Name: 1237535-76-0|tert-Butyl (4-fluoropyridin-2-yl)carbamate|95%
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[ 1237535-76-0 ]
[ 1237535-77-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78 - -70℃; Stage #2: With iodine In tetrahydrofuran; hexane at -78 - -70℃;	1.2 Step 2 Preparation of tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (method 1) An oven-dried 3-neck round bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel was charged with tert-butyl (4-fluoropyridin-2-yl)carbamate (31.8 g, 150 mmol), TMEDA (56.6 mL, 375 mmol) and THF (200 mL). The solution was cooled to -78° C. and a solution of n-BuLi (2.50 M in hexane, 150 mL, 375 mmol) was added dropwise so that the reaction mixture temperature remained below -70° C. The reaction mixture was stirred at -78° C. for 1 h, and a solution of I2 (95.2 g, 375 mmol) in THF (160 mL) was added via addition funnel. The addition was controlled to keep the reaction mixture temperature below -70° C., and the resulting mixture was stirred at -78° C. for 1 h. A solution of NaHSO4 (61 g, 580 mmol) in water (200 mL) was added to the reaction mixture as it warmed to rt. Ethyl acetate was added and the 2 phase mixture was stirred at rt for 1 h. Water (500 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (3*400 mL), the organic phases were combined, dried over MgSO4, filtered and concentrated to give an off white solid. This solid was suspended in DCM (50 mL) and the solid was isolated by filtration and washed with a minimum of DCM. The filtrate was concentrated and filtered to give a second crop of product. The solids were combined and dried under vacuum to give 45.63 g of a white solid (86% yield). LC/MS: (FA) ES+ 339. 1H NMR (400 MHz, d6 DMSO): δ 9.47 (s, 1H), 8.33-8.30 (m, 1H), 7.20-7.17 (m, 1H), and 1.44 (s, 9H).
86%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 1h;
86%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78 - -70℃; for 1h; Stage #2: With iodine In tetrahydrofuran; hexane at -78 - -70℃; for 1h;	5.18.2 Step 2: tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate Intermediate-27 [00200] An oven-dried 3 -neck round bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel was charged with teri-butyl (4-fluoropyridin-2-yl)carbamate (Int-26, 31.8 g, 150 mmol), TMEDA (56.6 mL, 375 mmol) and THF (200 mL). The solution was cooled to -78 °C and a solution of rt-butyllithium (2.50 M in hexane, 150 mL, 375 mmol) was added dropwise such that the reaction mixture temperature remained below -70 °C. Upon completion of addition, the reaction mixture was stirred at -78 °C for 1 h, and a solution of I2 (95.2 g, 375 mmol) in THF (160 mL) was added via addition funnel. The addition was again controlled to keep the reaction mixture temperature below -70 °C, and the resulting mixture was stirred at -78 °C for 1 h. A solution of NaHSff-DMSO) δ ppm 9.47 (s, 1 H), 8.32 (dd, J = 8.9, 5.5 Hz, 1 H), 7.18 (dd, J = 7.2, 5.5 Hz, 1 H), 1.44 (s, 9 H).

