Name: 203866-14-2|(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid|97%
Brand: Ambeed
SKU: A1371754
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1
[ 203866-14-2 ]
[ 2438-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 3h;	(2S,4R)-4-Fluoropyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (400 mg, 1.71 mmol) was dissolved in DCM (2 mL). TFA (1 mL, 13 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure to give awhite solid which was used for the next step without further purification.1H NMR (400 MHz, DMSO) 9.81 (2H, bs), 5.53 - 5.40 (1H, m), 4.52 (1H, dd, J=7.6,11.0 Hz), 3.64 - 3.46 (1 H, m), 3.49 (1 H, 5), 2.62 - 2.54 (1 H, m), 2.39 - 2.20 (1 H, m).

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1169 - 1172
[2]Patent: WO2019/58132,2019,A1 .Location in patent: Page/Page column 106; 107

2
[ 203866-18-6 ]
[ 203866-14-2 ]

Yield	Reaction Conditions	Operation in experiment
		The fluorination of the above cis-hydroxy provides the trans-4-fluoro derivative which on saponification gives the corresponding acid. The amine is prepared from 4-R-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester and 5-methyl-pyridin-2-ylamine under HATU condition to give proline amide derivative which on treatment with 4 M HCl in dioxane provides the desired amine.
	With water; sodium hydroxide; In 1,4-dioxane; at 7 - 15℃;	To a solution of (2S,4R)-2-methyl N-Boc-4-fluoro-pyrrolidine-2-carboxylate (13.0 g, 52.58 mmol) in dioxane (270 mL) at 15 C. was added a solution of sodium hydroxide (4.2 g, 105.00 mmol) in water (30 mL) dropwise. The mixture was cooled to 7 C. and the slurry was stirred at 7 C. overnight. Acetic acid (80 mL) was added and the mixture was diluted with DCM. The layers were separated, the aqueous layer was back-extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was crystallized from diethyl ether/hexane to afford INT 33 as a white solid. MS (ESI): [M+H-]232.2. 1H NMR (DMSO-d6): delta (ppm) rotamers 12.72 (s, br, 1H), 5.40-5.21 (m, 1H), 4.22-4.13 (m, 1H), 3.72-3.58 (m, 1H), 3.58-3.36 (m, 1H), 2.60-2.44 (m, 1H, overlapping with solvent peak), 2.19-1.97 (m, 1H), 1.41 and 1.36 (s, total 9H).
	With sodium hydroxide; In 1,4-dioxane; water; at 7 - 15℃;	(1) (2S,4R)-N-Boc-4-fluoropyrrolidine-2-carboxylic acid, INT 33 A solution of (2S,AR) methyl A/-Boc-4-hydroxypyrrolidine-2-carboxylate (250 g, 1 .02 mol), triphenylphosphine (401 g, 1 .53 mmol) and benzoic acid (187 g, 1 .53 mol) in TH F (3.50 L) was cooled to reach an internal temperature of -4 C, then a diethylazodicarboxylate solution (40% in toluene, 625 ml_, 1 .43 mmol) in THF (1 .50 L) was added within 1 hr. The reaction mixture was warmed to RT and stirred at RT overnight. The mixture was concentrated. The residue was taken up in diethyl ether (2.5 L) and the mixture was refluxed for 1 hr. The suspension was cooled to 0 C, the white solid was filtered off, and washed with cold ethanol. The filtrate was concentrated. The residue was dissolved in a 4: 1 mixture of warm hexane/EtOAc (1 .5 L) and stirred at RT for 1 hr. The mixture was cooled to 10 C and treated with hexane (250 ml_). The mixture was stirred at RT for 30 min and a precipitate was formed. The solid was filtered off and washed with cold hexane (150 ml_). The filtrate was concentrated. The residue was purified by flash chromatography (silica; hexane/EtOAc 4: 1 ) to afford (2S,4S)-2-methyl A/-Boc-4-(benzoyloxy)pyrrolidine-2-carboxylate as a white solid.To a solution of (2S,4S)-2-methyl A/-Boc-4-(benzoyloxy)pyrrolidine-2-carboxylate (248 g, 0.71 mol) in MeOH (4.5 L) was added sodium carbonate (98 g, 0.92 mol) followed by more MeOH (0.5 L). The reaction mixture was stirred at RT for 4 hr. The mixture was filtered, and the filtrated was concentrated to a volume of approximately 1 L. The solution was diluted with EtOAc (5.0 L), cooled to 5 C and washed with water. The aqueous layer was back-extracted with EtOAc (2x). The combined organic layers were washed with brine and a 1 : 1 mixture of brine and water, dried over sodium sulfate, filtered and concentrated. The residue was crystallized from DCM/hexane to afford (2S,4S)-2-methyl A/-Boc-4-hydroxy-pyrrolidine-2-carboxylate as a white solid.To a solution of (2S,4S)-2-methyl A/-Boc-4-hydroxy-pyrrolidine-2-carboxylate (270 g, 1 .10 mol) in DCM (2.6 L) at -80 C was added (diethylamino)sulfur trifluoride (567 ml_, 4.29 mol) dropwise. The reaction mixture was stirred at RT overnight. The mixture was cooled to -78 C and then added to a saturated aquous sodium hydrogen carbonate solution cooled to -10 C. During the addition the inner temperature was kept below 5 C. The mixture was then stirred at 0 C for 30 min. The layers were separted, the aqueous layer was back-extracted with DCM. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; hexane/EtOAc gradient, 10-40%) to afford (2S,4f?)-2-methyl A/-Boc-4-fluoro- pyrrolidine-2-carboxylate as a yellow oil.To a solution of (2S,4f?)-2-methyl A/-Boc-4-fluoro-pyrrolidine-2-carboxylate (13.0 g, 52.58 mmol) in dioxane (270 mL) at 15 C was added a solution of sodium hydroxide (4.2 g, 105.00 mmol) in water (30 mL) dropwise. The mixture was cooled to 7 C and the slurry was stirred at 7 C overnight. Acetic acid (80 mL) was added and the mixture was diluted with DCM. The layers were separated, the aqueous layer was back-extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was crystallized from diethyl ether/hexane to afford INT 33 as a white solid.MS (ESI): [M-H]- 232.2.1H NMR (DMSO-d6): delta (ppm) rotamers 12.72 (s, br, 1 H), 5.40- 5.21 (m, 1 H), 4.22-4.13 (m, 1 H), 3.72-3.58 (m, 1 H), 3.58-3.36 (m, 1 H), 2.60-2.44 (m, 1 H, overlapping with solvent peak), 2.19-1 .97 (m, 1 H), 1.41 and 1 .36 (s, total 9 H).

With water; sodium hydroxide; In 1,4-dioxane; at 7 - 15℃;

To a solution of (2S,4R)-2-methyl N-Boc-4-fluoro-pyrrolidine-2-carboxylate (13.0 g, 52.58 mmol) in dioxane (270 mL) at 15 DC was added a solution of sodium hydroxide (4.2 g, 105.00 mmol) in water (30 mL) dropwise. The mixture was cooled to 7 C and the slurry was stirred at 7 DC overnight. Acetic acid (80 mL) was added and the mixture was diluted with DCM. The layers were separated, the aqueous layer was back-extracted with DCM. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was crystallized from diethyl ether/hexane to afford INT 33 as a white solid.MS (ESI): [M-Hf 232.2. ?H NMR (DMSO-d6): 8 (ppm) rotamers 12.72 (s, br, 1H), 5.40-5.21 (m, 1H), 4.22-4.13 (m, 1H), 3.72-3.5 8 (m, 1H), 3.58-3.36 (m, 1H), 2.60-2.44 (m, 1H, overlapping with solvent peak), 2.19-1.97 (m, 1H), 1.41 and 1.36 (s, total 9 H).

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2725 - 2746
[2]Tetrahedron Letters,1998,vol. 39,p. 1169 - 1172
[3]Patent: US2009/62537,2009,A1 .Location in patent: Page/Page column 10
[4]Patent: US2015/152068,2015,A1 .Location in patent: Paragraph 0333; 0334
[5]Patent: WO2015/79417,2015,A1 .Location in patent: Page/Page column 68; 69; 70
[6]Patent: WO2016/164580,2016,A1 .Location in patent: Page/Page column 237

3
[ 587887-98-7 ]
[ 203866-14-2 ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 15923 - 15932
[2]Journal of the American Chemical Society,2003,vol. 125,p. 9262 - 9263
[3]Journal of Fluorine Chemistry,2008,vol. 129,p. 286 - 293

4
[ 1738-76-7 ]
[ 203866-14-2 ]
[ 870992-70-4 ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 15923 - 15932

5
[ 40004-08-8 ]
[ 203866-14-2 ]
[ 886447-87-6 ]

Yield	Reaction Conditions	Operation in experiment
66%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h;

Reference： [1]Chiba, Jun; Takayama, Gensuke; Takashi, Tohru; Yokoyama, Mika; Nakayama, Atsushi; Baldwin, John J.; McDonald, Edward; Moriarty, Kevin J.; Sarko, Christopher R.; Saionz, Kurt W.; Swanson, Robert; Hussain, Zahid; Wong, Angela; MacHinaga, Nobuo [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2725 - 2746]

6
[ 203866-14-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		Commercially available <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (3.0 g, 12.9 mmol) was dissolved in 2,2-dimethoxyethane (43 mL). After cooling the mixture to -20C, isobutyl chloroformate (1.86 mL, 14.2 mmol) and N-methylmorpholine (1.56 mL, 14.2 mmol) were added, and the mixture was stirred at -20C for 30 minutes. After removing the precipitate by filtration, the filtrate was cooled to -20C, and a sodium borohydride (0.535 g, 14.2 mmol) aqueous solution (15 mL) was added. The mixture was stirred at -20C for 30 minutes. After concentrating the reaction mixture under reduced pressure, a 1 mol/L sodium hydroxide aqueous solution was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane/ethyl acetate = 3/1) to give (2S,4R)-tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.81 g, quant.). ESI-MS: m/z 120 [M - Boc + H]+. 1H-NMR (CDCl3, 80C) delta (ppm): 1.49 (s, 9H), 1.87 (m, 1H), 2.35 (m, 1H), 3.44 (ddd, J = 3.3, 13.2, 35.9 Hz, 1H), 3.58 (dd, J = 5.9, 11.7 Hz, 1H), 3.77-3.94 (m, 2H), 4.12 (m, 1H), 5.09 (ddd, J = 4.0, 4.0, 53.1 Hz, 1H)
80%		Amino alcohol B-09: ((2S,4R)-4-Fluoropyrrolidin-2-yl)methanol hydrochloride(i) (2S,4R)-N-Boc-4-fluoropyrrolidine-2-carboxylic acid (2 g, 8.58 mmol) was dissolved in tetrahydrofuran (31 ml) and cooled, and boron hydride-tetrahydrofuran complex (1 mol/l, 12.87 ml) was added slowly at 0 C. The reaction mixture slowly warmed to room temperature, and after 30 minutes' stirring it was cooled to 0 C. again. Water (3.9 ml) was slowly added dropwise; potassium carbonate (2 g, 14.59 mmol) was then added slowly and stirring was carried out for 30 minutes at RT. The mixture was diluted with water (10 ml) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×20 ml), and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, diethyl ether/dichloromethane/hexane, 2:1:1). Yield: 1.5 g (80%).
80.3%	With borane-THF; In tetrahydrofuran; at 0 - 20℃;	Step A - Preparation of Compound Int-lOb(2S,4R)- 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (Int- 10a, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 C. BH3-THF (1M in THF, 171 mL, 171 mmol) was added via an addition funnel. The solution was gradually warmed up to room temperature and stirred at room temperature for about 15 hours. MeOH was added until no bubbles came out. The solution was concentrated and the product was purified using silica gel chromatography (330g, 0% to 60% of EtOAc in Hexane) to provide Int-10b (15.1 g, 80.3%)

