Name: 34306-42-8|Boc-Abu-OH|97%
Brand: Ambeed
SKU: A169982
Price: 13.0 USD
Availability: InStock
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1
[ 1492-24-6 ]
[ 24424-99-5 ]
[ 34306-42-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; sodium hydroxide In water; <i>tert</i>-butyl alcohol	45.A A. A. (S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]butyric acid A mixture of (S)-(+)-2-aminobutyric acid (5.0 g, 48.5 mmol), sodium hydroxide pellets (2.0 g, 50 mmol), water (5 mL), t-butanol (20 mL), and di-t-butyldicarbonate (11.0 g, 50 mmol) was stirred at 25°C for 18 hours. The mixture was then poured into water and washed with ether. The aqueous layer was acidified by addition of dilute hydrochloric acid and was extracted with ethyl acetate (2x). The extract was dried and concentrated to give Compound A as a colorless oil (10.3 g, >100%), which was used without further purification.
99%	With sodium hydroxide In tetrahydrofuran; water at 20℃; for 12h;	31.1 Step 1: (S) -2- ( (tert-Butoxycarbonyl) amino) butanoic acid Step 1: (S) -2- ( (tert-Butoxycarbonyl) amino) butanoic acid[0869]To a solution of L-2-aminobutyric acid (2.0 g, 19.40 mmol) and di-tert-butyl dicarbonate (4.67 g, 21.4 mmol) in tetrahydrofuran (25 mL) was added dropwise aqueous sodium hydroxide (1 M, 23 mL) at 0 . The mixture was stirred at rt for 12 hours and hydrochloric acid (1 M) was added to adjust the pH of the mixture to 1. The resulting mixture was extracted with ethyl acetate (20 mL × 3) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound as a white solid (4.4 g, 99) .[0870]1H NMR (400 MHz, CDCl3) : δ ppm 10.52 (s, 1H) , 4.32 -4.08 (m, 1H) , 1.95 -1.89 (m, 1H) , 1.78 -1.69 (m, 1H) , 1.45 (s, 9H) , 1.00 -0.96 (m, 3H) .
98%	Stage #1: L-2-aminobutyric acid With sodium hydroxide In tetrahydrofuran; water at 0℃; for 0.166667h; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran; water at 0 - 20℃; for 24h;

93%	With sodium hydroxide In methanol at 0 - 20℃; for 12h;
91%	With sodium hydroxide In 1,4-dioxane; water for 5h; Ambient temperature;
91%	With sodium hydroxide In methanol at 0 - 20℃;
	With sodium hydroxide
	With sodium hydroxide In 1,4-dioxane at 20℃;
	Stage #1: L-2-aminobutyric acid; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h; Stage #2: With hydrogenchloride In tetrahydrofuran; water; ethyl acetate	74.1 Step 74-1: Synthesis of (2S)-2-[(tert-butoxy carbonyl)amino]butanoic acid In an aqueous solution of 2 mol/L NaOH (30 ml), 3.00 g of (2S)-2-amino butanoic acid was dissolved, THF (10 ml) and (Boc)2O (25 ml) were added, and the solution was stirred at room temperature for 4 hours. EtOAc was added, liquid separation was performed, the pH of the aqueous layer was adjusted to 2 with 1 mol/L hydrochloric acid, and then, this was extracted with EtOAc. The organic layers were combined, washed with water and saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure to obtain 4.50 g of the title compound. The present compound was used in the next reaction without purification. MS (ESI pos.) m/z: 226 ([M+Na]+) 1H-NMR (300 MHz, CDCl3) δ (ppm); 0.99 (t, J=7.5 Hz, 3H), 1.45 (s, 9H), 1.65-1.82 (m, 1H), 1.84-2.01 (m, 1H), 4.20-4.34 (m, 1H), 5.00 (d, J=7.6 Hz, 1H)
	With sodium carbonate In 1,4-dioxane; water
	With potassium carbonate In tetrahydrofuran; water for 24h;

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP618221, 1994, A2
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2015/161830, 2015, A1 Location in patent: Paragraph 00388
[3]Yadav, Vitthal N.; Comotti, Angiolina; Sozzani, Piero; Bracco, Silvia; Bonge-Hansen, Tore; Hennum, Martin; Görbitz, Carl Henrik [Angewandte Chemie - International Edition, 2015, vol. 54, # 52, p. 15684 - 15688][Angew. Chem., 2015, vol. 127, # 52, p. 15910 - 15914]
[4]Szczes̈niak, Piotr; Pieczykolan, Michał; Stecko, Sebastian [Journal of Organic Chemistry, 2016, vol. 81, # 3, p. 1057 - 1074]
[5]Cheung, Kam Sing; Boisvert, William; Lerner, Stephen A.; Johnston, Michael [Journal of Medicinal Chemistry, 1986, vol. 29, # 10, p. 2060 - 2068]
[6]Zhang, Wei; Ma, Zhen-Hua; Mei, Duo; Li, Chun-Xia; Zhang, Xiu-Li; Li, Ying-Xia [Tetrahedron, 2006, vol. 62, # 42, p. 9966 - 9972]
[7]Bower, Justin; Drysdale, Martin; Hebdon, Richard; Jordan, Allan; Lentzen, Georg; Matassova, Natalia; Murchie, Alastair; Powles, Jenifer; Roughley, Stephen [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2455 - 2458]
[8]Catalano, John G; Deaton, David N; Furfine, Eric S; Hassell, Annie M; McFadyen, Robert B; Miller, Aaron B; Miller, Larry R; Shewchuk, Lisa M; Willard Jr., Derril H; Wright, Lois L [Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 275 - 278]
[9]Current Patent Assignee: TAISHO PHARMACEUTICAL HOLDINGS CO., LTD. - US2008/318923, 2008, A1 Location in patent: Page/Page column 87-88
[10]Van De Vijver, Pieter; Ostrowski, Tomasz; Sproat, Brian; Goebels, Jozef; Rutgeerts, Omer; Van Aerschot, Arthur; Waer, Mark; Herdewijn, Piet [Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 3020 - 3029]
[11]Silva, Marcus V. de M.; Costa, Ingrid C. R.; de Souza, Rodrigo O. M. A.; Bornscheuer, Uwe T. [ChemCatChem, 2019, vol. 11, # 1, p. 407 - 411]

2
[ 34306-42-8 ]
[ 74-88-4 ]
[ 140224-14-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 18h;	Step 1: To a 0 C. solution of (S)-2-(tert-butoxycarbonylamino)butanoic acid (1.00 g, 4.92 mmol) in THF (16.4 ml) was added iodomethane (2.45 ml, 39.4 mmol) followed by sodium hydride (60% w/w dispersion in mineral oil, 590 mg, 14.8 mmol), portionwise. The reaction was allowed to warm to rt and stirred for 18 h, then cooled to 0 C., quenched by the careful addition of H2O, and washed with Et20. The aqueous layer was acidified by the addition of 1 M aq. HCl and extracted with Et20. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated to provide (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (1.05 g, 98%) as a white solid. MS m/z 240 (MNa)+.

Reference： [1]Patent: US2015/225449,2015,A1 .Location in patent: Paragraph 0371
[2]Helvetica Chimica Acta,1994,vol. 77,p. 1124 - 1165
[3]Tetrahedron,1991,vol. 47,p. 5453 - 5462

3
[ 34306-42-8 ]
[ 6638-79-5 ]
[ 160801-72-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: Boc-Abu With 1,1′-carbonyldiimidazole In tetrahydrofuran at 20℃; for 0.666667h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 2h;	1 Intermediate 1; 1,1-dimethylethyl ((l -l-[methyl(methyloxy)amino]carbonyl}propyl)carbamate; To a solution of (2S)-2-( [(1,1 -dimethylethyl)oxy]carbonyl} amino)butanoic acid(2.50 g, 12.3 mmol) in THF (15.0 mL) was added 1 , -carbonyldiimidazole (2.39 g, 14.8 mmol) portionwise over about 10 min. After stirring 30 min at RT, a solution of Ν,Ο- dimethylhydroxylamine hydrochloride (1.32 g, 13.5 mmol) and DIPEA (2.36 mL, 13.5 mmol) in DMF (4.0 mL) was added. The reaction mixture was stirred for 2 h at RT, followed by concentration in vacuo. The residue was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (2 x 20 mL), saturated aq. NaHC03 (2 x 20 mL), and brine (20 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (2.60 g, 88%) as a clear, colorless oil. LC-MS m/z 247 (M+H)+, 0.94 min (ret time).
85%	With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at -5 - 20℃;	1.2 Step 2) (S)-tert-butyl-(1-(methoxy(methyl)amino)-1-oxobutan-2-1 carbamate To a mixture of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (36.00 g, 177.13 mmol), N,O-dimethylhydroxylamine hydrochloride (20.73 g, 212.56 mmol), DMAP (21.64 g, 177.13 mmol) and triethylamine (96.89 mL, 690.82 mmol) in DCM (370 mL) was added EDCI (40.75 g, 212.56 mmol) portionwise at -5° C. The resulted mixture was stirred at rt overnight, then washed with H2O (200 mL×2), saturated NaHCO3 aqueous solution (200 mL) and brine (200 mL), The separated organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as colorless oil (37.16 g, 85%). [0499] 1H NMR (400 MHz, CDCl3) δ (ppm): 5.17-5.16 (d, J=7.6 Hz, 1H), 4.62 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 1.79-1.70 (m, 1H), 1.61-1.50 (m, 1H), 1.43 (s, 9H), 0.95-0.91 (t, J=7.5 Hz, 3H).
82%	Stage #1: Boc-Abu With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at -10℃; for 0.25h; Green chemistry; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride In dichloromethane at 0℃; for 0.25h; Green chemistry; Stage #3: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 0.416667h; Green chemistry;	(S)-tert-Butyl{1-[methoxy(methyl)amino]-4-methyl-1-oxopentan-2-yl}carbamate 2R1 General procedure: N-Boc-protected amino acid 1R1 (7.5 mmol) was dissolved indichloromethane (20 mL) and stirred at -10 °C. Then HOBt (7.5 mmol)and EDCI (11.3 mmol) were added. The reaction was carried out for15 min, then N, O-dimethylhydroxylamine hydrochloride (7.5 mmol) was added and after 15 min, DIPEA (18.9 mmol) was added. Thereaction temperature was allowed to rise to room temperature 25 minlater and the mixture was left overnight. The resulting mixture waswashed with 1 M HCl (20 mL), 5% NaHCO3 (20 mL) and saturatedbrine (20 mL) respectively and dried over anhydrous Na2SO4. It wasfiltered, and the solvent was evaporated to provide crude product 2R1which was used without further purification in the next reaction.

77%	With N-ethyl-N,N-diisopropylamine; 1,1′-carbonyldiimidazole In tetrahydrofuran; N,N-dimethyl-formamide Ambient temperature;
53%	Stage #1: Boc-Abu With 1-propanephosphonic acid cyclic anhydride In tetrahydrofuran; ethyl acetate at 0 - 20℃; for 0.5h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 20℃; for 18h;	1 Step 1: ferf-butyl {(2S)-1-[methoxy(methyl)amino]-1-oxobutan-2-yl}carbamate (3a) A solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (2.0 g, 9.84 mmol) in THF (49.2 mL, 0.2M) was cooled to 0 °C. Propylphosphonic anhydride solution (50% solution in EtOAc, 12.9 mL, 21.6 mmol) was added to the solution at 0 °C before the bath was removed and the reaction mixture was allowed to warm to RT and stirred for 30 min. Then, N,N- diisopropylethylamine (10.3 mL, 59.0 mmol) and methoxy(methyl)amine hydrochloride (1.06 g, 10.8 mmol) were added and the reaction mixture was stirred at RT for 18 h. LCMS analysis showed consumption of the starting material. The reaction was quenched with water (40 mL) and transferred to a separatory funnel with EtOAc (40 mL). The layers were separated, and the organic phase was washed sequentially with 20% citric acid (40 mL), a saturated solution of NaHCC>3 (40 mL), and brine (40 mL). The organic extract was then dried over MgS04, filtered, and concentrated to dryness to provide the title compound (3a) (1.29 g, 53% yield) as a yellow oil, which was taken on without further purification. 1H NMR (400 MHz, CDCI3) d 5.28 - 5.12 (m, 1H), 4.74 - 4.52 (m, 1H), 3.79 (s, 3H), 3.23 (s, 3H), 1.85 - 1.73 (m, 1 H), 1.64 - 1.54 (m, 1 H), 1.46 (s, 9H), 0.96 (t, J = 7.5 Hz, 3H). LCMS m/z (APCI) for (C11H22N2O4), 247.1 (M+H)+.
53%	Stage #1: Boc-Abu With 1-propanephosphonic acid cyclic anhydride In tetrahydrofuran; ethyl acetate at 0 - 20℃; for 0.5h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethyl acetate at 20℃; for 18h;	1 Step 1: ferf-butyl {(2S)-1-[methoxy(methyl)amino]-1-oxobutan-2-yl}carbamate (3a) A solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (2.0 g, 9.84 mmol) in THF (49.2 mL, 0.2M) was cooled to 0 °C. Propylphosphonic anhydride solution (50% solution in EtOAc, 12.9 mL, 21.6 mmol) was added to the solution at 0 °C before the bath was removed and the reaction mixture was allowed to warm to RT and stirred for 30 min. Then, N,N- diisopropylethylamine (10.3 mL, 59.0 mmol) and methoxy(methyl)amine hydrochloride (1.06 g, 10.8 mmol) were added and the reaction mixture was stirred at RT for 18 h. LCMS analysis showed consumption of the starting material. The reaction was quenched with water (40 mL) and transferred to a separatory funnel with EtOAc (40 mL). The layers were separated, and the organic phase was washed sequentially with 20% citric acid (40 mL), a saturated solution of NaHCC>3 (40 mL), and brine (40 mL). The organic extract was then dried over MgS04, filtered, and concentrated to dryness to provide the title compound (3a) (1.29 g, 53% yield) as a yellow oil, which was taken on without further purification. 1H NMR (400 MHz, CDCI3) d 5.28 - 5.12 (m, 1H), 4.74 - 4.52 (m, 1H), 3.79 (s, 3H), 3.23 (s, 3H), 1.85 - 1.73 (m, 1 H), 1.64 - 1.54 (m, 1 H), 1.46 (s, 9H), 0.96 (t, J = 7.5 Hz, 3H). LCMS m/z (APCI) for (C11H22N2O4), 247.1 (M+H)+.
	With 4-methyl-morpholine; 4-dimethylaminopyridine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
	With TEA; N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate In N,N-dimethyl-formamide
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 1h;
	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 12h;
	Stage #1: Boc-Abu With 1,1′-carbonyldiimidazole In dichloromethane at 20℃; for 1.25h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride In dichloromethane at 20℃;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/109415, 2012, A1 Location in patent: Page/Page column 30
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - US2015/87658, 2015, A1 Location in patent: Paragraph 0498; 0499
[3]Du, Xiao; Zhang, Hao-Yang; Lei, Meng; Li, Zi-Yuan; Zhu, Yong-Qiang [Journal of Chemical Research, 2016, vol. 40, # 2, p. 82 - 86]
[4]Harbeson, Scott L.; Abelleira, Susan M.; Akiyama, Alan; Barrett, Robert; Carroll, Renee M.; et al. [Journal of Medicinal Chemistry, 1994, vol. 37, # 18, p. 2918 - 2929]
[5]Current Patent Assignee: PFIZER INC - WO2021/220185, 2021, A1 Location in patent: Page/Page column 54
[6]Current Patent Assignee: PFIZER INC - WO2021/220185, 2021, A1 Location in patent: Page/Page column 54
[7]Johansson, Anja; Poliakov, Anton; Akerblom, Eva; Wiklund, Karin; Lindeberg, Gunnar; Winiwarter, Susanne; Danielson, U. Helena; Samuelsson, Bertil; Hallberg, Anders [Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 12, p. 2551 - 2568]
[8]Soroka, Anna; der Veken, Pieter Van; Meester, Ingrid De; Lambeir, Anne-Marie; Maes, Marie-Berthe; Scharpe, Simon; Haemers, Achiel; Augustyns, Koen [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4777 - 4779]
[9]Yoo, Euna; Stokes, Barbara H.; De Jong, Hanna; Vanaerschot, Manu; Kumar; Lawrence, Nina; Njoroge, Mathew; Garcia, Arnold; Van Der Westhuyzen, Renier; Momper, Jeremiah D.; Ng, Caroline L.; Fidock, David A.; Bogyo, Matthew [Journal of the American Chemical Society, 2018, vol. 140, # 36, p. 11424 - 11437]
[10]Lei, Meng; Zhang, Haoyang; Miao, Hang; Du, Xiao; Zhou, Hui; Wang, Jia; Wang, Xueyuan; Feng, Huayun; Shi, Jingmiao; Liu, Zhaogang; Shen, Jian; Zhu, Yongqiang [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 18, p. 4151 - 4162]
[11]Dehaen, Wim; Hrabinová, Martina; Kuchař, Martin; Maryška, Michal; Rumlová, Michaela; Soukup, Ondřej; Svobodová, Lucie [Pharmaceuticals, 2021, vol. 14, # 12]

4
[ 6066-82-6 ]
[ 34306-42-8 ]
[ 103290-07-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dicyclohexyl-carbodiimide In dichloromethane at 10 - 20℃; for 2h; Inert atmosphere;
98.6%	With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃;	1.2 Step 2) (S) -2,5-Dioxopyrrolidin-1-yl 2- (tert-butoxycarbonyl) amino) butanoate The compound 1-hydroxypyrrolidine-2,5-dione (5.80 g, 50.4 mmol) and (S) -2 - ((tert-butoxycarbonyl) ammoniaYl) butanoic acid (10.00 g, 49.2 mmol) was dissolved in THF (120 mL) and then DCC (10.20 g,49.4 mmol) was added and the reaction mixture was stirred overnight at 0 ° C then suction filtered and the filter cake washed with ethyl acetate (50 mLx3) to giveThe filtrate was concentrated under reduced pressure and the residue was dissolved by adding ethyl acetate (500 mL). The resulting mixture was washed with saturated NaHCO 3The mixture was washed with water (100 mL) and brine (100 mL). The separated organic phase was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. TheThe residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 3/1) to give the title compound as a white solid (14.57 g,98.6%).
66%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃;

	With dicyclohexyl-carbodiimide In tetrahydrofuran at -5 - 20℃; for 3h;
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Cooling with ice;	7.3 3) Dissolve Boc-L-2-aminobutyric acid (10 g), N-hydroxysuccinimide (NHS, 8.5 g) and DMAP (9.1 g) in 100 mL of dry dichloromethane, add dicyclohexylcarbodiimide (DCC, 15.2 g) in dichloromethane (40 mL) dropwise in an ice bath, remove the ice bath, react at room temperature overnight, filter to remove dicyclohexylurea (DCU), concentrate the filtrate, and to recrystallize Boc-L-2-aminobutyric acid-NHS ester as white crystals under ethyl acetate/n-hexane. Compound 6 (3.88 g) was dissolved in 10 mL of dichloromethane, and an equal volume of trifluoroacetic acid was added to deprotect it. The raw materials disappeared by TLC monitoring and concentrated. 20 mL of dichloromethane and 8 mL of triethylamine were added, and a solution of Boc-L-2-aminobutyric acid-NHS ester (4.4 g) in dichloromethane was added dropwise at room temperature, and the reaction was carried out for 3 hours, spin dry to remove dichloromethane. Add 100 mL of ethyl acetate, washed three times each with 3% HCl, saturated sodium bicarbonate, and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a colorless viscous liquid 7.