86%	With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane; dichloromethane; water monomer; ethyl acetate	10.2 Step 2: tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate Intermediate 30 An oven-dried 3-neck round bottom flask equipped with an overhead stirrer, temperature probe, and addition funnel was charged with tert-butyl (4-fluoropyridin-2-yl)carbamate (Int-29, 31.8 g, 150 mmol), TMEDA (56.6 mL, 375 mmol) and THF (200 mL). The solution was cooled to -78° C. and a solution of n-butyllithium (2.50 M in hexane, 150 mL, 375 mmol) was added dropwise such that the reaction mixture temperature remained below -70° C. Upon completion of addition, the reaction mixture was stirred at -78° C. for 1 h, and a solution of h (95.2 g, 375 mmol) in THF (160 mL) was added via addition funnel. The addition was again controlled to keep the reaction mixture temperature below -70° C., and the resulting mixture was stirred at -78° C. for 1 h. A solution of NaHSO3 (61 g, 580 mmol) in water (200 mL) was added to the reaction mixture as it warmed to room temperature. Ethyl acetate was added and the biphasic mixture was stirred at room temperature for 1 h. Water (500 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (3*400 mL); the organic phases were combined, dried over magnesium sulfate, filtered and concentrated to give an off-white solid. This solid was suspended in methylene chloride (50 mL), isolated by suction filtration and washed with a minimum of methylene chloride. The filtrate was concentrated and filtered to give a second crop of product. The solids were combined and dried under vacuum to give tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate as a white solid (45.63 g, 86% yield). LC-MS: (FA) ES+ 339. 1H NMR (400 MHz, d6-DMSO) δ ppm 9.47 (s, 1H), 8.32 (dd, J=8.9, 5.5 Hz, 1H), 7.18 (dd, J=7.2, 5.5 Hz, 1H), 1.44 (s, 9H).
77%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane for 0.166667h; Inert atmosphere; Cooling; Stage #2: With sec.-butyllithium In tetrahydrofuran; hexane; cyclohexane at -70℃; for 1h; Inert atmosphere; Stage #3: With iodine In tetrahydrofuran; hexane; cyclohexane at -70 - -65℃; for 0.666667h; Inert atmosphere;	1.2 Step 2 - tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate Tert-butyl N-(4-fluoro-2-pyridyl)carbamate (126g, 593.7mmol) and N,N,N,N- tetramethylethylenediamine (223mL, 1.48mol) were taken up in dry THF (1.7L) and then cooled to -78°C under a nitrogen atmosphere. To this solution was added n-BuLi (2.5M in hexane - 285mL, 712.5mmol) and then allowed to stir for a further 10 minutes. sec-BuLi (1.2M in cyclohexane - 509mL, 712.5mmol) was then added keeping the reaction temperature below -70°C and stirred for 1 hour. After this time, iodine (226g, 890.6mmol) in THF (300mL) was added dropwise over 30 minutes and the temperature kept below -65°C. The reaction was stirred at -70°C for another 10 minutes then quenched by the addition of sat. aq. NH4Cl (400mL) and then a solution of sodium thiosulphate (134.1g, 848.2mmol) dissolved in water (600mL) which raised the temperature to -25°C. The reaction was warmed to rt, transferred to a 5L separator and extracted with EtOAc (2x1.5L) and then washed with brine (500ml). The organic phase was dried over MgSO4and the solvent removed in vacuo. The residue was taken up in DCM (500mL) and passed through a 2Kg silica pad, which was washed with DCM (10x1L) and then the product was eluted from the column using as eluent a gradient 10-100% EtOAc in petroleum ether (1L at each 10% increase) tert-butyl N-(4-fluoro-3-iodo-2- pyridyl)carbamate (154.6g, 457.1mmol, 77% yield) as a white solid. UPLC-MS (ES+, Short acidic): 1.60 min, m/z 339.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ/ppm: 9.47 (1H, s), 8.33 (1H, dd, J = 8.7Hz, 5.5Hz), 7.19 (1H, dd, J = 7.3Hz, 5.5Hz), 1.46 (9H, s).
77%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane for 0.166667h; Inert atmosphere; Cooling; Stage #2: With sec.-butyllithium In tetrahydrofuran; hexane; cyclohexane at -70℃; for 1h; Inert atmosphere; Stage #3: With iodine In tetrahydrofuran; hexane; cyclohexane at -70 - -65℃; for 0.666667h; Inert atmosphere;	1.2 Step 2 - tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate Tert-butyl N-(4-fluoro-2-pyridyl)carbamate (126g, 593.7mmol) and N,N,N,N- tetramethylethylenediamine (223mL, 1.48mol) were taken up in dry THF (1.7L) and then cooled to -78°C under a nitrogen atmosphere. To this solution was added n-BuLi (2.5M in hexane - 285mL, 712.5mmol) and then allowed to stir for a further 10 minutes. sec-BuLi (1.2M in cyclohexane - 509mL, 712.5mmol) was then added keeping the reaction temperature below -70°C and stirred for 1 hour. After this time, iodine (226g, 890.6mmol) in THF (300mL) was added dropwise over 30 minutes and the temperature kept below -65°C. The reaction was stirred at -70°C for another 10 minutes then quenched by the addition of sat. aq. NH4Cl (400mL) and then a solution of sodium thiosulphate (134.1g, 848.2mmol) dissolved in water (600mL) which raised the temperature to -25°C. The reaction was warmed to rt, transferred to a 5L separator and extracted with EtOAc (2x1.5L) and then washed with brine (500ml). The organic phase was dried over MgSO4and the solvent removed in vacuo. The residue was taken up in DCM (500mL) and passed through a 2Kg silica pad, which was washed with DCM (10x1L) and then the product was eluted from the column using as eluent a gradient 10-100% EtOAc in petroleum ether (1L at each 10% increase) tert-butyl N-(4-fluoro-3-iodo-2- pyridyl)carbamate (154.6g, 457.1mmol, 77% yield) as a white solid. UPLC-MS (ES+, Short acidic): 1.60 min, m/z 339.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ/ppm: 9.47 (1H, s), 8.33 (1H, dd, J = 8.7Hz, 5.5Hz), 7.19 (1H, dd, J = 7.3Hz, 5.5Hz), 1.46 (9H, s).
75.2%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -40℃; for 0.233333h; Flow reactor; Large scale; Stage #2: With iodine In tetrahydrofuran; hexane at -55 - -40℃; for 0.233333h; Large scale;	3.B.2; 4. B.2 Step 2 Solutions of (4-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester (12.6 kg, 59.36 mol) and TMEDA (17.78 kg, 153.0 mol) in THF (130 kg, 12 vol.) at 111.4 mL min 1 and n-BuLi (1.6 M in n-hexane) (45.25 kg, 168.8 mol) at 40 mL min-1 were each fed into a flow reactor at - 40 °C. Residency time in this flow reactor was 14 min before the solution entered another flow reactor at -55 to -40 °C. Simultaneously, I2 (26.7 kg, 95.3 mol) in THF (105.3 kg) was fed into this flow reactor at 70 mL min-1. Residency time for the iodination was 14 min at -55 to -40 °C before being adjusted to 0 - 10 °C and being quenched with a feed of 5.0 eq. AcOH in water, for 10 min before being transferred to a separation vessel. (0465) [0455] The organic layer was separated and treated with 2.0 eq. of Na2S2O3 (16.7% in water), and the organic layer was separated and diluted with EtOAc (88.2L) and water (37.8 L). The organics were collected and washed with water (3 x 38.2 kg) and concentrated in vacuo below 30 °C to 50 L. IP Ac (58 kg) was added and the resulting mixture concentrated in vacuo to around 4 vol. This process was repeated to remove residual THF to below 1% and the resulting mixture was stirred at 10 to 25 °C for 3 h, filtered and the filter cake was washed with IP Ac (37 kg). The wet cake was dried at 30-40 °C in vacuo to give the product (4-fluoro-3-iodo-pyridin-2-yl)- carbamic acid tert-butyl ester (15.1 kg, 75.2% yield). LCMS (Method A, ES+): 14.49 min, m/z 282.73 [M-tBu]+.
75.2%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -40℃; for 0.233333h; Flow reactor; Large scale; Stage #2: With iodine In tetrahydrofuran; hexane at -55 - -40℃; for 0.233333h; Large scale;	3.B.2; 4. B.2 Step 2 Solutions of (4-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester (12.6 kg, 59.36 mol) and TMEDA (17.78 kg, 153.0 mol) in THF (130 kg, 12 vol.) at 111.4 mL min 1 and n-BuLi (1.6 M in n-hexane) (45.25 kg, 168.8 mol) at 40 mL min-1 were each fed into a flow reactor at - 40 °C. Residency time in this flow reactor was 14 min before the solution entered another flow reactor at -55 to -40 °C. Simultaneously, I2 (26.7 kg, 95.3 mol) in THF (105.3 kg) was fed into this flow reactor at 70 mL min-1. Residency time for the iodination was 14 min at -55 to -40 °C before being adjusted to 0 - 10 °C and being quenched with a feed of 5.0 eq. AcOH in water, for 10 min before being transferred to a separation vessel. (0465) [0455] The organic layer was separated and treated with 2.0 eq. of Na2S2O3 (16.7% in water), and the organic layer was separated and diluted with EtOAc (88.2L) and water (37.8 L). The organics were collected and washed with water (3 x 38.2 kg) and concentrated in vacuo below 30 °C to 50 L. IP Ac (58 kg) was added and the resulting mixture concentrated in vacuo to around 4 vol. This process was repeated to remove residual THF to below 1% and the resulting mixture was stirred at 10 to 25 °C for 3 h, filtered and the filter cake was washed with IP Ac (37 kg). The wet cake was dried at 30-40 °C in vacuo to give the product (4-fluoro-3-iodo-pyridin-2-yl)- carbamic acid tert-butyl ester (15.1 kg, 75.2% yield). LCMS (Method A, ES+): 14.49 min, m/z 282.73 [M-tBu]+.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2010/197924, 2010, A1 Location in patent: Page/Page column 11
[2]Location in patent: experimental part Gould, Alexandra E.; Adams, Ruth; Adhikari, Sharmila; Aertgeerts, Kathleen; Afroze, Roushan; Blackburn, Christopher; Calderwood, Emily F.; Chau, Ryan; Chouitar, Jouhara; Duffey, Matthew O.; England, Dylan B.; Farrer, Cheryl; Forsyth, Nancy; Garcia, Khristofer; Gaulin, Jeffery; Greenspan, Paul D.; Guo, Ribo; Harrison, Sean J.; Huang, Shih-Chung; Iartchouk, Natalia; Janowik, Dave; Kim, Mi-Sook; Kulkarni, Bheemashankar; Langston, Steven P.; Liu, Jane X.; Ma, Li-Ting; Menon, Saurabh; Mizutani, Hirotake; Paske, Erin; Renou, Christelle C.; Rezaei, Mansoureh; Rowland, R. Scott; Sintchak, Michael D.; Smith, Michael D.; Stroud, Stephen G.; Tregay, Ming; Tian, Yuan; Veiby, Ole P.; Vos, Tricia J.; Vyskocil, Stepan; Williams, Juliet; Xu, Tianlin; Yang, Johnny J.; Yano, Jason; Zeng, Hongbo; Zhang, Dong Mei; Zhang, Qin; Galvin, Katherine M. [Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1836 - 1846]
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2011/146591, 2011, A1 Location in patent: Page/Page column 75-76
[4]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2012/15942, 2012, A1 Location in patent: Page/Page column 54
[5]Current Patent Assignee: JAZZ PHARMACEUTICALS PLC; REDX PHARMA PLC - WO2022/23447, 2022, A2 Location in patent: Paragraph 0241; 0244; 0245
[6]Current Patent Assignee: JAZZ PHARMACEUTICALS PLC; REDX PHARMA PLC - WO2022/23447, 2022, A2 Location in patent: Paragraph 0241; 0244; 0245
[7]Current Patent Assignee: JAZZ PHARMACEUTICALS PLC; REDX PHARMA PLC - WO2022/23450, 2022, A1 Location in patent: Paragraph 0402; 0409; 0411; 0437; 0451; 0454-0455
[8]Current Patent Assignee: JAZZ PHARMACEUTICALS PLC; REDX PHARMA PLC - WO2022/23450, 2022, A1 Location in patent: Paragraph 0402; 0409; 0411; 0437; 0451; 0454-0455

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[ 34941-91-8 ]
[ 4248-19-5 ]
[ 1237535-76-0 ]

Yield	Reaction Conditions	Operation in experiment
79.5%	With sodium hydroxide In 1,4-dioxane; water at 100℃; for 1.5h; Inert atmosphere;	1.1 Example 1; 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one; Step 1 Preparation of tert-butyl (4-fluoropyridin-2-yl)carbamate Palladium acetate (341 mg, 1.52 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.76 g, 3.04 mmol) were added to a 3-necked round bottomed flask, and the flask was purged three times with argon. Degassed 1,4-dioxane (240 mL) was added and the mixture was stirred and degassed again with argon. To this solution was added a solution of 2-chloro-4-fluoropyridine (20 g, 152 mmol) in degassed 1,4-dioxane (120 mL), t-butyl carbamate (19.6 g, 167 mmol), NaOH (8.88 g, 222 mmol) and degassed water (4.0 mL, 222 mmol). The resulting mixture was stirred at 100° C. After 1.5 h, the reaction mixture was cooled to rt and filtered through a pad of Celite. The pad was washed well with dioxane and the filtrate was concentrated under reduced pressure to dryness. The resulting solid was recrystallized from 2-propanol (~250 mL) to give 25.65 g of a pale yellow crystalline solid (79.5% yield). LC/MS: (FA) ES+ 213. 1H NMR (400 MHz, d6 DMSO): δ 10.14 (s, 1H), 8.28-8.25 (m, 1H), 7.62-7.58 (m, 1H), 6.97-6.93 (m, 1H), and 1.47 (s, 9H).
79.5%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 100℃; for 1.5h; Inert atmosphere;
79.5%	With sodium hydroxide In 1,4-dioxane; water at 100℃; for 1.5h; Inert atmosphere;	5.18.1 Example 18: ALhydroxy-6-[(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yl)oxy]quinoline-3- carboxamide Compound 1-26 Step 1: tert-butyl (4-fluoropyridin-2-yl)cai'bamate Intermediate-26 [00199] Palladium(II) acetate (341 mg, 1.52 mmol) and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (1.76 g, 3.04 mmol) were added to a 3-necked round bottomed flask, and the flask was purged three times with argon. Degassed 1,4-dioxane (240 mL) was added and the mixture was stirred and degassed again with argon. To this solution was added a solution of 2-chloro-4-fluoropyridine (20 g, 152 mmol) in degassed 1 ,4-dioxane (120 mL), tert-butyl carbamate (19.6 g, 167 mmol), NaOH (8.88 g, 222 mmol) and degassed water (4 mL, 222 mmol). The resulting mixture was stirred at 100 °C under argon. After 1.5 h, the reaction mixture was cooled to room temperature and filtered through a pad of Celite. The pad was washed well with dioxane and the filtrate was concentrated under reduced pressure to dryness. The resulting solid was recrystallized from 2-propanol (-250 mL) to give tert-butyl (4- fluoropyridin-2-yl)carbamate as a pale yellow crystalline solid (25.65 g, 79.5% yield). LC-MS: (FA) ES+ 213; NMR (400 MHz, t^-DMSO) δ ppm 10.1 (s, 1 H), 8.26 (dd, J = 9.5, 5.6 Hz, 1 H), 7.60 (dd, J = 12.3, 2.3 Hz, 1 H), 6.95 (ddd, J = 8.3, 5.6, 2.3 Hz, 1 H), 1.47 (s, 9 H).