80.3%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 15h;	(2S,4R)- 1 -(½ /-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxy lie acid (Int-lOa, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 C.BH3 THF (1M in THF, 171 mL, 171 mmol) was added via an addition funnel. The solution was gradually warmed up to room temperature and allowed to stir at room temperature for about 15 hours. MeOH was added until no bubbles came out. The solution was concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (330g, 0% to 60% of EtOAc in Hexane) to provide Compound Int-lOb (15.1 g, 80.3%)
80.3%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 15h;	(2S,4R)- 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (Int- 10a, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 C. BH3 HF (1M in THF, 171 mL, 171 mmol) was added via an addition funnel. The solution was gradually warmed up to room temperature and allowed to stir at room temperature for about 15 hours. MeOH was added until no bubbles came out. The solution was concentrated in vacuo and the residue obtained was purified using silica gel chromatography (330g, 0% to 60% of EtOAc in Hexane) to provide Compound Int-lOb (15.1 g, 80.3%)
80.3%	With borane-THF; In tetrahydrofuran; at 0 - 20℃;	Step A - Preparation of Compound Int-lOb(2S,4R)- 1 -(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (Int- 10a, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 C. BH3-THF (1M in THF, 171 mL, 171 mmol) was added via an addition funnel. The solution was gradually warmed up to room temperature and stirred at room temperature for about 15 hours. MeOH was added until no bubbles came out. The solution was concentrated and the product was purified using silica gel chromatography (330g, 0% to 60% of EtOAc in Hexane) to provide Int-10b (15.1 g, 80.3%)
80.3%		EXAMPLE 5; Preparation of Intermediate Compound Int-5f; Synthesis of Compound Int-Sb; (25,4R)-l -(/eA-/-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (Int-5a, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 C. BH3-THF (I M in THF, 171 mL, 171 mmol) was added via an addition funnel and the reaction was allowed to warm to room temperature on its own and stir for a total of about 15 hours. MeOH was added to the reaction mixture until gas evolution ceased, then the resulting solution was concentrated in vacuo, and the residue obtained was purified using silica gel chromatography (330g, 0% to 60% of EtOAc in Hexane) to provide Compound Int-5b ( 1 .1 g, 80.3%)
80.3%	With borane-THF; In tetrahydrofuran; anhydrous THF; at 0 - 20℃; for 15h;	Step A - Synthesis of Compound Int-5b(2S,4R)- l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (Int-5a, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 C. BH3 HF (1M in THF, 171 mL, 171 mmol) was added via an addition funnel and the reaction was allowed to warm to room temperature on its own and stir for a total of about 15 hours. MeOH was added to the reaction mixture until gas evolution ceased, then the resulting solution was concentrated in vacuo, and the residue obtained was purified using silica gel chromatography (330g, 0% to 60% of EtOAc in Hexane) to provide Compound Int-5b (15.1 g, 80.3%)
	With borane-THF; In tetrahydrofuran; at 20℃; for 3h;	(2) (2S,4R)-N-Boc-2-(hydroxymethyl)-4-fluoropyrrolidine, INT 34 To a solution of INT 33 (5.00 g, 21.44 mmol) in THF (105 mL) at 0 C. was added borane tetrahydrofuran complex solution (1 M in THF, 32.2 mL, 32.20 mmol). The reaction mixture was stirred at RT for 3 hr. The mixture was cooled to 0 C. and water (100 mL) was added dropwise. The resulting mixture was stirred at 0 C. for 1 hr, then extracted with EtOAc. The organic layer was washed with aqueous 10% citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to afford crude INT 34 as a yellow oil. MS (ESI): [M+H-tBu]+ 164.2. 1H NMR (DMSO-d6): delta (ppm) 5.23 (d, 1H), 4.74 (t, 1H), 3.84 (m, 1H), 3.74-3.62 (m, 1H), 3.57-3.44 (m, 2H), 3.41-3.23 (m, 1H), 2.22-2.05 (m, 2H), 1.41 (s, 9H).
		(2) (2S,4R)-N-Boc-2-(hydroxymethyl)-4-fluoropyrrolidine, INT 34 To a solution of INT 33 (5.00 g, 21 .44 mmol) in THF (105 mL) at 0 C was added borane tetrahydrofuran complex solution (1 M in THF, 32.2 mL, 32.20 mmol). The reaction mixture was stirred at RT for 3 hr. The mixture was cooled to 0 C and water (100 mL) was added dropwise. The resulting mixture was stirred at 0 C for 1 hr, then extracted with EtOAc. The organic layer was washed with aqueous 10% citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to afford crude INT 34 as a yellow oil. MS (ESI): [M+H-tBuf 164.2.1H NMR (DMSO-d6): delta (ppm) 5.23 (d, 1 H), 4.74 (t, 1 H), 3.84 (m, 1 H), 3.74-3.62 (m, 1 H), 3.57-3.44 (m, 2H), 3.41 -3.23 (m, 1 H), 2.22-2.05 (m, 2H), 1 .41 (s, 9H).
	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 2h;	168 [0562] To a solution of 93 (1 equiv) in THF (10 vol) at 0 C was added boron hydride- tetrahydrofuran complex (2.1 equiv). The reaction mixture was stirred at room temperature for 2 h and then cooled at 0 C. The resulting mixture was quenched with saturated K2CO3 solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2S04, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to give compound 163.
	With borane-THF; In tetrahydrofuran; at 20℃; for 2h;	To a solution of (2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in THF (10 vol) at 0 C was added borane tetrahydrofuran complex (2.1 equiv). The reaction mixture was stirred at room temperature for 2 h and then cooled at 0 C. The resulting mixture was quenched with saturated K2CO3 solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to afford the title compound (86).
	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 2h;	Step 1 : terf-Butyl (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-l-carboxylate (48) [0641] To a solution of (2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in THF (10 vol) at 0 C was added borane tetrahydrofuran complex (2.1 equiv). The reaction mixture was stirred at room temperature for 2 h and then cooled at 0 C. The resulting mixture was quenched with saturated K2CO3 solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous aiSO-f, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to afford the title compound.
	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3h;	To a solution of INT 33 (5.00 g, 21.44 mmol) in THF (105 mL) at 0 C was added borane tetrahydrofuran complex solution (1 M in THF, 32.2 mL, 32.20 mmol). The reaction mixture was stirred at RT for 3 hr. The mixture was cooled to 0 C and water (100 mL) was added dropwise. The resultingmixture was stirred at 0 C for 1 hr, then extracted with EtOAc. The organic layer was washed with aqueous 10% citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to afford crude INT 34 as a yellow oil. MS (ESI): [M+H-tBu] 164.2. ?H NMR (DMSO-d6): (ppm) 5.23 (d, 1H), 4.74 (t, 1H), 3.84 (m, 1H), 3.74-3.62 (m, 1H), 3.57-3.44 (m, 2H), 3.41-3.23 (m, 1H), 2.22-2.05 (m, 2H), 1.41 (s, 9H).
	In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;	[0550] To a solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (1 equiv) in THF (10 vol) at 0 C was added boron hydride-tetrahydrofuran complex (2.1 equiv). The reaction mixture was stirred at room temperature for 2 h and then cooled at 0 C. The resulting mixture was quenched with saturated K2CO3 solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to afford the compound (89).
	In tetrahydrofuran; at 0 - 20℃; for 2h;	To a solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (1 equiv) in THF (10 vol) at 0 C. was added boron hydride-tetrahydrofuran complex (2.1 equiv). The reaction mixture was stirred at room temperature for 2 h and then cooled at 0 C. The resulting mixture was quenched with saturated K2CO3solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to afford the title compound.tert-Butyl (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (S2)

Reference： [1]Patent: EP2708540,2014,A1 .Location in patent: Paragraph 0298
[2]Patent: US2010/173889,2010,A1 .Location in patent: Page/Page column 33
[3]Patent: WO2012/41227,2012,A1 .Location in patent: Page/Page column 82
[4]Patent: WO2012/41014,2012,A1 .Location in patent: Page/Page column 103-104
[5]Patent: WO2012/40923,2012,A1 .Location in patent: Page/Page column 89
[6]Patent: WO2012/40924,2012,A1 .Location in patent: Example 10
[7]Patent: WO2012/125926,2012,A2 .Location in patent: Page/Page column 38
[8]Patent: WO2012/122716,2012,A1 .Location in patent: Page/Page column 57
[9]ChemMedChem,2015,vol. 10,p. 1071 - 1078
[10]Chemical and Pharmaceutical Bulletin,2006,vol. 54,p. 1515 - 1529
[11]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5296 - 5300
[12]Patent: US2015/152068,2015,A1 .Location in patent: Paragraph 0335; 0336; 0337
[13]Patent: WO2015/79417,2015,A1 .Location in patent: Page/Page column 70
[14]Patent: WO2017/35348,2017,A1 .Location in patent: Paragraph 0562
[15]Patent: WO2017/35349,2017,A1 .Location in patent: Paragraph 0521
[16]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0641
[17]Patent: WO2016/164580,2016,A1 .Location in patent: Page/Page column 273; 274
[18]Patent: WO2017/35357,2017,A1 .Location in patent: Paragraph 0461; 0550
[19]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0635

7
[ 87691-27-8 ]
[ 203866-14-2 ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 15923 - 15932

8
[ 21717-96-4 ]
[ 203866-14-2 ]
[ 915280-66-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then 5-fluoropyridin-2-amine (200 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 430 mg (quantitative yield) of titled compound was obtained.
71%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	To a DMF solution (15 mL) of Boc-L-Pro-4-F-OH (2.5 g, 10.73 mmol, 1 equiv) Hunig's base (Diisopropylethylamine, abbrev. DIEA) (6.73 mL, 38.61 mmol, 3.6 eq) is added and the mixture cooled to 0 C. This is followed by the addition of 2-Amino-5-fluoro pyridine (1.44 g, 12.87 mmol, 1.2 equiv), and HATU (4.89 g, 12.87 mmol, 1.2 equiv) at 0 C. The resulting mixture is stirred at room temperature for 16 h. The mixture is partitioned between excess ethyl acetate and 10% citric acid. The organic layer is washed with brine and sat. NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified by silica gel chromatography (Hexanes:Ethyl acetate=1:0-7:3) to give the title compound as a colorless syrup (2.5 g, 71%).

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1463
[2]Patent: US2009/62537,2009,A1 .Location in patent: Page/Page column 13

9
[ 5469-70-5 ]
[ 203866-14-2 ]
[ 1010422-96-4 ]

Yield	Reaction Conditions	Operation in experiment
77.4%	Stage #1: (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid With 1-methyl-1H-imidazole In N,N-dimethyl-formamide at -10℃; for 0.25h; Inert atmosphere; Stage #2: With methanesulfonyl chloride In N,N-dimethyl-formamide at -10℃; for 1.33333h; Inert atmosphere; Stage #3: 3-aminopyridazine In N,N-dimethyl-formamide at -10 - 20℃; for 7h; Inert atmosphere;
	Stage #1: (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid With [(3,3,3-triethoxypropyl)sulfonyl]benzene In dichloromethane at 0℃; for 1h; Stage #2: 3-aminopyridazine With pyridine In dichloromethane at 0 - 20℃; for 16h;	13 To a solution of Boc-Pro(F)-OH (5 g, 21.46 mmol, 1 equiv,) in DCM at 0° C., Ghosez Reagent (3.1 ml, 23.61 mmol, 1.1 equiv) is added and the reaction mixture was stirred at 0° C. for 1 h. To this the amine (2.65 g, 27.9 mmol, 1.3 equiv) in Pyridine is added at 0° C. and the reaction mixture is stirred at room temperature for 16 h. It is then concentrated to remove all volatiles and redissolved in excess DCM. The organic layer is washed with 10% Citric acid, NaCl(sat) and NaHCO3(sat), dried over Na2SO4 and concentrated. The resulting residue is purified by flash chromatography using 10-15% Acetone in Dichloromethane to provide the title compound.