Reference： [1]Yadav, Vitthal N.; Comotti, Angiolina; Sozzani, Piero; Bracco, Silvia; Bonge-Hansen, Tore; Hennum, Martin; Görbitz, Carl Henrik [Angewandte Chemie - International Edition, 2015, vol. 54, # 52, p. 15684 - 15688][Angew. Chem., 2015, vol. 127, # 52, p. 15910 - 15914]
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 0576; 0577; 0578; 0579
[3]Van De Vijver, Pieter; Ostrowski, Tomasz; Sproat, Brian; Goebels, Jozef; Rutgeerts, Omer; Van Aerschot, Arthur; Waer, Mark; Herdewijn, Piet [Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 3020 - 3029]
[4]Marrone; Siemann; Beecroft; Viswanatha [Bioorganic Chemistry, 1996, vol. 24, # 4, p. 401 - 416]
[5]Current Patent Assignee: HAINAN POLY PHARM CO, LTD - US2020/215197, 2020, A1 Location in patent: Paragraph 0076

5
[ 1066-51-9 ]
[ 34306-42-8 ]
[ 71448-00-5 ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,1996,vol. 111,p. 92

6
[ 185509-01-7 ]
[ 45121-22-0 ]
[ 34306-42-8 ]

Reference： [1]Journal of the American Chemical Society,1997,vol. 119,p. 656 - 673

7
[ 34306-42-8 ]
[ 150736-72-4 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 4067 - 4069
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3321 - 3324
[3]Bioorganic and medicinal chemistry letters,2004,vol. 14,p. 275 - 278

8
[ 34306-42-8 ]
[ 422572-59-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With trifluoro-[1,3,5]triazine; triethylamine In dichloromethane at -40 - -10℃; for 1h;	31.2 Step 2: (S) -tert-Butyl (1-fluoro-1-oxobutan-2-yl) carbamate Step 2: (S) -tert-Butyl (1-fluoro-1-oxobutan-2-yl) carbamate[0872]To a solution of (S) -2- ( (tert-butoxycarbonyl) amino) butanoic acid (1.0 g, 4.93 mmol) and triethylamine (0.8 mL, 5.43 mmol) in dichloromethane (20 mL) was added dropwise slowly cyanuric fluoride (1.0 mL, 9.86 mmol) at -40 . The resulting mixture was stirred at -10 for 1 hour. The reaction mixture was washed with ice-water (20 mL × 3) . The organic layer was dried over anhydrous sodium sulfate and the organic solvent was removed to give the title compound as a white solid (0.89 g, 88) .[0873]1H NMR (400 MHz, d6-DMSO) : δ ppm 4.15 -4.13 (m, 1H) , 1.78 -1.71 (m, 2H) , 1.40 (s, 9H) , 0.95 -0.89 (m, 3H) and MS-ESI: m/z 206.2 [M+H]+.
22%	With tetramethylfluoroformamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;	047 (S)-2-(tert-butoxycarbonylamino)butyric acid (40.6 mg, 0.20mmol) and TFFH (50.0mg, 0.20 mmol) were dissolve in tetrahydrofuran (1 mL), added with N,N-diisopropylethylamine (69.7 µL, 0.40 mmol) and stirred at room temperature for one hour to prepared an acid fluoride. The compound of Reference Example 001 (43.4 mg, 0.20 mmol) was suspended in tetrahydrofuran (2 mL) and added with hexamethyldisilazane lithium salt (1M tetrahydrofuran solution, 0.5 mL) and stirred at room temperature for 10 minutes. The acid fluoride solution prepared above was added to this reaction liquid and stirred at room temperature for 10 minutes. After added with N,N-dimethylethylenediamine (44 µL) and stirred for one hour, the mixture was diluted with methylene chloride (4 mL) and methanol (1 mL), and washed with 4M hydrochloric acid (3 mL x 2), distilled water (3 mL), 5% potassium carbonate aqueous solution (3 mL x 2) and then with distilled water (3 mL). The solvent was distilled off under reduced pressure, and the title compound was obtained (23.6 mg, yield 29%).
	With pyridine; trifluoro-[1,3,5]triazine In dichloromethane for 1h;

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2015/161830, 2015, A1 Location in patent: Paragraph 00389
[2]Current Patent Assignee: NIPPON KAYAKU CO LTD - EP1674454, 2006, A1 Location in patent: Page/Page column 22
[3]Breslin, Henry J.; Miskowski, Tamara A.; Kukla, Michael J.; Leister, William H.; De Winter, Hans L.; Gauthier, Diane A.; Somers, Maria V. F.; Peeters, Daniëlle C. G.; Roevens, Peter W. M. [Journal of Medicinal Chemistry, 2002, vol. 45, # 24, p. 5303 - 5310]

9
[ 34306-42-8 ]
[ 1738-76-7 ]
[ 90281-99-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 337 - 361

10
[ 34306-42-8 ]
[ 77128-73-5 ]
2-amino-<i>N</i>-(1-carbamoyl-2-phenyl-ethyl)-<i>N</i>-methyl-butyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Fmoc-Rink-PEGA800 resin (0.8 g, L = 0.4 mmol/g, 0.32 mmol) was Fmoc deprotectedand washed with DMF (x5). Fmoc-N-Me-Phe-OH (385 mg, 0.96 mmol) was coupled viaTBTU (295 mg, 0.92 mmol) with NEM (365 pL, 1.28 mmol) in dry DMF. The resin waswashed with DMF (x5), Fmoc deprotected and washed with DMF (x5). Na-Boc-L-aminobutyric acid (195 mg, 0.96 mmol) was then similarly coupled via TBTU. Washwith DMF (x5), DCM (x2) and CH3CN (x2) followed by lyophilization. The dipeptideamide was cleaved from the resin by treatment with TFA:TIPS 95:5 for 30 min. followedby wash with TFA:TIPS 95:5 (x5). The combined fractions were concentrated in vacuoand the resulting oil was lyophilized. The amino group was re-protected with Boc byreaction with Boc2O (139 mg, 0.32 mmol) and DIPEA (53 juL, 0.38 mmol) in dry CH3CN(2 mL) at rt o.n. Purification by HPLC gave the Boc-protected dipeptide amide as awhite residue (18 mg, 15percent). The amide was dehydrated with POCI3/pyridine/imidazole(15 \|iL/1.2 mL/4.7 mg) and subsequently Boc-deprotected as described in example 2.Purification by HPLC gave the title compound as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3614 - 3617
[2]Patent: WO2004/110988,2004,A1 .Location in patent: Page/Page column 29

11
[ 34306-42-8 ]
[ 132684-59-4 ]
(S)-2-Amino-N-((S)-1-carbamoyl-3-phenyl-propyl)-butyramide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3614 - 3617

12
[ 34306-42-8 ]
[ 199110-64-0 ]
(S)-2-Amino-N-((S)-2-biphenyl-4-yl-1-carbamoyl-ethyl)-butyramide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3614 - 3617

13
[ 34306-42-8 ]
[ 78-81-9 ]
[ 827579-57-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 23℃; for 17h;	1 Synthesis of Compound 12a General procedure: Synthesis of Compound 12a To a mixture of (S)-2-[(tert-butoxycarbonyl)amino]butanoic acid 10a (2.3 mmol, 0.47 g) and iPr2NEt (2.76 mmol, 0.48 mL) in CH2Cl2 (12 mL), HOBt.H2O (2.76 mmol, 0.37 g), isobutyl amine (2.76 mmol, 0.27 mL), and EDC.HCl (2.76 mmol, 0.53 g) were added simultaneously at 23° C., and the resulting mixture was stirred for 17 hr at 23° C. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (1-3% MeOH/CH2Cl2) to furnish (S)-tert-butyl [1-(isobutylamino)-oxobutan-2-yl]carbamate in 86% yield (0.51 g). 1H NMR (400 348 MHz, CDCl3): δ 6.24 (brs, 1H), 5.08 (br, 1H), 4.07-3.89 (m, 1H), 3.18-2.96 (m, 2H), 1.92-1.70 (m, 2H), 1.62 (hept, J=7.3 Hz, 1H), 1.43 (s, 9H), 0.93 (t, J=7.4 Hz, 3H), 0.89 (d, J=6.8 Hz, 6H).
86%	With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 23℃; for 17h;
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane

Reference： [1]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM - US2014/66488, 2014, A1 Location in patent: Paragraph 0109
[2]Ghosh, Arun K.; Venkateswara Rao, Kalapala; Yadav, Navnath D.; Anderson, David D.; Gavande, Navnath; Huang, Xiangping; Terzyan, Simon; Tang, Jordan [Journal of Medicinal Chemistry, 2012, vol. 55, # 21, p. 9195 - 9207,13]
[3]Coburn, Craig A.; Stachel, Shawn J.; Jones, Kristen G.; Steele, Thomas G.; Rush, Diane M.; DiMuzio, Jillian; Pietrak, Beth L.; Lai, Ming-Tain; Huang, Qian; Lineberger, Janet; Jin, Lixia; Munshi, Sanjeev; Katharine Holloway; Espeseth, Amy; Simon, Adam; Hazuda, Daria; Graham, Samuel L.; Vacca, Joseph P. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 14, p. 3635 - 3638]

14
[ 34306-42-8 ]
[ 148528-89-6 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: Boc-Abu With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide for 0.166667h; Stage #2: With 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; Stage #3: With hydrogenchloride; water In ethyl acetate	40 Intermediate 40: ferf-butyl N-[(lS)-l-carbamoylpropyllcarbamate A solution of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (4.92 mmol, 1000 mg), DIPEA (12.30 mmol, 2.14 mL) and HBTU (6.40 mmol, 2054 mg) in DCM/DMF (7 mL/3 mL) was stirred for 10 minutes, then HMDS (5.41 mmol, 1.13 mL) was added and the reaction was stirred at r.t. for 1 h. The mixture was concentrated under reduced pressure, the residue was taken up in EtOAc (50 mL), washed with HCI 1M (5 mL) and then with a saturated aqueous solution of NaHC03 (5 mL). The organic layer was dried over Na2S04 and concentrated to dryness under reduced pressure. The crude was purified by flash chromatography (Biotage system) on silica gel using a SNAP 50g as column and cHex/EtOAc from 80:20 to 0:100 as eluent, affording the title compound (820 mg, 83%, Intermediate 16) as a white solid. HPLC-MS 3 minutes, RT=1.69, MS=147 [M-55].
80%	Stage #1: Boc-Abu With 4-methyl-morpholine; isobutyl chloroformate In N,N-dimethyl-formamide at -20℃; for 0.166667h; Stage #2: With ammonia In water; N,N-dimethyl-formamide at -20℃; for 3h;	9.6 Intermediate 9-6: tert-Butyl [(lSVl-carbamoylpropyllcarbamateTo a solution of (25)-2-[(ter£-butoxycarbonyl)amino]butanoic acid (1.01 g, 4.99 mmol) in DMF (5 mL) at -20 0C was added NMM (1.10 mL, 9.99 mmol) and isobutyl chloroformate (1.30 mL, 9.99 mmol). The reaction was stirred for 10 min at -20 0C. The precipitate was removed by filtration. 26 % NH4OH (aq) solution (0.39 mL, 9.99 mmol) was added and the reaction was stirred at -20 0C for 3 h. The volume was reduced under vacuum and hexane was added. A white precipitate was formed after a few minutes. The precipitate was collected in a filter and washed with additional hexane. The precipitate was recrystallised from EtOAc and hexane to give the title compound (0.811 g, 80 %) as white solid.1H NMR (500 MHz, CD3OD) δ 0.96 (t, 3H), 1.45 (s, 9H), 1.61 (m, IH), 1.78 (m, IH), 3.93 (t, IH), 6.63 (s, IH), 6.96 (s, IH), 7.51 (s, IH).
	Multi-step reaction with 2 steps 1: tetrahydrofuran 2: aq. NH₃ / tetrahydrofuran

Multi-step reaction with 2 steps 1: NMM / tetrahydrofuran / 0.03 h / -15 °C 2: 58percent NH₄OH / tetrahydrofuran / 2 h / -15 °C

Reference： [1]Current Patent Assignee: AUTIFONY THERAPEUTICS LIMITED - WO2018/20263, 2018, A1 Location in patent: Page/Page column 112
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2009/81195, 2009, A1 Location in patent: Page/Page column 69
[3]Bower, Justin; Drysdale, Martin; Hebdon, Richard; Jordan, Allan; Lentzen, Georg; Matassova, Natalia; Murchie, Alastair; Powles, Jenifer; Roughley, Stephen [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2455 - 2458]
[4]Manolopoulou; Poulos; Tsegenidis [European Journal of Medicinal Chemistry, 1992, vol. 27, # 9, p. 949 - 954]

15
C₁₃H₈ClFN₂O₃ [ No CAS ]
[ 34306-42-8 ]
[ 870281-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 10 - 20℃; for 3h;	Preparation of (S)-[1-(2-fluoro-6-nitro- benzoyl)-phenyl-aminocarbonyl]-propyl)-carbamic acid tert-butyl ester (3a).; A suspension of 2-fluoro-6- nitro-N-phenyl-benzamide 2 (130 g, 0.5 mol) and DMF . (5 mL) in SOC12 (256 mL, 2.5 mol, 5 eq) was stirred at 85C for 5 hours. The reaction mixture was con- centrated in vacuo to a brown syrup. The syrup was dissolved in CH2C12 (200 mL) and was slowly added to a solution of N-BOC-L-2-aminobutyric acid (112 g, 0.55 mol, 1.1 eq) and Et3N (77 mL, 0.55 mol, 1.1 eq) in CH2C12 (600 mL) at 10C. After stirring at room temperature for 3 h, salts were removed by filtra- tion, and the solution was washed with 100 mL of H20, sat'd. NaHC03, H20, 5% citric acid, and saturated NaCl. The organic phase was dried with MgS04 and concentrated to a red syrup. The syrup was dis- solved in CH2C12 (450 mL) and purified by flash chromatography on a silica gel plug (15 x 22 cm, 4 L dry silica) eluted with hexanes/EtOAc (10%, 8 L; 15%, 8 L; 20%, 8 L; 25%, 4 L) to yield the product as an off-white solid (147 g, 66%). ¹H NMR (300 MHz, DMSO-d6) 5: 8.13 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 8.6 Hz, 1H), 7.78-7.67 (m, 1H), 7.65-7.49 (m, 3H), 7.40-7.28 ( m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 4.05 (broad s, 1H), 1.75-1.30 (m, 2H), 1.34 (s, 9H), 0.93 (broad s, 3H) . ESI-MS m/z 446.3 (MH+).