79.5%	With sodium hydroxide In 1,4-dioxane; water at 100℃; for 1.5h; Inert atmosphere;	10.1 Step 1: tert-butyl (4-fluoropyridin-2-yl)carbamate Intermediate 29 Palladium(II) acetate (341 mg, 1.52 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.76 g, 3.04 mmol) were added to a 3-necked round bottomed flask, and the flask was purged three times with argon. Degassed 1,4-dioxane (240 mL) was added and the mixture was stirred and degassed again with argon. To this solution was added a solution of 2-chloro-4-fluoropyridine (20 g, 152 mmol) in degassed 1,4-dioxane (120 mL), tert-butyl carbamate (19.6 g, 167 mmol), NaOH (8.88 g, 222 mmol) and degassed water (4 mL, 222 mmol). The resulting mixture was stirred at 100° C. under argon. After 1.5 h, the reaction mixture was cooled to room temperature and filtered through Celite. The pad was washed well with dioxane and the filtrate was concentrated under reduced pressure to dryness. The resulting solid was recrystallized from 2-propanol (approx. 250 mL) to give tert-butyl (4-fluoropyridin-2-yl)carbamate as a pale yellow crystalline solid (25.65 g, 79.5% yield). LC-MS: (FA) ES+ 213; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.1 (s, 1H), 8.26 (dd, J=9.5, 5.6 Hz, 1H), 7.60 (dd, J=12.3, 2.3 Hz, 1H), 6.95 (ddd, J=8.3, 5.6, 2.3 Hz, 1H), 1.47 (s, 9H).
73.1%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; XPhos In tetrahydrofuran at 80℃; Inert atmosphere;	37.1 Step 1 tert-Butyl (4-fluoropyridin-2-yl) carbamate A solution of dicyclohexyl (2′ 4′ 6′-triisopropyl- [1 1′-biphenyl] -2-yl) phosphine (0.072 g 0.152 mmol) 2-chloro-4-fluoropyridine (1 g 7.60 mmol) tert-butyl carbamate (4.45 g 38.0 mmol) Pd2(dba)3(0.070 g 0.076 mmol) and Cs2CO3(12.39 g 38.0 mmol) in THF (80 mL) was stirred at 80 under N2overnight. After LCMS analysis showed the starting material was disappeared. The mixture was washed with H2O (100 mL) and extracted by EA (100 mL) . The organic layer was dried and concentrated which was purified by column chromatography to give tert-butyl (4-fluoropyridin-2-yl) carbamate (1.3g 5.55 mmol 73.1yield) as a light yellow solid1HNMR(400 MHz CD3OD) δ 8.20-8.16 (m 1H) 7.65 (dd J 12.0 2.4 Hz 1H) 6.81-6.77 (m 1H) 1.52 (s 9H) ES-LCMS m/z 213.1 (M+H) .
40%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 100℃; Inert atmosphere;	1 Step 1: terf-Butyl-(4-fluoropyridin-2-yl)carbamate Palladium (II) acetate (85.3 mg, 0.38 mmol) was added to a solution of 2-chloro-4- fluoropyridine (5 g, 38 mmol), /er/-butyl carbamate (4.9 g, 41.8 mmol), Xantphos (439.9 mg, 0.76 mmol), NaOH (2.28 g, 57.0 mmol), dioxane (30 mL), and H20 (1 mL) at rt. The mixture was degassed with 3 vacuum/N2 cycles, stirred at 100 °C overnight, allowed to cool to rt, and then filtered. The filter cake was washed with EtOAc (10 mL c 3), and the filtrate was concentrated. The residue was partitioned between H20 (100 mL) and EtOAc (100 mL), and the aqueous layer was extracted with EtOAc (100 mL c 2). The combined organic layers were washed with brine (100 mL), dried over Na2S04, and concentrated. 2-Propanol (15 mL) was added to the residue, and the mixture was heated at 80 °C until a clear solution formed. The solution was allowed to cool to rt with moderate agitation. After 14 h, the mixture was filtered. The filter cake was washed with cold z-PrOH (2 mL c 2), and then dried under vacuum to give fer/-butyl-(4-fluoropyridin-2-yl)carbamate (2.5 g, 40%) as a white solid. 1H NMR (400 MHz, CDCl3): d 9.44 (s, 1H), 8.29 (d, 1H), 7.80 (d, 1H), 6.72-6.68 (m, 1H), 1.56 (s, 9H); LCMS: 213.1 [M+H]+
	With caesium carbonate In tetrahydrofuran for 14h; Inert atmosphere; Reflux;	I.A; 75.A To a 2L flask was charged 2-chloro-4-fluoropyridine (20 g, 152 mmol), tert-butyl carbamate (89 g, 760 mmol), tris(dibenzylideneacetone) dipalladium (1.39 g, 1.52 mmol), X-PHOS (2- (dicyclohexylphosphino)-2',4',6'-triisopropyl-l, -biphenyl) (1.48 g, 3.10 mmol), cesium carbonate (99 g, 588 mmol), and tetrahydrofuran (500 mL) under an atmosphere of dry nitrogen. This mixture was heated at reflux under nitrogen for 7 hours. A further 1 equivalent of cesium carbonate was added to drive the reaction to completion (heated a further 7 hours). The mixture was cooled to ambient temperature, filtered through Celite and washed with ethyl acetate. The filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate twice. The combined organic phases were washed with brine and dried with sodium sulfate, concentrated under vacuum, and purified by column chromatography to give tert-butyl 4-fluoropyridin-2-ylcarbamate as a pale yellow solid (22.6 g).
	Stage #1: 2-chloro-4-fluoropyridine; tert-butyl carbazate With caesium carbonate; XPhos In tetrahydrofuran for 14h; Inert atmosphere; Reflux; Stage #2: Saturated solution;	C.A; 64.A Step A: Preparation of tert-butyl 4-fluoropyridin-2-ylcarbamate: A flask was charged with 2-chloro-4-fluoropyridine (20 g, 152 mmol), tert-butyl carbamate (89 g, 760 mmol), tris(dibenzylideneacetone) dipalladium (1.39 g, 1.52 mmol), X-PHOS (1.48 g, 3.10 mmol), cesium carbonate (99 g, 588 mmol), and tetrahydrofuran (500 mL) under an atmosphere of dry nitrogen. The mixture was heated at reflux under nitrogen for 7 hours. A further 1 equivalent of cesium carbonate was added and the reaction was heated a further 7 hours. The mixture was cooled to ambient temperature, filtered through Celite and washed with ethyl acetate. The filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine and dried with sodium sulfate, concentrated under vacuum, and purified by column chromatography to give tert-butyl 4-fluoropyridin-2- ylcarbamate as a pale yellow solid (22.6 g).
206 g	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 100℃; for 2h; Inert atmosphere;	tert-Butyl 4-fluoropyridin-2-ylcarbamate Palladium (II) acetate (1.69 g, 7.53 mmol) and Xantphos (8.71 g, 15.05 mmol) were dissolved/suspended in degassed 1,4-dioxane (1200 mL) in a nitrogen atmosphere.2-Chloro-4-fluoropyridine (99 g, 753 mmol) and tert-butyl carbamate (97 g, 828 mmol) in 1,4-dioxane (550 mL) were added, followed by sodium hydroxide (45.2 g, 1.12 mol) and water (20 mL). The resulting mixture was heated at 100°C for 2 h. The mixture was cooled to ambient temperature and filtered over celite. The residue was washed with 1,4-dioxane and the filtrate was concentrated to afford a yellow solid (206 g). The crude material was recrystallized from 2-propanol (400 mL) and dried to afford the title compound (120.8 g) as a white solid. LCMS 213 [M+H], RT 1.96 minutes, purity 94%.
120.8 g	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 100℃; for 2h; Inert atmosphere;	11 INTERMEDIATE 11 tert-Butyl 4-fluoropyridin-2-ylcarbamate INTERMEDIATE 11tert-Butyl 4-fluoropyridin-2-ylcarbamatePalladium (II) acetate (1.69 g, 7.53 mmol) and Xantphos (8.71 g, 15.05 mmol) were dissolved/suspended in degassed 1,4-dioxane (1200 mL) in a nitrogen atmosphere. 2-Chloro-4-fluoropyridine (99 g, 753 mmol) and tert-butyl carbamate (97 g, 828 mmol) in 1 ,4-dioxane (550 mL) were added, followed by sodium hydroxide (45.2 g, 1.12 mol) and water (20 mL). The resulting mixture was heated at 100°C for 2 h. The mixture wascooled to ambient temperature and filtered over celite. The residue was washed with 1,4- dioxane and the filtrate was concentrated to afford a yellow solid (206 g). The crude material was recrystallized from 2-propanol (400 mL) and dried to afford the title compound(120.8 g) as a white solid. Method B HPLC-MS m/z 213 [M+H], RT 1.96 minutes.