Reference： [1]Liu, Yugang; Prashad, Mahavir; Ciszewski, Lech; Vargas, Kevin; Repic, Oljan; Blacklock, Thomas J. [Organic Process Research and Development, 2008, vol. 12, # 2, p. 183 - 191]
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2009/62537, 2009, A1 Location in patent: Page/Page column 18

10
[ 203866-14-2 ]
[ 1235447-44-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium fluoride; 2,2-difluoro-1,3-dimethyl-imidazolidine; In dichloromethane; at 20℃; for 0.333333h;Cooling with ice;	Example 13. Preparation of(2S,4R)-N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Ie); [0090] (2S,4R)-N-Boc-4-fluoropyrrolidine-2-carboxylic acid (1.17g, 5.0 mmol) andNaF (0.63g, 15 mmol) were taken in a Teflon reactor and suspended in 10 ml of anhydrous dichloromethane. It was cooled with ice. A solution of 2,2-difluoro-l,3- dimethylimidazolidine (0.817g, 6.0 mmol) in 2 ml of dichloromethane was slowly added. After 5 minutes stirring, the ice bath was removed and stirring was continued at room temperature for 20 minutes. All the volatiles were removed at reduced pressure and the obtained viscous liquid was mixed with 50 ml of pentane and washed with water (50 ml x 2). The organic layer was dried over anhydrous magnesium sulfate and filtered. Removal of solvent at reduced pressure gave 1.06 g of (2S,4R)-N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride (Ie) as a colorless oil. Yield; 90 %. 19F NMR (282MHz, CDCl3) (as a 4:6 mixture of rotamers) delta (ppm) 28.66 (s, 0.4F, COF), 28.10 (s, 0.6F, COF), -177.16 (m, 0.4F, CF), - 177.83 (m, 0.6F, CF): 1H NMR (300MHz, CDCl3) (as a mixture of rotamers) delta 1.42 (s, 0.6x9H, t-Bu), 1.44 (s, 0.4x9H, t-Bu), 2.0-2.8 (m, 2H), 3.45-4.0 (m, 2H), 4.51 (m. IH), 5.22 (dm, IH, J = 51.6 Hz): 13C NMR (75MHz, CDCl3) (as a mixture of two rotamers) delta 90.70 (d, J = 179.9 Hz, CF), 91.61 (d, J = 179.9 Hz, CF), 153.07 (s, CON), 154.17 (s, CON), 161.90 (d, J = 368.4 Hz, COF), 162.11 (d, J = 368.4 Hz, COF): IR (Neat, KBr) 1848 (COF) cm"1: High Resolution Mass/ESI- APCI method (solvent; methanol); (M-F+OCH3+Na)+ 270.1114 [calcd 270.1112 for (CUH18FNO4+Na)].

Reference： [1]Patent: WO2010/81014,2010,A1 .Location in patent: Page/Page column 30
[2]Journal of Organic Chemistry,2011,vol. 76,p. 3113 - 3121

11
[ 6638-79-5 ]
[ 203866-14-2 ]
[ 1232835-03-8 ]

Yield	Reaction Conditions	Operation in experiment
92.88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere;	To a solution of Scheme 5-9 compond SI (5 g, 21.43 mmol) in DCM (100 mL) was added Nu,Omicron-dimethylhydroxylamine hydrochloride (2.5 g, 25.72 mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followed by TEA (5.4 g, 53.58 mmol) at 0 C. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water and brine, dried over anhydrous Na2S04 and concentrated to afford crude product which was washed with PE/EtOAc (2/1) to afford the title compound (5.5 g, 92.88% yield) as a white solid.
92.88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere;	To a solution of scheme 5-9 compound S1 (5 g, 21.43 mmol) in DCM (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.72 mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followed by TEA (5.4 g, 53.58 mmol) at 0 oC. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with DCM and washed with water and brine, dried over anhydrous Na2SO4, and concentrated to give crude product that was washed withpetroleum ether/EtOAc (2/1) to afford the title compound (5.5 g, 92.88% yield) as a white solid.
92.88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;	To a solution of Scheme 5-8 compound SI (5 g, 21.43 mmol) in DCM (100 mL) was added Nu,Omicron-dimethylhydroxylamine hydrochloride (2.5 g, 25.72 mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followed by TEA (5.4 g, 53.58 mmol) at 0 C. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water and brine, dried over anhydrous Na2S04 and concentrated to afford crude product, which was washed with petroleum ether/EtOAc (2/1) to afford the title compound (S2) (5.5 g, 92.88% yield) as a white solid.

92.88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;	To a solution of compound scheme 5-7 compound 51 (5 g, 21.43 mmol) in DCM (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.72 mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followed by TEA (5.4 g, 53.58 mmol) at 0C. The reaction was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water and brine, dried over anhydrous Na2504 and concentrated to afford crude product, which was washed with petroleum ether/EtOAc (2/1) to afford Scheme 5-7 compound S2 (5.5 g, 92.88% yield) as a white solid.
74%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.25h;	A. (2S,4R)-4-Fluoro-2-(methoxy-methyl-carbamoyl)-pyrrolidine-l-carboxylic acid tert-butyl ester (7b).; HBTU (12.3 g, 32.3 mmol) was added in portions to a solution of Compound 7a (6.26 g, 26.9 mmol), Lambda ,Omicron-dimethylhydroxylamine hydrochloride (3.15 g, 32.3 mmol), and DIEA (5.62 mL, 4.17 g, 32.3 mmol) in 60 mL of DMF at 0C. After 15 min, the cooling bath was removed and the mixture was stirred 16 h at 20C. EtOAc (200 mL) and saturated aqueous NH4CI (100 mL) were added. The organic layer was separated, washed with saturated aqueous NaHC03 (100 mL), and brine (100 mL), and dried over MgS04. The solution was concentrated to give 7.7 g of off-white oil that was purified by flash column chromatography (S1O2), eluting with 10% MeOH/CH2Cl2, to yield Compound 7b (5.47 g, 74% yield). 1H-NMR (DMSO-d6): delta 5.29 (1H, dt), 4.70 (1H, dd), 3.50 (2H, m), 3.13 (3H, s), 2.69 (3H, s),2.00 (2H, m), 1.34 (9H, s).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;	To a solution of scheme 5-10 compound S1 (5 g, 21.43 mmol) in DCM (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.72 mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followed by TEA (5.4 g, 53.58 mmol) at 0 oC. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water and brine, dried over anhydrous Na2SO4 and concentrated to afford crude product that was washed with petroleum ether/EtOAc (2/1) to afford the title compound (5.5 g, 92.88% yield) as a white solid.

Reference： [1]Patent: WO2017/35405,2017,A1 .Location in patent: Paragraph 0495
[2]Patent: WO2017/35415,2017,A1 .Location in patent: Paragraph 0566; 0619; 0620
[3]Patent: WO2017/35401,2017,A1 .Location in patent: Paragraph 0480
[4]Patent: WO2017/35417,2017,A1 .Location in patent: Paragraph 0570; 0568
[5]Patent: WO2011/53706,2011,A1 .Location in patent: Page/Page column 59
[6]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0638

12
[ 1199792-92-1 ]
[ 203866-14-2 ]
[ 1235576-41-6 ]

Yield	Reaction Conditions	Operation in experiment
77%		Step 1: tert-butyl (2S,4R)-4-fluoro-2-[4-(trifluoroacetyl)-4,7-diazaspiro[2.5]oct-7-yl]carbonyl}pyrrolidine-1-carboxylate 1-hydroxybenzotriazole (46 mg, 0.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (502 mg, 2.61 mmol) were added to a dimethylformamide (8 ml) solution of (9R)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (400 mg, 1.71 mmol) and the resulting mixture was stirred at room temperature for 15 minutes. Subsequently, the compound (460 mg, 2.05 mmol) obtained in Step 5 of Reference Example 2 and diisopropylethylamine (0.45 ml, 2.57 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate = 1:1 (v/v)] to give the title compound (560 mg, 77%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6, 90C) delta: 0.98-1.10 (4H, m), 1.37 (9H, s), 1.95-2.09 (1H, m), 2.49-2.54 (1H, m), 3.41-3.54 (3H, m), 3.60-3.75 (5H, m), 4.73-4.80 (1H, m), 5.26 (1H, d, J=53.7 Hz). MS (ESI) m/z: 424 [(M+H)+]

Reference： [1]Patent: EP2380892,2011,A1 .Location in patent: Page/Page column 57

13
[ 1199793-24-2 ]
[ 203866-14-2 ]
[ 1235576-57-4 ]

Yield	Reaction Conditions	Operation in experiment
77%		Step 1: tert-butyl (2S,4R)-2-[(6S)-5-ethyl-4-(trifluoroacetyl)-4,7-diazaspiro[2.5]oct-7-yl]carbonyl}-4-fluoropyrrolidine-1-carboxylate 1-chloro-N,N,2-trimethyl-1-propenylamine (0.35 ml, 2.68 mmol) was added to a dichloromethane (8 ml) solution of (4R)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (520 mg, 2.23 mmol) under ice cooling. The resulting mixture was stirred at the same temperature for 1 hour, then the compound (730 mg, 2.68 mmol) obtained in Step 4 of Reference Example 8 and triethylamine (0.78 ml, 5.58 mmol) were added and the resulting mixture was further stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate = 2:1 (v/v)] to give the title compound (780 mg, 77%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6, 90C) delta: 0.67-0.73 (2H, m), 0.83-0.88 (3H, m), 1.29-1.33 (1H, m), 1.39 (9H, s), 1.45-1.52 (3H, m), 2.07-2.17 (1H, m), 2.43-2.47 (1H, m), 3.36-3.77 (6H, m), 4.40-4.55 (1H, m), 4.70-4.86 (1H, m), 5.30 (1H, d, J=54.9 Hz). MS (ESI) m/z: 452 [(M+H)+]

Reference： [1]Patent: EP2380892,2011,A1 .Location in patent: Page/Page column 62

14
[ 203866-14-2 ]
[ 74-88-4 ]
[ 203866-18-6 ]

Yield	Reaction Conditions	Operation in experiment
95.3%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;Inert atmosphere;	To a solution of compound 37-1 (1.0 g, 4.29 mmol) in DMF (10mL) was added K2CO3 (1.18 g, 8.58 mmol) followed by MeI (1.83 g,12.9 mmol) at 0 C and the mixture was stirred at room temperature under N2 atmosphere for 2 hours. The mixture was poured into iced-water and extracted with EtOAc twice. The combined organic layers were washed with saturated aqueous NH4Cl solution and brine, dried with anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel (eluted with PE: EtOAc= 20: 1) to afford compound 37-2 (1.01 g, yield 95.3%) as a light yellow oil. LC/MS (ESI)m/z: 248 (M+H)+.
38%	With potassium carbonate; In tetrahydrofuran; at 20℃; for 12h;	A mixture of (2S,4R)- 1- [(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (2 g, 8.57 mmol), potassium carbonate (5.9 g, 42.69 mmol), THF (80 mL) and CH3I (6.1 g, 42.98 mmol) was stirred for 12 h at room temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/petroleum ether (1:5) to afford the title compound (800 mg, 38%) as colorless oil.

Reference： [1]Patent: WO2020/41301,2020,A1 .Location in patent: Page/Page column 289; 338-339
[2]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 0521; 0522; 01714; 01715

15
ethyl 4-(aminomethyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate hydrochloride [ No CAS ]
[ 203866-14-2 ]
ethyl 4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	A solution of (2S,4R)- 1- [(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (824 mg, 3.53 mmol, 1.30 equiv), HATU (1.55 g, 4.08 mmol, 1.50 equiv), DIEA (1.05 g, 8.12 mmol, 3.00 equiv), and ethyl 4-(aminomethyl)- 1 -[4-(trifluoromethyl)phenyl] - 1H-pyrazole-3-carboxylate hydrochloride (950 mg, 2.72 mmol, 1.00 equiv) in N, N-dimethylformamide (30 mL) was stirred for 1 h at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:3) to afford the title compound (1.35 g, 94%) as a light yellow solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 0799; 0800

16
(3-bromo-5-fluoro-phenyl)methanamine [ No CAS ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 2-((3-bromo-5-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of (2S ,4R)- 1 -tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (A, 2000 mg, 8.6 mmol) and (3-bromo-5-fluoro-phenyl)methanamine (1.9 g, 9.4 mmol) in N,Ndimethylformamide (34 ml) was added N,N-diisopropylethylamine (2.2 mL, 13 mmol) and HATU (4.0 g, 10 mmol). The reaction mixture was stuffed at RT 2h.The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated via rotovap. The crude product was purified by flash chromatography (EtOAc/Heptaneeluted at 50%EtOAc) to give 3.24g, 90% yield. LCMS (ESI) mlz:419. 1 [M+H]+

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01125; 01126

17
[ 88579-63-9 ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 2-(((2,6-dichloropyridin-4-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20.0℃; for 2.0h;	To a solution of (2S ,4R)- 1 -tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (500 mg, 2.1437 mmol) and <strong>[88579-63-9]2,6-dichloropyridine-4-methylamine</strong> (426 mg, 2.36 mmol) in N,Ndimethylformamide (8.6 mL) was added N,N-diisopropylethylamine (0.561 mL, 3.2156 mmol) and HATU (998.09 mg, 2.5725 mmol). The reaction mixture was stuffed at RT 2h.The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated via rotovap. The crude product was carried to next step. LCMS (ESI) m/z:392.10 [M+H]+

