Name: 70396-18-8|(S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutanamido)propanoic acid|95%
Brand: Ambeed
SKU: A266251
Price: 9.0 USD
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1
[ 37519-04-3 ]
[ 70396-18-8 ]
[ 109953-33-5 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1986,p. 1655 - 1664

2
[ 15275-65-7 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In methanol for 3h; Ambient temperature;
	With sodium hydroxide In methanol
	hydrolysis;

	With lithium hydroxide monohydrate In tetrahydrofuran; water at 0℃; for 2.5h;	33; 34 A cooled (0°C) solution of 33c (317.0 mg, 1.048 mmol) in tetrahydrofuran/water (12 mL, 5:1 ) was treated with lithium hydroxide hydrate (88.0 mg, 2.096 mmol). After stirring at 0°C for 2.5 h, the reaction was quenched with hydrochloric acid (1 M, 30 mL). The aqueous layer was extracted with dichloromethane (2 x 30 mL). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo to provide crude acid as a white solid
	With lithium hydroxide monohydrate; water In tetrahydrofuran at 0℃; for 2.5h;	33 A cooled (0° C.) solution of 33c (317.0 mg, 1.048 mmol) in tetrahydrofuran/ water (12 mL, 5:1) was treated with lithium hydroxide hydrate (88.0 mg, 2.096 mmol). After stirring at 0° C. for 2.5 h, the reaction was quenched with hydrochloric acid (1 M, 30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo to provide crude acid as a white solid.
	With water; sodium hydroxide In methanol for 10h;
	Stage #1: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)propanoate With sodium hydroxide In methanol; water at 60℃; for 1h; Stage #2: With potassium hydrogensulfate In methanol; water
	With water; sodium hydroxide In methanol at 0℃; for 2.5h;
	With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; for 14h;	N-(tert-butoxycarbonyl)-L-valyl-L-alanine A mixture of methyl N-(tert-butoxycarbonyl)-L-valyl-L-alaninate (9.70 g, 32.1 mmol), lithium hydroxide monohydrate (2.69 g, 64.2 mmol), THF (170 mL) and water (76 mL) was stirred at r.t. for 14 h. After that the mixture was acidified with trifluoroacetic acid and extracted with ethyl acetate. The organic extract was washed with brine, filtered through a silicone filter and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, dichloromethane/ethanol gradient) to give the title compound (7.14 g, 90 % purity, 69 % yield). LC-MS (Method 2): Rt = 0.53 min; MS (ESIpos): m/z = 289 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.797 (2.15), 0.813 (2.32), 0.851 (2.38), 0.868 (2.52), 0.945 (0.58), 0.955 (0.62), 0.962 (0.64), 0.972 (0.60), 1.251 (3.61), 1.270 (3.70), 1.306 (0.73), 1.324 (0.76), 1.350 (0.94), 1.373 (16.00), 1.528 (2.71), 1.903 (0.41), 3.822 (0.47), 4.171 (0.45), 4.189 (0.71), 4.207 (0.48), 6.590 (0.60), 6.613 (0.58), 8.101 (0.89), 8.119 (0.80).

Reference： [1]Howard; Hsu; Rogers; Nelson [Analytical Chemistry, 1985, vol. 57, # 3, p. 606 - 610]
[2]Lamar, Jason; Hu, Jingdan; Bueno, Ana Belen; Yang, Hsiu-Chiung; Guo, Deqi; Copp, James D; McGee, James; Gitter, Bruce; Timm, David; May, Patrick; McCarthy, James; Chen, Shu-Hui [Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 239 - 243]
[3]Rella, Maria Rosaria; Williard, Paul G. [Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 525 - 531]
[4]Current Patent Assignee: CYPRALIS LTD - WO2013/185103, 2013, A1 Location in patent: Page/Page column 142
[5]Current Patent Assignee: CYPRALIS LTD - US2017/190737, 2017, A1 Location in patent: Paragraph 0393
[6]Podder, Debasish; Chowdhury, Srayoshi Roy; Nandi, Sujay Kumar; Haldar, Debasish [New Journal of Chemistry, 2019, vol. 43, # 9, p. 3743 - 3749]
[7]Bernadat, Guillaume; Correia, Isabelle; Lequin, Olivier; Lesma, Jacopo; Ongeri, Sandrine; Tonali, Nicolo [Organic and biomolecular chemistry, 2020, vol. 18, # 18, p. 3452 - 3458]
[8]Current Patent Assignee: IMMUNOGEN INC - WO2020/205564, 2020, A1 Location in patent: Paragraph 00240
[9]Current Patent Assignee: BAYER AG - WO2021/13693, 2021, A1 Location in patent: Page/Page column 350-351