	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 65℃; for 5h; Inert atmosphere; Large scale;
	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 65℃; for 5h; Inert atmosphere;	1.1 Step 1: Synthesis of INTQ-1 1,4-Dioxane (1.5 volumes) was added to a 2L 4-neck round bottom flask, the flask was evacuated and flushed with nitrogen three times. Then Pd(OAc)2 (2wt%, 0.50kg) and XantPhos (9wt%, 2.25kg) were added to the flask, and the flask was evacuated and flushed with nitrogen three times. The mixture was stirred at room temperature for 0.5 to 1 hour under a nitrogen atmosphere. NaOH (12.25kg, 1.6 equivalents), H2O (1 volume, 25L), and 1,4-dioxane (8 volumes, 200L) were added to the 20L reactor. The mixture was stirred until clear, then SM3 (26.75 kg, 1.2 equivalents) was added to the mixture. The catalyst solution was transferred to the above-mentioned reactor under a nitrogen atmosphere. Then SM1 (25.00 kg, 1.0 equivalent) was added dropwise to the reactor. Heat the system to 65±5°C and keep it at 65±5°C for at least 5 hours. HPLC is used to monitor the reaction until the content of SM1 does not exceed 1.0%. The reaction mixture was cooled to 30±5°C, then filtered, and the filter cake was washed with 1,4-dioxane (1.0 volume). H2O (4 volumes) was added to the filtrate and concentrated to 5 volumes. Then H2O (2 volumes) was added to the residue and concentrated to 5 volumes. The residue was cooled to room temperature and filtered. The filter cake was washed with H2O (2 volumes). The filter cake was then slurried with IPA (2 volumes) at 25±5°C for 3 hours. The mixture was filtered and the filter cake was washed with IPA (0.5 volume). The solid was dried in an oven under reduced pressure.
	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 65℃; Inert atmosphere;	1.1 Step 1: Synthesis of INTQ-1 1,4-Dioxane (1.5 volumes) was added to a 2L 4-neck round bottom flask, the flask was evacuated and flushed with nitrogen three times. Then Pd(OAc)2 (2wt%, 0.50kg) and XantPhos (9wt%, 2.25kg) were added to the flask, and the flask was evacuated and flushed with nitrogen three times. The mixture was stirred at room temperature for 0.5 to 1 hour under a nitrogen atmosphere. NaOH (12.25 kg, 1.6 equivalents), H2O (1 volume, 25 L), and 1,4-dioxane (8 volumes, 200 L) were added to the 20 L reactor. The mixture was stirred until clear, then SM3 (26.75 kg, 1.2 equivalents) was added to the mixture. The catalyst solution was transferred to the above-mentioned reactor under a nitrogen atmosphere. Then SM1 (25.00 kg, 1.0 equivalent) was added dropwise to the reactor. Heat the system to 65±5°C and keep it at 65±5°C for at least 5 hours. HPLC is used to monitor the reaction until the content of SM1 does not exceed 1.0%. The reaction mixture was cooled to 30±5°C, then filtered, and the filter cake was washed with 1,4-dioxane (1.0 volume). H2O (4 volumes) was added to the filtrate and concentrated to 5 volumes. Then H2O (2 volumes) was added to the residue and concentrated to 5 volumes. The residue was cooled to room temperature and filtered. The filter cake was washed with H2O (2 volumes). The filter cake was then slurried with IPA (2 volumes) at 25±5°C for 3 hours. The mixture was filtered and the filter cake was washed with IPA (0.5 volume). The solid was dried in an oven under reduced pressure.
	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium hydroxide In 1,4-dioxane; water at 65℃; for 5h; Inert atmosphere; Large scale;	1.1 Step 1: Synthesis of INTQ-1 1,4-Dioxane (1.5 volumes) was added to a 2L 4-neck round bottom flask, the flask was evacuated and flushed with nitrogen three times.Then Pd(OAc)2 (2wt%, 0.50kg) and XantPhos (9wt%, 2.25kg) were added to the flask, and the flask was evacuated and flushed with nitrogen three times.The mixture was stirred at room temperature for 0.5 to 1 hour under a nitrogen atmosphere.NaOH (12.25kg, 1.6 equivalents), H2O (1 volume, 25L), and 1,4-dioxane (8 volumes, 200L) were added to the 20L reactor.The mixture was stirred until clear, then SM3 (26.75 kg, 1.2 equivalents) was added to the mixture. The catalyst solution was transferred to the above-mentioned reactor under a nitrogen atmosphere.Then SM1 (25.00 kg, 1.0 equivalent) was added dropwise to the reactor.Heat the system to 65±5°C and keep it at 65±5°C for at least 5 hours.HPLC is used to monitor the reaction until the content of SM1 does not exceed 1.0%.The reaction mixture was cooled to 30±5°C, then filtered, and the filter cake was washed with 1,4-dioxane (1.0 volume).H2O (4 volumes) was added to the filtrate and concentrated to 5 volumes.Then H2O (2 volumes) was added to the residue and concentrated to 5 volumes.The residue was cooled to room temperature and filtered.The filter cake was washed with H2O (2 volumes).The filter cake was then slurried with IPA (2 volumes) at 25±5°C for 3 hours.The mixture was filtered and the filter cake was washed with IPA (0.5 volume).The solid was dried in an oven under reduced pressure.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2010/197924, 2010, A1 Location in patent: Page/Page column 10-11
[2]Location in patent: experimental part Gould, Alexandra E.; Adams, Ruth; Adhikari, Sharmila; Aertgeerts, Kathleen; Afroze, Roushan; Blackburn, Christopher; Calderwood, Emily F.; Chau, Ryan; Chouitar, Jouhara; Duffey, Matthew O.; England, Dylan B.; Farrer, Cheryl; Forsyth, Nancy; Garcia, Khristofer; Gaulin, Jeffery; Greenspan, Paul D.; Guo, Ribo; Harrison, Sean J.; Huang, Shih-Chung; Iartchouk, Natalia; Janowik, Dave; Kim, Mi-Sook; Kulkarni, Bheemashankar; Langston, Steven P.; Liu, Jane X.; Ma, Li-Ting; Menon, Saurabh; Mizutani, Hirotake; Paske, Erin; Renou, Christelle C.; Rezaei, Mansoureh; Rowland, R. Scott; Sintchak, Michael D.; Smith, Michael D.; Stroud, Stephen G.; Tregay, Ming; Tian, Yuan; Veiby, Ole P.; Vos, Tricia J.; Vyskocil, Stepan; Williams, Juliet; Xu, Tianlin; Yang, Johnny J.; Yano, Jason; Zeng, Hongbo; Zhang, Dong Mei; Zhang, Qin; Galvin, Katherine M. [Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1836 - 1846]
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2011/146591, 2011, A1 Location in patent: Page/Page column 74-75
[4]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2012/15942, 2012, A1 Location in patent: Page/Page column 54
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/37578, 2016, A1 Location in patent: Page/Page column 186
[6]Current Patent Assignee: METACRINE INC - WO2020/61118, 2020, A1 Location in patent: Paragraph 00454
[7]Current Patent Assignee: PFIZER INC - WO2011/79076, 2011, A1 Location in patent: Page/Page column 71; 150
[8]Current Patent Assignee: PFIZER INC - WO2012/82689, 2012, A1 Location in patent: Page/Page column 55; 114-115
[9]Current Patent Assignee: UCB - WO2014/9295, 2014, A1 Location in patent: Page/Page column 134
[10]Current Patent Assignee: UCB - WO2015/86498, 2015, A1 Location in patent: Page/Page column 91
[11]Current Patent Assignee: BEIGENE LTD. - WO2020/151756, 2020, A1 Location in patent: Paragraph 0179-0180
[12]Current Patent Assignee: BEIGENE LTD. - CN111484490, 2020, A Location in patent: Paragraph 0053-0054
[13]Current Patent Assignee: BEIGENE LTD. - CN111484488, 2020, A Location in patent: Paragraph 0059; 0060-0061
[14]Current Patent Assignee: BEIGENE LTD. - CN111484489, 2020, A Location in patent: Paragraph 0069; 0070