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 0892; 0893

18
methyl 4-(aminomethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate hydrochloride [ No CAS ]
[ 203866-14-2 ]
methyl 4-([[(2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidin-2-yl]formamido]methyl)-6-[4-(trifluoromethyl)phenyl]pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃; for 14h;	A solution of (2S,4R)- 1- [(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (67 mg, 0.29 mmol, 1.00 equiv), methyl 4-(aminomethyl)-6- [4-(trifluoromethyl)phenyl]pyridine-3-carboxylate hydrochloride (100 mg, 0.29 mmol, 1.00 equiv), HATU (131 mg, 0.34 mmol, 1.20 equiv), and DIEA (111 mg, 0.86 mmol, 3.00 equiv) in tetrahydrofuran (5 mL) was stirred for 14 h at room temperature. The reaction was then quenched by water, extracted with ethyl acetate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (2:1) to afford the title compound (100 mg, 66%) as a white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01026; 01027

19
[4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl]methanamine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-[([4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2-yl] methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;	A mixture of (2S,4R)- 1- [(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (92 mg, 0.39 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), DIEA (154 mg, 1.19 mmol, 3.00 equiv), HATU (226 mg, 0.59 mmol, 1.50 equiv), and [4-[4-(difluoromethyl)phenyl]-5-fluoropyridin-2- yl]methanamine (100 mg, 0.40 mmol, 1.00 equiv) was stuffed for 12 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with petroleum ether/ethyl acetate (5:1). This resulted in the title compound (120 mg, 65%) as an off-white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01111; 01112

20
[5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine hydrochloride [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-[([5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	A mixture of [5-methyl-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl] methanamine hydrochloride (260 mg, 0.86 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), (2S,4R)- 1- [(tertbutoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid (200 mg, 0.86 mmol, 1.00 equiv), DIEA (1.11 g, 8.59 mmol, 10.00 equiv), and HATU (392 mg, 1.03 mmol, 1.20 equiv) was stirred for 2 h at room temperature. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with dichloromethane/methanol (100:5) to afford the title compound (380 mg, 92%) as brown oil.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01169; 01170

21
[5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-[([5-methyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	A solution of (2S,4R)- 1- [(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (130.43 mg, 0.559 mmol, 1.000 equiv), HATU (318.95 mg, 0.839 mmol, 1.500 equiv), DIEA (216.83 mg, 1.678 mmol, 3.000 equiv), and [5-methyl-2- [2-(trifluoromethyl)pyrimidin-5 -yl]pyridin-4- yl]methanamine (150.0 mg, 0.559 mmol, 1.0 equiv) in DMF (5 mL) was stirred for 2 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:1) to afford the title compound (200 mg, 74%) as a white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01885; 01886

22
[6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methanamine hydrochloride [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2R,4S)-4-fluoro-2-([[6-(2-methoxyethoxy)-4-[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl]methyl]carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.166667h;	A mixture of (2S,4R)- 1 -[(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (235 mg, 1.008 mmol, 1.00 equiv), DIEA (355 mg, 2.747 mmol, 2.73 equiv), HATU (418 mg, 1.099 mmol, 1.09 equiv), and 6-(2-methoxyethoxy)-4- [6-(trifluoromethyl)pyridin-3-yl]pyridin-2-yl] methanamine (300 mg, 0.917 mmol, 0.91 equiv) in N,N-dimethylformamide (8 mL) was stuffed for 10 mm at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1/1) to afford the title compound (450 mg, 82%) as a white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01901; 01902

23
1-(2-bromopyridin-4-yl)methanamine [ No CAS ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 2-(((2-bromopyridin-4-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: A mixture of (2S,3R)- 1- [(tert-butoxy)carbonyl] -3-hydroxypyrrolidine-2-carboxylic acid (200 mg, 0.86 mmol, 1.00 equiv), DMF (10 mL), HATU (493.6 mg, 1.30 mmol, 1.50 equiv), DIEA (446.9 mg, 3.46 mmol, 4.00 equiv), and [6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methanamine hydrochloride (302.3 mg, 1.04 mmol, 1.20 equiv) was stuffed for 3 h at room temperature. The reaction was quenched by addition of 15 mL of water and extracted with ethyl acetate (3x15 mL). The organic layers were combined, washed with water (2x25 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 400 mg (99%) of the title compound as orange oil.[01948] The title compound (4812 mg, 98%) was prepared following the amide coupling procedure of Example 35, Step 1 from (2-bromo-4-pyridyl)methanamine (2020 mg, 10.800 mmol) , (25,4R)-1- tert-butoxycarbonyl-4-fluoro-pyffolidine-2-carboxylic acid (2771 mg, 11.88 mmol), HATU (4610 mg, 11.88 mmol) and triethylamine (3.31 mL, 23.7 mmol) in N,N-dimethylformamide (25 mL). LC/MS (ESI+): mlz 402 (M+H).

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 0606; 0607; 01677; 01678; 01947; 01948

24
[5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-[([5-chloro-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		A solution of (2S,4R)- 1- [(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (161.60 mg, 0.693 mmol, 1.0 equiv), DIEA (268.64 mg, 2.079 mmol, 3.0 equiv), and HATU (316.14 mg, 0.83 1 mmol, 1.2 equiv) in DMF (5 mL) was stirred for 30 mm at room temperature. [5-Chloro-2-[2- (trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine (200.00 mg, 0.693 mmol, 1.0 equiv) was then added to the solution. The resulting solution was stirred for 12 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:3) to afford the title compound (250 mg, 72%) as a white solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01989; 01990

25
[5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methanamine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-[([5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl]methyl)carbamoyl]-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	A solution of (2S,4R)- 1 -[(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (690 mg, 2.95 mmol, 1.23 equiv), HATU (1.091 g, 2.86 mmol, 1.20 equiv), DIEA (618 mg, 4.78 mmol, 2.00 equiv), and [5-chloro-4-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl] methanamine (690 mg,2.39 mmol, 1.00 equiv) in DMF (15 mL) was stuffed for 2 h at room temperature. The resulting solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with acetate/petroleum ether (1/5) to afford the title compound (800 mg, 66%) as a yellow solid.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 02078; 02079

26
[5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methanamine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-[([5-methoxy-2-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-4-yl]methyl)carbamoyl]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 0.5h;	A solution of (2S,4R)- 1- [(tert-butoxy)carbonyl] -4-fluoropyrrolidine-2-carboxylic acid (108 mg, 0.463 mmol, 1.097 equiv), DIEA (164 mg, 1.269 mmol, 3.0 equiv), HATU (193 mg, 0.508 mmol,1.202 equiv), and [5-methoxy-2- [2-(trifluoromethyl)pyrimidin-5 -yl]pyridin-4-yl]methanamine (120 mg, 0.422 mmol, 1.000 equiv) in N,N-dimethylformamide (8 mL) was stirred for 30 mm at 25C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1/5). This resulted in the title compound (180 mg, 85%) as light yellow oil.

Reference： [1]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 02131; 02132

27
2’-chloro-2-fluoro-[1,1’-biphenyl]-3-amine hydrochloride [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((2′-chloro-2-fluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(2S,4R)-tert-Butyl 2-02'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (16) To an ice-cold solution of 15 (530 mg) in 20 mL of CH2Cl2, 1-chloro-N,N,2-trimethylpropenylamine (0.333 mL, 1.1 equiv.) was added dropwise with stirring. The stirring was continued for 3 h at this temperature, then solid 14 (640 mg, 1.1 equiv) was added, followed by 1.12 mL of iPr2NEt (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. After completion of the reaction monitored by HPLC, the reaction mixture was added to water (20 mL) and extracted with DCM (2*25 mL). The organic layer was washed successively with an aqueous solution of NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with Hexanes/EtOAC) to give 16.
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	Scheme 5-1: In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 2 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. In Step 3 the appropriately substituted amine is Cbz-protected as known in the art to form a protected carboxylic acid. In Step 4 the appropriately substituted carboxylic acid can be orthogonally protected as known in the art to form an ester. In Step 5 the appropriately substituted and protected alkene is subjected to a carbene to form a bicyclic ring. In Step 6 the appropriately substituted ester is saponified with acid to liberate the carboxylic acid. In Step 7 the appropriately substituted Cbz-protected species is deprotected with hydrogen to liberate the free amine.
		To an ice-cold solution of 78 (530 mg) in 20 mL of CH2CI2, 1-chloro-N,N,2-trimethyl-1-propenylamine (0.333 mL, 1.1 equiv) was added dropwise with stirring. The stirring was continued for 3 h at this temperature, then solid 108 (640 mg, 1.1 equiv) was added, followed by 1.12 mL of iPnNEt (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. After completion of the reaction monitored by HPLC, the reaction mixture was added to water (20 mL) and extracted with DCM (2 x 25 mL). The organic layer was washed successively with an aqueous solution of NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2S04 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with Hexanes/EtOAC) to give 109.

		[0435] To an ice-cold solution of S4 (530 mg) in DCM (20 mL) was added 1-chloro- N,N,2-trimethyl-1-propenylamine (0.333 mL, 1.1 equiv) dropwise with stirring. The stirring was continued for 3 h at this temperature and then solid S5 (640 mg, 1.1 equiv) was added, followed by DIEA (1.12 mL, 3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at a The reaction mixture was then added to water (20 mL) and extracted with DCM (2 x 25 mL). The organic layer was washed successively with an aqueous solution of NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by column chromatography (eluted with hexanes/EtOAc) to give S6.
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	EXAMPLE 5. SYNTHESIS OF C-L-B MOIETIES Scheme 5-1 : In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 2 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. In Step 3 the appropriately substituted amine is Cbz-protected as known in the art to form a protected carboxylic acid. In Step 4 the appropriately substituted carboxylic acid can be orthogonally protected as known in the art to form an ester. In Step 5 the appropriately substituted and protected alkene is subjected to a carbene to form a bicyclic ring. In Step 6 the appropriately substituted ester is saponified with acid to liberate the carboxylic acid. In Step 7 the appropriately substituted Cbz-protected species is deprotected with hydrogen to liberate the free amine.
		(2S,4R)-ferf-ButyI 2-((2'-chloro-2-fluoro-[l,l'-biphenyl]-3-yl)carbamoyI)-4- fluoropyrrolidine-l-carboxylate [0551 ] To an ice-cold solution of 48 (530 nig) in 20 mL of CH2CI2, 1 -chloro-N,N,2- trimethylpropenylamine (0.333 mL, 1.1 equiv.) was added dropwise with stirring. The stirring was continued for 3 h at this temperature, then solid 65 (640 mg, 1 .1 equiv) was added, followed by 1.12 mL of iPnNEt (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at it. After completion of the reaction monitored by I [PLC, the reaction mixture was added to water (20 mL) and extracted with DCM (2 x 25 mL). The organic layer was washed successively with an aqueous solution of NaHCC (20 mL), water (20 mL), and brine (20 mL), then dried over a2S04 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with Hexanes/EtOAC) to give 66.
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	General procedure: Scheme 5-1: In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 2 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. In Step 3 the appropriately substituted amine is Cbz-protected as known in the art to form a protected carboxylic acid. In Step 4 the appropriately substituted carboxylic acid can be orthogonally protected as known in the art to form an ester. In Step 5 the appropriately substituted and protected alkene is subjected to a carbene to form a bicyclic ring. In Step 6 the appropriately substituted ester is saponified with acid to liberate the carboxylic acid. In Step 7 the appropriately substituted Cbz-protected species is deprotected with hydrogen to liberate the free amine.
		[04941 To an ice-cold solution of 3 (530 rng) in 20 mL of CH2CI2, ichloroN,N,2- trimethyi-J--propenylamine (C.3 33 mL, 1.1 equiv) was added dropwise with stirring. The stirring was continued for 3 h at this temperature and solid 4 (640 mg, 1. 1 equiv) was added followed by 1.12 mL of iPr2NEt (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. After completion of the reaction, which was monitored by HPLC, the reaction mixture was added to water (20 mL.) and extracted with DCM (2 x 25 mL). The organic layer was washed successively wth an aqueous solution of NaHCO3 (20 mL), water (20 rnL), and brine (20 mL), then dried over NaZSO4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with Hexanes/EtOAC) to give 5.
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 2 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. In Step 3 the appropriately substituted amine is Cbz-protected as known in the art to form a protected carboxylic acid. In Step 4 the appropriately substituted carboxylic acid can be orthogonally protected as known in the art to form an ester. In Step 5 the appropriately substituted and protected alkene is subjected to a carbene to form a bicyclic ring. In Step 6 the appropriately substituted ester is saponified with acid to liberate the carboxylic acid. In Step 7 the appropriately substituted Cbz-protected species is deprotected with hydrogen to liberate the free amine.
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	Scheme 5-1: In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 2 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. In Step 3 the appropriately substituted amine is Cbz-protected as known in the art to form a protected carboxylic acid. In Step 4 the appropriately substituted carboxylic acid can be orthogonally protected as known in the art to form an ester. In Step 5 the appropriately substituted and protected alkene is subjected to a carbene to form a bicyclic ring. In Step 6 the appropriately substituted ester is saponified with acid to liberate the carboxylic acid. In Step 7 the appropriately substituted Cbz- protected species is deprotected with hydrogen to liberate the free amine.
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	Scheme 5-1: In Step 1 the appropriately substituted carboxylic acid is coupled to the appropriately substituted amine as known in the art to form an amide. In Step 2 the appropriately substituted Boc-protected species is deprotected with acid to liberate the free amine. In Step 3 the appropriately substituted amine is Cbz-protected as known in the art to form a protected carboxylicacid. In Step 4 the appropriately substituted carboxylic acid can be orthogonally protected as known in the art to form an ester. In Step 5 the appropriately substituted and protected alkene is subjected to a carbene to form a bicyclic ring. In Step 6 the appropriately substituted ester is saponified with acid to liberate the carboxylic acid. In Step 7 the appropriately substituted Cbzprotected species is deprotected with hydrogen to liberate the free amine.