3
[ 70396-18-8 ]
[ 109953-68-6 ]
[ 112383-17-2 ]

Yield	Reaction Conditions	Operation in experiment
58.2%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide

Reference： [1]Dutta, Anand S.; Giles, Michael, B.; Gormley, James J.; Williams, Joseph C.; Kusner, Edward J. [Journal of the Chemical Society. Perkin transactions I, 1987, p. 111 - 120]

4
[ 130380-44-8 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydroxide; Na-phosphate buffer; phenylmethylsulphonyl fluoride In acetone for 37h; pH 7.0; Rhizopus niveus lipase;
96%	In water; acetone at 37℃; lipase from Rhizopus niveus, pH 7;

Reference： [1]Braun, Peter; Waldmann, Herbert; Vogt, Walter; Kunz, Horst [Liebigs Annalen der Chemie, 1991, # 2, p. 165 - 170]
[2]Waldmann, H; Heuser, A; Braun, P; Kunz, H [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1992, vol. 31, # 12, p. 799 - 802]

5
[ 2577-90-4 ]
[ 70396-18-8 ]
[ 197781-20-7 ]

Yield	Reaction Conditions	Operation in experiment
57%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 72h;

Reference： [1]Banerjee, Arindam; Raghothama; Balaram [Journal of the Chemical Society. Perkin Transactions 2 (2001), 1997, # 10, p. 2087 - 2094]

6
[ 226543-65-3 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With oxygen In acetonitrile for 16h; tyrosinase, phosphate buffer pH 7;
90%	With phosphate buffer; oxygen; tyrosinase In water; acetonitrile at 20℃; for 16h;

Reference： [1]Mueller, Gernot H.; Waldmann, Herbert [Tetrahedron Letters, 1999, vol. 40, # 18, p. 3549 - 3552]
[2]Voelkert, Martin; Koul, Surrinder; Mueller, Gernot H.; Lehnig, Manfred; Waldmann, Herbert [Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6902 - 6910]

7
[ 70396-18-8 ]
[ 669074-36-6 ]
{(S)-1-[(S)-1-((1S,2S,4R)-1-Benzyl-2-hydroxy-4-{(S)-2-methyl-1-[(pyridin-4-ylmethyl)-carbamoyl]-propylcarbamoyl}-pentylcarbamoyl)-ethylcarbamoyl]-2-methyl-propyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran

Reference： [1]Lamar, Jason; Hu, Jingdan; Bueno, Ana Belen; Yang, Hsiu-Chiung; Guo, Deqi; Copp, James D; McGee, James; Gitter, Bruce; Timm, David; May, Patrick; McCarthy, James; Chen, Shu-Hui [Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 239 - 243]

8
[ 70396-18-8 ]
N-hydroxy-N-tert-butoxycarbonyl-valinylalanylalanine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 70.8 percent / 3-methyl-3-(trifluoromethyl)dioxiran / CH₂Cl₂; various solvent(s) / 4 h / 0 °C

Reference： [1]Rella, Maria Rosaria; Williard, Paul G. [Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 525 - 531]

9
[ 13734-41-3 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: PyBOP; i-Pr₂NEt / CH₂Cl₂ 2: aq. NaOH / methanol
	Multi-step reaction with 2 steps 1: 42 percent / N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide; HOBt / CH₂Cl₂ / 0 - 20 °C 2: 90 percent / tyrosinase; phosphate buffer; O₂ / H₂O; acetonitrile / 16 h / 20 °C / pH 7.0