3
[ 1237535-76-0 ]
[ 1237535-78-2 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1836 - 1846
[2]Patent: WO2011/146591,2011,A1
[3]Patent: US2012/15942,2012,A1

4
[ 1237535-76-0 ]
[ 944401-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	I.B; 75.B To a 1L flask was added tert- butyl 4-fluoropyridin-2-ylcarbamate (3.5 g, 16.5 mmol) and dichloromethane (100 mL). The mixture was cooled to 0-5°C using an ice/water bath. Trifluoroacetic acid (75 mL) was added slowly with continued stirring. The mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated under vacuum before partitioning between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was washed with ethyl acetate twice. The combined organic phases were washed with brine and dried with sodium sulfate before concentrating under vacuum to give 4-fluoropyridin-2-amine as a pale yellow solid (1.76 g).
	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 0 - 20℃; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate Saturated solution;	C.B; 64.B Step B: Preparation of 4-fluoropyridin-2-amine: A flask was charged with tert-butyl 4-fluoropyridin-2-ylcarbamate (3.5 g, 16.5 mmol) and dichloromethane (100 mL). The mixture was cooled to 0-5°C using an ice/water bath. Trifluoroacetic acid (75 mL) was added slowly with continued stirring. The mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated under vacuum before partitioning between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was washed with ethyl acetate twice. The combined organic phases were washed with brine and dried with sodium sulfate before concentrating under vacuum to give 4-fluoropyridin-2-amine as a pale yellow solid (1.76 g).
65.5 g	With trifluoroacetic acid In dichloromethane at 20℃;	4-Fluoropyridin-2-amine Intermediate 50 (120 g, 565 mmol) was dissolved in DCM (1250 mL) and cooled with an ice bath. Trifluoroacetic acid (250 mL) was added dropwise. The resulting mixture was stirred overnight at ambient temperature. The mixture was concentrated andpartitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried with sodium sulphate, filtered and concentrated, to afford the title compound (65.5 g) as a yellow solid. LCMS 113 [M+H], RT 0.17 minutes.

65.5 g

With trifluoroacetic acid In dichloromethane at 20℃; Cooling with ice;

12 INTERMEDIATE 12 4-Fluoropyridin-2-amine INTERMEDIATE 124-Fluoropyridin-2-amineIntermediate 11 (120 g, 565 mmol) was dissolved in DCM (1250 mL) and cooledwith an ice bath. Trifluoroacetic acid (250 mL) was added dropwise. The resultingmixture was stirred overnight at ambient temperature. The mixture was concentrated and partitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried with sodium sulphate, filtered and concentrated, to afford thetitle compound (65.5 g) as a yellow solid. Method B HPLC-MS m/z 113 [M+H], RT0.17 minutes.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/79076, 2011, A1 Location in patent: Page/Page column 71; 72; 150
[2]Current Patent Assignee: PFIZER INC - WO2012/82689, 2012, A1 Location in patent: Page/Page column 55-56; 115
[3]Current Patent Assignee: UCB - WO2014/9295, 2014, A1 Location in patent: Page/Page column 134
[4]Current Patent Assignee: UCB - WO2015/86498, 2015, A1 Location in patent: Page/Page column 91

5
[ 1237535-76-0 ]
[ 1159827-76-5 ]

Reference： [1]Patent: WO2012/82689,2012,A1
[2]Patent: WO2011/79076,2011,A1

6
[ 1237535-76-0 ]
[ 1350750-76-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N,N,N,N,-tetramethylethylenediamine; n-butyllithium / hexane; tetrahydrofuran / 1 h / -78 - -70 °C 1.2: 1 h / -78 - -70 °C 2.1: N-ethyl-N,N-diisopropylamine / Pd catalyst / N,N-dimethyl-formamide / 5 h / 140 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 4 h / 150 °C / Microwave irradiation; Sealed vial 3.2: pH 3

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2011/146591, 2011, A1

7
[ 1237535-76-0 ]
(S)-7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yloxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N,N,N,-tetramethylethylenediamine; n-butyllithium / dichloromethane; ethyl acetate; hexane; water; tetrahydrofuran 2: N-ethyl-N,N-diisopropylamine / Palladacyle 1 / N,N-dimethyl-formamide / 5 h / 140 °C 3: caesium carbonate / ISOPROPYLAMIDE / 1 h / 150 °C / Microwave irradiation; Sealed vial

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2012/15942, 2012, A1

8
[ 1237535-76-0 ]
C₂₄H₂₉N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N,N,N,-tetramethylethylenediamine; n-butyllithium / dichloromethane; ethyl acetate; hexane; water; tetrahydrofuran 2: N-ethyl-N,N-diisopropylamine / Palladacyle 1 / N,N-dimethyl-formamide / 5 h / 140 °C 3: caesium carbonate / ISOPROPYLAMIDE / 1 h / 150 °C / Microwave irradiation; Sealed vial 4: fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2012/15942, 2012, A1

9
[ 1237535-76-0 ]
[ 944401-69-8 ]

Reference： [1]Patent: WO2014/9295,2014,A1
[2]Patent: WO2015/86498,2015,A1
[3]Patent: WO2016/37578,2016,A1

10
[ 1237535-76-0 ]
4-fluoro-3-(hydroxymethyl)pyridin-2-ylcarbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 - -70 °C 2.1: sodium tetrahydroborate / methanol / 0.5 h / 0 °C
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 - -70 °C / Inert atmosphere 2.1: methanol; sodium tetrahydroborate / 0.5 h / 0 °C
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C

Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2014/206343, 2014, A1
[2]Current Patent Assignee: BEIGENE LTD. - WO2014/206344, 2014, A1
[3]Current Patent Assignee: BEIGENE LTD. - US2015/45355, 2015, A1 Current Patent Assignee: BEIGENE LTD. - TWI640518, 2018, B
[4]Current Patent Assignee: BEIGENE LTD. - CN105348299, 2016, A Current Patent Assignee: BEIGENE LTD. - JP2016/196446, 2016, A

11
[ 1237535-76-0 ]
3-(bromomethyl)-4-fluoropyridin-2-ylcarbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 - -70 °C 2.1: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3.1: carbon tetrabromide; triphenylphosphine / 3 h / 20 °C
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 - -70 °C / Inert atmosphere 2.1: methanol; sodium tetrahydroborate / 0.5 h / 0 °C 3.1: triphenylphosphine; carbon tetrabromide / tetrahydrofuran / 3 h / 20 °C
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 3 h / 20 °C

	Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 3 h / 20 °C
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triphenylphosphine; carbon tetrabromide / tetrahydrofuran / 3 h / 20 °C

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2014/206343, 2014, A1
[2]Current Patent Assignee: BEIGENE LTD. - WO2014/206344, 2014, A1
[3]Current Patent Assignee: BEIGENE LTD. - US2015/45355, 2015, A1
[4]Current Patent Assignee: BEIGENE LTD. - CN105348299, 2016, A Current Patent Assignee: BEIGENE LTD. - JP2016/196446, 2016, A
[5]Current Patent Assignee: BEIGENE LTD. - TWI640518, 2018, B

12
[ 1237535-76-0 ]
5-fluoro-1H-pyrido[2,3-d][1,3]oxazine-2(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 - -70 °C 2.1: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3.1: carbon tetrabromide; triphenylphosphine / 3 h / 20 °C 4.1: dimethyl sulfoxide / 4 h / 60 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 - -70 °C / Inert atmosphere 2.1: methanol; sodium tetrahydroborate / 0.5 h / 0 °C 3.1: triphenylphosphine; carbon tetrabromide / tetrahydrofuran / 3 h / 20 °C 4.1: dimethyl sulfoxide / 4 h / 60 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 3 h / 20 °C 4.1: dimethyl sulfoxide / 4 h / 60 °C / Inert atmosphere