Reference： [1]Patent: US2015/239920,2015,A1 .Location in patent: Paragraph 0475; 0479
[2]Patent: WO2017/35411,2017,A1 .Location in patent: Paragraph 0554
[3]Patent: WO2017/35351,2017,A1 .Location in patent: Paragraph 0524; 0525
[4]Patent: WO2017/35360,2017,A1 .Location in patent: Paragraph 0435
[5]Patent: WO2017/35413,2017,A2 .Location in patent: Paragraph 0504
[6]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0551
[7]Patent: WO2017/35415,2017,A1 .Location in patent: Paragraph 0566; 0592; 0593
[8]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0494
[9]Patent: WO2017/35417,2017,A1 .Location in patent: Paragraph 0564
[10]Patent: WO2018/160891,2018,A1 .Location in patent: Page/Page column 489-491
[11]Patent: WO2018/160889,2018,A1 .Location in patent: Page/Page column 408; 410

28
[ 203866-14-2 ]
[ 72235-55-3 ]
tert-butyl (2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 5 - 20℃; for 18h;	Example 4 Synthesis of 4A. (2S,4R)-tert-butyl 2-((3-chloro-2-fluoro-benzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (2.33 mum, 10 mmol) was dissolved in DMF (50 ml) and iPr2NEt (8.6 ml, 5 eq.) was added, followed by the addition of (3-chloro-2-fluorophenyl) methanamine (3.18 mum 20 mmol) at 5 C. Then HATU (8 mum, 2.1 eq) was added slowly at same temperature. The reaction mixture was then stirred for 18 h at RT. After completion of the reaction monitored by HPLC, The reaction mixture was diluted with 1M citric acid solution (200 ml+NaCl solid 20 mum) and extracted with DCM (150 mL*2), the organic layer was then washed with an aqueous solution of NaHCO3 (100 ml) and washed with water (100 ml), brine (100 ml) and dried over Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by column chromatography (eluted with DCM/EtOAc) to give (2S,4R)-tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 5 - 20℃; for 18h;	[0488] (2S,4R)-l-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2.33 g, 10 mmol) was dissolved in DMF (50ml) and Psieta Epsilon (8.6 ml, 5 eq.) was added followed by the addition of (3-chloro-2-fluorophenyl) methanamine (3.18 g 20mmol) at 5 C. Then HATU (8 g, 2.1 eq) was added slowly at same temperature. The reaction mixture was then stirred for 18 h at RT. After completion of the reaction, which was monitored by HPLC, the reaction mixture was diluted with 1M citric acid solution (200ml + NaCl solid 20g), extracted with DCM (150 mL x 2), washed with an aqueous solution of NaHCCb (100 ml) water (100 ml), and brine (100 ml), dried over Na2S04 and concentrated under reduced pressure. The remaining residue was purified by column chromatography (eluted with DCM/EtOAc) to afford (2S,4R)-tert-butyl 2-((3-chloro-2- fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-l-carboxylate (95).
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 5 - 20℃; for 18h;	<strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> 78 (2.33 g, 10 mmol) was dissolved in DMF (50ml) and iPr2NEt (8.6 ml, 5 eq.) was added, followed by the addition of (3-chloro-2-fluorophenyl) methanamine 79 (3.18 g 20mmol) at 5 C. Then HATU (8 g, 2.1 eq) was added slowly at same temperature. The reaction mixture was then stirred for 18 h at RT. After completion of the reaction monitored by HPLC, the reaction mixture was diluted with 1M citric acid solution (200ml + NaCl solid 20gm) and extracted with DCM (150 mL x 2), the organic layer was then washed with an aqueous solution of NaHCO3 (100 ml) and washed with water (100 ml), brine (100 ml) and dried over Na2S04 and concentrated under reduced pressure. The remaining residue was purified by column chromatography (eluted with DCM/EtOAc) to give (2S,4R)-tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (80).

Reference： [1]Patent: US2015/239920,2015,A1 .Location in patent: Paragraph 0460; 0461; 0481
[2]Patent: WO2017/35348,2017,A1 .Location in patent: Paragraph 0488
[3]Patent: WO2017/35351,2017,A1 .Location in patent: Paragraph 0505; 0506
[4]Patent: WO2017/35349,2017,A1 .Location in patent: Paragraph 0508
[5]Patent: WO2017/35355,2017,A1 .Location in patent: Page/Page column 0539
[6]Patent: WO2017/35357,2017,A1 .Location in patent: Paragraph 0461; 0491

29
C₁₂H₁₀BrF₃O₄S [ No CAS ]
[ 203866-14-2 ]
C₂₂H₂₅F₄NO₈S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In acetonitrile; at 0 - 20℃; for 2h;	To the solution of compound 22-1 (0.63 g, 2.7 mmol, 1.05 eq) and compound 1-6 (1.0 g, 2.6 mmol, 1.0 eq) in acetonitrile (10 mL) was added dropwise triethylamine (0.39 g, 3.9 mmol, 1.5 eq) at 0 . After the addition, the mixture was stirred at rt for 2 h. The reaction mixture was concentrated to remove the solvent and to the residue was added 20 mL of water. Then the mixture was extracted with DCM (20 mL × 3) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the product as brown oil (1.43 g, 100) . 1H NMR (400 MHz, CDCl3) : delta 7.68 (d, J 8.5 Hz, 1H) , 7.21 (d, J 8.3 Hz, 1H) , 5.54 -5.35 (m, 1H) , 5.20 (dd, J 25.2, 13.6 Hz, 1H) , 4.62 (dt, J 21.6, 8.3 Hz, 1H) , 4.06 -3.52 (m, 3H) , 3.31 (t, J 7.4 Hz, 2H) , 3.06 (t, J 7.5 Hz, 2H) , 2.83 -2.64 (m, 1H) , 2.58 -2.33 (m, 1H) , 2.20 (dt, J 14.2, 7.3 Hz, 2H) , 1.48 (d, J 10.1 Hz, 10H) ppm.

Reference： [1]Patent: WO2016/141890,2016,A1 .Location in patent: Paragraph 00276; 00277

30
[ 13214-66-9 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;	11 To a solution of 93 (1 equiv) in DMF (10 vol) at 0 °C under nitrogen atmosphere was added 4-phenylbutan-l -amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water (30 vol). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/ MeOH to afford 160.
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	8 To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in DMF (10 vol) at 0 °C under nitrogen atmosphere was added 4-phenylbutan-1-amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water (30 ml). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous NaiSCn, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM MeOH to afford tert-butyl (2S,4R)-4-fluoro- 2-((4-phenylbutyl)carbamoyl)pyrroiidine-1-carboxyate. To a solution of tert-butyl (2S,4R)-4- fluoro-2-((4-phenylbutyl)carbamoyi)pyrrolidine-1-carboxylate (1 equiv) in 1,4-dioxane (3 mi) at 0 °C under nitrogen atmosphere was added 4 N HCl in 1,4-dioxane (10 ml) and stirred at room temperature for 3 h. The reaction mixture was concentrated to afford (2S,4R)-4-fluoro-N-(4- phenylbutyl)pyrrolidine-2-carboxamide (144).
	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;	12 To a solution of (2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in DMF (10 vol) at 0 °C under nitrogen atmosphere was added 4-phenylbutan-l- amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water (30 vol). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/ MeOH to afford tert-butyl (2S,4R)-4-fluoro- 2- ((4-phenylbutyl)carbamoyl)pyrrolidine-l-carboxylate. To a solution of tert-butyl (2S,4R)-4- fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidine-l-carboxylate (1 equiv) in 1,4-dioxane (3 vol) at 0 °C under nitrogen atmosphere was added 4 N HC1 in 1,4-dioxane (10 vol) and stirred at room temperature for 3 h. The reaction mixture was concentrated to afford (2S,4R)-4-fluoro-N-(4- phenylbutyl)pyrrolidine-2-carboxamide.

	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 3h;	6 To a solution of (2S,4R)-l-(rerr-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in DMF (10 vol) at 0 °C under nitrogen was added 4-phenylbutan-l -amine (1.2 equiv), HATIJ ( 1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water (30 voi). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2S0 , filtered and then concentrated. The residue was purified by column chromatography on silica, gel using DCM/ MeOH to afford iert-hutyi (2S,4R)-4-fluoro- 2-((4-phenylbutyl)carbamoyl)pyrroiidine-l-carboxylate.
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;	25 [0545] To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in DMF (10 vol) at 0 °C under nitrogen atmosphere was added 4-phenylbutan-1- amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water (30 vol). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/ MeOH to afford tert-butyl (2S,4R)-4-fluoro- 2-((4-phenylbutyl)carbamoyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (2S,4R)-4- fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidine-1-carboxylate (1 equiv) in 1,4-dioxane (3 vol) at 0 °C under nitrogen atmosphere was added 4 N HCl in 1,4-dioxane (10 vol) and stirred at room temperature for 3 h. The reaction mixture was concentrated to afford (2S,4R)-4-fluoro-N-(4- phenylbutyl)pyrrolidine-2-carboxamide. (85)
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;	6 To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in DMF (10 mL) at 0° C. under nitrogen atmosphere was added 4-phenylbutan-1-amine (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water (30 mL). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to afford tert-butyl (2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (2S,4R)-4-fluoro-2-((4-phenylbutyl)carbamoyl)pyrrolidine-1-carboxylate (1 equiv) in 1,4-dioxane (3 mL) at 0° C. under nitrogen atmosphere was added 4 N HCl in 1,4-dioxane (10 vol) and the reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated to afford (2S,4R)-4-fluoro-N-(4-phenylbutyl)pyrrolidine-2-carboxamide

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35348, 2017, A1 Location in patent: Paragraph 0558; 0559
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35351, 2017, A1 Location in patent: Paragraph 0560; 0561
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35349, 2017, A1 Location in patent: Paragraph 0617
[4]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35355, 2017, A1 Location in patent: Paragraph 0615
[5]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35357, 2017, A1 Location in patent: Paragraph 0461; 0545
[6]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 0626

31
[ 6638-79-5 ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;	To a solution of scheme 5-9 compound S1(5 g, 21.43 mmol)inDCM(100 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.72 mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followed by TEA (5.4 g, 53.58 mmol) at 0 C. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give crude product, which was washed with petroleum ether/EtOAc (2/1) to give the title compound (5.5 g, 92.88% yield) as a white solid.

Reference： [1]Patent: WO2017/35411,2017,A1 .Location in patent: Paragraph 0581

32
[ 1195768-18-3 ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-((2-fluoro-3-(methoxycarbonyl)phenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To an ice-cold solution of (2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxylic acid (1.24 g) in DCM (25 mL), was added l-chloro-N,N,2-trimethylprop-l-en-l- amine (0.845 mL, 1.2 equiv) dropwise with stirring. The stirring was continued for 3 hours at this temperature. Methyl <strong>[1195768-18-3]3-amino-2-fluorobenzoate</strong> (0.9 g) was then added followed by DIEA (2.78 mL, 3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The solvent was co-evaporated with MeOH (3 mL). The remaining residue was then dissolved in chloroform (30 mL) and washed successively with cold 1 N aq HC1 (3 x 20 mL), water (30 mL), and a saturated aq NaHCCb solution (30 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure to afford the title compound as an amber oil. Used without purification for the next step.