Reference： [1]Patent: WO2005/113554,2005,A2 .Location in patent: Page/Page column 24; 26-27

16
[ 34306-42-8 ]
[ 75-04-7 ]
[ 187680-40-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: Boc-Abu; ethylamine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 5℃; Stage #2: With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran at 5 - 20℃;	18.a 24.8 ml (49.5 mmol) ethylamine, 8.6 ml (50.0 mmol) DIPEA were metered at 5° C. into a solution of 10.0 g (49.2 mmol) (S)-2-tert-butoxycarbonylamino-butyric acid in 100 ml THF and then 16.1 g (50.0 mmol) TBTU and 6.8 g (50.0 mmol) HOBT were added batchwise. The reaction solution was stirred overnight at ambient temperature, evaporated to dryness i. vac., combined with ethyl acetate and washed with NaHCO3 solution and NaCl solution. The organic phase was dried and evaporated to dryness i. vac. Quantitative yield of 18-a. ES-MS (M+H)+=118 RT(HPLC 1)=2.8 min

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/223759, 2006, A1 Location in patent: Page/Page column 232

17
[ 943771-13-9 ]
[ 34306-42-8 ]
4-[4-(2-amino-butyrylamino)-phenylsulfanyl]-N-(4-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 4-(4-amino-phenylsulfanyl)-N-(4-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide; Boc-Abu With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In tetrahydrofuran at 20℃; for 16h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 1h; Stage #3: With ammonia In water	70 Example 70; 4-[4-(2-Amino-butyrylamino)-phenylsulfanyl]-N-(4-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3- c(Jpyrimidin-4-ylamino)-benzamide; [0415] To a solution of the product from Example 13E (59 mg, 0.1 mmol) and Boc-Abu-OH (22 mg, 0.1 1 mmol) in tetrohydrofuran (5 ml) was added 3-(diethoxyphosphoryloxy)-l,2,3-benzo-triazin- 4(3H)-one (36 mg, 0.11 mmol) and triethylamine (0.07 ml, 0.5 mmol). The mixture was stirred at room temperature for 16 hours then poured into saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and evaporated. To the residue was added dichloromethane (2ml) and trifluoroacetic acid (2ml) then stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by ηPLC with Nη4Oη to provide the title compound. (62mg, 85%). IH NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.54 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 1.48 (m, 1 H) 1.66 (m, 1 H) 1.90 (s, 3 H) 3.22 (m, 2 H) 7.02 (m, 2 H) 7.40 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.46 Hz, 2 H) 7.61 (d, J=8.46 Hz, 1 H) 7.72 (m, 5 H) 7.94 (s, 1 H) 8.52 (s, 1 H) 8.79 (s, 1 H) 10.33 (s, 1 H); MS (ESI+) m/z 67O5 672 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2007/76034, 2007, A2 Location in patent: Page/Page column 112-113

18
[ 34306-42-8 ]
[ 120571-58-6 ]
[ 906810-48-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: Boc-Abu; N-benzyl D-alanine methyl ester With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2.5h; Stage #2: With hydrogenchloride In dichloromethane at 20℃; for 3h; Stage #3: With sodium hydrogencarbonate In dichloromethane; water	To a solution 20.0 g (0.103 mol, 1 X) of Compound V-b and 23.2 g (1.16X1 1.13 eq.) of N-Boc-2-(S)-aminobutyric acid in 160 ml (8X) of methylene chloride was added 11 g (0.55 X, 0.55 eq.) of EDCI. HCI at room temperature. The mixture was stirred one hour at ambient temperature and another 11 g (0.55X, 0.55 eq.) of EDCI. HCI was charged in two equal portions over 30 minutes. After the mixture was stirred for an additional hour, the batch was analyzed by HPLC and additional EDCI. HCI could be charged in small quantities until a conversion over 96% was reached. The reaction mixture was then mixed with 160 ml (8X) of 0.5 N HCI solution and 10 g (0.5X) of Celite. The organic layer was separated after the mixture was filtered. The organic layer was then neutralized with sodium bicarbonate and aqueous layer was removed. Hydrogen chloride gas was then bubbled through the organic layer at room temperature for about 3 hours until the Boc-deprotection reaction was complete. The acidic solution was then neutralized with saturated sodium bicarbonate to a pH of about 8 to initiate the cyclization reaction. The organic layer containing Compound ll-a was then separated and the aqueous layer extracted with 30 ml (1.5X) of methylene chloride. The solvent was removed under vacuum and the residue crystallized from a mixture of 60 m. of tert-buty. methytether and 40 ml of heptane, resulting in 25.6 g (79%) white solids, de 97%. H NMR (400 MHz, in CDCI3): 7.3(m, 5H), 6.8(S1I H), 5.28 (d, 1 H, J=14.9 Hz), 4.08(m,1 H), 4.00 (d, 1 H, J=14.9 Hz), 3.85(q, 1 H), 2.03 (m, 2H), 1.45 (d, 3H), 0.99(t, 3H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2009/79490, 2009, A1 Location in patent: Page/Page column 26; 27

19
[ 1366595-89-2 ]
[ 34306-42-8 ]
[ 1099616-12-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;
70%	Stage #1: Boc-Abu With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C₁₂H₂₀N₂O₄ In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere;	STEP 3 The coupling with N-Boc (S)-2-aminobutyric acid was performed with a modified procedure with respect to Seneci et al., Bioorg. Med. Chem. 2009, 17, 5834-5856. Namely, dry DIPEA (3 equiv) was added to a solution of N-Boc (S)-2-aminobutyric acid (1.2 equiv), HATU (1.2 equiv) and HOAt (1.2 equiv) in dry DMF at room temperature and under a nitrogen atmosphere. The solution was stirred for 10 min before adding a solution of the aminoalcohol (1 equiv) in dry DMF (final concentration of aminoalcohol: ≈0.1M). The reaction mixture was stirred at room temperature and monitored by LC-MS. After 20 hrs, the solvent was evaporated under reduced pressure. The crude was diluted with CH2Cl2 and then washed once with 1M KHSO4, saturated NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by direct phase chromatography (EtOAc as eluent), yielding pure 4-hydroxy, 3-amide in an improved 70% yield. Its full analytical characterization was previously reported in Seneci et al., Bioorg. Med. Chem. 2009, 17, 5834-5856.

Reference： [1]Location in patent: experimental part Seneci, Pierfausto; Bianchi, Aldo; Battaglia, Cristina; Belvisi, Laura; Bolognesi, Martino; Caprini, Andrea; Cossu, Federica; Franco, Elena de; Matteo, Marilenia de; Delia, Domenico; Drago, Carmelo; Khaled, Amira; Lecis, Daniele; Manzoni, Leonardo; Marizzoni, Moira; Mastrangelo, Eloise; Milani, Mario; Motto, Ilaria; Moroni, Elisabetta; Potenza, Donatella; Rizzo, Vincenzo; Servida, Federica; Turlizzi, Elisa; Varrone, Maurizio; Vasile, Francesca; Scolastico, Carlo [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 16, p. 5834 - 5856]
[2]Seneci, Pierfausto; Rizzi, Mattia; Ballabio, Luigi; Lecis, Daniele; Conti, Annalisa; Carrara, Claudio; Licandro, Emanuela [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2374 - 2378]

20
[ 1099616-09-7 ]
[ 34306-42-8 ]
[ 1099616-12-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: C₁₉H₂₄N₂O₄ With hydrogen In methanol at 20℃; for 72h; Stage #2: Boc-Abu With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	1.1.3 1.3 General procedure for the synthesis of compounds 4; Catalytic amounts of 10% Pd-C were added to solutions of compounds 3 (1 mmol) in MeOH (10 ml). The resulting mixtures were stirred at room temperature for ca. 72 hours under hydrogen (5 atm). After reaction completion, the mixtures were filtered through a Celite pad, and then washed with MeOH (3 x 10 ml). The combined organic solutions were concentrated under reduced pressure. The crude products were dissolved in dry CH2Cl2 (10 ml), and then Boc-NH-CH(R])CO2H (1.0 mmol), EDC (1.2 mmol). HOBt (1.2 mmol) and DIPEA (4.0 mmol) were sequentially added. The reaction mixtures were stirred at room temperature overnight and then the solvent was removed under reduced pressure. The residues were purified by flash chromatography. Compound 4a was synthesized by the general procedure described above.4a. Eluant mixture: Petroleum ether/EtOAc 10 : 90. Yield 75 % (331 mg, MW 441.25, 0.75 mmol) of pure 4a. Analytical characterization: [a]2^ - 146.5 (c 0.71, MeOH); 1H-NMR (400 MHz, CDCl3): δ: 7.53 (d, J = 3.5 Hz, IH). 5.07 (d, J = 7.6 Hz, IH), 4.56 (dd, J = 8.5, 4.0 Hz, IH), 4.48 (dd. J = 10.0 Hz, 7.5, IH). 4.03 (m, IH), 3.89 (m, IH), 3.73 (s. 3H), 3.71 (bs, IH), 3.31 (dd. J = 12.0, 3.0 Hz. IH), 2.30-2.23 (m, IH), 2.15-1.97 (m, 4H), 1.90-1.75 (m. 4H), 1.69-1.58 (m, 2H). 1.43 (s, 9H), 0.95 (t. 7.5 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ: 173.9, 172.4, 170.2, 155.6, 80.2, 64.3, 60.6, 58.8, 56.6, 54.1 , 52.7, 41.5, 32.4, 31.7, 31.3, 29.2, 27.6, 25.7, 10.1.

Reference： [1]Current Patent Assignee: FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI; THE UNIVERSITY OF MILAN; CISI S.C.R.L. - WO2009/60292, 2009, A2 Location in patent: Page/Page column 41

21
[ 67-56-1 ]
[ 34306-42-8 ]
[ 7682-18-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; at 0 - 20℃;	10.0 g (49.2 mmol) BOC-L-2-aminobutyric acid was dissolved in 100 ml of methanol and 6 ml (82.2 mmol) thionyl chloride were added dropwise at 0 C. The solution was stirred for 14 h at ambient temperature and then evaporated down in vacuo.Yield: 7.6 g (101%) 2-a.ES-MS (M+H)+=118

Reference： [1]Patent: US2010/144681,2010,A1 .Location in patent: Page/Page column 67

22
[ 1218930-37-0 ]
[ 34306-42-8 ]
[ 1218930-38-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 4-methyl-morpholine; HATU In 1-methyl-pyrrolidin-2-one at 0 - 20℃;	LIX To a solution containing Boc-L- Abu-OH (170 mg, 0.83 mmol) in anhydrous NMP (2 mL) was cooled to 0 °C. HATU (316 mg, 0.83 mmol) and NMM (115 mg, 1.08 mmol) were added followed by the addition of crude 63 (242 mg, 0.75 mmol) in anhydrous NMP (4 mL). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and EtOAc (10:1) and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2" Dynamax C 18, 40-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 270 mg (71%) of 64. Mass spectrum, m/z [509.2] (M + H)+.

Reference： [1]Current Patent Assignee: TETRALOGIC PHARMACEUTICALS CORP - WO2010/33531, 2010, A1 Location in patent: Page/Page column 123; 124

23
[ 123-75-1 ]
[ 34306-42-8 ]
[ 1258066-42-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; HATU In dichloromethane at 20℃; for 5h;	C.A PREPARATION C: (5)-2-amino-l-(pyrrolidin-l-yl)butan-l-one[0197] STEP A: (S)-tert-butyl 1 -oxo- 1 -(pyrrolidin- 1 -yl)butan-2-ylcarbamate[0198] To a mixture of (5)-2-(tert-butoxycarbonylamino)butanoic acid (1.4 g, 6.89 mmol), HATU (3.14 g, 8.27 mmol), and pyrrolidine (1.216 mL, 13.78 mmol) in DCM (50 mL) was added Et3N (1.920 mL, 13.78 mmol). The reaction mixture was stirred at room temperature for 5 h and then washed with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil(1.75 g, 99%). 1H NMR (500 MHz, CDCl3) δ 0.94 (t, J=7.57 Hz, 3 H) 1.34 - 1.48 (m, 9H),1.49 - 1.68 (m, 1 H) 1.68 - 1.81 (m, 1 H) 1.81 - 1.92 (m, 2 H) 1.92 - 2.03 (m, 2 H) 3.34- 3.47 (m,2 H) 3.52 (dt, J=12.08, 7.14 Hz, 1 H) 3.65 (dt, J=10.13, 6.65 Hz, 1 H) 4.30 -4.42 (m, 1 H) 5.35 (d, J=8.30 Hz, 1 H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2010/144486, 2010, A1 Location in patent: Page/Page column 41-42

24
[ 1269407-16-0 ]
[ 34306-42-8 ]
[ 1269407-18-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; HATU In methanol; dichloromethane at 20℃; for 0.5h;	61 To a solution of 2-[(35)-3-amino-l-pyrrolidinyl]-5-fluorobenzonitrilehydrochloride (34 mg, 0.141 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}amino)- butanoic acid (29 mg, 0.143 mmol), and HATU (54 mg, 0.142 mmol) in CH2Cl2 (1.0 mL) and MeOH (0.5 mL) was added Et3N (0.058 mL, 0.422 mmol). The reaction mixture was stirred at RT for 30 min and then concentrated under a stream of nitrogen at 50 0C. Water (3 mL) and EtOAc (2 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were concentrated under a stream of nitrogen at 50 0C onto Isolute. Purification via flash column chromatography (0-80% EtOAc/hexanes) afforded the title compound (53.7 mg, 98%). LC-MS m/z 391 (M+H)+, 1.03 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 65

25
[ 1269407-34-2 ]
[ 34306-42-8 ]
[ 1269407-35-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine; HATU In dichloromethane at 20℃; for 1h;	79 To a solution of 2-[(3S)-3-amino-l-pyrrolidinyl]-3-pyridinecarbonitrile hydrochloride (100 mg, 0.445 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}- amino)butanoic acid (90 mg, 0.445 mmol), and HATU (215 mg, 0.566 mmol) in CH2Cl2 (5.0 mL) was added Et3N (0.223 mL, 1.602 mmol). The reaction mixture was stirred at RT for 1 h. Water (5 mL) was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were concentrated in vacuo and the residue was dissolved in EtOAc (15 mL) and washed with saturated aq. NaHCO3 (10 mL), brine (10 mL), and water (20 mL). The organic solution was concentrated in vacuo and the residue was purified via flash column chromatography (30-100% EtOAc/hexanes) to afford the title compound (145.7 mg, 88%). LC-MS m/z 374 (M+H)+, 0.86 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 74

26
[ 1269407-39-7 ]
[ 34306-42-8 ]
[ 1269407-60-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; HATU In dichloromethane at 20℃; for 1.66667h;	104 To a solution of 3-[(35)-3-amino-l-pyrrolidinyl]-2-thiophenecarbonitrile hydrochloride (101 mg, 0.440 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}- amino)butanoic acid (89 mg, 0.440 mmol), and HATU (184 mg, 0.484 mmol) in CH2Cl2 (2.0 mL) was added Et3N (0.184 mL, 1.319 mmol). The reaction mixture was stirred at RT for 1 h 40 min. Water (2 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic layers were concentrated under a stream of nitrogen at 50 0C onto Isolute. Purification twice via flash column chromatography (20-80% then 20-100% EtOAc/hexanes) afforded the title compound (156 mg, 94%). LC-MS m/z 379 (M+H)+, 0.85 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 87

27
[ 1269407-44-4 ]
[ 34306-42-8 ]
[ 1269407-46-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine; HATU In methanol; dichloromethane at 20℃; for 0.25h;	90 To a solution of 2-[(35)-3-amino-l-pyrrolidinyl]-4-(trifluoromethyl)benzonitrile hydrochloride (60 mg, 0.206 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}amino)- butanoic acid (42 mg, 0.207 mmol), and HATU (78 mg, 0.206 mmol) in CH2Cl2 (1.5 mL) and MeOH (0.75 mL) was added Et3N (0.086 mL, 0.617 mmol). The reaction mixture was stirred at RT for 15 min and then concentrated under a stream of nitrogen at 50 0C. Water (3 mL) and EtOAc (2 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (2 x 1 mL) and then concentrated under a stream of nitrogen at 50 0C onto Isolute. Purification via flash column chromatography (0-80% EtOAc/hexanes) afforded the title compound (76 mg, 84%). LC-MS m/z 441 (M+H)+, 1.14 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 80

28
[ 1269407-49-9 ]
[ 34306-42-8 ]
[ 1269407-51-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; HATU In methanol; dichloromethane at 20℃; for 0.25h;	96 To a solution of 2-[(35)-3-amino-l-pyrrolidinyl]benzonitrile hydrochloride (54 mg, 0.241 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}amino)butanoic acid (50 mg, 0.246 mmol), and HATU (92 mg, 0.241 mmol) in CH2Cl2 (1.5 mL) and MeOH (0.75 mL) was added Et3N (0.100 mL, 0.724 mmol). The reaction mixture was stirred at RT for 15 min and then concentrated under a stream of nitrogen at 50 0C. Water (3 mL) and EtOAc (2 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (2 x 1 mL) and then concentrated under a stream of nitrogen at 50 0C onto Isolute. Purification via flash column chromatography (0-80% EtOAc/hexanes) afforded the title compound (89.5 mg, 100%). LC-MS m/z 373 (M+H)+, 1.02 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 83

29
[ 1269406-70-3 ]
[ 34306-42-8 ]
[ 1269406-77-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; HATU In dichloromethane at 20℃; for 0.5h;	12 To a solution of 2-[(35)-3-amino-l-pyrrolidinyl]-5-nitrobenzonitrile hydrochloride(75 mg, 0.279 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}-amino)butanoic acid (62.4 mg, 0.307 mmol), and HATU (135 mg, 0.355 mmol) in CH2Cl2 (5.0 mL) was added Et3N (0.14 mL, 1.004 mmol). The reaction mixture was stirred at RT for 30 min. Water (5 mL) was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 x 3 mL). The combined organic layers were concentrated in vacuo and the residue was dissolved in EtOAc (10 mL) and washed with saturated aq. NaHCO3 (10 mL), brine (20 mL), and water (20 mL). The solvent was removed and the residue was purified via flash column chromatography (30-100% EtOAc/hexanes) to afford the title compound (110 mg, 94%). LC-MS m/z 418 (M+H)+, 0.99 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 40-41

30
[ 1269407-82-0 ]
[ 34306-42-8 ]
[ 1269407-84-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine; HATU In methanol; dichloromethane at 20℃; for 0.666667h;	130 To a solution of 2-[(35)-3-amino-l-pyrrolidinyl]-5-(methyloxy)benzonitrile hydrochloride (100 mg, 0.394 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}- amino)butanoic acid (80 mg, 0.394 mmol), and HATU (150 mg, 0.394 mmol) in CH2Cl2 (1.0 mL) and MeOH (0.5 mL) was added Et3N (0.17 mL, 1.226 mmol). The reaction mixture was stirred at RT for 40 min and then concentrated under a stream of nitrogen at 50 0C. Water (4 mL) and EtOAc (3 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with saturated aq. NH4Cl (1 mL) and then concentrated under a stream of nitrogen at 50 0C onto Isolute. Purification via flash column chromatography (0-80% EtOAc/hexanes) afforded the title compound (108 mg, 68%). LC-MS m/z 403 (M+H)+, 1.17 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 99-100

31
[ 1269407-87-5 ]
[ 34306-42-8 ]
[ 1269407-88-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; HATU In dichloromethane at 20℃; for 1h;	135 To a solution of 4-[(35)-3-amino-l-pyrrolidinyl]-4'-fluoro-3-biphenylcarbonitrile hydrochloride (517 mg, 1.464 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}- amino)butanoic acid (298 mg, 1.464 mmol), and HATU (708 mg, 1.862 mmol) in CH2Cl2 (10.0 mL) was added Et3N (0.735 mL, 5.27 mmol). The reaction mixture was stirred at RT for 1 h and then concentrated. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL), saturated aq. NH4Cl (50 mL), saturated aq. NaHCO3 (50 mL), and brine (2 x 100 mL). The organic solution was concentrated in vacuo and the residue was purified via flash column chromatography (20-100% EtOAc/hexanes) to afford the title compound (564 mg, 82%). LC-MS m/z 467 (M+H)+, 1.32 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 102