	Multi-step reaction with 4 steps 1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 2: sodium tetrahydroborate / methanol / 0.5 h / 0 °C 3: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 3 h / 20 °C 4: dimethyl sulfoxide / 4 h / 60 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 1.2: -78 °C 2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C 3.1: triphenylphosphine; carbon tetrabromide / tetrahydrofuran / 3 h / 20 °C 4.1: dimethyl sulfoxide / 4 h / 60 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2014/206343, 2014, A1
[2]Current Patent Assignee: BEIGENE LTD. - WO2014/206344, 2014, A1
[3]Current Patent Assignee: BEIGENE LTD. - US2015/45355, 2015, A1
[4]Current Patent Assignee: BEIGENE LTD. - CN105348299, 2016, A Current Patent Assignee: BEIGENE LTD. - JP2016/196446, 2016, A
[5]Current Patent Assignee: BEIGENE LTD. - TWI640518, 2018, B

13
[ 1237535-76-0 ]
[ 33513-42-7 ]
(4-fluoro-3-formylpyridin-2-yl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃;	3.A Step A: tert-butyl (4-fluoro-3-formylpyridin-2-yl)carbamate To a stirred solution of tert-butyl 4-fluoropyridin-2-ylcarbamate (1 g, 4.72 mmol) in THF (20 mL) was added dropwise n-BuLi (4.7 mL, 11.8 mmol) at -78° C. After stirring for 0.5 h, a solution of DMF (2 mL) in THF (2 mL) was added dropwise at -78° C. TLC indicated the reaction was completed. The reaction was quenched with 1N HCl at -78° C. to pH=4. Then water (20 mL) was added and extracted with ethyl acetate (3*20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE=1:2) to give the title compound (0.65 g, 57%) as a white solid. 1H-NMR (600 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.99 (s, 1H), 8.58-8.56 (m, 1H), 7.23-7.21 (m, 1H), 1.46 (s, 9H) ppm.
57%	With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h;	3.A Example 3: Synthesis of compounds 3.1-3.8 Step A: (4-fluoro-3-formylpyridin-2-yl)carbamic acid tert-butyl ester Example 3: Synthesis of compounds 3.1-3.8 Step A: (4-fluoro-3-formylpyridin-2-yl)carbamic acid tert-butyl ester Stirring at -78°C, 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester (1g, 4.72mmol) in THF (20mL) was added dropwise n-BuLi (4.7mL, 11.8mmol). DMF (2mL) in THF (2mL) was added dropwise. After stirring for 0.5 hours at -78°C, TLC showed the reaction was complete. The reaction was quenched with 1N HCl to pH = 4. Water (20 mL) was added and extracted with ethyl acetate (3 × 20mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by column chromatography (ethyl acetate: petroleum ether = 1: 2) to give the title compound as a white solid (0.65g, 57%).
57%	With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h;	3.A tert-butyl (4-fluoro-3-formylpyridin-2-yl)carbamate To a stirred solution of tert-butyl 4-fluoropyridin-2-ylcarbamate (1 g, 4.72 mmol) in THF (20 mL) was added dropwise n-BuLi (4.7 mL, 11.8 mmol) at -78° C. After stirring for 0.5 h, a solution of DMF (2 mL) in THF (2 mL) was added dropwise at -78° C. TLC indicated the reaction was completed. The reaction was quenched with 1N HCl at -78° C. to pH=4. Then water (20 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE=1:2) to give the title compound (0.65 g, 57%) as a white solid.