Reference： [1]Patent: WO2017/35408,2017,A1 .Location in patent: Paragraph 0642

33
[ 19798-81-3 ]
[ 203866-14-2 ]
(2S,4R)-1-tert-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.13%		In Scheme 2 below, boc-/ray-4-fluoroproine (intermediate 1) was reacted with 2-amino- (0601) 6-bromo pyridine (intermediate 2) in the presence of methyl imidazole (NMI) and methane sulfonyl chloride (MsCl). The reaction completion was monitored by HPLC and the product was extracted with dichlorom ethane and precipitated with dichioromethane/-heptane. The product was dried under vacuum in a vacuum tray dryer. (0602) Scheme 2 Synthesis of Intermediate 3 (0603) (0604) The process description is as follows: The reactor was charged with DCM (dry) (20.0 vol.) and boc-trans-4-fluoroproline (1.0 w/w) at 25±5 C under N2 atmosphere. The reaction mass was cooled to 0±5 C and stirred for 15 minutes. The reactor was slowly charged with 1 -methyl imidazole (0.88 w/w) at 0±5 C and stirred for 15 minutes (a change in temperature was observed from 0.8C to 3.8C). Methane sulfonyl chloride (0.59 w/w) was slowly added into the reactor at 0±5 C and stirred for 60 minutes. 2-Amino-6-bromo pyridine was added (0.74 w/w) at 0±5 C and the mass temperature was maintained between 0C to 25±5 C and stirred until reaction was complete. After completion of reaction, the reactor was charged with purified water (10.0 vol.), stirred for 20 minutes, and the layers were separated. The aqueous layer was extracted with DCM (20 vol.) and then with an additional (10 vol.) of DCM. The organic layers w^ere combined and washed with 10% HC1 solution (purified water 9.0 w/w, HC1 1.0 w/w), sodium bicarbonate solution (purified water 9.5 w/w, NaHC03 0.5 w/w) and brine (purified water 9.0 w/w, NaCl 1.0 w/w). The organic layer was concentrated under vacuum below 40 C'C until no distillate was observed. The reactor was charged with DCM (2 vol.) and -heptane (6 vol.) and stirred for 30 minutes. The reaction mass was cooled to 25±5 C and stirred for 1 hour. The mass ws filtered through A Nutsche filter and the cake was washed with n-heptane (2 vol .). The cake was vacuumed-dried on the filter for 40-50 minutes wiiile keeping the Nutsche filter under suction. The material was dried in a vacuum tray drier at 25±5 C for 2 hours and then at 30±5 C for 6 hours or until water content was achieved (acceptance criteria: water content: NMT 1.0%). The product was stored at the controlled temperature.
84.86%	With 1-methyl-1H-imidazole; methanesulfonyl chloride; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere; Large scale;	A'-Boc-troros^-Fluoro-L-proline (50.8 kg) was added to DCM (1000 L) in a glass-lined reactor under an atmosphere of nitrogen. The reaction mixture was cooled to 0 ± 5C and N-methylimidazole (44.7 kg) was added while maintaining the temperature at 0 ± 5C. Methanesulfonyl chloride (29.97kg) was slowly added to the reaction mixture followed by the addition of 2-amino-6-bromopyridine (2). The reaction temperature was warmed to room temperature and stirred for 12h. The reaction was monitored by HPLC. After completion of the reaction water (2,000 kg) was added, the reaction was stirred and the DCM layer separated. The aqueous layer was once more extracted with DCM (1000 L). The combined DCM layer was washed in succession with dilute HC1, aqueous NaHCCb and brine. The DCM extract was evaporated to dryness and tert-butyl (2S,4R)-2-((6-bromopyridin-2- yl)carbamoyl)-4-fluoropyrrolidine-l-carboxylate (3) was isolated using DCM heptane mixture and dried. Yield, 71.76 Kg (84.86%))
		To an ice cold solution of (2S,4R)-1-tert-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxylic acid (1 equiv) in DCM (10 vol), was added 1-chloro-N,N,2-trimethyl-1-propenylamine (1.1 equiv) dropwise with stirring. The stirring was continued for 3 h at this temperature, and then 6-bromopyridin-2-amine (1.1 equiv) was added, followed by DIEA (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water and extracted with DCM . The organic layer was washed successively with an aqueous solution of NaHCC , water and brine , then dried over NaiSC and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (hexanes/EtOAc) to give compound 189.

		To an ice-cold solution of (2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxylic acid (63, 530 mg) and DCM (20 mL) was added l-chloro-N,N,2-trimethyl-l- propenylamine (0.333 mL, 1.1 eq.) dropwise with stirring. The stirring was continued for 3 h at this temperature and 6-bromopyridin-2-amine (125, 427 mg) was added followed by 1.12 mL of DIEA (3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at RT. After completion of the reaction, the reaction mixture was added to water (20 mL) and extracted with DCM (2 x 25 mL). The organic layer was washed successively with an aqueous solution of NaHCCb (20 mL), water (20 mL), and brine (20 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent Hexanes/EtOAC) to afford (2S,4R)-tert-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4- fluoropyrrolidine- 1 -carboxylate (126).
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere;	General procedure: To a solution of Scheme 9-2 compound S1 (1 equiv) and 6-bromopyridin-2-amine (1.2 equiv) in DMF (10 vol) at 0 C was added DIPEA (2 equiv) and HATU (1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours and then quenched with water. The resultant solid was filtered, washed with MTBE to afford Scheme 9-2 compound S2.
		To an ice-cold solution of (2S,4R)-1-tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1.59 g) in DCM (20 mL), was added 1-chloro-N,N,2-trimethyl-1-propenylamine (998 mg, 1.1 equiv) dropwise with stirring. The stirring was continued for 3 h at this temperature, and then solid 6-bromopyridin-2-amine (1.3 g, 1.1 equiv) was added, followed by DIEA (3.34 mL, 3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water (20 mL) and extracted with DCM (2×25 mL). The organic layer was washed successively with an aqueous solution of NaHCO3(20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with hexanes/EtOAc) to give (2S,4R)-1-tert-Butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate.

Reference： [1]Patent: WO2020/69024,2020,A1 .Location in patent: Page/Page column 117-118
[2]Patent: WO2020/51538,2020,A1 .Location in patent: Page/Page column 77; 78
[3]Patent: WO2017/35351,2017,A1 .Location in patent: Paragraph 0594; 0595
[4]Patent: WO2017/35349,2017,A1 .Location in patent: Paragraph 0554
[5]Patent: WO2017/35415,2017,A1 .Location in patent: Paragraph 0566; 0648; 0658
[6]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0523

34
[ 42182-65-0 ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 2-(benzo[d]thiazol-2-ylmethylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;	To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (640 mg, 2.74 mmol) 78, HBTU (1.13 g, 3.0 mmol), and DIPEA (1.29 g, 10.0 mmol) in DCM (10 mL) was added <strong>[42182-65-0]benzo[d]thiazol-2-ylmethanamine</strong> (500 mg, 2.5 mmol) in one portion and the resulting reaction mixture was stirred at rt under nitrogen overnight, then diluted with DCM (50 mL). The resulting mixture was washed successively with 1 N aq HCl (2 x 25 mL), water (2 x 25 mL), saturated NaHCC (2 x 25 mL), and brine (25 mL). The organic layer was dried over anhydrous Na2S04, filtered, and then concentrated to afford the desired product (2S,4R)-tert-butyl 2-(benzo[d]thiazol-2-ylmethylcarbamoyl)-4-fluoropyrrolidine- 1 -carboxylate (124) without further purification.

Reference： [1]Patent: WO2017/35351,2017,A1 .Location in patent: Paragraph 0546; 0547

35
[ 89466-16-0 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-50° C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-50° C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5° C. Then <strong>[89466-16-0]6-bromo-3-methylpyridin-2-amine</strong> (200 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 430 mg (quantitative yield) of titled compound was obtained.
		Step 1: terf-Butyl (2S,4R)-2-((6-bromo-3-methylpyridin-2-yl)carbamoyI)-4- fluoropyrrolidine-l-carboxylate (209) [0696] To an ice cold solution of (2S,4R)-l -(feri-butoxycarbonyl)-4-fluoropyrrolidine-2- carbox lic acid (1 equiv) in DCM (10 vol) was added l-chloro-N,N,2-trimethyl-l-propenylamine ( 1 , 1 equiv) dropwise with stirring. Stirring was continued for 3 h at this temperature, and then 6- bromo-3-methylpyridin-2-amine (1.1 equiv) was added, followed by DIEA (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water and extracted with DCM. The organic layer was washed successively with an aqueous solution of NaHCCb, water and brine, then dried over Na2SO<i and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (DCM EtOAc) to give compound 209.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1460
[2]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0696

36
[ 1158786-59-4 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((6-bromo-4-methoxypyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		To an ice cold solution of (2S,4R)- 1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.1 mmole) in 6 mL of CH2Cl2, 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.15 mL, 1.1 equiv) was added drop-wise with stirring. The stirring was continued for 3 hours at the same temperature. Then <strong>[1158786-59-4]6-bromo-4-methoxypyridin-2-amine</strong> (239 mg, 1.0 equiv) was added, followed by 0.50 mL (3 equiv) Hunig's base. The cooling bath was removed and the reaction mixture was stirred at room temperature for overnight. The solvent was co-evaporated with 5 mL of MeOH, and the residue was purified by ISCO (eluted with ethyl acetate in hexane, gradient) to obtain 436 mg (97%) of tert-butyl-(2S,4R)-2-((6-bromo-4-methoxypyridine-2-yl)carbamoyl-4-fluoropyrrolidine-1-carboxylate as clear oil.
		Step 1: ferf-Butyl (2S,4R)-2-((6-bromo-4-methoxypyridin-2-yl)carbamoyl)-4- fluoropyrrolidine-l-carboxylate (211) [0698] To an ice-cold solution of (2S,4R)~l-(/m-butoxycarbonyl)-4-fluoropyrro]idine-2- carboxylic acid (1 equiv) in DCM (10 vol) was added l-chloro-N,N,2-trimethyl-l-propenylamine ( 1.1 equiv) dropwise with stirring. The stirring was continued for 3 h at this temperature, and then <strong>[1158786-59-4]6-bromo-4-methoxypyridin-2-amine</strong> (1.1 equiv) was added, followed by DIEA (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water and extracted with DCM. The organic layer was washed successively with an aqueous solution of NaHCCb, water and brine, then dried over Na SC and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (DCM/EtOAc) to give compound 211.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1415
[2]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0698

37
[ 1257294-51-1 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((6-bromo-5-fluoropyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then 6-bromo-5-fluoropyridin-2-amine (204 mg, 1 equiv) was added, and stirred for 18 h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and to obtain titled compound 400 mg (quantitative yield).
		Step 1: ieri-Butyl (2S,4R)-2-((6-bromo-5-fluoropyridin-2-yl)carbamoyl)-4- fluoropyrrolidine-l-carboxylate (213) [0700] To an ice cold solution of (2S,4R)-l-(t<?rt-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxyiic acid (1 equiv) in DCM (10 vol) was added l-chloro-N,N,2-trimethyl-l-propenylamine ( 1.1 equiv) dropwise with stirring. The stirring was continued for 3 h at this temperature, and then 6-bromo-5-fluoropyridin-2-amine (1.1 equiv) was added, followed by DIEA (3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water and extracted with DCM. The organic layer was washed successively with an aqueous solution of aHCO , water and brine, then dried over NaaSOt and concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel (DCM/EtOAc) to give compound 213

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1451
[2]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0700

38
[ 1824-81-3 ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-(6-methylpyridin-2-ylcarbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.9%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 90℃;Inert atmosphere;	[0597] To a mixture of compound 34 (7.0 g, 0.03 mol) in DCE (60 mL) was added ethyl 2-ethoxyquinoline-1(2H)-carboxylate (14.84 g, 0.06 mol), N, N'-diisopropylethylamine (11.63 g, 0.09 mol) and 6-methylpyridin-2-amine (3.24 g, 0.03 mol), then the reaction was stirred at 90 oC under N2 atmosphere overnight. The mixture was cooled, quenched with water and extracted with DCM twice. The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (eluted with PE/ EtOAc = 30: 1 to 2: 1) to give the title compound (9.50 g, 97.9 % yield) as white solid. LC/MS (ESI) m/z: 324 (M+H)+.

