (2:1) as an eluent to afford title compound,phenylN-1,3-benzothiazol-2-yl-N’-phenylphosphorodiamidate(3a). The same experimental procedure was adopted for the preparation of the remaining title compounds (3b-j) (Scheme 1).

Reference： [1]Nayab Rasool; Babu, P. Hari; Janaki Ramudu; Jyothi Kumar; Appa Rao, Ch.; Raju, C. Naga [Phosphorus, Sulfur and Silicon and the Related Elements, 2018, vol. 193, # 1, p. 10 - 13]

77
[ 3430-10-2 ]
[ 72093-03-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogenchloride; nitric acid; trichlorophosphate; In water; at 20 - 25℃;	54g 3-amino-2-methylpyridine was added to 130g of concentrated hydrochloric acid (mass fraction 36-38%).Then pass hydrogen chloride to saturation, and add 222.45g of phosphorus oxychloride and 90g of nitric acid of 70% mass concentration at a temperature of 20-25C. Stir the reaction and control the reaction.57.3 g of 3-chloro-2-methylpyridine was isolated (yield 89%, purity 99%).

Reference： [1]Patent: CN105061300,2018,B .Location in patent: Paragraph 0020; 0021

78
[ 3430-10-2 ]
1-(5-(5-(((5-methylpyridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)piperidine-4-carboxylic acid [ No CAS ]
1-(5-(5-(((5-methylpyridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)-N-(2-methylpyridin-3-yl)piperidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;	1-(5-Bromo-1,3,4-thiadiazol-2-yl)-N-(2-methylcyclohexyl)piperidine-4-carboxamide (4-4) General procedure: A mixture of 4-3 (1 g, 3.4 mmol), 2-methylcyclohexylamine (576 mg, 5.1 mmol), DIPEA (877 mg, 6.8 mmol) and HATU (1.7 g, 4.5 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction was diluted with EtOAc (100 mL) and washed with brine (50 mL*4). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1) to give the title compound as a white solid (1 g, 75%).

Reference： [1]Song, Shiwei; Jiang, Jinyi; Zhao, Li; Wang, Qin; Lu, Wenfeng; Zheng, Chaonan; Zhang, Jie; Ma, Haikuo; Tian, Sheng; Zheng, Jiyue; Luo, Lusong; Li, Youyong; Yang, Zeng-Jie; Zhang, Xiaohu [European Journal of Medicinal Chemistry, 2019, vol. 172, p. 1 - 15]

79
[ 3430-10-2 ]
4-(((4-fluorophenyl)sulfonamido)methyl)benzoic acid [ No CAS ]
4-(((4-fluorophenyl)sulfonamido)methyl)-N-(2-methylpyridin-3-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl acetamide at 20℃; for 24h;	Step 1. To a mixture of 211 (0.62 g, 2.0 mmol), 3-amino-6-methylpyridine (0.25 g, 2.3 mmol), HOBt (0.30 g, 0.22 mmol), and TEA (1 mL) in DMA (5 mL) was added EDCI (0.42 g, 0.22 mmol). After stirring at rt for 24 h, the reaction was quenched with water (100 mL). The resulting precipitate was filtered and recrystallized from CH3CN to give 4-(((4-fluorophenyl)sulfonamido)methyl)-N-(2-methylpyridin-3-yl)benzamide (26) (0.5 g, 63%) as a white solid.

Reference： [1]Wang, Xiaofang; Cal, Monica; Kaiser, Marcel; Buckner, Frederick S.; Lepesheva, Galina I.; Sanford, Austin G.; Wallick, Alexander I.; Davis, Paul H.; Vennerstrom, Jonathan L. [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 1]