32
[ 1269406-81-6 ]
[ 34306-42-8 ]
[ 1269407-42-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; HATU In methanol; dichloromethane at 20℃; for 0.25h;	86 To a solution of 4-[(35)-3-amino-l-pyrrolidinyl]-3-biphenylcarbonitrilehydrochloride (36 mg, 0.120 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}amino)- butanoic acid (24.4 mg, 0.120 mmol), and HATU (49 mg, 0.129 mmol) in CH2Cl2 (0.8 mL) and MeOH (0.4 mL) was added Et3N (0.05 mL, 0.360 mmol). The reaction mixture was stirred at RT for 15 min and then concentrated under a stream of nitrogen at 50 0C. Water (3 mL) and EtOAc (2 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (2 x 1 mL) and then concentrated under a stream of nitrogen at 50 0C onto Isolute. Purification via flash column chromatography (0-80% EtOAc/hexanes) afforded the title compound (39 mg, 72%). LC-MS m/z 449 (M+H)+, 1.21 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 78

33
[ 1269406-98-5 ]
[ 34306-42-8 ]
[ 1269406-99-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine; HATU In dichloromethane at 20℃; for 0.333333h;	39 To a solution of 2- [(35)-3 -amino- 1 -pyrrolidinyl] -5 -(2-pyrimidinyl)benzonitrile hydrochloride (5.3 mg, 0.018 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}amino)- butanoic acid (3.6 mg, 0.018 mmol), and HATU (6.7 mg, 0.018 mmol) in CH2Cl2 (0.5 mL) was added Et3N (0.0073 mL, 0.053 mmol). The reaction mixture was stirred at RT for 20 min and then concentrated under a stream of nitrogen at 50 0C onto Isolute.Purification via flash column chromatography (20-70% EtOAc/hexanes) afforded the title compound (6.5 mg, 82%). LC-MS m/z 451 (M+H)+, 0.99 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 54

34
[ 1269407-03-5 ]
[ 34306-42-8 ]
[ 1269407-05-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; HATU In methanol; dichloromethane at 20℃; for 0.25h;	45 To a solution of 2-[(35)-3-amino-l-pyrrolidinyl]-5-(trifluoromethyl)benzonitrile hydrochloride (54.5 mg, 0.187 mmol), (25)-2-([(l,l-dimethylethyl)oxy]carbonyl}- amino)butanoic acid (38.0 mg, 0.187 mmol), and HATU (71.0 mg, 0.187 mmol) in CH2Cl2 (1.0 mL) and MeOH (0.5 mL) was added Et3N (0.078 mL, 0.561 mmol). The reaction mixture was stirred at RT for 15 min and then concentrated under a stream of nitrogen at 50 0C. Water (3 mL) and EtOAc (2 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were concentrated under a stream of nitrogen at 50 0C onto Isolute.Purification via flash column chromatography (0-60% EtOAc/hexanes) afforded the title compound (82 mg, 100%). LC-MS m/z 441 (M+H)+, 1.11 min (ret time).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/25799, 2011, A1 Location in patent: Page/Page column 57

35
[ 110-91-8 ]
[ 34306-42-8 ]
[ 1355040-44-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In 1,2-dichloro-ethane at 0℃; for 16h;	Preparation of Compound 126Step 1: Tert-butyl N-[(lS)-l-(morpholine-4-carbonyl)propyl]carbamate. To a solution of (5)- 2-(tert-butoxycarbonylamino)butanoic acid (18.5 g, 91.1 mmol), HBTU (43.4 g, 109 mmol), DIPEA (47.6 mL, 273 mmol) in CH2C12 (400 mL) at 0 °C, morpholine (9.5 mL, 110 mmol) was added and the reaction stirred at RT for 16h. Reaction progress was monitored by TLC. The mixture was diluted with CH2CI2 (200 mL), washed with water (3 x lOO mL), brine (100 mL), dried over a2S04 and concentrated. The residue was purified by column chromatography (100-200 mesh silica gel, 50 % EtOAc in petroleum ether) to afford tert-butyl N-[(15)-l-(morpholine-4-carbonyl)propyl]carbamate (22 g, 89 %, colorless gum). TLC system: 50 % EtOAc: petroleum ether, Rf: 0.53. MH+= 273.0. ¾ NMR (CDC13, 400MHz): 5.38 (d, J=7.6 Hz; 1H), 4.55-4.50 (m, 1H), 3.71 (m, 8H), 1.77- 1.71 (m, 1H), 1.56-1.51 (m, 1H), 1.43 (m, 9H).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2012/6055, 2012, A2 Location in patent: Page/Page column 146-147

36
[ 1161813-60-0 ]
[ 34306-42-8 ]
[ 1401625-43-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: Boc-Abu With 4-methyl-morpholine; chloroformic acid ethyl ester In dichloromethane at 0℃; for 1h; Stage #2: (1R,2R)-methyl 1-amino-2-(4-bromophenyl)cyclopropanecarboxylate In dichloromethane at 20℃;	16 (1«,2«)-Methyl 2-(4-bromophenyl)-1-((S)-2-(tert- butoxycarbonylamlno)butanamldo)cyclopropanecarboxylate (CP-12-(S,/?,/?)): To a solution of Boc-Abu-OH (1.2 g, 4.4 mmol) and NMM (0.9 g, 8.8 mmol) in dichloromethane (20 mL) at 0 °C was added ethyl chlorofomate (0.4 g, 4.4 mmol). The reaction was stirred for 1 h at 0 °C, and a solution of CP-3-(R,R) (see example 15); 1 g, 3.7 mmol) in dichloromethane (10 mL) was added. The cooling system was removed and the reaction was stirred overnight at ambient temperature. The solution was poured Into a mixture of water (50 mL) and dichloromethane (50 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2) and ethyl acetate (50 mL x 2). The organic phases were collected, dried over anhydrous Na2S04, and concentrated. The residue was purified by HPFC (PE:EA = 3: 1) to yield CP-12-(S,R,R) (1.4 g, 83% yield). LC-MS: 455.1 [M+H]+.

Reference： [1]Current Patent Assignee: PROZYMEX AS - WO2012/130299, 2012, A1 Location in patent: Page/Page column 164

37
[ 1401624-53-0 ]
[ 34306-42-8 ]
[ 1401624-54-1 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: Boc-Abu With 4-methyl-morpholine; chloroformic acid ethyl ester In dichloromethane at 0℃; for 0.5h; Stage #2: (1R,2R)-methyl 1-amino-2-(4-fluorobipheny-4-yl)cyclopropanecarboxylate In dichloromethane at 20℃; for 2h;	1 (lR,2R)-methyl l-((S)-2-(tert-butoxycarbonylamino)butanamldo)-2-(4I-fluorobiphenyl-4- yl)cydopropanecarboxylate (Compound 23)To a solution of Boc-Abu-QH (1.6 g, 6.4 mmol) and NM (1.07 g, 10.6 mmol) Indlchloromethane (50 ml) at 0 °C, was added ethyl chloroformate (0.7 g, 6.4 mmol). The reaction was stirred for 30 mln at 0 °C, and a solution of (lR,2R)-methy. l-amlno-2-(4'- fluoroblphenyI-4-yl)cydopropanecarboxylate (1.5 g, 5.3 mmol) In dlchloromethane (10 ml) was added In. The cooling system was removed and the reaction was stirred for 2 h at ambient temperature. After washing with 5% HCl, the organic phase was collected, dried over anhydrous Na2S04, and concentrated. The residue was purified by HPFC (PE: EA = 4: 1) to afford the title compound (1.8 g, 73%). LC-MS: 471.2 (M+l), 493.1 (M+Na).

Reference： [1]Current Patent Assignee: PROZYMEX AS - WO2012/130299, 2012, A1 Location in patent: Page/Page column 110

38
[ 1401625-52-2 ]
[ 34306-42-8 ]
[ 1401625-47-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: Boc-Abu With 4-methyl-morpholine; chloroformic acid ethyl ester In dichloromethane at 0℃; for 1h; Stage #2: (1R,2R)-1-amino-2-(4-bromophenyl)cyclopropanecarbonitrile In dichloromethane at 20℃;	15 tert- Butyl (S)-1 -((2/¾,2/?)-2-(4-bromophenyl)-1 -cyanocyclopropylamino)-1 -oxobutan-2- yicarbamate (CP-8-(5,fl,K)): To a solution of Boc-Abu-OH (0.8 g, 3 mmol) and NMM (0.5 g, 5.1 mmol) in dlchloromethane (20 mL) at 0 °C was added ethyl chlorofomate (0.3 g, 3 mmol). The reaction was stirred for 1 h at 0 °C, and a solution of CP-7-(R,R) (0.6 g, 2,5 mmol) in dlchloromethane (10 mL) was added. The cooling system was removed and the reaction was stirred overnight at ambient temperature. The solution was poured Into a mixture of water (50 mL) and dlchloromethane (50 mL). The organic phase was separated, and the aqueous phase was extracted with dlchloromethane (50 mL x 2) and ethyl acetate (50 mL x 2). The organic phases were collected, dried over anhydrous Na2S04, and concentrated. The residue was purified by HPFC (PE:EA - 3: 1) to yield CP-8-(S,R,R) (780 mg, 73% yield). LC-MS: 422.2 [M+H]+.

Reference： [1]Current Patent Assignee: PROZYMEX AS - WO2012/130299, 2012, A1 Location in patent: Page/Page column 162

39
[ 1401625-62-4 ]
[ 34306-42-8 ]
[ 1401624-61-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: Boc-Abu With 4-methyl-morpholine; chloroformic acid ethyl ester In dichloromethane at 0℃; for 0.5h; Stage #2: (1R,2R)-methyl 1-amino-2-(4'-trifluoromethylbipheny-4-yl)cyclopropanecarboxylate In dichloromethane at 20℃; for 2h;	2 1R,2R)- methyl l-((S)-2-(tert-butoxycarbonylamlno)butanamldo)-2-(4'- trifiuoromethyl biphenyl-4-yl)cyclopropanecarboxylate (Compound 28)To a solution of Boc-Abu-OH (1.1 g, 5.4 mmol) and NMM (0.91 g, 9.0 mmol) Indichloromethane (30 ml) at 0 °C, was added ethyl chloroformate (0.59 g, 5.4 mmol). The reaction was stirred for 30 min at 0 °C, and a solution of (lR,2R)-methyl l-amlno-2-(4*- trifluoromethyl biphenyl-4-yl)cyclopropane-carboxylate (1.5 g, 4.5 mmol) In dlchloromethane (10 ml) was added in. The cooling system was removed and the reaction was stirred for 2 h at ambient temperature. After washing with 5% HCl, the organic phase was collected, dried over anhydrous Na2S04, and concentrated. The residue was purified by HPFC (PE: EA « 4: 1) to afford the title compound (1.9 g, 81%). LC-MS: 543.1 (M+Na).

Reference： [1]Current Patent Assignee: PROZYMEX AS - WO2012/130299, 2012, A1 Location in patent: Page/Page column 114

40
[ 68765-56-0 ]
[ 34306-42-8 ]
[ 1404085-68-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	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 dichloromethane; N,N-dimethyl-formamide at 20℃;	80 PREPARATION 80 (S)-tert-Butyl 1-oxo-1-(3-(phenylamino)pyridin-2-ylamino)butan-2-ylcarbamate To a solution of (S)-2-(tert-butoxycarbonylamino)butanoic acid (392 mg, 1.89 mmol) in dichloromethane (15 mL) was added HATU (790 mg, 2.08 mmol) and N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 10 min. To the reaction mixture were added N3-phenylpyridine-2,3-diamine (350 mg, 1.89 mmol, Preparation 67) and DIEA (0.3 mL, 1.89 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, transferred straight onto a silica gel column and was purified by flash chromatography (SQ16, silica gel, heptane/Ethyl acetate) to afford (S)-tert-butyl 1-oxo-1-(3-(phenylamino)pyridin-2-ylamino)butan-2-ylcarbamate (685 mg, 1.71 mmol, 91 % yield) as a colourless sticky solid.
91%	Stage #1: Boc-Abu With HATU In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3-N-phenylpyridine-2,3-diamine With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;	To a solution of (SJ-2-(fe/f-butoxycarbonylamino)butanoic acid (392 mg, 1.89 mmol) in dichloromethane (15 mL) was added HATU (790 mg, 2.08 mmol) and N,N- dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 10 min. To the reaction mixture were added N3-phenylpyridine-2,3-diamine (350 mg, 1.89 mmol, Preparation 67) and DIEA (0.3 mL, 1.89 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, transferred straight onto a silica gel column and was purified by flash chromatography (SQ16, silica gel, heptane/Ethyl acetate) to afford (S)-ieri-butyl 1 -OXO-1 -(3-(phenylamino)pyridin-2-ylamino)butan-2 -ylcarbamate (685 mg, 1 .71 mmol, 91 % yield) as a colourless sticky solid.LRMS (m/z): 371 (M+1 )+.

Reference： [1]Current Patent Assignee: ALMIRALL SA - EP2518071, 2012, A1 Location in patent: Page/Page column 48
[2]Current Patent Assignee: ALMIRALL SA - WO2012/146667, 2012, A1 Location in patent: Page/Page column 106-107

41
[ 34306-42-8 ]
[ 86499-35-6 ]
[(S)-1-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)propyl]carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
860 mg	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; for 1.33333h;	Step 1: 3-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (416 mg, 2.36 mmol, Eq: 1.00),(S)-2-(BOC-amino)butyric acid (578 mg, 2.84 mmol, Eq: 1.2) and TEA (717 mg, 987 )lL, 7.085 mmol, Eq: 3.00) were combined with DMF (10 mL) and HOBT?H20 (383 mg, 2.83 mmol, Eq:1.20) and HBTU (1.34 g, 3.54 mmol, Eq: 1.50) were added. After 1 h 20 min., the mixture wasdiluted with 1 N HCl and extracted with EtOAc. The combined extracts were washed with 1 NNaOH and brine, dried over Na2S04 and concentrated to afford [(S)-1-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b ]azepin-3-ylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (860 mg) as a mixture10 of diastereomers which was used without purification.

Reference： [1]Patent: WO2014/9495,2014,A1 .Location in patent: Page/Page column 71

42
[ 34306-42-8 ]
[ 86499-35-6 ]
[ 1539309-85-7 ]

Reference： [1]Patent: WO2014/9495,2014,A1

43
[ 34306-42-8 ]
[ 541-23-1 ]
(S)-2-(tert-butoxycarbonylamino)-N-isopentylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	2 4.2.6. General procedure for amide coupling General procedure: To a cooled solution of Boc-L-leucine (1.0 equiv.), the amine/α-aminoester HCl (1.2-1.5 equiv.), and PyBop 1.2 equiv. (or EDCI*HCl1.2 equiv. and HOBt 1.2 equiv.) in anhydrous DMF was added diisopropylethylamine (3.3-4.0 equiv.) gradually. The reaction mixture was stirred at room temperature for 5 h to overnight, diluted with ethyl acetate (50 mL for every 5 mL DMF), then extracted with 1 M HCl (3), saturated sodium bicarbonate (3), and brine (2). The organic layer was then dried with anhydrous sodium sulfate and the solvent was evaporated under vacuum to give the products which were purified by flash chromatography whenever needed.

Reference： [1]Nasief, Nader N.; Hangauer, David [European Journal of Medicinal Chemistry, 2015, vol. 90, p. 897 - 915]

44
[ 34306-42-8 ]
[ 7517-19-3 ]
((S)-2-(tert-butoxycarbonylamino)butanoyl)-L-leucine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	5 4.2.6. General procedure for amide coupling General procedure: To a cooled solution of Boc-L-leucine (1.0 equiv.), the amine/α-aminoester HCl (1.2-1.5 equiv.), and PyBop 1.2 equiv. (or EDCI*HCl1.2 equiv. and HOBt 1.2 equiv.) in anhydrous DMF was added diisopropylethylamine (3.3-4.0 equiv.) gradually. The reaction mixture was stirred at room temperature for 5 h to overnight, diluted with ethyl acetate (50 mL for every 5 mL DMF), then extracted with 1 M HCl (3), saturated sodium bicarbonate (3), and brine (2). The organic layer was then dried with anhydrous sodium sulfate and the solvent was evaporated under vacuum to give the products which were purified by flash chromatography whenever needed.

Reference： [1]Nasief, Nader N.; Hangauer, David [European Journal of Medicinal Chemistry, 2015, vol. 90, p. 897 - 915]

45
[ 34306-42-8 ]
[ 38330-80-2 ]
(S)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		To a mixture of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (200 g, 0.985 mol) in THF (1 L) was added 1,1?-carbonyldiimidazole (176 g, 1.084 mol) at room temperature. The mixture was stirred at room temperature for 1 h. Then magnesium chloride (101 g, 1.084 mol) and potassium 3-methoxy-3-oxopropanoate (169 g, 1.084 mol) were added. After addition, the mixture was stirred at 50° C. for 3 h. TLC (petroleum ether:ethyl acetate=5:1) showed the starting material was consumed. The mixture was cooled and filtered; the filter cake was washed with THF (300 mL) and filtered. The combined filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (1 L) washed with water (800 mL), brine (800 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 45percent) as a yellow oil, which was used in the next step directly without further purification.
45%		To a mixture of (S)-2-((tert-butoxycarbonyl)amino)bu- tanoic acid (200 g, 0.985 mol) in THF (1 L) was added 1,1?-carbonyldiimidazole (176 g, 1.084 mol) at rt.mixture was stirred at it for 1 h. Then magnesium chloride(101 g, 1.084 mol) and potassium 3-methoxy-3-oxopro- panoate (169 g, 1.084 mol) were added. After addition,mixture was stirred at 50° C. for 3 h. TLC (petroleum ether:ethyl acetate=5: 1) showed the starting material was consumed. The mixture was cooled and filtered; the filtercake was washed with THF (300 mE) and filtered.combined filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (1 E) washed with water (800 mE), brine (800 mE), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 45percent) as a yellow oil, which was used in the next step directly without thrther purification.
		[0089] To a mixture of (lS')-2-((ieri-butoxycarbonyl)amino)butanoic acid (200 g, 0.985 mol) in THF (1 L) was added Iota,Gamma-carbonyldiimidazole (176 g, 1.084 mol) at rt. The mixture was stirred at rt for 1 h. Then magnesium chloride (101 g, 1.084 mol) and potassium 3- methoxy-3-oxopropanoate (169 g, 1.084 mol) were added. After addition, the mixture was stirred at 50 °C for 3 h. TLC (petroleum ether: ethyl acetate = 5: 1) showed the starting material was consumed. The mixture was cooled and filtered; the filter cake was washed with THF (300 mL) and filtered. The combined filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (1 L) washed with water (800 mL), brine (800 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (^-methyl 4-((ieri-butoxycarbonyl)amino)-3-oxohexanoate (117 g, 45percent) as a yellow oil, which was used in the next step directly without further purification.