57%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃;	3 Step A: tert-butyl N-(4-fluoro-3-(hydroxymethyl)pyridin-2-yl)carbamate Under stirring at -78°C, n-BuLi (4.7 mL, 11.8 mmol) was added dropwise to a THF (20 mL) solution of tert-butyl N-(4-fluoropyridin-2-yl)carbamate (1 g, 4.72 mmol). After stirring for 0.5 hour, a solution of DMF (2 mL) in THF (2 mL) was added dropwise at -78°C. TLC showed that the reaction was complete. The reaction was quenched with 1N HCl at -78°C to pH=4. Then water (20 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.The obtained residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain the target compound (0.65 g, 57%) as a white solid.
45%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78 - -70℃; for 1.5h; Inert atmosphere;	2.A Step A: tert-butyl (4-fluoro-3-formylpyridin-2-yl)carbamate To a solution of tert-butyl (4-fluoropyridin-2-yl)carbamate ( 10.0 g, 47.12 mmol ) in 100 mL of tetrahydrofuran was added dropwise 49 mL of n-Butyllithium ( 2.4 M, 117.80 mmol) at -78 °C under N2. The mixture was stirred for 1 hour at -78 °C. Then DMF (6.88 g, 94.24 mmol) was added dropwise at -78 °C in 0.5 hour. The mixture was stirred at -70 °C for 1 hour (monitored by TLC) and quenched by 2N HC1 (100 mL) at -60 °C. Make sure the pH of mixture solution was under 6 .Then the solution was warmed to rt, washed by water (200 mL), extracted with EtOAc (100 mL><3). The combined organic phase was dried over Na2S04, concentrated and purified by silica gel column chromatography ( eluting with PE:EA = 1 : 1 ) to get the title compound (5.0, yield: 45%) as a white solid. 1H NMR (400 MHz, CDC13) δ 10.54 (s, 1H), 10.37 (s, 1H), 8.62 (dd, J= 8.4, 5.6 Hz, 1H), 6.80 (dd, J= 10.0, 5.6 Hz, 1H), 1.55 (s, 9H).
	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78 - -70℃; for 1.5h;	2.4.A tert-butyl (4-fluoro-3 -formylpyridin-2-yl)carbamate To a solution of tert-butyl (4-fluoropyridin-2-yl)carbamate (20.0 g, 94.24 mmol ) in 200mL of tetrahydrofuran was added dropwise 98 mL of n-Butyllithium (2.4 M, 235.60 mmol) at -78 °C under N2. The mixture was stirred for 1 hour at -78 °C. Then DMF (13.7 g, 188.48 mmol) was added dropwise at -78 °C in 0.5 hour. The mixture was stirred at -70 °C for 1 hour(monitored by TLC) and quenched by HOAc (25.44 g, 424.08 mmol) at -60 °C. Make sure the pH of mixture solution was under 6 .Then the solution was warmed to rt, washed by water (200mL), extracted with EtOAc (100 mLx3). The combined organic phases were dried over Na2504, concentrated and purified by silica gel column chromatography (eluting with PE:EA = 1:1) to get the title compound (3.2, yield: 14%) as a white solid. ‘H NMR (400 MHz, CDC13) 10.54 (s, 1H), 10.37 (s, 1H), 8.62 (dd, J= 8.4, 5.6 Hz, 1H), 6.80 (dd, J= 10.0, 5.6 Hz, 1H), 1.55 (s, 9H).
	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran; hexane at -80 - -70℃; Large scale; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -80 - -70℃; Large scale;
	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran; hexane at -80 - -70℃; Stage #2: N,N-dimethyl-formamide With acetic acid In tetrahydrofuran at -80 - -70℃;	1.2; 1.3 Steps 2 and 3: Synthesis of INTQ-3 THF (25 volumes) and INTQ-1 (16.00 kg, 1.0 equivalent) were added to the reactor. The mixture was stirred and cooled to -80 ~ -70°C. Then n-BuLi (n-hexane solution, 2.5M, 51.20kg, 2.5 equivalents) was added dropwise to the mixture at -80-70°C. After reacting at -80 to -70°C for 1-2 hours, the reaction was monitored by TLC. Then, a solution of DMF (9.92 kg, 1.8 equivalents) in THF (1.4 volumes) was added dropwise to the reaction system at -80 to -70°C. After reacting at -80 to -70°C for 1-2 hours, the reaction was monitored by TLC. A solution of AcOH in THF (1.4 volumes) was added dropwise to the mixture at -80~-70°C to adjust the pH to 6-7. Then TEA (8.00 kg, 1.05 equivalent) was added to the reaction at -80 ~ -70°C. A solution of methyltriphenylphosphoranylidene acetate (26.4 kg, 1.05 equivalent) in DCM (19 volumes) was added dropwise to the reaction mixture. The mixture was stirred at -80 to -70°C for 10 hours, and then the reaction was monitored by TLC. H2O (10.5 volume) and citric acid (32.00 kg, 2.1 equivalents) were added to another reactor. The mixture was stirred to dissolve and cooled to 0-5°C. The temperature was cooled to -20°C and the solution was transferred to the above 3L 4-neck round bottom flask. Then the mixture was stirred at 20°C or less for 1 hour, and the pH value was confirmed to be between 4-7. The organic layer was separated and washed with 25% NaCl (17 vol). The organic phase was then concentrated to 5 volumes and EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes. EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes. This solution was used directly in the next step.
	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran; hexane at -80 - -70℃; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -80 - -70℃;	1.2 Steps 2 and 3: Synthesis of INTQ-3 THF (25 volumes) and INTQ-1 (16.00 kg, 1.0 equivalent) were added to the reactor. The mixture was stirred and cooled to -80 ~ -70°C. Then n-BuLi (n-hexane solution, 2.5M, 51.20kg, 2.5 equivalents) was added dropwise to the mixture at -80-70°C. After reacting at -80 to -70°C for 1-2 hours, the reaction was monitored by TLC. Then, a solution of DMF (9.92 kg, 1.8 equivalents) in THF (1.4 volumes) was added dropwise to the reaction system at -80 to -70°C. After reacting at -80 to -70°C for 1-2 hours, the reaction was monitored by TLC. A solution of AcOH in THF (1.4 volumes) was added dropwise to the mixture at -80~-70°C to adjust the pH to 6-7. Then TEA (8.00 kg, 1.05 equivalent) was added to the reaction at -80 to -70°C. A solution of methyltriphenylphosphoranylidene acetate (26.4 kg, 1.05 equivalents) in DCM (19 volumes) was added dropwise to the reaction mixture. The mixture was stirred at -80 to -70°C for 10 hours, and then the reaction was monitored by TLC. H2O (10.5 volume) and citric acid (32.00 kg, 2.1 equivalents) were added to another reactor. The mixture was stirred to dissolve and cooled to 0-5°C. The temperature was cooled to -20°C and the solution was transferred to the above 3L 4-neck round bottom flask. The mixture was then stirred below 20°C for 1 hour, and the pH was confirmed to be between 4-7. The organic layer was separated and washed with 25% NaCl (17 volumes). The organic phase was then concentrated to 5 volumes and EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes. EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes. This solution was used directly in the next step.
	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With n-butyllithium In tetrahydrofuran; hexane at -80 - -70℃; Large scale; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -80 - -70℃; Large scale; Stage #3: With acetic acid In tetrahydrofuran; hexane at -80 - -70℃; Large scale;	1.2; 1.3 Steps 2 and 3: Synthesis of INTQ-3 THF (25 volumes) and INTQ-1 (16.00 kg, 1.0 equivalent) were added to the reactor. The mixture was stirred and cooled to -80 ~ -70°C.Then n-BuLi (n-hexane solution, 2.5M, 51.20kg, 2.5 equivalents) was added dropwise to the mixture at -80-70°C.After reacting at -80 to -70°C for 1-2 hours, the reaction was monitored by TLC.Then, a solution of DMF (9.92 kg, 1.8 equivalents) in THF (1.4 volumes) was added dropwise to the reaction system at -80 to -70°C.After reacting at -80 to -70°C for 1-2 hours, the reaction was monitored by TLC.A solution of AcOH in THF (1.4 volumes) was added dropwise to the mixture at -80~-70°C to adjust the pH to 6~7.Then TEA (8.00 kg, 1.05 equivalent) was added to the reaction at -80 ~ -70°C.A solution of methyltriphenylphosphoranylidene acetate (26.4 kg, 1.05 equivalent) in DCM (19 volumes) was added dropwise to the reaction mixture.The mixture was stirred at -80 to -70°C for 10 hours, and then the reaction was monitored by TLC.H2O (10.5 volume) and citric acid (32.00 kg, 2.1 equivalents) were added to another reactor.The mixture was stirred to dissolve and cooled to 0-5°C.The temperature was cooled to -20°C and the solution was transferred to the above 3L 4-neck round bottom flask.Then, the mixture was stirred below 20°C for 1 hour to confirm that the pH value was between 4-7.The organic layer was separated and washed with 25% NaCl (17 vol).The organic phase was then concentrated to 5 volumes and EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes.EtOAc (17 volumes) was added to the mixture and concentrated to 5 volumes.This solution was used directly in the next step.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - US2015/45355, 2015, A1 Location in patent: Paragraph 0470-0472
[2]Current Patent Assignee: BEIGENE LTD. - CN105348299, 2016, A Location in patent: Paragraph 0619; 0705; 0706; 0707; 0708; 0709
[3]Current Patent Assignee: BEIGENE LTD. - JP2016/196446, 2016, A Location in patent: Paragraph 0266; 0267
[4]Current Patent Assignee: BEIGENE LTD. - TWI640518, 2018, B Location in patent: Paragraph 0375; 0431-0433
[5]Current Patent Assignee: BEIGENE LTD. - WO2014/206344, 2014, A1 Location in patent: Page/Page column 149
[6]Current Patent Assignee: BEIGENE LTD. - WO2014/206343, 2014, A1 Location in patent: Page/Page column 94; 95
[7]Current Patent Assignee: BEIGENE LTD. - WO2020/151756, 2020, A1 Location in patent: Paragraph 0179; 0181-0182
[8]Current Patent Assignee: BEIGENE LTD. - CN111484490, 2020, A Location in patent: Paragraph 0053; 0055-0056
[9]Current Patent Assignee: BEIGENE LTD. - CN111484488, 2020, A Location in patent: Paragraph 0059; 0062-0063
[10]Current Patent Assignee: BEIGENE LTD. - CN111484489, 2020, A Location in patent: Paragraph 0069; 0071; 0072

14
[ 1237535-76-0 ]
[ 1446091-43-5 ]
(1S,1aS,6bR)-ethyl-5-((2-aminopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;	2.14.A Step A: (1S,1 aS,6bR)-ethyls-((2-aminopyridin-4-yl)oxy)- 1 a,6b-dihydro- 1H- cyclopropa[b]benzofuran- 1 -carboxylate The mixture of (1 S,1 aS, 6bR)-ethyl 5 -hydroxy- 1 a, 6b-dihydro- 1 H-cyclopropa [b]benzofuran1-carboxylate (the product of Step Gin synthesis of Compound 1.1, 2.2 g, 10 mmol), tert-butyl (4-fluoropyridin-2-yl)carbamate (2.1 g, 10 mmol) and cesium carbonate (6.5 g, 20 mmol) in DMF (50 mL) was stirred at 100 °C for 2 hours. The reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was diluted with EA (300 mL), washed with brine (100 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica weight: 20 g,petroleum ether/EA: 2/3, 1500 mL) to give the target compound (1.0 g, 30%) as brown oil. ‘HNMR (400 IVIFIz, DMSO-d6) 7.83 (d, J= 6.0 Hz, 1H), 7.37 (d, J= 2.4 Hz, 1H), 7.08 - 6.96 (m,2H), 6.16 (dd, J= 6.0, 2.4 Hz, 1H), 5.95 (s, 2H), 5.81 (d, J 2.4 Hz, 1H), 5.35 (dd, J 5.2, 1.2Hz, 1H), 4.17 (q, J= 7.2 Hz, 2H), 3.44 (dd, J 5.2, 3.2 Hz, 1H), 1.39 (dd, J 3.2, 1.2 Hz, 1H),1.27 (t, J= 7.2 Hz, 3H)ppm.
30%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;	2.A Step A: (l S, laS,6bR)-ethyl 5-((2-aminopyridin-4-yl)oxy)-la,6b-dihydi cyclopropa[b]benzofuran- 1 -carboxylate The mixture of (l S, laS,6bR)-ethyl 5-hydroxy-la,6b-dihydro-lH-cyclopropa [b]benzofuran-l-carboxylate (the product of Step G in synthesis of the product obtained from Step G in synthesis of Intermediate I (2.2 g, 10 mmol), tert-butyl (4-fluoropyridin-2- yl)carbamate (2.1 g, 10 mmol) and cesium carbonate (6.5 g, 20 mmol) in DMF (50 mL) was stirred at 100 °C for 2 hours. The reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was diluted with EA (300 mL), washed with brine (100 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica weight: 20 g, eluted with petroleum ether/EA: 2/3, 1500 mL) to give the target compound (1.0 g, 30%) as brown oil. 1H MR (400 MHz, DMSO-^6) δ 7.83 (d, J= 6.0 Hz, 1H), 7.37 (d, J= 2.4 Hz, 1H), 7.08 - 6.96 (m, 2H), 6.16 (dd, J= 6.0, 2.4 Hz, 1H), 5.95 (s, 2H), 5.81 (d, J= 2.4 Hz, 1H), 5.35 (dd, J = 5.2, 1.2 Hz, 1H), 4.17 (q, J= 7.2 Hz, 2H), 3.44 (dd, J= 5.2, 3.2 Hz, 1H), 1.39 (dd, J= 3.2, 1.2 Hz, 1H), 1.27 (t, J= 7.2 Hz, 3H)ppm.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2014/206343, 2014, A1 Location in patent: Page/Page column 109
[2]Current Patent Assignee: BEIGENE LTD. - WO2014/206344, 2014, A1 Location in patent: Page/Page column 145; 146