80
[ 3430-10-2 ]
(5S)-5-amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ No CAS ]
[ 1005-56-7 ]
(5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(2-methyl-3-pyridyl)carbamothioylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (5S)-5-amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide; phenylcarbonochloridothioate With triethylamine In dichloromethane at 0 - 20℃; Stage #2: 2-methyl-3-pyridinamine In 1,4-dioxane at 80 - 120℃; for 2h;	(5S)-2-(Cvclopropanecarbonylamino)-N-(cvclopropylmethyl)-5-[(2-methyl-3- (2227) Pyridyl)carbamothioylamino]-4,5,6,7-tetrahvdrobenzothiophene-3-carboxamide Phenyl chloromethanethioate [1005-56-7] (91 pL, 0.66 mmol) was stirred in DCM (5 mL) and cooled to 0 °C. Intermediate 117 (200 mg, 0.6 mmol) in DCM (5 mL) and triethylamine (0.25 mL, 1.8 mmol) was added dropwise. The reaction was stirred for 30 minutes at r.t. and the reaction was concentrated in vacuo and the residue dissolved in 1,4-dioxane (5 mL). 2-Methylpyridin-3-amine [3430-10-2] (130 mg, 1.2 mmol) was added and the reaction stirred at 80 °C for 30 minutes followed by heating at 120 °C for 90 minutes. The reaction was diluted with EtOAc (40 mL) and washed with 0.5 M aqueous citric acid solution (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL), dried (Na SC> ), filtered and concentrated in vacuo to give a brown residue. The acidic aqueous phase was basified to pH 9 with saturated aqueous sodium hydrogen carbonate solution and was extracted with EtOAc (2 x 20 mL). The organic phases were combined and concentrated in vacuo. The brown residues were purified by flash column chromatography on silica (gradient elution with 0 - 100 % EtOAc followed by 0 - 10 % MeOH in DCM) to afford the title compound (172 mg, 54%, 91% purity) as a brown oil. LCMS [M+H]+ 484.2, RT 1.668 minutes, 90.5% purity (Method 12).

Reference： [1]Current Patent Assignee: UCB - WO2019/243550, 2019, A1 Location in patent: Page/Page column 208

81
[ 3430-10-2 ]
[ 124-38-9 ]
[ 116286-64-7 ]

Yield	Reaction Conditions	Operation in experiment
48%	With sodium (phenyltrihydroxyborate); phenylsilane In diethylene glycol dimethyl ether at 60℃; for 12h; Sealed tube; Glovebox; Autoclave;

Reference： [1]Du, Chen-Xia; Huang, Zijun; Jiang, Xiaolin; Li, Yuehui; Makha, Mohamed; Wang, Fang; Zhao, Dongmei [Green Chemistry, 2020, vol. 22, # 16, p. 5317 - 5324]

82
[ 3430-10-2 ]
5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-4-isopropyl-1-oxo-1H-isochromen-6-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
C₃₀H₃₀FN₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylaluminum In 1,2-dichloro-ethane; toluene at 0 - 90℃; for 24h; Inert atmosphere;	138 Step A. 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-(5- chloro-3-methyl-1H-pyrazol-4-yl)-7-fluoro-4-isopropylisoquinolin-1(2H)-one. General procedure: To a solution of 5-chloro-3-methyl-4-amino-1H-pyrazole (260 mg, 2.0 mmol) in DCM (3.0 mL) at 0 °C under a N2 atmosphere was added AlMe3 (0.74 mL, 2 M in toluene, 1.5 mmol). The mixture was stirred for 5 min then 5-((benzyloxy)methyl)-4-ethyl-2-(7-fluoro-4-isopropyl-1-oxo-1H-isochromen-6- yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 4, 216 mg, 0.5 mmol) in DCM (1.5 mL) was added. The reaction was slowly warmed to room temperature then heated to 60 °C overnight. The reaction was cooled to 0 °C then carefully quenched by dropwise addition of MeOH followed by water. The organics were extracted with DCM (2x). The combined organics layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude mixture was dissolved in AcOH (1.0 mL) and heated at 90 °C for 24 h. The mixture was then cooled to room temperature and neutralized with K2CO3. The organics were extracted with EtOAc (3x), washed with brine, dried over sodium sulfate, filtered and concentrated. The crude oil was purified by flash column chromatography (SiO2, 50-70% EtOAc/heptane) to afford the title compound as a colorless oil (183 mg, 67% yield over two steps). LCMS (ES-API): mass calcd. for C28H28ClFN6O3, 550.2; m/z found, 551.3 [M+H]+.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC; ZHAN SEN BIOTECHNOLOGY - WO2020/212897, 2020, A1 Location in patent: Page/Page column 75; 145; 146; 238; 239