Reference： [1]Patent: US2016/122345,2016,A1 .Location in patent: Paragraph 0107
[2]Patent: US9481674,2016,B1 .Location in patent: Page/Page column 23; 24
[3]Patent: WO2016/61160,2016,A1 .Location in patent: Paragraph 0089

46
(Z)-2-fluoro-6-nitro-N-phenylbenzimidoyl chloride [ No CAS ]
[ 34306-42-8 ]
[ 870281-84-8 ]

Reference： [1]Organic Preparations and Procedures International,2016,vol. 48,p. 337 - 341

47
[ 34306-42-8 ]
2-amino-6-fluoro-N-phenyl-benzamide [ No CAS ]
(S)-N-[2-[[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino]-1-ethyl-2-oxoethyl]-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: Boc-Abu With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15 - -10℃; for 2h; Stage #2: 2-amino-6-fluoro-N-phenyl-benzamide In tetrahydrofuran at 60℃; for 0.5h;	tert-Butyl [(1S)-1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)propyl]carbamate (11) To a solution of the acid 3 (256.8 g, 1.26 mol) in dry THF (1600 ml) at 15C wasslowly added N-methylmorpholine (165 ml, 1.48 mol) dropwise followed by isobutylchloroformate (165 ml, 1.26 mol). The reaction mixture was stirred at 10C for 2 h. Asolution of 10 (121 g, 0.53 mol) was added to the above reaction mixture over 0.5 h.After stirring overnight at 60C, the mixture was cooled to 25C and then the solvent wasremoved in vacuo at 30C. The resulting residue was triturated with water (2000 ml), andthe suspension was filtered. The filter cake was washed with water (200 ml £ 3) and driedunder vacuum. The resulting solid was triturated with isopropyl ether to afford 11(214.3 g, 98.0%) as a white powder. mp. 179-180C. ESI-MS (m/z): 438 ([MCNa]C);1H-NMR: d 8.52 (d, J D 8.4 Hz, 1H), 8.38 (d, J D 14.4 Hz, 1H), 7.63 (d, J D 8 Hz, 2H),7.46-7.37 (m, 4H), 7.21 (t, J D 7.6 Hz, 1H), 6.90 (dd, J D 12, 8.4 Hz, 1H), 5.11 (s, 1H),4.26 (s, 1H), 1.80-1.73 (m, 2H), 1.44(s, 9H), 1.03 (t, J D 7.6 Hz, 3H).Anal.CalcdforC22H26FN3O4:C,63.60;H,6.31;N,10.11.Found:C,63.45;H,6.40;N,10.12.
91.46%	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 dichloromethane at -10℃; Reflux;	39.3 Step 3) tert-Butyl (S) - (1 - ((3-fluoro- 2- (phenylcarbamoyl) phenyl) amino) - 1 -oxobutan-2-yl) carbamate The compound 2-amino-6-fluoro-N-phenylbenzamide (700 mg, 3.0 mmol) and(S) -2- ((tert- butoxycarbonyl) amino) butanoic acid (610 mg, 3.0 mmol) was suspended in DCM (11 mL) and then HATU (1.37 g, 3.6 mmol) And DIPEA (1.16 g, 9.0 mmol). The resulting mixture was stirred at -10 ° C for 1 hour, then heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature and washed sequentially with water (20 mL × 2) and saturated aqueous NaHCO 3 solution (20 mL × 2). The organic phase was washed with anhydrous sulfuric acid Dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EtOAc(v / v) = 10/1) to give the title compound as a yellow solid (1.14 g, 91.46%).
90%	With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0 - 60℃; for 4h;	1 Example 1 (S) -N- [2_ [[3E_2_ [(phenylamino) poly] phenyl] amino] -1-ethyl-Ethyl] -carbamic acid tert-butyl ester (compound of formula (IV) N-B0C-L-2-aminobutyric acid (compound of formula III, 64 g, 2 eq) and N-methylmorpholine (35 g, 2.2 eq) were dissolved in tetrahydrofuran (240 mL)A solution of isobutyl chloroformate (43 g, 2.2 eq) was added dropwise at 0 ° C,A solution of 2-amino-6-fluoro-N-phenylbenzamide (compound of formula II, 36 g, leq) in tetrahydrofuran (300 mL) was added dropwise and reacted at 60 ° C for 4 hours,After the completion of the reaction, a saturated sodium bicarbonate solution was added,Layered,The aqueous extract of the extract was extracted with ethyl acetate,The organic layer was washed with saturated sodium chloride solution,Concentrated to the oil after adding n-hexane pulp to precipitate 58g solid,Yield:90%,purity:99% (area normalization).

87.4%	Stage #1: Boc-Abu With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 3h; Inert atmosphere; Stage #2: 2-amino-6-fluoro-N-phenyl-benzamide In tetrahydrofuran at 60℃;	4 Example 4. Synthesis of intermediate I Boc-L-2-aminobutyric acid (31.8 g, 156.5 mmol) was dissolved in anhydrous tetrahydrofuran (250 ml)N2, cooled to -15 ° C and slowly added N-methylmorpholine (20.4 ml, 182.6 mmol)And isobutyl chloroformate (20.4 ml, 156.5 mmol), After the addition was complete, the reaction was continued for 3h. A solution of compound II (15g, 65.2mmol) in dry tetrahydrofuran (80ml) was slowly added dropwise. After the addition was completed, the mixture was stirred for 1 h at low temperature, and then slowly warmed to 60 ° C. for overnight stirring. The reaction was complete by TLC analysis.The reaction mixture was cooled to room temperature, quenched with water (100 ml), concentrated under reduced pressure to remove the organic solvent,The suspension is treated with water (100 ml)Filter, the filter cake was dried to give a light brown crude,Recrystallization from acetone gave 23.6 g of intermediate I as a white solid,Yield 87.4%(HPLC: 99%).
67%	With benzotriazol-1-ol; 1,1'-carbonyldiimidazole In toluene at 8 - 15℃;
82 g	With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -5 - 28℃; for 20h;	3 Example 3: Preparation of (S)-tert-butyl-l-(3-fluoro-2-(phenylcarbamoyl)phenylamino)- l-oxobutan-2-yl carbamate Example 3: Preparation of (S)-tert-butyl-l-(3-fluoro-2-(phenylcarbamoyl)phenylamino)- l-oxobutan-2-yl carbamate N-methyl morpholine (48.22 g, 0.48 mole) was added to a solution of (S)-2-(tert- butoxycarbonylamino)butanoic acid (88.2 g, 0.43 mole) in tetrahydrofuran (100 mL). The resulting mixture was cooled to 0 °C- -5 °C and a solution of isobutyl chloroformate (59.3 g (0.43 mole) in 100 mL of tetrahydrofuran) was added. A solution of 2-amino-6-fluoro-N- phenyl-benzamide (50 g, 0.27 mole) in tetrahydrofuran (200 mL) was slowly added at 0 °C- 5 °C. The reaction mixture temperature was raised to 25 °C- 28 °C and the solution was stirred for 20 hours. After completion of the reaction, water (500 mL) and ethyl acetate (500 mL) were added to the reaction mixture. The organic layer was separated, washed with water, and dried on sodium sulfate. Solvent was removed by vacuum distillation. The residue was dissolved in tetrahydrofuran (250 mL) and n-heptane was added to precipitate (S)-tert-butyl-l- (3-fluoro-2-(phenyl carbamoyl)phenylamino)-l-oxobutan-2-yl carbamateas a solid. The solution was filtered, the solid was washed with n-heptane, and finally dried at 55 °C under vacuum to get a light brown colored solid (82 g, 90% molar).
120 g	Stage #1: Boc-Abu With 1,1'-carbonyldiimidazole In toluene at 0 - 5℃; for 1h; Stage #2: 2-amino-6-fluoro-N-phenyl-benzamide In toluene at 0 - 35℃; for 12h;	3 Preparation of compound of Formula VIa Toluene (500 mL) was charged in a reaction flask and N-boc-L-2-amino butyric acid (50 g) and carbonyldiimidazole (140.8 g) were added at 0-5 °C and stirred for 1 hr at same temperature. To the reaction mass, 2-fluoro-6-amino-phenylbenzamide (100 g) was added at 0-5°C, heated to 25-35°C and stirred for 12 hrs at same temperature. After completion of the reaction, precipitated solid was filtered and washed with toluene (100 mL) and dried at 60-65 °C under vacuum. Then the dried solid was dissolved in acetonitrile (300 mL) at 75- 80°C and stirred for 2 hrs at same temperature. Reaction mass was allowed to cool to 25- 35 °C and stirred for 3 hrs at same temperature. Precipitated solid was filtered and washed with acetonitrile (100 mL) and dried at 60-65 °C under vacuum to get the title compound. Yield: 120 g; HPLC Purity: 99.1%; PXRD: Fig. 6; DSC: endothermic peak at 167.48°C;1HNMR(DMSO-d6):50.84-0.89 (t,3H),1.3-1.74 (m,9H),1.76 (m,lH),1.78 (t,lH),3.82-3.93 (m,lH),7.02-7.08 (m,2H),7.11-7.15 (m,3H),7.22 (m,lH),7.3-7.9 (m,2H),8.0 (d,lH),10.4 (s,lH),10.61 (s,lH); MS (ESI)[M+H]:-415.47.
135 g	With 1-methyl-1H-imidazole; methanesulfonyl chloride In dichloromethane at -35 - -30℃; for 0.5h;	3 Example-3: Preparation of (S)-tert-butyl(1-((3-fluoro-2-(phenylcarbamoyl) phenyl)30 amino )-1-oxobutan-2-yl)carbamate (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (124 gm) was added to dichloromethane(500 ml) at 20-30°C and the obtained solution was cooled to -35°C. N-methylimidazole(143 gm) was added to the solution followed by the addition of methane sulfonyl chloridesolution in dichloromethane -30 to -35 oc. A solution of 2-amino-6-fluoro-N-5 phenylbenzamide (100 gm) in dichloromethane (60 ml) was slowly added over 30 min at-30 to -35 oc to the reaction mixture. After completion of the reaction, water (800 ml)was added to the reaction mixture. The organic layer was separated and the aqueous layerwas washed with dichloromethane. Both the dichloromethane layers were combined andconcentrated under vacuum at 45 oc up to 2.5-3.5 volume. Isopropanol (600ml) was10 added to the reaction mass and the isopropanol was recovered under vacuum. Thereaction mass was filtered and washed twice with isopropanol (50ml). Obtained solid wasdried under vacuum at 50-55 octo get the title compound (135gm).
	Stage #1: Boc-Abu With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -20℃; for 0.5h; Stage #2: 2-amino-6-fluoro-N-phenyl-benzamide In tetrahydrofuran at 60℃; for 6h;	3 Preparation of tert-butyl N-[(1S)-1-[[3-fluoro-2-(phenylcarbamoyl)phenyl]carbamoyl] propyl]carbamate A mixture of (2S)-2-[(tert-butoxycarbonyl)amino)butanoic acid and N-methyl morpholine in dry tetrahydrofuran (300 mL) were stirred and cooled at -20 °C temperature. A solution of isobutyl chloroformate in dry tetrahydrofuran (200 mL) was drop wise added into the reaction mass at -20 °C temperature. The reaction mass was stirred for half an hour at -20 °Ctemperature. Then a solution of 2-amino-6-fluoro-N-phenylbenzamide in dry tetrahydrofuran (300 mL) was added to it dropwise. After addition, the reaction mixture temperature was slowly increased up to 60 °C and stirred for 6 hours. The reaction mixture was then concentrated and partitioned between dichloromethane and water. The organic layer was again washed with water and concentrated up to dryness to provide solid product. The solidproduct was treated with hexane and filtered to get an off white solid of the title compound

Reference： [1]Liu, Jian; Huang, Yu; Chang, Xiao-Hui; Liu, Xiang-Kui; Jiang, Hui-Juan; Zhu, Xue-Yan [Organic Preparations and Procedures International, 2016, vol. 48, # 4, p. 337 - 341]
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 1150; 1151; 1152; 1153
[3]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; NANJING GEAR PHARMA TECHNOLOGY CO LTD - CN106279171, 2017, A Location in patent: Paragraph 0058; 0059; 0060; 0061; 0062
[4]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN106146502, 2016, A Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066; 0067; 0068-0071
[5]Mekala, Nagaraju; Buddepu, Srinivasa Rao; Dehury, Sanjay K.; Moturu, Krishna Murthy V. R.; Indukuri, Sunil Kumar V.; Vasireddi, Umamaheswara Rao; Parimi, Atchuta R. [RSC Advances, 2018, vol. 8, # 28, p. 15863 - 15869]
[6]Current Patent Assignee: VIATRIS INC - WO2016/147206, 2016, A1 Location in patent: Page/Page column 14-15
[7]Current Patent Assignee: LAURUS LABS LIMITED - WO2017/191608, 2017, A1 Location in patent: Page/Page column 50
[8]Current Patent Assignee: LUPIN LIMITED - WO2017/134607, 2017, A1 Location in patent: Page/Page column 28; 29
[9]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2017/221272, 2017, A1 Location in patent: Page/Page column 10; 11

48
[ 870281-83-7 ]
[ 34306-42-8 ]
[ 870281-84-8 ]

Yield	Reaction Conditions	Operation in experiment
85%		2. preparation of tert-butyl (1S)-1-[(2- fluoro-6-nitrobenzoyl)phenylaminocarbonyl]propylcarbamateIn 200 ml in the reaction bottle, by adding N-BOC-L-2-aminobutyric acid (10.2g, 0 . 05mol) and CDI (carbonyl diimidazole) (8.9g, 0 . 055mol) dissolved in 75mlDMF in, room temperature (25 C) reaction under 1 hour, board display raw material disappeared, in the reaction system by adding <strong>[870281-83-7]2-fluoro-6-nitro-N-phenylbenzamide</strong>(15.6g, 0 . 06mol) thermal insulation is continuously stirred for 8 hours, board display the reaction is complete, dry concentrated to the reaction liquid, by adding 150 ml water and 150 ml dichloromethane, extraction layered, dichloromethane is used for water washing 2 times, combined with the organic layer with saturated salt water washing 2 times, drying by anhydrous sodium sulfate, concentrated under reduced pressure, to obtain tert-butyl (1S)-1-[(2- fluoro-6-nitrobenzoyl)phenylaminocarbonyl]propylcarbamate (18.9g), yield 85%
		50 g of <strong>[870281-83-7]2-fluoro-6-nitro-N-phenylbenzamide</strong> (1) was suspended in 80 g of SOCl2 and 1.5 g of dimethylformamide. The mixture was refluxed at 70 C. for 1 hour under nitrogen atmosphere. The reaction mixture was evaporated at 85 C. under reduced pressure. The rest was dissolved in 80 g of dichloromethane and the mixture was concentrated. The rest was dissolved in 120 g of dichloromethane and 7.3 g of dry triethylamine were added. pH of the solution was set up at 8 (at 20-25 C.) using triethylamine. pH was measured using water wetted pH indicator strips. 43 g of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid was mixed with 150 g of dichloromethane and 21.5 g of dry triethylamine to obtain a second solution. pH of the second solution was set up at 8 (at 20-25 C.) using triethylamine. pH was measured using water wetted pH indicator strips. Both solutions were mixed together. The mixture was stirred at 25 C. for 1.5 hour. The mixture was concentrated. To the rest 150 g of ethylacetate and 240 g of water were added. The mixture was stirred at 65 C. for 10 minutes, the mixture was cooled at 20 C. and the phases were separated. The water phase was extracted with 30 g of ethylacetate. Phases were separated, the organic phases were collected and concentrated.

Reference： [1]Patent: CN104130261,2016,B .Location in patent: Paragraph 0037; 0038; 0039
[2]RSC Advances,2018,vol. 8,p. 15863 - 15869
[3]Patent: US2019/144452,2019,A1 .Location in patent: Paragraph 0040-0041; 0051-0052

49
[ 34306-42-8 ]
[ 88229-20-3 ]
(S)-(1-(N-cyclopropyl-2-nitrobenzamido)-1-oxobutan-2-yl)carbamate tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: N-cyclopropyl-2-nitrobenzamide With thionyl chloride In toluene at 120℃; for 6h; Stage #2: Boc-Abu With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 18.25h;	6.2 Step 2) (S) - (1- (N-Cyclopropyl-2-nitrobenzamido) -1-oxobutan-2-yl) carbamate The compound N-cyclopropyl-2-nitrobenzamide (1.5 g, 7.3 mmol) was dissolved in toluene (15 mL)Then, thionyl chloride (1.73 g, 14.5 mmol) was added to the reaction solution in one portion, and the mixture was stirred at 120 ° C for 6 hours and concentrated under reduced pressure to give a yellow solution A;The compound (2S) -2- (tert-butoxycarbonylamino) butanoic acid (1.50 g, 7.38 mmol) and DIPEA (1.90 g, 14.7 mmol) was dissolved in dichloromethane (32 mL)At 0 ° CStir for 15 minutes,A solution of the resulting yellow solution A in dichloromethane (16 mL) was added to the resulting solution and the reaction was stirred at room temperature for 18 hours. The mixture was then washed successively with water (30 mL) and saturated brine (30 mL). The organic phase was washed with Dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel(PE / EtOAc (v / v) = 7/1) to give the title compound as a yellow solid (1.83 g, 64%).
1.83 g	Stage #1: Boc-Abu With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: N-cyclopropyl-2-nitrobenzamide In dichloromethane at 0 - 20℃; for 18h;	5.2 Step 2) (S)-tert-but \ (l-(N-cvclopropyl-2-nitrobenzamido)-l-oxobutan-2-yl)carbamate [333] To a solution of N-cyclopropyl-2-nitrobenzamide (1.5 g, 7.3 mmol) in toluene (15 mL) was added thionyl chloride (1.73 g, 14.5 mmol) in one portion. The mixture was stirred at 120 °C for 6 hours, and concentration in vacuo to give the yellow liquid. A solution of (2,S)-2-(tert-butoxycarbonylamino)butanoic acid (1.50 g, 7.38 mmol) and DIPEA (1.90 g, 14.7 mmol) in DCM (32 mL) was stirred at 0 °C for 15 minutes, then a solution of the above yellow liquid in DCM (16 mL) was added to the above solution slowly at 0 °C. The mixture was stirred at room temperature for 18 hours. The reation mixture was washed with water (30 mL) and brine (30 mL). The separated organic phase was dried over anhydrous Na2SC>4, and concentration in vacuo. The residue was purified by a silica gel column chromatography (PE EtOAc (v/v) = 7/1) to give the title compound as a yellow solid (1.83 g, 64%). MS (ESI, pos. ion) m/z: 292.2 [M-Boc+2H]+; NMR (400 MHz, CDCb) δ (ppm): 8.19 (d, J= 8.0 Hz, 1 H), 7.71 (t, J= 8.0 Hz, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.33 (d, J= 8.0 Hz, 1 H), 5.40-5.19 (m, 1 H), 4.95 (d, J = 8.0 Hz, 1 H), 4.17- 4.12 (m, 1 H), 2.86 (s, 1 H), 1.97-1.91 (m, 1 H), 1.44 (s, 9 H), 1.28 (t, J = 8.0 Hz, 2 H), 1.10-0.96 (m, 5 H).