Reference： [1]Lamar, Jason; Hu, Jingdan; Bueno, Ana Belen; Yang, Hsiu-Chiung; Guo, Deqi; Copp, James D; McGee, James; Gitter, Bruce; Timm, David; May, Patrick; McCarthy, James; Chen, Shu-Hui [Bioorganic and medicinal chemistry letters, 2004, vol. 14, # 1, p. 239 - 243]
[2]Voelkert, Martin; Koul, Surrinder; Mueller, Gernot H.; Lehnig, Manfred; Waldmann, Herbert [Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6902 - 6910]

10
[ 95499-91-5 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 99 percent / tyrosinase; phosphate buffer; O₂ / H₂O; acetonitrile / 16 h / 20 °C / pH 7.0 2: 42 percent / N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide; HOBt / CH₂Cl₂ / 0 - 20 °C 3: 90 percent / tyrosinase; phosphate buffer; O₂ / H₂O; acetonitrile / 16 h / 20 °C / pH 7.0

Reference： [1]Voelkert, Martin; Koul, Surrinder; Mueller, Gernot H.; Lehnig, Manfred; Waldmann, Herbert [Journal of Organic Chemistry, 2002, vol. 67, # 20, p. 6902 - 6910]

11
[ 70396-18-8 ]
[ 1027174-07-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 57 percent / DCC, HOBT / dimethylformamide / 72 h 2: formic acid / 8 h

Reference： [1]Banerjee, Arindam; Raghothama; Balaram [Journal of the Chemical Society. Perkin Transactions 2 (2001), 1997, # 10, p. 2087 - 2094]

12
[ 70396-18-8 ]
(S)-2-{(S)-2-[(S)-2-(2-{(S)-2-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-methyl-pentanoylamino}-2-methyl-propionylamino)-3-methyl-butyrylamino]-propionylamino}-3-phenyl-propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 57 percent / DCC, HOBT / dimethylformamide / 72 h 2: formic acid / 8 h 3: DCC, HOBT / dimethylformamide / 72 h

Reference： [1]Banerjee, Arindam; Raghothama; Balaram [Journal of the Chemical Society. Perkin Transactions 2 (2001), 1997, # 10, p. 2087 - 2094]

13
[ 13734-41-3 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1) isobutylchloroformate, N-methylmorpholine, 2) N-methylmorpholine / THF 1) 30 min, 2) 12 h 2: NaOH / methanol / 3 h / Ambient temperature
	Multi-step reaction with 2 steps 1: 88 percent / Et₃N, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / CH₂Cl₂ / 12 h / Ambient temperature 2: 96 percent / 0.2M Na-phosphate buffer, 0.1N NaOH, phenylmethylsulfonyl fluoride / acetone / 37 h / pH 7.0; Rhizopus niveus lipase
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / acetonitrile / 0 - 20 °C 2: lithium hydroxyde monohydrate / tetrahydrofuran; lithium hydroxide monohydrate / 2.5 h / 0 °C

	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate / acetonitrile / 6 h / 0 - 20 °C 2: lithium hydroxide monohydrate; lithium hydroxyde monohydrate / tetrahydrofuran / 2.5 h / 0 °C
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 48 h / 20 °C / Cooling with ice 2: sodium hydroxide; lithium hydroxide monohydrate / methanol / 10 h
	Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: sodium hydroxide / methanol; lithium hydroxide monohydrate / 1 h / 60 °C 2.2: pH 2-3
	Multi-step reaction with 2 steps 1.1: 1,1′-carbonyldiimidazole / dichloromethane / 2.5 h / 20 °C / Inert atmosphere 1.2: Cooling with acetone-dry ice 2.1: lithium hydroxide monohydrate; sodium hydroxide / methanol / 2.5 h / 0 °C
	Multi-step reaction with 2 steps 1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 14 h / 20 °C 2: lithium hydroxyde monohydrate; lithium hydroxide monohydrate / tetrahydrofuran / 14 h / 20 °C