83
[ 3430-10-2 ]
[ 88-67-5 ]
C₁₃H₁₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 20h; Schlenk technique; Inert atmosphere;	4.3 General procedure for the preparation of compounds General procedure: A mixture of K2CO3 (1.0mmol, 1.0 eq), amine (1.2mmol, 1.2 eq), ortho-iodo benzoic acid (1.0mmol, 1.0 eq) and DMF (2.0mL) and copper powder (0.001mmol, 0.1% eq) were stirred in the schlenk tube for 12h at 100°C under argon condition, and stopped heat and cooled to 25°C. The solid (bottle green) was diluted with water, acidified with 2.0N HCl until pH 2 was adjusted. The black solid was precipitated and filtered. The filter cake was washed with an excess of water to remove the excess amine, dissolved in dichloromethane. The dichloromethan was concentrated by rotary evaporation under reduced pressure and dried over Na2SO4. The crude compounds, o-aminobenzoic acid derivatives, were obtained. Then o-aminobenzoic acid derivatives (1.0 eq), tryptamine (1.0 eq), EDCI·HCl (1.2 eq), HOBT (1.1 eq) were dissolved in dichloromethane (3mL), and Et3N (2.5 eq) was added at room temperature and stirred for 8h. After completion of the reaction detected by TLC, the reaction liquid was concentrated by rotary evaporation under reduced pressure. Then the resulting residue was purified by silica gel flash column chromatography to afford the desired product as a solid and the total yield was 49-95%.

Reference： [1]Fan, Xiaohong; Li, Junfang; Long, Lin; Shi, Tao; Liu, Dan; Tan, Wen; Zhang, Honghua; Wu, Xiaoyan; Lei, Xiaoyong; Wang, Zhen [European Journal of Medicinal Chemistry, 2021, vol. 222]

84
[ 3430-10-2 ]
[ 303776-43-4 ]
4-hydroxy-1-isobutyl-N-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.33%	In dimethyl sulfoxide at 100℃; for 2h;	1 Synthesis of 4-hydroxy- 1 -isobutyl-N-(2-methylpyridin-3 -yl)-2-oxo-l ,2- dihydroquinoline-3 -carboxamide (SSTN-540) To a stirred mixture of ethyl 4-hydroxy- 1 -wobutyl-2-oxo- 1 ,2-dihydroquinoline-3 - carboxylate (1) (200 mg, 0.691 mmol, 1 eq) in DMSO (5 mL), 2-methylpyridin-3 -amine (2) (112.1 mg, 1.03 mmol, 1.5 eq) was added at RT. The reaction mixture was stirred at 100 °C for 2 h. The reaction was monitored by TLC (M.Ph: 20% EtOAc in n-hexane). The reaction mixture was quenched with chilled water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The crude was purified through silica gel column chromatography (elution: 0-20% EtOAc in -hexane) to afford SSTN-540 (71 mg, 29.33%) as an off-white solid. NMR (DMSO-*, 400 MHz): δ 16.42 (s, 1H), 12.69 (s, 1H), 8.39 (d, J= 7.6 Hz, 1H), 8.29 (d, J= 4.4 Hz, 1H), 8.17 (d, J= 8.4 Hz, 1H), 7.86 (t, J= 7.6 Hz, 1H), 7.74 (d, J= (0960) 8.8 Hz, 1H), 7.43 (t, J= 7.2 Hz, 1H), 7.31-7.28 (m, 1H), 4.24 (d, J= 6.8 Hz, 2H), 2.58 (s, 3H), 2.19-2.16 (m, 1H), 0.94 (d, J= 7.2 Hz, 6H); LC-MS: m/z 351.9 [M+H]+; HPLC: 99.41%.
29.33%	In dimethyl sulfoxide at 100℃; for 2h;	1 Synthesis of 4-hydroxy- 1 -isobutyl-N-(2-methylpyridin-3 -yl)-2-oxo-l ,2- dihydroquinoline-3 -carboxamide (SSTN-540) To a stirred mixture of ethyl 4-hydroxy- 1 -wobutyl-2-oxo- 1 ,2-dihydroquinoline-3 - carboxylate (1) (200 mg, 0.691 mmol, 1 eq) in DMSO (5 mL), 2-methylpyridin-3 -amine (2) (112.1 mg, 1.03 mmol, 1.5 eq) was added at RT. The reaction mixture was stirred at 100 °C for 2 h. The reaction was monitored by TLC (M.Ph: 20% EtOAc in n-hexane). The reaction mixture was quenched with chilled water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The crude was purified through silica gel column chromatography (elution: 0-20% EtOAc in -hexane) to afford SSTN-540 (71 mg, 29.33%) as an off-white solid. NMR (DMSO-*, 400 MHz): δ 16.42 (s, 1H), 12.69 (s, 1H), 8.39 (d, J= 7.6 Hz, 1H), 8.29 (d, J= 4.4 Hz, 1H), 8.17 (d, J= 8.4 Hz, 1H), 7.86 (t, J= 7.6 Hz, 1H), 7.74 (d, J= (0960) 8.8 Hz, 1H), 7.43 (t, J= 7.2 Hz, 1H), 7.31-7.28 (m, 1H), 4.24 (d, J= 6.8 Hz, 2H), 2.58 (s, 3H), 2.19-2.16 (m, 1H), 0.94 (d, J= 7.2 Hz, 6H); LC-MS: m/z 351.9 [M+H]+; HPLC: 99.41%.