Reference： [1]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN105924434, 2016, A Location in patent: Paragraph 0546; 0547; 0548; 0549; 0550
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - WO2016/149160, 2016, A1 Location in patent: Paragraph 333

50
[ 34306-42-8 ]
[ 20776-48-1 ]
(S)-tert-butyl (1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 1156 - 1171

51
[ 34306-42-8 ]
[ 20776-48-1 ]
C₁₆H₁₉BrN₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; triphenyl phosphite; at 70℃; for 3h;	To a mixture of <strong>[20776-48-1]2-amino-6-bromobenzoic acid</strong> (4.0g, 18.5mmol, 1 equiv and (S)-2-(tert-butoxycarbonylamino)butanoic acid (3.76g, 18.5mmol, 1 equiv) in pyridine, degassed with N2, was added triphenyl phosphite (12.1mL, 46.3mmol, 2.5 equiv). The solution was heated at 70C for 3h. Then aniline (2mL, 22.2mmol, 1.2 equiv) was added dropwise. The solution was heated at 70C for another 3h. The solvent was removed under reduced pressure. The residue was redissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude was further purified via silica gel chromatography to give compound 5 as a yellow solid (5.0g, 59%). 1H NMR (300MHz, CDCl3) delta 7.72-7.64 (m, 2H), 7.57-7.48 (m, 4H), 7.35 (d, J=7.2Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 5.42 (d, J=8.1Hz, 1H), 4.37 (s, 1H), 1.73-1.67 (m, 1H), 1.53-1.46 (m, 1H), 1.40 (s, 9H), 0.74 (t, J=7.2Hz, 3H).

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 1156 - 1171

52
[ 34306-42-8 ]
2-amino-6-fluoro-N-phenyl-benzamide [ No CAS ]
[ 870281-85-9 ]

Reference： [1]Patent: WO2016/147206,2016,A1

53
[ 453-20-3 ]
[ 34306-42-8 ]
(2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	Intermediate 36: (2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)butanoate Intermediate 36: (2S)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)butanoate A mixture of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (2.5 g, 12.3 mmol), diisopropylethylamine (3.18 g, 4.3 mL, 24.6 mmol), 1-hydroxybenzotriazole hydrate (2.26g, 14.76 mmol), EDC (2.83 g, 14.76 mmol), and tetrahydrofuran-3-ol (10.84 g, 9.97 mL, 123 mmol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated NaHCO3 (50 mL). The organic phase was washed with 1M hydrochloric acid (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried and evporated to give the title compound (3.07 g, 11.23 mmol, 91 % yield), as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 5.30-5.34 (m, 1H), 5.00-5.04 (m, 1H), 4.16-4.22 (m,1H), 3.92-3.94 (m, 1H), 2.12-2.22 (m, 1H). 1.93-2.03 (m, 1H), 1.78-1.84 (m, 1H), 1.60-1.69 (m, 1H), 1.43 (s, 9H), 0.92 (t, J = 12.0 Hz, 3H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/146738, 2016, A1 Location in patent: Page/Page column 59

54
[ 107-98-2 ]
[ 34306-42-8 ]
(2S)-1-methoxypropan-2-yl 2-((tert-butoxycarbonyl)amino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	Intermediate 38: (2S)-1-methoxypropan-2-yl 2-((tert-butoxycarbonyl)amino)butanoate Intermediate 38: (2S)-1-methoxypropan-2-yl 2-((tert-butoxycarbonyl)amino)butanoate A mixture of (S)-2-((tert-butoxycarbonyl)amino)butanoic acid (2.5 g, 12.3 mmol), diisopropylethylamine (3.18 g, 4.3 mL, 24.6 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (2.26g, 14.76 mmol), EDC (2.83 g, 14.76 mmol), and 1-methoxy-2-propanol (11.09 g, 12.02 mL, 123 mmol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated NaHCO3 (50 mL). The organic phase was washed with 1M hydrochloric acid (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried and evporated to give the title compound (2.98 g, 10.82 mmol, 88 % yield), as a colourless oil.1H NMR (400 MHz, CDCl3) δ ppm 5.05-5.15 (m, 2H), 4.20-4.30 (m, 1H), 3.37-3.48 (m,2H), 3.34 (d, J = 10.0 Hz, 1H), 1.80-1.90 (m, 1H). 1.64-1.72 (m, 1H), 1.78-1.84 (m, 1H), 1.44 (s, 9H), 1.22-1.27 (m, 3H), 0.89-0.96 (m, 3H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/146738, 2016, A1 Location in patent: Page/Page column 60

55
[ 34306-42-8 ]
[ 870281-85-9 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1555 - 1567
[2]Patent: CN106146505,2016,A
[3]Patent: CN106146505,2016,A
[4]Patent: CN106854183,2017,A

56
[ 34306-42-8 ]
2-amino-6-fluoro-N-phenyl-benzamide [ No CAS ]
[ 543-27-1 ]
(S)-2-[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}carbamic acid isobutyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.4%	Stage #1: Boc-Abu; isobutyl chloroformate With 4-methyl-morpholine In tetrahydrofuran at -15℃; for 1h; Stage #2: 2-amino-6-fluoro-N-phenyl-benzamide In tetrahydrofuran at -15℃; for 4.5h; Reflux;	5 Preparation of (S)-2-[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamic acid isobutyl ester A solution of BOC-L-2-aminobutyric acid (20.3 g), N-methylmorpholine (11.2 g) was dissolved in anhydrous THF (120 ml) and isobutyl chloroformate was added dropwise at -15 °C in dry THF (40 ml) and the mixture was stirred at -15 °C for 1 hour. A solution of 2-amino-6-fluoro-N-phenyl-benzamide (11.5 g). The reaction was carried out for 1 hour. The solid was filtered off and the filtrate was heated to reflux for 3.5 hours. The reaction solution was concentrated and the ethyl acetate (150 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and water (200 ml). The layers were separated and extracted with ethyl acetate (100 ml x 2). The organic layers were combined with water, washed with brine, dried, filtered and concentrated to give crude 19.2 g, The title compound (S)-2-[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamic acid isobutyl ester was obtained in a yield of 82.4%.

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN106146352, 2016, A Location in patent: Paragraph 0030; 0031

57
2-amino-6-fluorobenzoic acid hydrochloride [ No CAS ]
[ 34306-42-8 ]
[ 62-53-3 ]
[ 870281-85-9 ]

Yield	Reaction Conditions	Operation in experiment
300 mg		A solution of (S) -N-Boc-L-2- aminobutyric acid (655mg, 3.2mmol) and 10ml of methylene chloride were added to 50mL three-necked flask and stirred until the solids dissolved.Was cooled to -20 , were added dropwise NMM (652mg, 8.4mmol), isobutyl chloroformate (440mg, 3.2mmol), incubated for 5 hours.2-amino-6-fluoro-benzoic acid hydrochloride (500mg, 2.6mmol), natural warming to 5 , incubated for 16 hours.Was added dropwise the aniline (600mg, 3.2mmol), naturally warmed to room temperature for 6 hours.The reaction mixture was concentrated under reduced pressure to dryness.The residue was added n-butanol 20ml.Triethylamine (10ml), was added dropwise TMSCl (10ml).Dropwise addition, the reaction flask was placed in an oil bath heated at reflux for 50 hours.Cooled to room temperature, the reaction mixture was poured into ice water and extracted twice with 50ml of dichloromethane.Washed twice with 0.1M hydrochloric acid solution and the organic phase, washed with saturated aqueous sodium hydrogen carbonate three times.Dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give crude compound of formula IV under reduced pressure.The crude product was dissolved in ethyl acetate 2ml, 2ml petroleum ether added dropwise with stirring, the precipitated brown solid was filtered.Cake was washed with 1: 1 ethyl acetate: petroleum ether solvent mixture and recrystallized to give a pale yellow solid of about 300mg.

Reference： [1]Patent: CN106146505,2016,A .Location in patent: Paragraph 0191; 0192; 0193; 0194

58
[ 34306-42-8 ]
[ 434-76-4 ]
C₁₆H₂₀FN₂O₅^(1-)*K⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2 g		(S) -N-Boc-L-2- aminobutyric acid (1.3g, 6.3mmol) and 20ml of methylene chloride was added to a 50mL three-necked flask.Stirred until the solids dissolved.Was cooled to -20 , were added dropwise NMM (1.4ml, 12.8mmol), isobutyl chloroformate (0.9ml, 6.9mmol).After the dropwise addition, heat -10 ~ -5 1.5 hours.<strong>[434-76-4]2-amino-6-fluorobenzoic acid</strong> (1.0g, 6.5mmol).Warm naturally to 5 , incubated for 16 hours.Addition of cold 5% aqueous potassium carbonate was quenched reaction was lyophilized to give a compound of formula I to about 2.0g.

Reference： [1]Patent: CN106146505,2016,A .Location in patent: Paragraph 0167; 0168; 0169; 0170

59
[ 34306-42-8 ]
1-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-oxo-pentyl]-3-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5-yl)sulfonyl]guanidine hydrochloride [ No CAS ]
tert-butyl-N-[(1S)-1-[[(1S)-1-(1,3-benzothiazole-2-carbonyl)-4-[[N-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5-yl)sulfonyl]carbamimidoyl]amino]butyl]carbamoyl]propyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.6%	Stage #1: Boc-Abu 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 tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-oxo-pentyl]-3-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5-yl)sulfonyl]guanidine hydrochloride In tetrahydrofuran at 0 - 30℃; for 2h;	13 Tert-butyl-iV-Iil^-l-IIil^-l-il^-benzothiazole-l-carbony ^-II/V-Iil,^^,?- pentamethyl-3H-benzofuran-5-yl)sulfonyl]carbamimidoyl]amino]butyl]carbamoyl] propyl] carbamate (11c). Tert-butyl-iV-Iil^-l-IIil^-l-il^-benzothiazole-l-carbony ^-II/V-Iil,^^,?- pentamethyl-3H-benzofuran-5-yl)sulfonyl]carbamimidoyl]amino]butyl]carbamoyl] propyl] carbamate (11c). A mixture of (25 -2-(tert-butoxycarbonylamino)butanoic acid (251 mg, 1.24 mmol, 1.20 eq), HATU (470 mg, 1.24 mmol, 1.20 eq), DIPEA (400 mg, 3.09 mmol, 3.00 eq) in THF (10 mL) was stirred at 0 °C for 0.5 hr. Then l-[(45 -4-amino-5-(l,3- benzothiazol-2-yl) -5-oxo-pentyl]-3-[(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]guanidine hydrochloride (600 mg, 1.03 mmol, 1.00 eq) was added and the mixture was stirred at 30 °C for 2 hr. LC-MS indicated the starting material was consumed completely. EA (50 mL) was added and the mixture was washed with water (20 mL x 3), dried over Na2SC>4, concentrated to give the crude product, which was purified by flash chromatography to give tert-butyl-N-[(15)-l-[[(15 -l-(l,3-benzothiazole-2- carbonyl)-4-[[N- [(2,2,4,6,7-pentamethyl-3H-benzofuran-5- yl)sulfonyl]carbamimidoyl]amino]butyl]carbamoyl]propyl]carbamate (500 mg, 685.95 /miol, 66.6% yield) as a yellow solid.

Reference： [1]Current Patent Assignee: CORTEXYME INC - WO2017/83433, 2017, A1 Location in patent: Paragraph 0208

60
[ 2385-27-5 ]
[ 34306-42-8 ]
(S)-(1-(2-nitro-N-phenylbenzamido)-1-oxobutan-2-yl)carbamate tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: N-phenyl-2-nitrobenzamide With thionyl chloride In toluene Reflux; Stage #2: Boc-Abu With triethylamine In dichloromethane at 0 - 20℃; for 26h;	7.2 Step 2) (S) - (1- (2-nitro-N-phenylbenzamido) -1-oxobutan-2-yl)CarbamateTert-butyl ester The compound 2-nitro-N-phenylbenzamide (1.50 g, 6.19 mmol) was suspended in toluene (10 mL) and then To the reaction solution was added thionyl chloride (2.25 mL, 31.2 mmol), the mixture was heated to reflux and stirred overnight, then concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) at 0 ° C. The resulting solution was added to a mixture of (2S) -2- (tert-butoxycarbonylamino) butanoic acid (1.01 g, 4.97 mmol) and triethylamine (628 mg, 6.2061 mmol) in dichloromethane (2 mL) The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and the reaction was continued for 24 hours. The mixture was washed with water(20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated saturated brine (20 mL), separated, and the organic phase was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 10/1) to give the title compound as a pale yellow solid(1.8 g, 68%).

Reference： [1]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN105924434, 2016, A Location in patent: Paragraph 0570; 0571; 0572; 0573

61
[ 77284-64-1 ]
[ 34306-42-8 ]
C₁₂H₂₃NO₄ [ No CAS ]
C₁₂H₂₃NO₄ [ No CAS ]

Reference： [1]Catalysis Letters,2017,vol. 147,p. 837 - 844

62
[ 77284-64-1 ]
[ 34306-42-8 ]
C₁₄H₂₇NO₄ [ No CAS ]
C₁₄H₂₇NO₄ [ No CAS ]

Reference： [1]Catalysis Letters,2017,vol. 147,p. 837 - 844

63
[ 77284-64-1 ]
[ 34306-42-8 ]
ethyl (2R)-2-(tert-butoxycarbonylamino)butanoate [ No CAS ]

Reference： [1]Catalysis Letters,2017,vol. 147,p. 837 - 844

64
[ 77284-64-1 ]
[ 34306-42-8 ]

Reference： [1]Catalysis Letters,2017,vol. 147,p. 837 - 844

65
[ 34306-42-8 ]
2-chloro-N-cyclopropyl-6-nitrobenzamide [ No CAS ]
(S)-(1-(2-chloro-N-cyclopropyl-6-nitrobenzamido)-1-oxobutan-2-yl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.6%	Stage #1: 2-chloro-N-cyclopropyl-6-nitrobenzamide With thionyl chloride In toluene at 120℃; Stage #2: Boc-Abu With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 0 - 20℃; for 24h;	2.2 Step 2)(S) - (1- (2-chloro-N-cyclopropyl-6-nitrobenzamide)-1-oxobutan-2-yl) carbamic acidTert-butyl ester The compound 2-chloro-N-cyclopropyl-6-nitrobenzamide (1.19 g, 4.9 mmol) was dissolved in toluene (20 mL), And then SOCl2 (3.35 mL, 49.2 mmol) was added dropwise thereto.After addition was complete, the reaction was stirred at 120 ° C overnight and then concentrated under reduced pressure to give a brown oil (2.79 g, 100%) which was used in the next reaction without further purification. The compoundBoc-L-2-aminobutyric acid (1.50 g, 7.38 mmol) and DIPEA (1.68 g, 12.98 mmol)In dichloromethane (10 mL), and then thereto was added at 0 ° C dichloromethane (30 mL) of the brown oil obtained above,The resulting reaction was stirred at room temperature for 24 hours, then washed with 4% aqueous citric acid solution (100 mL), saturatedAqueous NaHCO3 solution (100 mL) and brine (30 mL) and the layers were separated. The resulting organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressureconcentrate. The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 8/1) to give the title compound as a yellow solid(1.41 g, 67.6%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 0611; 0612; 0613; 0614

66
[ 936024-98-5 ]
[ 34306-42-8 ]
tert-butyl (S)-(1-(2-methyl-6-nitro-N-(o-tolyl)benzamido)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 2-methyl-6-nitro-N-(o-tolyl)benzamide With thionyl chloride In N,N-dimethyl-formamide; toluene Reflux; Stage #2: Boc-Abu With N-ethyl-N,N-diisopropylamine In DClO₄; N,N-dimethyl-formamide; toluene at 0 - 20℃; for 24h;	15.2 Step 2)Tert-Butyl (S) - (1- (2-methyl-6-nitro-N- (o-tolyl) benzamido) -1 -oxobutan-2-yl) carbamate The compound 2-methyl-6-nitro-N- (o-tolyl) benzamide (7.44 g, 27.5 mmol) was suspended in toluene(150 mL), and then DMF (0.5 mL) SOCl2 (15.84 mL, 220 mmol) was added dropwise thereto in that order. The reaction mixture was refluxed overnight and then concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride (100 mL)A pale yellow solution A was obtained.(S) -2 - ((tert-butoxycarbonyl) amino) butanoic acid (5.6 g, 27.5 mmol) and DIPEA (10 mL,60.5 mmol) was dissolved in dry dichloromethane (100 mL) and then the solution A was added to the reaction solution at 0 ° C. The resulting mixture was stirred at room temperature for 24 hours and then washed with acetic acid / water (1/100 (v / v), 100 mL x 3), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography / EtOAc (v / v) = 10/1) to give the title compound as a light yellow solid (11.35 g,91%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 0843; 0844; 0845; 0846