Reference： [1]Howard; Hsu; Rogers; Nelson [Analytical Chemistry, 1985, vol. 57, # 3, p. 606 - 610]
[2]Braun, Peter; Waldmann, Herbert; Vogt, Walter; Kunz, Horst [Liebigs Annalen der Chemie, 1991, # 2, p. 165 - 170]
[3]Current Patent Assignee: CYPRALIS LTD - WO2013/185103, 2013, A1
[4]Current Patent Assignee: CYPRALIS LTD - US2017/190737, 2017, A1
[5]Podder, Debasish; Chowdhury, Srayoshi Roy; Nandi, Sujay Kumar; Haldar, Debasish [New Journal of Chemistry, 2019, vol. 43, # 9, p. 3743 - 3749]
[6]Bernadat, Guillaume; Correia, Isabelle; Lequin, Olivier; Lesma, Jacopo; Ongeri, Sandrine; Tonali, Nicolo [Organic and biomolecular chemistry, 2020, vol. 18, # 18, p. 3452 - 3458]
[7]Current Patent Assignee: IMMUNOGEN INC - WO2020/205564, 2020, A1
[8]Current Patent Assignee: BAYER AG - WO2021/13693, 2021, A1
[9]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2022/202948, 2022, A1

14
[ 70396-18-8 ]
[ 109953-36-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) N-methylmorpholine, ethyl chloroformate, 2.) N-methylmorpholine / 1.) DMF, -20 deg C, 2 min,2.) DMF, -20 deg C, then 0 deg C, 2 h, then overnight, room temperature 2: HCl / ethyl acetate 3: triethylamine / CHCl₃ / 1.) 2 h, 2.) room temperature, overnight

Reference： [1]Dutta, Anand S.; Giles, Michael B.; Williams, Joseph C. [Journal of the Chemical Society. Perkin transactions I, 1986, p. 1655 - 1664]

15
[ 70396-18-8 ]
N'-[(S)-2-((S)-2-Amino-3-methyl-butyrylamino)-propionyl]-N-methyl-hydrazinecarboxylic acid benzyl ester; hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) N-methylmorpholine, ethyl chloroformate, 2.) N-methylmorpholine / 1.) DMF, -20 deg C, 2 min,2.) DMF, -20 deg C, then 0 deg C, 2 h, then overnight, room temperature 2: HCl / ethyl acetate

Reference： [1]Dutta, Anand S.; Giles, Michael B.; Williams, Joseph C. [Journal of the Chemical Society. Perkin transactions I, 1986, p. 1655 - 1664]

16
[ 70396-18-8 ]
[ 112383-22-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 58.2 percent / dicyclohexylcarbodi-imide, 1-hydroxybenzotriazole / dimethylformamide 2: HCl / ethyl acetate

Reference： [1]Dutta, Anand S.; Giles, Michael, B.; Gormley, James J.; Williams, Joseph C.; Kusner, Edward J. [Journal of the Chemical Society. Perkin transactions I, 1987, p. 111 - 120]

17
[ 70396-18-8 ]
[ 112382-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 58.2 percent / dicyclohexylcarbodi-imide, 1-hydroxybenzotriazole / dimethylformamide 2: HCl / ethyl acetate 3: 76.1 percent / triethylamine / CHCl₃

Reference： [1]Dutta, Anand S.; Giles, Michael, B.; Gormley, James J.; Williams, Joseph C.; Kusner, Edward J. [Journal of the Chemical Society. Perkin transactions I, 1987, p. 111 - 120]

18
[ 70396-18-8 ]
[ 112382-90-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 58.2 percent / dicyclohexylcarbodi-imide, 1-hydroxybenzotriazole / dimethylformamide 2: HCl / ethyl acetate 3: 76.2 percent / triethylamine / CHCl₃

Reference： [1]Dutta, Anand S.; Giles, Michael, B.; Gormley, James J.; Williams, Joseph C.; Kusner, Edward J. [Journal of the Chemical Society. Perkin transactions I, 1987, p. 111 - 120]