Reference： [1]Patent: WO2017/35357,2017,A1 .Location in patent: Paragraph 0461; 0597

39
[ 203866-14-2 ]
[ 188637-63-0 ]
tert-butyl (2S,4R)-2-(((6-bromopyridin-2-yl)methyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
101 mg	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3h;	To the mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (233 mg, 1.0 mmol), <strong>[188637-63-0](6-bromopyridin-2-yl)methanamine</strong> (205 mg, 1.1 mmol) in CH3CN (10.0 mL), EDCI (1.3 eq) was added, followed by dropwise addition of DIEA (4.0 eq) at room temperature. The mixture was stirred for 3 h at room temperature and the volatiles are evaporated. The residue was diluted with 50 mL of 10% sodium carbonate and extracted with ethyl acetate. The combined organic solution was successively washed with water, brine and dried over MgSO4. The solution was filtered and the solvent was removed. The residue was purified to afford 101 mg of the title compound.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1110

40
[ 36052-26-3 ]
[ 203866-14-2 ]
methyl 6-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxamido)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.65 g	With pyridine; trichlorophosphate In dichloromethane at 0℃; for 1h;	6.1 Step-1: Methyl 6-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxamido)picolinate (S3) In a pre-dried flask, (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1.17 g, 5.0 mmol), methyl 6-aminopicolinate (837 mg, 5.5 mmol) are placed, and then anhydrous DCM (20 mL) was added. The flask was placed in an ice bath. To the solution, dry pyridine (0.81 mL, 10.0 mmol) was added in one portion, followed by addition of POCl3(0.48 mL, 5.0 mmol). After completion of addition, the mixture was stirred for 1 hours at 0° C., and then the reaction was quenched with water (15 mL). The DCM layer was collected and the aqueous phase was extracted with DCM (15 mL×2). The combined DCM solution was washed with brine, and dried over MgSO4. The solution was filtered and concentrated; the resulting residue was purified to give 1.65 g desire product.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 1128

41
[ 89466-17-1 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((6-bromo-5-methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then <strong>[89466-17-1]6-bromo-5-methylpyridin-2-amine</strong> (200 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and to obtain titled compound 404 mg (quantitative yield).

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1457

42
[ 89088-55-1 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((5-bromo-1-methyl-1H-pyrazol-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (158 mg, 0.68 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.14 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.06 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then <strong>[89088-55-1]5-bromo-1-methyl-1H-pyrazol-3-amine</strong> (120 mg, 1 equiv) was added, and stirred for 18 h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3(10 mL) and with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and ready to use in step-2.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1439

43
[ 916737-77-4 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((6-bromo-3-methoxypyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then <strong>[916737-77-4]6-bromo-3-methoxypyridin-2-amine</strong> (217 mg, 1 equiv) was added, and stirred for 18 h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and purified by ISCO (SiO2, 5% MeOH in DCM gradient) to obtain titled compound 220 mg (50% yield).

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1442

44
[ 1005508-80-4 ]
[ 203866-14-2 ]
methyl 2-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxamido)-6-chloroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then <strong>[1005508-80-4]methyl 2-amino-6-chloroisonicotinate</strong> (201 mg, 1 equiv) was added, and stirred for 18 h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and purified by ISCO (5% MeOH in DCM gradient) to obtain titled compound 130 mg (32% yield).

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1448

45
[ 56131-46-5 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((3-bromo-2-chlorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
301 mg		To an ice cold solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.1 mmole) in 6 mL of CH2Cl2, 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.15 mL, 1.1 equiv) was added drop-wise with stirring. The stirring was continued for 3 hours at the same temperature. Then <strong>[56131-46-5]3-bromo-2-chloroaniline</strong> (244 mg, 1.1 equiv) was added, followed by 0.50 mL (3 equiv) Hunig's base. The cooling bath was removed and the reaction mixture was stirred at room temperature for overnight. The solvent was co-evaporated with 5 mL of MeOH, and the residue was purified by ISCO (eluted with ethyl acetate in hexane, gradient) to obtain 301 mg of tert-butyl (2S,4R)-2-((3-bromo-2-chlorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate as yellow solid.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1424

46
[ 1206249-65-1 ]
[ 203866-14-2 ]
[ 2086188-68-1 ]

Yield	Reaction Conditions	Operation in experiment
286 mg	Stage #1: (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In dichloromethane at 20℃; for 3h; Cooling with ice; Stage #2: 6-bromo-4-chloro-pyridin-2-ylamine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	6.1 Step-1: tert-Butyl (2S,4R)-2-((6-bromo-4-chloropyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (S3) To an ice cold solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (221 mg, 0.95 mmole) in 6 mL of CH2Cl2, 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.14 mL, 1.1 equiv) was added drop-wise with stirring. The stirring was continued for 3 hours at the same temperature. Then 6-bromo-4-chloropyridin-2-amine (217 mg, 1.1 equiv) was added, followed by 0.40 mL (3 equiv) Hunig's base. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was co-evaporated with 5 mL of MeOH, and the residue was purified by ISCO (eluted with ethyl acetate in hexane, gradient) to obtain 286 mg of tert-butyl (2S,4R)-2-((6-bromo-4-chloropyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate as yellow solid.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 1427

47
1-(2,2-difluoroethyl)-1H-pyrazol-3-amine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then 1-(2,2-difluoroethyl)-1H-pyrazol-3-amine (157 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and to obtain titled compound 386 mg as a white solid (quantitative yield).

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1454

48
[ 869557-43-7 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((3-bromo-5-fluoropyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then <strong>[869557-43-7]3-bromo-5-fluoropyridin-2-amine</strong> (204 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 195 mg (48%) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1466

49
4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine (261 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 455 mg (98%, white solid) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1469

50
4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then 4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine (192 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 401 mg (quantitative yield) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1472

51
5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then 5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine (192 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 421 mg (quantitative yield) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1475

52
5-bromo-2-fluoropyridin-4-amine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((5-bromo-2-fluoropyridin-4-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then 5-bromo-2-fluoropyridin-4-amine (189 mg, 1 equiv) was added, and stirred for 18 h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 365 mg (84%) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1485; 1486

53
[ 72583-83-6 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-((1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then <strong>[72583-83-6]1-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine</strong> (159 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 259 mg (71%) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1489

54
[ 502145-18-8 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((4-bromothiazol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50 C. Then <strong>[502145-18-8]4-bromothiazol-2-amine</strong> (179 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 390 mg (97%) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1492

55
4-bromo-5-methylthiazol-2-amine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((4-bromo-5-methylthiazol-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then 4-bromo-5-methylthiazol-2-amine (207 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 409 mg (quantitative yield) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1495

56
[ 55361-49-4 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((1-ethyl-1H-pyrazol-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
304 mg	Stage #1: (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid With 1-methyl-1H-imidazole In dichloromethane at 0 - 5℃; for 0.166667h; Inert atmosphere; Stage #2: With methanesulfonyl chloride In dichloromethane at 0 - 5℃; for 1h; Stage #3: 1-ethyl-1H-pyrazole-3-amine In dichloromethane at 20℃; for 18h;	6.1 Step-1: tert-Butyl (2S,4R)-2-((1-ethyl-1H-pyrazol-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (S2) To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5° C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5° C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50° C. Then 1-ethyl-1H-pyrazol-3-amine (119 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 304 mg of titled compound was obtained.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 1499

57
[ 1060815-73-7 ]
[ 203866-14-2 ]
[ 2086189-37-7 ]

Yield	Reaction Conditions	Operation in experiment
181 mg	Stage #1: (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid With 1-methyl-1H-imidazole In dichloromethane at 0 - 5℃; for 0.166667h; Inert atmosphere; Stage #2: With methanesulfonyl chloride In dichloromethane at 0 - 5℃; for 1h; Stage #3: 6-bromo-3-chloropyridin-2-ylamine In dichloromethane at 20℃; for 18h;	6.1 Step-1: tert-Butyl (2S,4R)-2-((6-bromo-3-chloropyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate (S2) To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5° C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5° C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-50° C. Then 6-bromo-3-chloropyridin-2-amine (220 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and purified by ISCO (silica gel, eluted with 5% CH3OH in DCM gradient) 181 mg of titled compound was obtained.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 1502

58
1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-amine [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-((1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		To a stirred solution of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (250 mg, 1.07 mmole) in 10 mL of CH2Cl2, was added 1-methyl imidazole (0.21 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.1 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then 1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-amine (191 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (10 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with 1N HCl (10 mL), followed by Sat NaHCO3 (10 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and 395 mg (quantitative yield) of titled compound was obtained.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1505

59
[ 34486-24-3 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (125 mg, 0.54 mmole) in 8 mL of CH2Cl2, was added 1-methyl imidazole (0.11 mL, 2.5 equiv.) at 0-5 C. under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 C. and then added methane sulfonyl chloride (0.05 mL, 1.2 equiv) at the same temperature. It was stirred for 1 h at 0-5 C. Then <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (88 mg, 1 equiv) was added, and stirred for 18h at room temperature. Water (15 mL) was added to the reaction mixture, layers were separated and aqueous layer was extracted with DCM (3×15 mL). The combined organic layer was washed with IN HCl (15 mL), followed by Sat NaHCO3 (15 mL) and then with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and purified by ISCO (silica gel, eluted by 5% MeOH in DCM gradient) to obtained 200 mg (99%) of titled compound as a clear oil.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1529

60
[ 1227048-73-8 ]
[ 203866-14-2 ]
[ 2086189-70-8 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; trichlorophosphate In dichloromethane at 0 - 20℃; Inert atmosphere;	6.1 Step-1: Methyl 6-bromo-2-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxamido)nicotinate (S2) To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (128 mg, 0.55 mmole) and methyl 2-amino-6-bromonicotinate (126 mg, 1 equiv) in 10 mL of CH2Cl2, was added pyridine (0.22 mL, 5 equiv.), cooled to 0-5° C., added POCl3 drop wisely (0.051 mL, 1.0 equiv) at the same temperature under nitrogen. After addition, the reaction mixture was warmed up to room temperature and stirred until completion. It was diluted with 10 mL DCM, added Sat NaHCO3 solution and stirred for a while. Layers were separated and aqueous layer was extracted with DCM (1×5 mL). The combined organic layer was washed with brine (10 mL). Combined organic layer was dried over Na2SO4, concentrated and purified by ISCO (silica gel, eluted by 5% MeOH in DCM gradient) to obtained 74 mg (30%) of titled compound as yellow oil.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 1538

61
[ 17920-35-3 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-((6-methoxypyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To an ice cold solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (0.3 g) in 6 mL of CH2Cl2, 1-chloro-N,N,2-trimethyl-1-propenylamine (204 muL) was added dropwise with stirring. The stirring was continued for 3 hours at same temperature. Then, 6-methoxypyridin-2-amine (0.145 g) was added followed by 672 muL of Huenig's base. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The solvent was co-evaporated with MeOH (2 mL) and the residue was purified by ISCO (eluent: 0-0.5percent MeOH in CH2Cl2).

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1669

62
[ 17920-35-3 ]
[ 203866-14-2 ]
(2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4-fluoro-N-(6-methoxypyridin-2-yl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/35353,2017,A1

63
[ 103977-79-3 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((3-bromo-2,4-difluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;Inert atmosphere;	To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in DMF (10 vol) at 0 C. under nitrogen atmosphere was added <strong>[103977-79-3]3-bromo-2,4-difluoroaniline</strong> (1.2 equiv), HATU (1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to give compound S2.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0659

64
(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)methanamine [ No CAS ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.4%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a mixture of <strong>[203866-14-2](2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid</strong> (69 mg, 0.30 mmol) and 1-(2, 2, 2-trifluoroethyl) pyrrolidin-3-amine (50 mg, 0.30 mmol) in DMF (2 mL) was added DIPEA (154 mg, 1.19 mmol) and HATU (226 mg, 0.60 mmol). The reaction was stirred at room temperature for 2 hrs. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed by brine, dried over anhydrous Na2SO4and concentrated. The obtained crude product was purified by column chromatography on silica gel eluted with PE/EtOAc (30:1 to 3:1) to give the title compound (110 mg, 96.4% yield) as white soid; LC/MS (ESI) m/z: 384 [M+H]

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0792

65
[ 1824-81-3 ]
[ 203866-14-2 ]
(2S,4R)-tert-butyl 4-fluoro-2-(6-methylpyridin-2-ylcarbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.9%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 90℃;Inert atmosphere;	To a mixture of compound S1 (7.0 g, 0.03 mol) in DCE (60 mL) was added ethyl 2-ethoxyquinoline-1 (2H)-carboxylate (14.84 g, 0.06 mol), N, N?-diisopropylethylamine (11.63 g, 0.09 mol) and 6-methylpyridin-2-amine (3.24 g, 0.03 mol). The reaction was stirred at 90 C. under N2atmosphere overnight. Then the mixture was cooled, quenched with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by column chromatography on silica gel (eluted with PE/EtOAc=30:1 to 2:1) to give the title compound (9.50 g, 97.9% yield) as white solid. LC/MS (ESI) m/z: 324 (M+H)

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0958; 1526

66
[ 1159512-64-7 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-((2-fluoro-3-(trifluoromethoxy)phenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12.0h;	To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (1 equiv) in DMF (10 vol) at 0 C. under nitrogen atmosphere was added <strong>[1159512-64-7]2-fluoro-3-(trifluoromethoxy)aniline</strong> (1.2 equiv), HBTU (1.5 equiv) and DIPEA (3 equiv). The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel using DCM/MeOH to give compound 1239.