15
[ 1237535-76-0 ]
[ 947249-20-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride In methanol at 25℃;	37.2 Step 2 4-Fluoropyridin-2-amine A solution of tert-butyl (4-fluoropyridin-2-yl) carbamate (0.7 g 3.30 mmol) in HCl in MeOH (50 mL 200 mmol) was stirred at 25 . After TLC analysis showed the starting material was disappeared. The solvent was removed in vacuo to yield a solid of 4-fluoropyridin-2-amine hydrochloride (0.5 g 3.20 mmol 97yield) 1HNMR(400 MHz CD3OD) δ 7.96 (t J 6.6 Hz 1H) 6.83-6.78 (m 1H) 6.74-6.71 (m 1H) ES-LCMS m/z 134.9 (M+Na)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/37578, 2016, A1 Location in patent: Page/Page column 186

16
[ 1237535-76-0 ]
[ 74-88-4 ]
(4-fluoro-3-methylpyridin-2-yl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.6%	Stage #1: 4-fluoropyridin-2-ylcarbamic acid tert-butyl ester With N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #3: methyl iodide In tetrahydrofuran at -78 - 20℃; for 2.5h;	1.1; 2; 3; 4 Preparation of Compound 2 Add 40 g of 188.48 mmol of compound 1 to 600 ml of anhydrous THF,Add 52.4 g of 450.7 mmol of tetramethylethylenediamine, protect with argon,Minus 78 degrees Celsius for 30min,Then, 226.2 ml of 2.5M 565.4 mmol of n-butyl lithium was added dropwise,Reaction at minus 78 degrees Celsius for 1 h, and then 80.3 g of 565.4 mmol of methyl iodide was added dropwise.The reaction was carried out at minus 78 degrees Celsius for 30 minutes, and the temperature was raised to 25 degrees Celsius, followed by RT reaction for 2 hours.Washed into saturated ammonium chloride, EA extraction,Dry and spin-drying to obtain 25g of compound 2,The yield was 58.6%.

Reference： [1]Current Patent Assignee: BIDE PHARMATECH - CN110386897, 2019, A Location in patent: Paragraph 0041-0055

17
[ 1237535-76-0 ]
[ 196413-11-3 ]
4-(4-isopropyl-1H-imidazol-1-yl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 20 - 140℃;	4-(4-Isopropyl-Li/-imidazol-l-yl)pyridin-2-amine Potassium carbonate (15.68 g, 1 13.47 mmol) was added to a solution of 4- isopropyl-liT-imidazole (5 g, 45.39 mmol), Intermediate 8 (Step 1) (19.27 g, 90.78 mmol), and NMP (50 mL) at rt. The mixture was stirred at 140 °C overnight, allowed to cool to rt, poured into H20 (200 mL), and then extracted with EtOAc (5 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered, and then concentrated. The crude material was purified by silica gel chromatography (EtOH/EtOAc = 30/70) to give impure material, which was further purified by reverse-phase HPLC (water (0.05% HC1) -CELCN), and then triturated in MTBE (10 mL) at rt overnight. The mixture was filtered with cold MTBE washes (2 ^ 2 mL) and then dried under reduced pressure to give 4-(4-isopropyl-liT-imidazol-l-yl)pyridin-2-amine (600 mg, 9%) as a white solid. 1H NMR (400MHz, DMSO-r): d 8.17 (d, 1H), 7.95 (d, 1H), 7.36 (s, 1H), 6.79 (d, 1H), 6.58 (d, 1H), 6.10 (s, 2H), 2.88-2.72 (m, 1H), 1.21 (d, 6H); LCMS: 203.1 [M+H]+.

Reference： [1]Current Patent Assignee: METACRINE INC - WO2020/61118, 2020, A1 Location in patent: Paragraph 00522

18
[ 2075-45-8 ]
[ 1237535-76-0 ]
tert-butyl (4-(4-bromo-1H-pyrazol-1-yl)pyridin-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 2h; Inert atmosphere;	1 (1154) Step 1: tert- Butyl (4-(4-bromo-l -pyrazol-l-yl)pyridin-2-yl)carbamate A mixture of 4-bromo-lif-pyrazole (5 g, 34.02 mmol), Intermediate 8 (Step 1) (7.22 g, 34.02 mmol), K2C03 (7.05 g, 51.03 mmol), and NMP (50 mL) was degassed with 3 vacuum/N2 cycles, stirred at 100 °C for 2 h, allowed to cool to rt, and then poured into H20 (150 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2S04, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc = 70/30) to give tert- butyl (4- (4-bromo-lif-pyrazol-l-yl)pyridin-2-yl)carbamate (6 g, 52%) as a white solid. LCMS: 339.1 [M+H]+.

Reference： [1]Current Patent Assignee: METACRINE INC - WO2020/61118, 2020, A1 Location in patent: Paragraph 00523

19
[ 1211390-33-8 ]
[ 1237535-76-0 ]
tert-butyl-(4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)pyridin-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; Inert atmosphere;	2 Step 2 : fe/7-Butyl-(4-(3-cyclopropyl- 1 H- 1 ,2,4-triazol- l-yl)pyridin-2-yl)carbamate A mixture of /c/V-butyl - (4 -fl uoropyri di n-2-yl )carb am ate (2 g, 9.42 mmol), 3- cyclopropyl-liT-l, 2, 4-triazole (1.03 g, 9.42 mmol), K2C03 (1.95 g, 14.1 mmol), and NMP (25 mL) were degassed with 3 vacuum/N2 cycles, stirred at 100 °C overnight, allowed to cool to rt, poured into water (60 mL), and then extracted with CH2Cl2 (60 mL x 3). The combined organic layers were washed with aqueous LiCl (1 M, 100 mL), dried over Na2S04, filtered, and concentrated to give /c/V-butyl-(4-fl uoropyri din-2-yl (carba ate (2 g, crude) as a white solid. LCMS: 302.4 [M+H]+

Reference： [1]Current Patent Assignee: METACRINE INC - WO2020/61118, 2020, A1 Location in patent: Paragraph 00455

20
[ 1237535-76-0 ]
C₁₄H₁₇FN₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C / Large scale 1.2: -80 - -70 °C / Large scale 2.1: triethylamine / tetrahydrofuran; dichloromethane / 10 h / -80 - -70 °C / Large scale
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C 1.2: -80 - -70 °C / pH 6 - 7 2.1: triethylamine / dichloromethane / 10 h / -80 - -70 °C
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C 1.2: -80 - -70 °C 2.1: triethylamine / dichloromethane / 10 h / -80 - -70 °C

Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C / Large scale 1.2: -80 - -70 °C / Large scale 1.3: -80 - -70 °C / pH 6 - 7 / Large scale 2.1: triethylamine / dichloromethane / 10 h / -80 - -70 °C / Large scale 2.2: 1 h / -20 - 20 °C / pH 4 - 7 / Large scale

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2020/151756, 2020, A1
[2]Current Patent Assignee: BEIGENE LTD. - CN111484490, 2020, A
[3]Current Patent Assignee: BEIGENE LTD. - CN111484488, 2020, A
[4]Current Patent Assignee: BEIGENE LTD. - CN111484489, 2020, A

21
[ 1237535-76-0 ]
C₉H₉FN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C 1.2: -80 - -70 °C / pH 6 - 7 2.1: triethylamine / dichloromethane / 10 h / -80 - -70 °C 3.1: hydrogenchloride / 7 h / -5 - 30 °C / Large scale
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C 1.2: -80 - -70 °C 2.1: triethylamine / dichloromethane / 10 h / -80 - -70 °C 3.1: hydrogenchloride / water; ethyl acetate / 7 h / -5 - 30 °C / Large scale
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C / Large scale 1.2: -80 - -70 °C / Large scale 2.1: triethylamine / tetrahydrofuran; dichloromethane / 10 h / -80 - -70 °C / Large scale 3.1: hydrogenchloride / water; ethyl acetate / 7 h / -5 - 30 °C / Large scale

Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -80 - -70 °C / Large scale 1.2: -80 - -70 °C / Large scale 1.3: -80 - -70 °C / pH 6 - 7 / Large scale 2.1: triethylamine / dichloromethane / 10 h / -80 - -70 °C / Large scale 2.2: 1 h / -20 - 20 °C / pH 4 - 7 / Large scale 3.1: hydrogenchloride / ethyl acetate / 7 h / -5 - 30 °C / Large scale