Reference： [1]Current Patent Assignee: STEMSYNERGY THERAPEUTICS - WO2021/237112, 2021, A1 Location in patent: Page/Page column 0707-0708
[2]Current Patent Assignee: STEMSYNERGY THERAPEUTICS - WO2021/237112, 2021, A1 Location in patent: Page/Page column 0707-0708

85
[ 3430-10-2 ]
2-chloro-4-(oxetan-3-yl)benzonitrile [ No CAS ]
2-((2-methylpyridin-3-yl)amino)-4-(oxetan-3-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃;	2 General procedure II: Hartwig-Buchwald type cross coupling General procedure: previously. To a haloarene nitrile XI dissolved in dioxane (0.1-0.2 M) were added CS2CO3 (3 eq.) followed by amine or aniline (1.5-3 eq.) and the resulting reaction mixture was degassed by bubbling argon through the mixture with sonication. Pd(OAc)2 (0.1 eq.) and a ligand (xantphos or xphos, 0.2 eq.) were added and the reaction mixture heated to 90-100 °C until LCMS showed complete consumption of the starting material XI (0.5 h -16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2S04and concentrated. The crude product X could be purified using flash silica gel chromatography.
	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃;	2 General procedure II: Hartwig-Buchwald type cross coupling General procedure: previously. To a haloarene nitrile XI dissolved in dioxane (0.1-0.2 M) were added CS2CO3 (3 eq.) followed by amine or aniline (1.5-3 eq.) and the resulting reaction mixture was degassed by bubbling argon through the mixture with sonication. Pd(OAc)2 (0.1 eq.) and a ligand (xantphos or xphos, 0.2 eq.) were added and the reaction mixture heated to 90-100 °C until LCMS showed complete consumption of the starting material XI (0.5 h -16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2S04and concentrated. The crude product X could be purified using flash silica gel chromatography.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2021/259815, 2021, A1 Location in patent: Page/Page column 41; 42; 59
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2021/259815, 2021, A1 Location in patent: Page/Page column 41; 42; 59