Reference： [1]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 0966

67
methyl 2-(2-amino-6-bromopyridin-3-yl)acetate [ No CAS ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((6-bromo-3-(2-methoxy-2-oxoethyl)pyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With pyridine; trichlorophosphate; In dichloromethane; at 20℃;Inert atmosphere;	POC13 (0.08 mL, 2 equiv) was added dropwise at 0-5 C under an atmosphere of argon to a solution of (2S,4R)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (91 mg, lequiv) and 117-S4 (96mg, 1equiv) in DCM (10 mL) and pyridine (0.16 mL, 5 equiv). The reaction mixture was warmed to room temperature and stirred until complete. The reaction was diluted with DCM (10 mL) and neutralized with aqueous saturated NaHCO3 solution (10 mL). The aqueous layer was extracted with DCM (lx 10 mL) and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatographyon silica gel (eluted by 5% MeOH in DCM gradient) to afford 117-S5 (146 mg, 82 %).

Reference： [1]Patent: WO2018/160889,2018,A1 .Location in patent: Page/Page column 548; 549

68
[ 203866-14-2 ]
2-(trifluoromethoxy)ethan-1-amine [ No CAS ]
tert-butyl (2S,4R)-4-fluoro-2-((2-(trifluoromethoxy)ethyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To a stirred solution of (2S, 4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxylic acid (scheme 8-40 compound S1, 160 mg, 0.7 mmole) in 10 mL of DMF was added 2- (trifluoromethoxy)ethan-1-amine (116 mg, 1 equiv), DIEA (0.4 mL, 3 equiv). This was followed by addition of HATU (319 mg, 1.2 equiv) under nitrogen atmosphere. The reaction mixture was stirred at room temperature. Water (10 mL) and ethyl acetate (15mL) were added to the reaction mixture, layers were separated and the aqueous layer was extracted with EtOAc (1x10mL). The combined organic layer was washed with 1N HCl (10 mL), saturated NaHCO3 (10mL), and brine (10mL). Combined organic layers were dried over Na2SO4, concentrated and 250 mg (quantitative yield) of 557 was obtained.

Reference： [1]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0749

69
[ 15673-00-4 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((3,3-dimethylbutyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To a stirred solution of (2S, 4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxylic acid (scheme 8-41 compound S1, 157 mg, 0.7 mmole) in 10 mL of DMF was added 3,3-dimethylbutan-1-amine (0.1 mL, 1 equiv) and DIEA (0.4 mL, 3 equiv). This was followed by addition of HATU (319 mg, 1.2 equiv) under nitrogen atmosphere. The reaction mixture was stirred at room temperature. Water (10 mL) and ethyl acetate (15mL) were added to the reaction mixture, layers were separated and the aqueous layer was extracted with EtOAc (1x10mL). The combined organic layer was washed with 1N HCl (10 mL), saturated NaHCO3 (10mL) and brine (10mL). Combined organic layers were dried over Na2SO4 and concentrated to yield 225 mg (quantative yield) of the title compound.

Reference： [1]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0752

70
[ 81-05-0 ]
[ 203866-14-2 ]
6-((2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxamido)naphthalene-1-sulfonic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoropyrrolidine-2-carboxylic acid With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In dichloromethane for 3h; Stage #2: 6-aminonaphthalene-1-sulfonic acid With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	1 Step-1: 6-((2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2- carboxamido)naphthalene-1-sulfonic acid (S3) . To an ice-cold solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxylic acid (scheme 9-9 compound S1, 233 mg) in DCM (20 mL) was added 1-chloro-N,N,2- trimethyl-1-propenylamine (146 mg, 1.1 equiv) dropwise with stirring. Stirring was continued for 3 h at this temperature, and then solid 6-aminonaphthalene-1-sulfonic acid (256 mg, 1.1 equiv) was added, followed by DIPEA (0.49 mL, 3 equiv). The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to water (10 mL) and extracted with DCM (2 10 mL). The organic layer was washed successively with an aqueous solution of NaHCO3 (10 mL), water (10 mL), and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The remaining material was used directly in the next synthetic step.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35409, 2017, A1 Location in patent: Paragraph 0808

71
[ 129012-04-0 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-2-((2-amino-6-bromopyridin-3-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (2S,4R)-2-((3-amino-6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 2h;	To the solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2- carboxylic acid (456 mg, 1.95mmol), <strong>[129012-04-0]6-bromopyridine-2,3-diamine</strong> (scheme 9-28 compound S1, 405 mg, 2.15mmol) and EDCI (412 mg, 2.15mmol) in CH3CN (15mL), DIEA (775 mg, 6.0mmol) was added dropwise at 0 C. After completion of addition, the mixture was warmed to room temperature and stirred for additional 2 h. The volatiles were evaporated and the residue was mixed with water (25mL), the resulting solid was collected, washed with water and dried. The compounds scheme 9-28 S2a and S2 were carried forward without further purification.

Reference： [1]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0866

72
[ 129012-04-0 ]
[ 203866-14-2 ]
tert-butyl (4R)-2-(5-bromo-1H-imidazo[4,5-b]pyridin-2-yl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Scheme 9-28 compounds S2a and S2 were suspended in toluene (20ml) followed by addition of acetic acid (4mL). The mixture was heated at 130 C overnight. The reaction was cooled to room temperature and the volatiles were evaporated. The resulting residue was neutralized with ammonium hydroxide. The precipitation was dissolved in ethyl acetate, washed with water and dried over MgSO4. The solution was filtered and concentrated. The resulting title compounds were used in the next Step without further purification.

Reference： [1]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0867

73
[ 801282-00-8 ]
[ 203866-14-2 ]
tert-butyl (2S,4R)-4-fluoro-2-((2-fluoro-3-methoxyphenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a solution of <strong>[801282-00-8]2-fluoro-3-methoxyaniline</strong> (1.2 equiv) and compound 7 (lequiv) in DMF (10 vol) is added DIPEA (2equiv) and HATU (1.2 equiv). The reaction mixture is stirred at room temperature for 12 h then quenched with water. The resulting mixture is extracted with EtOAc. The organic layer is separated, dried over anhydrous Na2S04, filtered and then concentrated. The residue is purified by column chromatography on silica gel to afford compound 8.

Reference： [1]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0928

74
[ 2033-24-1 ]
[ 203866-14-2 ]
tert-butyl (2RS,4R)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)-4-fluoropyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.5%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 25℃; for 12h;	To a solution of (2S,4R)-l-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (450.0 g, 1.93 mol, 1.00 eq.) and 2, 2-dimethyl- l,3-dioxane-4,6-dione (278.0 g, 1.93 mol, l.OOeq.) in dichloromethane (3.00 L) was added DMAP (471.4 g, 3.86 mol, 2.00 eq.) and the mixture was cooled down to 0 C. DCC (398.0 g, 1.93 mol, 390.3 mL, 1.00 eq.) was added in several portions and the reaction mixture was stirred at 25 C for 12 hours. The reaction mixture was filtered and then the filtrate was washed with 1M HC1 (2.00 L) and then organic layer were concentrated in vacuum to give the desired product (1.20 kg, 3.34 mol, 86.5% yield) as a yellow solid used directly for next step.

Reference： [1]Patent: WO2020/2487,2020,A1 .Location in patent: Page/Page column 70-71

75
[ 203866-14-2 ]
[ 1903768-17-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1-methyl-1H-imidazole; methanesulfonyl chloride / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere; Large scale 2: hydrogenchloride / 1,4-dioxane / 1 h / 25 °C / Inert atmosphere; Large scale 3: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 10 - 25 °C / Large scale
	Multi-step reaction with 3 steps 1.1: 1-methyl-1H-imidazole; methanesulfonyl chloride / dichloromethane / 1 h / 0 °C / Inert atmosphere; Large scale 1.2: 0 - 25 °C / Inert atmosphere; Large scale 2.1: hydrogenchloride / 1,4-dioxane / 4 h / 20 °C / Inert atmosphere; Large scale 3.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 4.33 h / 10 - 25 °C / Inert atmosphere; Large scale

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2020/51538, 2020, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2020/69024, 2020, A1

76
[ 203866-14-2 ]
[ 60604-36-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 2h; Inert atmosphere;	Step A: (2S,4R)-4-Fluoropyrrolidine-2-carboxylic acid hydrochloride. To a suspension of (2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (3 g, 12.9 mmol) in dichloromethane (60 mL) was added hydrogen chloride (4.2 M in 1,4-dioxane, 30 mL, 126 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated. To the residue was added diethyl ether (20 mL) and the mixture was evaporated. This procedure was repeated twice to remove excess hydrochloric acid to give the title compound (2.15 g, 12.678 mmol, 99%) as a white powder. MS (ESI): mass calcd. for C5H8FNO2.HCl, 133.1; found 134.2 [M+H]+.
99%	With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 2h; Inert atmosphere;	Step A: (2S,4R)-4-Fluoropyrrolidine-2-carboxylic acid hydrochloride. To a suspension of (2S,4R)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (3 g, 12.9 mmol) in dichloromethane (60 mL) was added hydrogen chloride (4.2 M in 1,4-dioxane, 30 mL, 126 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated. To the residue was added diethyl ether (20 mL) and the mixture was evaporated. This procedure was repeated twice to remove excess hydrochloric acid to give the title compound (2.15 g, 12.678 mmol, 99%) as a white powder. MS (ESI): mass calcd. for C5H8FNO2.HCl, 133.1; found 134.2 [M+H]+.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2022/58920, 2022, A1 Location in patent: Page/Page column 134; 258-259
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2022/58920, 2022, A1 Location in patent: Page/Page column 134; 258-259

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	203866-14-2	MDL No. :	MFCD06796085
Formula :	C₁₀H₁₆FNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YGWZXQOYEBWUTH-RQJHMYQMSA-N
M.W :	233.24	Pubchem ID :	12043048
Synonyms :	N-Boc-trans-4-fluoro-L-proline	Chemical Name :	(2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	58.42
TPSA :	66.84 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) :	-6.81 cm/s

Log Po/w (iLOGP) :	1.8
Log Po/w (XLOGP3) :	1.28
Log Po/w (WLOGP) :	1.46
Log Po/w (MLOGP) :	0.89
Log Po/w (SILICOS-IT) :	0.26
Consensus Log Po/w :	1.14

[ CAS No. 203866-14-2 ] {[proInfo.proName]}

Quality Control of [ 203866-14-2 ]

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Calculated chemistry of [ 203866-14-2 ]

Physicochemical Properties

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Application In Synthesis of [ 203866-14-2 ]

[ 203866-14-2 ] Synthesis Path-Upstream 1~13

[ 203866-14-2 ] Synthesis Path-Downstream 1~76

Related Functional Groups of
[ 203866-14-2 ]

Carboxylic Acids

Related Parent Nucleus of
[ 203866-14-2 ]

Pyrrolidines

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Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Log S (ESOL) :	-1.83
Solubility :	3.46 mg/ml ; 0.0148 mol/l
Class :	Very soluble
Log S (Ali) :	-2.28
Solubility :	1.22 mg/ml ; 0.00521 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.42
Solubility :	87.7 mg/ml ; 0.376 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.24

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313	UN#:	N/A
Hazard Statements:	H315-H319	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
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