67
[ 34306-42-8 ]
2-fluoro-N-cyclopropyl-6-nitrobenzamide [ No CAS ]
tert-butyl (S)-(1-(N-cyclopropyl-2-fluoro-6-nitrobenzamido)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 2-fluoro-N-cyclopropyl-6-nitrobenzamide With thionyl chloride In N,N-dimethyl-formamide; toluene at 120℃; Stage #2: Boc-Abu With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide; toluene at 0 - 20℃;	16.2 Step 2) tert-Butyl (S) - (1- (N-cyclopropyl-2-fluoro-6-nitrobenzamido) -1 -oxobutan-2-yl) carbamate The compound 2-fluoro-N-cyclopropyl-6-nitrobenzamide (1.0 g, 4.46 mmol) was suspended in toluene (15 mL), And then thionyl chloride (3.0 mL, 40.14 mmol) and DMF (0.5 mL) were added thereto in that order. After the addition was completed, the reaction solution was stirred at 120 ° C overnight and then concentrated under reduced pressure to give a brown oil, The oil was used in the next reaction without further purification.The compound Boc-L-2-aminobutyric acid (1.20 g, 5.58 mmol) and DIPEA (1.73 g, 13.38 mmol) were dissolvedIn dichloromethane (8 mL) and then a solution of the brown oil obtained above in dichloromethane (23 mL) was added at 0 ° C. At the end of this time, the reaction mixture was stirred at room temperature overnight and then washed successively with 1% acetic acid Aqueous solution (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a yellow oil (1.72 g,94%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 0867; 0868; 0869; 0870

68
[ 34306-42-8 ]
N-cyclopropyl-2-methyl-6-nitrobenzamide [ No CAS ]
tert-butyl (S)-(1-(2-methyl-N-cyclopropyl-6-nitrobenzamido)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: N-cyclopropyl-2-methyl-6-nitrobenzamide With thionyl chloride In N,N-dimethyl-formamide; toluene at 120℃; Stage #2: Boc-Abu With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide; toluene at 0 - 20℃; for 5h;	17.2 Step 2) tert-Butyl (S) - (l- (2-methyl-N- cyclopropyl-6- nitrobenzamido) -l- oxobutan-2- yl) carbamate The compound 2-methyl-N-cyclopropyl-6-nitrobenzamide (3.2 g, 14.5 mmol) was suspended in toluene(48 mL) was added dropwise thereto with stirring. Thionyl chloride (10 mL, 130.8 mmol) was added dropwise thereto followed by DMF (0.5 mL). After the addition was complete, the reaction mixture was stirred at 120 ° C overnight and then concentrated under reduced pressure to give a brown Oil, which was used in the next reaction without purification.The compound Boc-L-2-aminobutyric acid (3.8 g, 18.8 mmol) and DIPEA (8 mL, 43.6 mmol)Was dissolved in dichloromethane (26 mL) and then a solution of the above brown oil in dichloromethane (73 mL) was added at 0 ° C. The reaction mixture was stirred at room temperature for 5 hours and then washed with 1% The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EtOAc (100 mL) (v / v) = 5/1) to give the title compound as a brown oil (5.9 g,99%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 0890; 0891; 0892; 0893

69
[ 34306-42-8 ]
2-amino-6-chloro-N-(3-fluorophenyl)benzamide [ No CAS ]
(S)-(1-((3-chloro-2-((3-fluorophenyl)carbamoyl)phenyl)amino)-1-oxobutan-2-yl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.7%	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 dichloromethane at -10℃; Reflux;	34.3 Step 3) (S) - (1 - ((3-Chloro-2 - ((3- fluorophenyl) carbamoyl) phenyl) -amino) - 1 -oxobutan-2-yl) carbamic acid Tert-butyl ester The compound 2-amino-6-chloro-N- (3-fluorophenyl) benzamide (1.5 g, 5.67 mmol) andBoc-L-2-aminobutyric acid(1.21 g, 5.95 mmol) was dissolved in DCM (20 mL) and then at -10 ° C,DIPEA (2.20 g, 17.01 mmol) and HATU (2.59 g, 6.80 mmol) were added thereto,After 1 hour at the temperature, the mixture was heated to reflux and stirred overnight, then washed sequentially with water (150 mL x 2) and saturated aqueous NaHCO3 (150 mL x 2). The organic phase was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography PE / EtOAc (v / v) = 5/1) to give the title compound as a light yellow solid(1.7 g, 66.7%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 1071; 1072; 1073

70
[ 50460-66-7 ]
[ 34306-42-8 ]
(S)-(1-((3-chloro-2-(o-tolylcarbamoyl)phenyl)amino)-1-oxobutan-2-yl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.3%	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 dichloromethane at -10℃; Reflux;	35.3 Step 3)(S) -(1 - ((3-chloro-2- (o-tolylcarbamoyl) phenyl) amino) -1 -oxobutan-2-yl)Carbamic acidTert-butyl ester The compound 2-amino-6-chloro-N- (o-tolyl) benzamide (2.7 g, 10.4 mmol), Boc-L-2-Butyric acid (2.2 g, 10.8 mmol) and DIPEA (5.4 mL, 31.1 mmol) were suspended in DCM (40 mL) and then HATU (4.7 g, 12.4 mmol) was added at -10 ° C and the mixture was stirred at -10 ° C The reaction mixture was stirred for one hour, then heated to reflux and stirred overnight. The mixture was washed with water (200 mL × 2) and saturated aqueous NaHCO 3 (200 mL × 2) successively. The layers were separated and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure . The resulting residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a pale yellow solid (3.25 g, 70.3%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 1095; 1096; 1097

71
[ 857000-47-6 ]
[ 34306-42-8 ]
tert-butyl (S)-(1-(2-methyl-6-nitro-N-phenylbenzamido)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.54%	Stage #1: 2-methyl-6-nitro-N-phenylbenzamide With thionyl chloride In toluene at 120℃; for 12h; Stage #2: Boc-Abu With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 0 - 20℃; for 24h;	37.2 Step 2) tert-Butyl (S) - (1- (2-methyl-6-nitro-N-phenylbenzamido) -1 -oxobutan-2-yl) carbamate The compound 2-methyl-6-nitro-N-phenylbenzamide (6.5 g, 25.4 mmol) was suspended in toluene (100 mL)And then SOCl2 (7.3 mL, 101.6 mmol) was added dropwise thereto. After the addition, the reaction was stirred at 120 ° C for 12 hours and then concentrated under reduced pressure to give a brown oil which was used in the next reaction without further purification.The compounds Boc-L-2-aminobutyric acid (5.17 g, 25.4 mmol) and DIPEA (9.85 g, 76.2 mmol) were dissolved inDCM (50 mL) and then at 0 ° C a solution of the brown oil obtained above in DCM (50 mL) was added. After the addition was completed, the reaction mixture was stirred at room temperature for 24 hours and then washed with 4% aqueous citric acid (100 mL x 3), saturated aqueous NaHCO 3 (100 mL × 2) and brine (100 mL), and the organic phase was washed with anhydrous sulfuric acid Sodium dried, concentrated under reduced pressure,The resulting residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 9/1) to give the title compound as a yellow oil(7.47 g, 66.54%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD; CALITOR SCIENCES LLC - CN104513235, 2017, B Location in patent: Paragraph 1121; 1122; 1123; 1124

72
[ 34306-42-8 ]
C₁₇H₂₀NO₃Pol [ No CAS ]
[ 135112-27-5 ]
C₃₈H₅₆N₅O₉Pol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 3930 - 3938

73
[ 887308-98-7 ]
[ 34306-42-8 ]
tert-butyl (S)-(1-((5-(6-chloro-5-(phenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)amino)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 13h; Inert atmosphere;	4.1.5.1 tert-Butyl(2-((5-(6-chloro-5-(phenylsulfonamido)pyridin-3-yl)-4-methylthiazol-2-yl)amino)-2-oxoethyl)carbamate (11b) General procedure: To a solution of 10a (40mg, 0.1mmol, 1.00 eq.) in anhydrous DMF (2mL), Boc-glycine (33mg, 0.15mmol, 1.50 eq.), HATU (57mg, 1.50 eq.) and DIPEA (0.89mL, 0.50mmol, 5.0 eq.) were added at 0°C under argon. The reaction mixture was stirred at 0°C for 1h, and then it was allowed to warm to room temperature for 12h. The resulting mixture was concentrated to dryness. The residue was diluted with water (30mL) and then extracted with EtOAc (3×30mL). The combined organic layers were washed with water (50mL), brine (50mL) and dried over anhydrous Na2SO4. Evaporation of the solvent provided the crude product, which was purified by flash chromatography (eluting with MeOH in DCM 0-1.5%) to give the title compound 11b as yellow solid (44mg, 76%).

Reference： [1]Liang, Xiaofei; Li, Feng; Chen, Cheng; Jiang, Zongru; Wang, Aoli; Liu, Xiaochuan; Ge, Juan; Hu, Zhenquan; Yu, Kailin; Wang, Wenliang; Zou, Fengming; Liu, Qingwang; Wang, Beilei; Wang, Li; Zhang, Shanchun; Wang, Yuxin; Liu, Qingsong; Liu, Jing [European Journal of Medicinal Chemistry, 2018, vol. 156, p. 831 - 846]

74
[ 34306-42-8 ]
[ 62-53-3 ]
[ 50424-88-9 ]
[ 870281-84-8 ]

Yield	Reaction Conditions	Operation in experiment
445 g		Add 1 L of dichloromethane to the reaction flask.Add 100g of aniline and stir for 5min.Add 225g DCC,Then add 220g of N-Boc-L-2-aminobutyric acid and stir at 0 C.Conduct a central control reaction. After the reaction is over,Add 300g of triethylamine,230 g of 2-fluoro-5-nitrobenzoyl chloride was added dropwise,After the addition is completed,Stir the reaction for 5 hours,Add the reaction solution to the water,Liquid separation,Organic phase concentrate,Crystallization, filtration, drying,445 g of the intermediate (S)-N-(2-Boc-aminobutyryl)-2-fluoro-6-nitro-N-phenylbenzamide were obtained.

Reference： [1]Patent: CN108409674,2018,A .Location in patent: Paragraph 0022; 0025

75
[ 107818-55-3 ]
[ 34306-42-8 ]
(S)-methyl 5-bromo-3-(2-((tert-butoxycarbonyl)amino)butanamido)thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With pyridine; trichlorophosphate; at -5 - 20℃; for 2.16667h;Inert atmosphere;	To a stirred solution of compound 1 (4.00 g, 16.94 mmol) in pyridine (60 mL) was added (S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (3.79 g, 18.64 mmol), cooled to -5C under N2 atmosphere, Phosphorus oxychloride (3.11 g, 20.33 mmol) was added dropwise in 10 minutes, after addition, the mixture was stirred at 0C for lh, rt for lh, LC-MS showed that most of the start materials was consumed up, stopped the reaction, H20 (80 mL) was added, then extracted with EtOAc (200 mL*2), the combined organic layer was washed with sat. NaHC03 aq, brine, dried over anhydrous Na2S04, concentrated in vacuo, the residue was purified by column (EtOAc/Hex 1/40 to 1/10) to give compound 8 (4.50 g, 63% yield) as a white solid. MS (ESI) (M/Z): [M+H]+ =421.0 ,423.0; 1H NMR (400 MHz, DMSO) delta 10.63 (s, 1H), 8.12 (s, 1H), 7.63 (d, 7 = 6.4 Hz, 1H), 3.93 (s, 1H), 3.85 (s, 3H), 1.82 (dd, = 12.9, 5.9 Hz, 1H), 1.63 (ddd, J = 13.9, 9.1, 7.3 Hz, 1H), 1.43 (s, 9H), 0.93 (t, = 7.3 Hz, 3H).

Reference： [1]Patent: WO2018/217439,2018,A1 .Location in patent: Page/Page column 25-26

76
[ 34306-42-8 ]
tert-butyl ((S)-1-((S)-2-((5-fluoro-2-(6-fluoro-3-(((S)-pyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]
tert-butyl ((S)-1-((S)-2-((2-(1-(((S)-1-((tert-butoxycarbonyl)-L-valyl)pyrrolidin-2-yl)methyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-6-fluoro-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.41%	With 4-methyl-morpholine; 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 1h;	2.D Step D: To a stirring solution of N-Boc-L-n-butyric acid(243.34 mg, 1.2 mmol) in DMF (1 mL) wereadded N-methylmorpholine (302.77 mg, 2.99 mmol) and HATU (569.06 mg, 1.5 mmol), and a solution oftert-butyl ((S)-1-((S)-2-((5-fluoro-2-(6-fluoro-3-(((S)-pyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1 H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamat e (380 mg, crude product) in DMF (1 mL) was added and the mixture was stirred for 1 h at room temperature, then diluted with water (50 mL) and extracted with EtOAc (50 mL X 2). The combined organic phase was washed with aq. NaCl, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography eluted with Pet. Ether/EtOAc (4/1 to 3/1) to givetert-butyl ((S)-1-((S)-2-((2-(1-(((S)-1-((tert-butoxycarbonyl)-L-valyl)pyrrolidin-2-yl)methyl)-5-f luoro-1H-benzo[d]imidazol-2-yl)-6-fluoro-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-ο xobutan-2-yl)carbamate (380 mg, 77.41%). MS (ESI) m/z: 820.5 [M+H+]

Reference： [1]Current Patent Assignee: WUXI APPTEC CO., LTD. - EP3450430, 2019, A1 Location in patent: Paragraph 0131; 0135

77
[ 34306-42-8 ]
5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1-(((2S,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-benzo[d]imidazole hydrochloride [ No CAS ]
tert-butyl-N-((1S)-1-((2R,4S)-2-((2-(1-(((2S,4S)-1-[(2S)-2-((tert-butoxycarbonyl)amino)butanoyl]-4-fluoropyrrolidin-2-yl)methyl)-5-fluorobenzimidazole-2-yl)-6-fluoro-1H-indol-3-yl)methyl)-4-fluoropyrrolidin-1-oxo)butyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.76%	Stage #1: Boc-Abu With 4-methyl-morpholine; 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 25℃; for 0.5h; Stage #2: 5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1-(((2S,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-benzo[d]imidazole hydrochloride In N,N-dimethyl-formamide at 25℃; for 0.5h;	13.D Step D: To a stirring solution of N-Boc-L-butyric acid(158.65 mg, 780.65 μmol) in DMF (3.00 mL) wereadded N-methylmorpholine (126.34 mg, 1.25 mmol, 137.33μL) and HATU (124.67 mg, 327.87 μmol) and the mixture was stirred for 30 min at 25°C. Then the mixture was added with 5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1-((( 2S,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-benzo[d]imidazole (85.25 mg, 156.13 μmol, hydrochloride) and the mixture was stirred for further 30 min at 25°C, diluted with EtOAc (100 mL) and water (100 mL). The organic phase was separated, washed with aq. NaCl and concentrated in vacuo. The residue was purified by flash column chromatography eluted with Pet. Ether/EtOAc (1/1) to give tert-butyl-N-[(1S)-1-[(2R,4S)-2-[[2-[1-(((2S,4S)-1-[(2S)-2-((tert-butoxycarbonyl)ami no)butanoyl]-4-fluoro-pyrrolidin-2-yl)methyl)-5-fluoro-benzimidazole-2-yl)-6-fluoro-1H-indol-3-yl)methyl)-4-fluoropyrrolidin-1-oxo)butyl)carbamate (110.00 mg, 127.65 μmol, 81.76%). MS (ESI) m/z: 842.1 [M+H+]

Reference： [1]Current Patent Assignee: WUXI APPTEC CO., LTD. - EP3450430, 2019, A1 Location in patent: Paragraph 0175; 0179

78
[ 34306-42-8 ]
tert-butyl ((S)-1-((2S,4S)-4-fluoro-2-((5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]
tert-butyl ((S)-1-((2S,4S)-2-((2-(3-(((2R,4S)-1-((S)-2-((tert-butoxycarbonyl)amino)butanoyl)-4-fluoropyrrolidin-2-yl)methyl)-6-fluoro-1H-indol-2-yl)-5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-4-fluoropyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.19%	Stage #1: Boc-Abu With 4-methyl-morpholine; 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 0.5h; Stage #2: tert-butyl ((S)-1-((2S,4S)-4-fluoro-2-((5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate In N,N-dimethyl-formamide at 20℃; for 1h;	18.D Step D: To a solution of N-Boc-L-n-butyric acid(160.95 mg, 791.96 μmol) in DMF (1.00 mL) wereadded N-methylmorpholine (120.16 mg, 1.19 mmol, 130.61 μL) and HATU (376.41 mg, 989.95 μmol) and the mixture was stirred for 30 min at 20°C. Then the mixture was added with tert-butyl ((S)-1-((2S,4S)-4-fluoro-2-((5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl) methyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (320.00 mg, 395.98 μmol) in DMF (1.00 mL) at 20°Cand stirred for further 1 h at the same temperature. The mixture was diluted with water (150 mL) and EtOAc (200 mL), then the organic phase was separated, washed with sat.aq. NaCl (100 mL X 3) and concentrated in vacuo at 45 °C. The residue was purified by flash column chromatography eluted with Pet. Ether/EtOAc (3/1 to 2/1) to give tert-butyl ((S)-1-((2S,4S)-2-((2-(3-(((2R,4S)-1-((S)-2-((tert-butoxycarbonyl)amino)butanoyl)-4-fluoropyrrolidin-2-yl)methyl)-6-fluoro-1H-indol-2-yl)-5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-4-fluoropyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (320.00 mg, 321.51 μmol, 81.19%). MS (ESI) m/z: 856.4 [M+H+]

Reference： [1]Current Patent Assignee: WUXI APPTEC CO., LTD. - EP3450430, 2019, A1 Location in patent: Paragraph 0193; 0197