19
[ 70396-18-8 ]
[ 112382-88-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 58.2 percent / dicyclohexylcarbodi-imide, 1-hydroxybenzotriazole / dimethylformamide 2: HCl / ethyl acetate 3: 43.3 percent / triethylamine / CHCl₃

Reference： [1]Dutta, Anand S.; Giles, Michael, B.; Gormley, James J.; Williams, Joseph C.; Kusner, Edward J. [Journal of the Chemical Society. Perkin transactions I, 1987, p. 111 - 120]

20
[ 6638-79-5 ]
[ 70396-18-8 ]
[ 909869-95-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 1,8-diazabicyclo[5.4.0]undec-7-ene In ethyl acetate; acetonitrile at 0℃; for 0.166667h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In ethyl acetate; acetonitrile at 0℃;	General procedure for the synthesis of N-Fmoc/Boc/Cbz-α-amino/peptidyl Weinreb amides 2 and 4 General procedure: To a solution of N-protected amino/peptide acid (1.0 mmol) in CH3CN (2.0 mL), DBU (1.1 mmol, 0.16 mL), and T3P (50% in EtOAc, 1.02 mL, 3.2 mmol) were added at 0 °C and the solution was stirred for about 10 min. Then, N,O-dimethylhydroxylamine (1.1 mmol, 0.11 g, hydrochloride salt was neutralized by the addition of 1.1 mmol, 0.12 mL TEA) was added to the reaction mixture and the reaction was allowed to stir till the completion of the reaction as indicated by TLC. After the evaporation of solvent, the crude product was extracted into EtOAc and the organic phase was washed with 5% citric acid (10 mL × 2), 5% Na2CO3 (10 mL × 2), water and brine solution and dried over anhydrous Na2SO4. The solvent was evaporated and pure product was isolated after followed by triturating with ether.

Reference： [1]Sharnabai; Nagendra; Vishwanatha; Sureshbabu, Vommina V. [Tetrahedron Letters, 2013, vol. 54, # 6, p. 478 - 482]

21
3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butylester 3-methyl ester [ No CAS ]
[ 70396-18-8 ]
C₂₀H₃₆N₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butylester 3-methyl ester With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 3.5h; Stage #2: (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In dichloromethane at 20℃; for 19h;	33; 34 A cooled (0°C) solution of 33b (376.0 mg, 1.049 mmol) in anhydrous dichloromethane (15 mL) was treated with trifluoroacetic acid (5 mL). After stirring at 0°C for 30 min and RT for 2 h, trifluoroacetic acid (4 mL) was added. After 1 h, the volatiles were removed in vacuo and the residual trifluoroacetic acid azeotroped off with toluene (3 x) to provide the bis- trifluoroacetic acid ammonium salt as an off-white solid. A cooled (0°C) solution of the bis- trifluoroacetic acid ammonium salt and crude (S)-2-((S)-2-ferf-butoxycarbonylamino-3-methyl-butyrylamino)- propionic acid as prepared in the previous step in anhydrous dichloromethane (15 mL) was subsequently treated with /V-methylmorpholine (580 μ, 5.240 mmol) and O-(benzotriazol-l-yl)- Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate (596.2 mg, 1.572 mmol). After stirring for 19 h at RT, the reaction was quenched with hydrochloric acid (1 M, 30 mL). The aqueous was extracted with dichloromethane (2 x 30 mL). The organics were combined, washed with saturated aqueous sodium bicarbonate and filtered through a phase separator. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of /'so-hexanes/ethyl acetate 1 :0 to 1 :2 to afford the title compound (373.1 mg, 83% over 2 steps) as a white foam and as a mixture of diastereoisomers

Reference： [1]Current Patent Assignee: CYPRALIS LTD - WO2013/185103, 2013, A1 Location in patent: Page/Page column 142