86
[ 3430-10-2 ]
2-chloro-6-((trans)-2-fluorocyclopropyl)nicotinonitrile [ No CAS ]
6-[(1RS,2SR)-2-fluorocyclopropyl]-2-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; XPhos In 1,4-dioxane at 80℃; Sonication;	3 General procedure Bl: Hartwig-Buchwald type cross coupling General procedure: To a 2-halo-3-nitirle pyridine B dissolved in dioxane (0.1-0.2 M) were added CS2CO3 (3 eq.) followed by amine or aniline (1.5-3 eq.) and the resulting reaction mixture was degassed by bubbling argon through the mixture with sonication. Pd(OAc)2 (0.1 eq.) and a ligand (xantphos or xphos, 0.2 eq.) were added and the reaction mixture heated to 100 °C until LCMS showed complete consumption of the pyridine starting material B (0.5 h -16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2S04and concentrated. The crude product C could be purified using flash silica gel chromatography.
	With palladium diacetate; caesium carbonate; XPhos In 1,4-dioxane at 80℃; Sonication;	3 General procedure Bl: Hartwig-Buchwald type cross coupling General procedure: To a 2-halo-3-nitirle pyridine B dissolved in dioxane (0.1-0.2 M) were added CS2CO3 (3 eq.) followed by amine or aniline (1.5-3 eq.) and the resulting reaction mixture was degassed by bubbling argon through the mixture with sonication. Pd(OAc)2 (0.1 eq.) and a ligand (xantphos or xphos, 0.2 eq.) were added and the reaction mixture heated to 100 °C until LCMS showed complete consumption of the pyridine starting material B (0.5 h -16 h). The reaction was then diluted with EtOAc, washed with brine, dried over Na2S04and concentrated. The crude product C could be purified using flash silica gel chromatography.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2021/259815, 2021, A1 Location in patent: Page/Page column 38; 67
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2021/259815, 2021, A1 Location in patent: Page/Page column 38; 67

87
[ 3430-10-2 ]
6-chloro-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one [ No CAS ]
1-cyclopentyl-3-methyl-6-((2-methylpyridin-3-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; Cs₂CO₃; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane In 1,4-dioxane at 120℃; for 16h; Sealed tube;	70 Example 70: SN39346 1-Cyclopentyl-3-methyl-6-((2-methylpyridin-3-yl)amino)-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2-one (76) A degassed mixture of chloride 6 (125 mg, 0.50 mmol), 2-methylpyridin-3-amine (64 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol) and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 h. The mixture was cooled, diluted with EtOAc (30 mL), filtered through diatomaceous earth and the filtrate was evaporated. The residue was partitioned between EtOAc (50 ml) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give imidazopyridinone 76 (103 mg, 64%) as tan crystals: mp (EtOAc) 144-146 °C; 1H NMR (CDCl3) δ 8.22 (dd, J = 4.8, 1.4 Hz, 1 H, H-6), 7.82-7.86 (m, 2 H, H-4, H-4), 7.14 (dd, J = 8.1, 4.8 Hz, 1 H, H-5), 6.41 (d, J = 0.6 Hz, 1 H, H-7), 6.14 (br s, 1 H, 6-NH), 4.75 (pent, J = 8.8 Hz, 1 H, 1-CH), 3.41 (s, 3 H, 3-CH3), 2.55 (s, 3 H, 2-CH3), 1.95-2.05 (m, 4 H, 2 × CH2), 1.80-1.88 (m, 2 H, CH2), 1.64-1.72 (m, 2 H, CH2); MS m/z 324.2 (MH+, 100%); HRMS calcd for C18H22N5O (MH+) m/z 324.1819, found 324.1819 (-0.1 ppm). HPLC purity 99.7
64%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; Cs₂CO₃; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane In 1,4-dioxane at 120℃; for 16h; Sealed tube;	70 Example 70: SN39346 1-Cyclopentyl-3-methyl-6-((2-methylpyridin-3-yl)amino)-1,3- dihydro-2H-imidazo[4,5-c]pyridin-2-one (76) A degassed mixture of chloride 6 (125 mg, 0.50 mmol), 2-methylpyridin-3-amine (64 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol) and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 h. The mixture was cooled, diluted with EtOAc (30 mL), filtered through diatomaceous earth and the filtrate was evaporated. The residue was partitioned between EtOAc (50 ml) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give imidazopyridinone 76 (103 mg, 64%) as tan crystals: mp (EtOAc) 144-146 °C; 1H NMR (CDCl3) δ 8.22 (dd, J = 4.8, 1.4 Hz, 1 H, H-6), 7.82-7.86 (m, 2 H, H-4, H-4), 7.14 (dd, J = 8.1, 4.8 Hz, 1 H, H-5), 6.41 (d, J = 0.6 Hz, 1 H, H-7), 6.14 (br s, 1 H, 6-NH), 4.75 (pent, J = 8.8 Hz, 1 H, 1-CH), 3.41 (s, 3 H, 3-CH3), 2.55 (s, 3 H, 2-CH3), 1.95-2.05 (m, 4 H, 2 × CH2), 1.80-1.88 (m, 2 H, CH2), 1.64-1.72 (m, 2 H, CH2); MS m/z 324.2 (MH+, 100%); HRMS calcd for C18H22N5O (MH+) m/z 324.1819, found 324.1819 (-0.1 ppm). HPLC purity 99.7