79
[ 34306-42-8 ]
tert-butyl ((S)-1-((S)-2-((5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2 -yl)carbamate [ No CAS ]
tert-butyl ((S)-1-((S)-2-((2-(3-(((2R,4S)-1-((S)-2-((tert-butoxycarbonyl)amino)butanoyl)-4-fluoropyrrolidin-2-yl)methyl)-6-fluoro-1H-indol-2-yl)-5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.5%	Stage #1: Boc-Abu With 4-methyl-morpholine; 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 18℃; for 0.5h; Stage #2: tert-butyl ((S)-1-((S)-2-((5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2 -yl)carbamate In N,N-dimethyl-formamide at 18℃; for 1h;	39.E StepE: To a solution of N-Boc-L-n-butyric acid(129.88 mg, 639.07 μmol) in DMF (3.00 mL) wereadded N-methylmorpholine (129.28 mg, 1.28 mmol, 140.52 μL) and HATU (259.19 mg, 681.67 μmol) at 18°Cand the mixture was stirred for 30 min at 18 °C , and then a solution oftert-butyl ((S)-1-((S)-2-((5-fluoro-2-(6-fluoro-3-(((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)-1H-i ndol-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2 -yl)carbamate (309.00 mg, crude product) in DMF (3.00 mL) was added to the mixture. After stirringfor 1 h at 18 °C, the mixture was poured into water (100 mL) and solid wasprecipitated. After stirring for further 10 min, the mixture was filtered and dried to give tert-butyl ((S)-1-((S)-2-((2-(3-(((2R,4S)-1-((S)-2-((tert-butoxycarbonyl)amino)butanoyl)-4-fluor opyrrolidin-2-yl)methyl)-6-fluoro-1H-indol-2-yl)-5-fluoro-1H-benzo[d]imidazol-1-yl) methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (346.00 mg, 334.45 μmol, 78.50%). MS (ESI) m/z: 838.4 [M+H+]

Reference： [1]Current Patent Assignee: WUXI APPTEC CO., LTD. - EP3450430, 2019, A1 Location in patent: Paragraph 0255; 0260

80
[ 101-02-0 ]
[ 34306-42-8 ]
[ 434-76-4 ]
(S)-2-((2-(((tert-butoxy)carbonyl)amino)-1-phenoxybutylidene)amino)-6-fluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In toluene; at 55℃; for 1.5h;	10 g (0.05 mol) of N-Boc-L-2-aminobutyric acid was dissolved in an appropriate amount of 100 mL of toluene solvent, and 4 g of pyridine and 17 g of P(OPh) 3 were added and stirred and mixed uniformly. Stirring was continued to complete the activation of the carboxylic acid, then 8.5 g of <strong>[434-76-4]2-amino-6-fluorobenzoic acid</strong> was added, and the temperature was raised to 55 C to carry out a condensation reaction for 1.5 hours, and then the trace was confirmed to be complete; After completion of the reaction, 1 M hydrochloric acid was added to carry out an acidification reaction solution, which was allowed to stand, and the layers were separated, and the organic layer was collected and concentrated to remove the solvent to obtain 15.2 g of an oil. That is (S)-2-((2-((tert-butoxycarbonyl))amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid, further the oil can be passed Purification by flash column separation. The obtained (S)-2-((2-((tert-butoxycarbonyl)amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid was analyzed by nuclear magnetic resonance spectroscopy. The result is shown in Figure 1. At the same time, the 31P-NMR spectrum was shown to contain no P. And the mass spectrum mainly contains fragment peaks such as 92.92, 339.1, It is shown that the (S)-2-((2-((tert-butoxycarbonyl))amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid is relatively active.

Reference： [1]Patent: CN109503430,2019,A .Location in patent: Paragraph 0048-0055

81
[ 34306-42-8 ]
[ 450-91-9 ]
tert-butyl (S)-(1-((4-fluoro-2-methoxyphenyl)amino)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere;

Reference： [1]Karasawa, Tomoya; Saito, Akira; Kumagai, Naoya; Shibasaki, Masakatsu [Organic Letters, 2019, vol. 21, # 10, p. 3581 - 3583]

82
[ 67-56-1 ]
[ 34306-42-8 ]
[ 2483-62-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 4151 - 4162

83
[ 34306-42-8 ]
4-(3-methoxy-4-methylphenoxy)pyridin-2-amine [ No CAS ]
tert-butyl N-[(1R)-1-[[4-(3-methoxy-4-methylphenoxy)-2-pyridyl]carbamoyl]propyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: Boc-Abu With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-(3-methoxy-4-methylphenoxy)pyridin-2-amine In N,N-dimethyl-formamide at 110℃; for 18h;	41.5-2 INTERMEDIATE 5-2: tert-butyl N-[(lR)-l-[[4-(3-methoxy-4-methyl-phenoxy)-2- pyridyl] carbamoyl] propyl] carbamate To a solution of Boc-D-Abu-OH (335 mg, 1.65 mmol) in DMF (3 mL) was added DIEA (430 pL, 2.48 mmol) followed by HBTU (750 mg, 1.98 mmol) and the mixture allowed to stir for 30 min at rt. Then a solution of intermediate 5-1 (190 mg, 0.82 mmol) in DMF (2 mL) was added and the mixture allowed to stir for 18 h at H0°C. The mixture was hydrolyzed with water, extracted with Et20, the organics were washed with brine, dried over MgS04 and concentrated in vacuo before purification by flash chromatography on silica, eluting with cyclohexane then gradient elution with 0%-50% EtOAc/Cyclohexane mixtures to give the title compound as a yellow oil (290 mg, 84% yield). ESIMS m/z [M+H]+ 416.1

Reference： [1]Current Patent Assignee: BIONOMICS LIMITED - WO2019/222816, 2019, A1 Location in patent: Page/Page column 69

84
[ 34306-42-8 ]
[ 74-88-4 ]
[ 112392-65-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h;	56.6-28 INTERMEDIATE 6-28: methyl (2R)-2-(tert-butoxycarbonylamino)butanoate To a stirred solution of Boc-D-Abu-OH (4.0 g, 19.68 mmol) and potassium carbonate (9.52 g, 68.88 mmol) in DMF (25mL) at room temperature was added Iodomethane (2.45 mL, 39.36 mmol). After addition, the mixture was stirred at room temperature for 24 h. The resulting mixture was diluted with water (20 mL), extracted with ethyl acetate (3 x 25 mL), the combined organic extracts were washed with saturated aqueous sodium chloride (15 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate - 100:0 to 75:25, to give the title compound as a colorless liquid (4.30 g, 100% yield). 1H NMR (300MHz, CHCb-d) 5.10-4.95 (m, 1H), 4.32-4.16 (m, 1H), 3.72 (s, 3H), 1.95-1.75 (m, 1H), 1.75-1.58 (m, 1H), 1.43 (s, 9H), 0.91 (t, 7 = 7.4 Hz, 3H).

Reference： [1]Current Patent Assignee: BIONOMICS LIMITED - WO2019/222816, 2019, A1 Location in patent: Page/Page column 91-92

85
[ 34306-42-8 ]
methyl (1R,2S)-1-((2S,4R)-4-((2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropane-1-carboxylate [ No CAS ]
methyl (1R,2R)-1-((2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)butanoyl)-4-((2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: methyl (1R,2S)-1-((2S,4R)-4-((2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropane-1-carboxylate With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; ethyl 3-hydroxy-2-cyanoacrylate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: Boc-Abu With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	General procedure for coupling of dipeptide S10. General procedure: Dipeptide S10 (100 mg, 0.22 mmol),Oxymapure (62 mg, 0.44 mmol), and EDCI (50 mg, 0.27 mmol) were mixed in DMF (2 mL) and stirredfor 5 min at 0 °C. NMM (0.3 mL, 0.66 mmol) and the appropriate amino acid (0.22 mmol, 1 eq) wereadded, and the reaction mixture was allowed to warm to room temperature, and then stirred overnight.The mixture was concentrated to dryness, and the residue was dissolved in EtOAC (10 mL). The organiclayer was washed with 1 N HCl (2 x 10 mL), 10% NAHCO3 (2 x 10 mL), and brine (1 x 10 mL), dried(MgSO4), filtered, and concentrated under reduced pressure.

Reference： [1]LaPlante, Steven R.; Martin, Stephen F.; White, Peter W.; Wypych, Rachel M. [European Journal of Medicinal Chemistry, 2020, vol. 192]

86
[ 34306-42-8 ]
2-benzyl 1-(tert-butyl) (2R,4S)-4-amino-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)piperidine-1,2-dicarboxylate [ No CAS ]
2-benzyl 1-(tert-butyl) (2R,4S)-4-((S)-2-((tert-butoxycarbonyl)amino)butanamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)piperidine-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16h;	5 intermediate 15: 2-benz vi I -(tert-butyl) (2R, 4S)-4-((S)-2-((tert- butoxycarbon yi)amino)butanamido)-2-(4-(4 , 4,5,5-fetrameth vi- 1,3, 2-dioxaboroian-2- vi)butvi)piperidine-1, 2-dicarbox vi ate N,N-Diisopropylethylamine (0.165 mL, 0.94 mmcl) was added slowly to a stirred solutionof 2-benzyl I -(tert-butyl) (2R,4S)-4-amino-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)butyl)piperidine-1 ,2-dicarboxylate (Intermediate 8, 244 mg, 0.47 mmol), Boc-Abu-OH (96 mg,0.47 mmol) and COMU (206 mg, 0.48 mmol) in DMF (3 mL) at 0 °C. The reaction stirred for 16h while slowly warming to room temperature. The crude reaction mixture was diluted with water(30 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washedsequentially with saturated aqueous NaHCO3 (20 mL) and saturated aqueous NaCI (15 mL).The organic layer was dried over MgSO4, filtered and concentrated to dryness. The resulting residue was purified by flash silica chromatography (15 to 60% EtOAc in hexanes) to afford 2- benzyl I -(tert-butyl) (2R,4S)-4-((S)-2-((tert-butoxycarbonyl)amino)butanamido)-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)butyl)piperidine-1 ,2-dicarboxylate (Intermediate 15, 215mg, 65% yield) as clear gum and as a mixture of rotamers. 1H NMR (500MHz, CDCI3) 5 0.71 -0.79(2H, m), 0.87(3H, brt), 1.19(4H, brs), 1.21 (9H, s), 1.36(5H, brs), 1.38(8H, s), 1.39-1.41 (8H, m), 1.48 - 1.58 (2H, m), 1.68 (1 H, br dd), 1.72 - 1.81 (1 H, m), 1.84 - 1.98 (3H, m), 1.99- 2.02 (1 H, m), 2.88 - 3.04 (1 H, m), 3.89 (1 H, br d), 3.95 - 4.07 (2H, m), 5.00 (1 H, br d), 5.05 -5.22 (2H, m), 6.20 (1 H, br s), 7.27 - 7.36 (5H, m); mz: (ES) [M+H] = 703.
215 mg	With 1-[(1-(cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 25℃; for 16h; Inert atmosphere;	5 Intermediate 15: 2-benzyl 1-(tert-butyl) (2R,4S)-4-((S)-2-((tert- butoxycarbonyl)amino)butanamido)-2-(4-(4,4.5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)butyl)piperidine-1,2-dicarboxylate N,N-Diisopropylethylamine (0.165 mL, 0.94 mmol) was added slowly to a stirred solution of 2-benzyl 1 -tert -butyl) (2R,4S)-4-amino-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)butyl)piperidine-1 ,2-dicarboxylate (Intermediate 8, 244 mg, 0.47 mmol), Boc-Abu-OH (96 mg, 0.47 mmol) and COMU (206 mg, 0.48 mmol) in DMF (3 mL) at 0 °C. The reaction stirred for 16 h while slowly warming to room temperature. The crude reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed sequentially with saturated aqueous NaHCO3 (20 mL) and saturated aqueous NaCI (15 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The resulting residue was purified by flash silica chromatography (15 to 60% EtOAc in hexanes) to afford 2- benzyl 1 -tert -butyl) (2R,4S)-4-((S)-2-(tert -butoxycarbonyl)amino)butanamido)-2-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)butyl)piperidine-1 ,2-dicarboxylate (Intermediate 15, 215 mg, 65% yield) as clear gum and as a mixture of rotamers. 1H NMR (500MHz, CDCI3) δ 0.71 - 0.79 (2H, m), 0.87 (3H, br t), 1.19 (4H, br s), 1.21 (9H, s), 1.36 (5H, br s), 1.38 (8H, s), 1.39 - 1.41 (8H, m), 1 .48 - 1 .58 (2H, m), 1 .68 (1 H, br dd), 1 .72 - 1.81 (1 H, m), 1.84 - 1 .98 (3H, m), 1.99 - 2.02 (1 H, m), 2.88 - 3.04 (1 H, m), 3.89 (1 H, br d), 3.95 - 4.07 (2H, m), 5.00 (1 H, br d), 5.05 - 5.22 (2H, m), 6.20 (1 H, br s), 7.27 - 7.36 (5H, m); m/z: (ES+) [M+H]+ = 703.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2020/161675, 2020, A1 Location in patent: Page/Page column 33; 34
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2021/90146, 2021, A1 Location in patent: Page/Page column 27; 40-41

87
[ 89853-53-2 ]
[ 34306-42-8 ]
tert-butyl (S)-(1-(3-(2-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)propyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With dicyclohexyl-carbodiimide In 1,4-dioxane at 100℃; for 16h;	154 Synthesis of tert-butyl (S)-(l-(3-(2-methylpyridin-4-yl)-l,2,4-oxadiazol-5- yl)propyl)carbamate (284) To a stirred solution of compound A-101 (1.1 g, 7.3 mmol) in 1,4-dioxane (20 mL) was added (2S)-2-(tert-butoxycarbonylamino)butanoic acid (1.41 g, 6.9 mmol) followed by DCC (1.57 g, 7.6 mmol). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was treated with water (60 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine (50 mL), dried over NaiSCL and concentrated. The crude compound was purified by column chromatography on silica gel with 12% EtO Ac/PE to afford compound 284 (1.7 g, 5.3 mmol, 76% yield) as a a liquid. LCMS: 319.2 (M+H), Rt 1.89 min; Column: ZORBAX XDB C-18 (50 x 4.6 mm), 3.5 pm; Mobile Phase: A: 0.1% HCOOH in watenACN (95:5), B: ACN; Flow Rate: 1.5 mL/min.

Reference： [1]Current Patent Assignee: PRAXIS PRECISION MEDICINES INC - WO2020/227101, 2020, A1 Location in patent: Paragraph 000709-000710

88
[ 34306-42-8 ]
C₁₈H₃₇N₅O₆ [ No CAS ]
C₂₇H₅₂N₆O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.6%	With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	1 To a solution of compounds 1 (0.610 g) and 2 (0.126 g) in DMF was added TBTU (0.116 g) and then DIPEA (0.157 mL) under ambient conditions. The reaction was stirred for 1 h until full conversion was observed by LC-MS. The reaction mixture was quenched with NaHCOs (8 mL), extracted with EtOAc and then 20% CF3CH2OH/DCM (3 x 8 mL), and then washed with water and brine (3 x 8 mL). Mixture was then dried over Na2SC>4, filtered, and concentrated. The residue was purified by CombiFlash using silica gel as the stationary phase with a gradient of DCM to 20% MeOH in DCM (0-45%), in which product eluted at 17% B. The product was concentrated under vacuum to provide a clear colorless oil. Yield: 0.110 g (60.6%.) LC-MS: calculated [M+H]+ 605.38 m/z, observed 605.52 m/z.
60.6%	With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	3 [00579] To a solution of compounds 1 (0.610 g) and 2 (0.126 g) in DMF was added TBTU (0.116 g) and then DIPEA (0.157 mL) under ambient conditions. The reaction was stirred for 1 h until full conversion was observed by LC-MS. The reaction mixture was quenched with NaHCO3 (8 mL), extracted with EtOAc and then 20% CF3CH2OH/DCM (3 x 8 mL), and then washed with water and brine (3 x 8 mL). Mixture was then dried over Na2SO4, filtered, and concentrated. The residue was purified by CombiFlash using silica gel as the stationary phase with a gradient of DCM to 20% MeOH in DCM (0-45%), in which product eluted at 17% B. The product was concentrated under vacuum to provide a clear colorless oil. Yield: 0.110 g (60.6%.) LC-MS: calculated [M+H]+ 605.38 m/z, observed 605.52 m/z.

Reference： [1]Current Patent Assignee: ARROWHEAD RESEARCH CORP - WO2022/56286, 2022, A1 Location in patent: Paragraph 00150; 00228-00229
[2]Current Patent Assignee: ARROWHEAD RESEARCH CORP - WO2022/56269, 2022, A1 Location in patent: Paragraph 00579

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CAS No. :	34306-42-8	MDL No. :	MFCD00037267
Formula :	C₉H₁₇NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PNFVIPIQXAIUAY-LURJTMIESA-N
M.W :	203.24	Pubchem ID :	2755934
Synonyms :	Boc-L-2-aminobutanoic acid;Butanoic acid, 2-[[(1,1-dimethylethoxy)carbonyl]amino]-, (S)-;(2S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]butanoic acid;(2S)-2-(tert-Butoxycarbonylamino)butanoic acid;Butyric acid, 2-(carboxyamino)-, N-tert-butyl ester, L- (8CI)

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.78
Num. rotatable bonds :	6
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	51.66
TPSA :	75.63 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.51 cm/s

Log Po/w (iLOGP) :	1.88
Log Po/w (XLOGP3) :	1.45
Log Po/w (WLOGP) :	1.37
Log Po/w (MLOGP) :	0.83
Log Po/w (SILICOS-IT) :	0.24
Consensus Log Po/w :	1.15

[ CAS No. 34306-42-8 ] {[proInfo.proName]}

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[ 34306-42-8 ] Synthesis Path-Downstream 1~88

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[ 34306-42-8 ]

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[ 34306-42-8 ]

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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) :	-1.62
Solubility :	4.9 mg/ml ; 0.0241 mol/l
Class :	Very soluble
Log S (Ali) :	-2.64
Solubility :	0.461 mg/ml ; 0.00227 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.05
Solubility :	18.1 mg/ml ; 0.0889 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.61

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

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P378
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P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
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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.
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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:
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P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
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[ CAS No. 34306-42-8 ] {[proInfo.proName]}

Quality Control of [ 34306-42-8 ]

Related Doc. of [ 34306-42-8 ]

Product Details of [ 34306-42-8 ]

Calculated chemistry of [ 34306-42-8 ]

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Application In Synthesis of [ 34306-42-8 ]

[ 34306-42-8 ] Synthesis Path-Upstream 1~4

[ 34306-42-8 ] Synthesis Path-Downstream 1~88

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Pharmaceutical Intermediates of
[ 34306-42-8 ]

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[ 34306-42-8 ]