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2022/64430, 2022, A1 Location in patent: Page/Page column 107
[2]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2022/64430, 2022, A1 Location in patent: Page/Page column 107

88
[ 3430-10-2 ]
[ 386704-06-9 ]
2-((2-methylpyridin-3-yl)amino)-6-(trifluoromethyl)-3-cyanopyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.3 g	Stage #1: 2-methyl-3-pyridinamine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 2-chloro-6-(trifluoromethyl)nicotinonitrile In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere;	28.1 Step 1: Synthesis of 2-((2-methylpyridin-3-yl)amino)-6-(trifluoromethyl)-3-cyanopyridine (Intermediate 28-2) Intermediate 28-1 (3.14 g, 29.05 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL) solution at 25 °C, the temperature was lowered to 0 °C, and NaH ( 1.94g, 48.41mmol, 60% effective content), after stirring for 30 minutes, the intermediate 3-1 (5g, 24.21mmol) was dissolved in anhydrous N,N-dimethylformamide (50mL) solution, and then added to the reaction In the system, the reaction solution was stirred for 16 hours at 25°C under nitrogen protection. After the reaction, ethyl acetate (100 mL) and water (200 mL) were added to the reaction solution, extracted twice with ethyl acetate solution (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative column chromatography (0-20% ethyl acetate/petroleum ether, flow rate: 50 mL/min) to give the title compound (4.3 g).

Reference： [1]Current Patent Assignee: JIANGSU SIMCERE PHARM - WO2021/254529, 2021, A1 Location in patent: Page/Page column 39

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	3430-10-2	MDL No. :	MFCD03788195
Formula :	C₆H₈N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZSFPJJJRNUZCEV-UHFFFAOYSA-N
M.W :	108.14	Pubchem ID :	572616
Synonyms :

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.61
TPSA :	38.91 Å²

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) :	-6.55 cm/s

Log Po/w (iLOGP) :	1.14
Log Po/w (XLOGP3) :	0.57
Log Po/w (WLOGP) :	0.98
Log Po/w (MLOGP) :	0.13
Log Po/w (SILICOS-IT) :	1.14
Consensus Log Po/w :	0.79

[ CAS No. 3430-10-2 ] {[proInfo.proName]}

Quality Control of [ 3430-10-2 ]

Related Doc. of [ 3430-10-2 ]

Product Details of [ 3430-10-2 ]

Calculated chemistry of [ 3430-10-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 3430-10-2 ]

Application In Synthesis of [ 3430-10-2 ]

[ 3430-10-2 ] Synthesis Path-Upstream 1~17

[ 3430-10-2 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 3430-10-2 ]

Amines

Related Parent Nucleus of
[ 3430-10-2 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-1.42
Solubility :	4.07 mg/ml ; 0.0376 mol/l
Class :	Very soluble
Log S (Ali) :	-0.96
Solubility :	11.9 mg/ml ; 0.11 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.99
Solubility :	1.11 mg/ml ; 0.0103 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.05

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

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P361	Remove/Take off immediately all contaminated clothing.
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
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P378
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P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 3430-10-2 ] {[proInfo.proName]}

Quality Control of [ 3430-10-2 ]

Related Doc. of [ 3430-10-2 ]

Product Details of [ 3430-10-2 ]

Calculated chemistry of [ 3430-10-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 3430-10-2 ]

Application In Synthesis of [ 3430-10-2 ]

[ 3430-10-2 ] Synthesis Path-Upstream 1~17

[ 3430-10-2 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 3430-10-2 ]

Amines

Related Parent Nucleus of [ 3430-10-2 ]

Pyridines

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Prevention

Response

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Disposal

Physical hazards

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[ 3430-10-2 ]

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[ 3430-10-2 ]