22
[ 70396-18-8 ]
1-{(2S)-2-[(2S)-2-((E)-(2R,3R)-3-methoxy-2-methylhex-4-enoylamino)-3-methylbutyrylamino]propionyl}-3-methylhexahydropyridazine-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / dichloromethane / 3.5 h / 0 - 20 °C 1.2: 19 h / 20 °C 2.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 1 h / 0 °C 3.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / acetonitrile / 18 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1: 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 19 h / 0 - 20 °C 2: trimethylsilyl methanesulfonate / dichloromethane / 1 h / 0 °C 3: N-ethyl-N,N-diisopropylamine; HATU / acetonitrile / 18 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: CYPRALIS LTD - WO2013/185103, 2013, A1
[2]Current Patent Assignee: CYPRALIS LTD - US2017/190737, 2017, A1

23
[ 70396-18-8 ]
C₁₅H₂₈N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / dichloromethane / 3.5 h / 0 - 20 °C 1.2: 19 h / 20 °C 2.1: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 1 h / 0 °C
	Multi-step reaction with 2 steps 1: 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 19 h / 0 - 20 °C 2: trimethylsilyl methanesulfonate / dichloromethane / 1 h / 0 °C

Reference： [1]Current Patent Assignee: CYPRALIS LTD - WO2013/185103, 2013, A1
[2]Current Patent Assignee: CYPRALIS LTD - US2017/190737, 2017, A1

24
[ 1609184-88-4 ]
[ 70396-18-8 ]
C₃₉H₇₈N₄O₉Si₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: (3S)-3-amino-[3,4,6-tri-O-(tert-butyldimethylsilyl)-1,2-dideoxy-α-D-glucopyranoso][2,3-b]-pyrrolidin-2-one; (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 0.0833333h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 10h;	1 Procedure for the synthesis of glucopeptide (7) To a stirred solution of a-amino c-lactam 2a (25 mg,0.04 mmol) in CH3CN (5 mL), diisopropylethylamine (0.03 mL,0.13 mmol) and Boc-valinylalanine (17 mg, 0.06 mmol) wereadded at 0 C. The mixture was stirred for 5 min, followed bythe addition of EDCHCl (13 mg, 0.07 mmol) and HOBt (6 mg,0.05 mmol). The reaction mixture was warmed to room temperatureand stirred for 10 hours. After the completion of the reactionthe residue was concentrated in vacuo and extracted withethyl acetate. The crude product was purified by column chromatographyusing 5% CHCl3/MeOH to furnish the glucopeptide 7(28 mg). 1.6.1 Glucopeptide (7) Yield: 75%; Gummy; -28.30 (c 0.8, CHCl3); Rf = 0.5 (CHCl3/MeOH, 95:5); IR (neat): 3313, 1685, 1702, 1709, 1254, 1093, 836 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.74 (d, 1H, J = 6.3 Hz), 6.23 (d, 1H, J = 7.7 Hz), 6.03 (s, 1H), 5.62 (d, 1H, J = 7.7 Hz), 5.12 (d, 1H, J = 7.9 Hz), 4.85 (dd, 1H, J = 8.2, 10.1 Hz), 4.57-4.50 (m, 1H), 3.99-3.96 (m, 1H), 3.89-3.70 (m, 6H), 3.04-2.99 (m, 1H), 1.45 (s, 9H), 0.97-0.95 (m, 9H), 0.91-0.89 (m, 27H), 0.19-0.18 (m, 6H), 0.08-0.01 (m, 12H); 13C NMR (100 MHz, CDCl3): δ 172.2, 171.8, 170.8, 155.7, 78.6, 75.5, 69.2, 67.1, 65.8, 50.7, 48.5, 40.6, 28.3, 26.3, 26.0, 25.7, 19.2, 18.6, 18.4, 17.9, 17.6, -3.8, -4.5, -4.8, -5.0, -5.2, -5.3; HRMS (ESI-QTOF) m/z: Calcd for C39H78N4O9Si3 [M+Na]+ 853.4974; Found 853.5358.

Reference： [1]Kishore, Gade; Gautam, Vibha; Chandrasekaran, Srinivasan [Carbohydrate Research, 2014, vol. 390, # 1, p. 1 - 8]

25
[ 3392-12-9 ]
[ 56-41-7 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃; for 12h; Inert atmosphere;	14 Example 14: (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutaneamido)propionic acid The flask was charged with Boc-Val-OSu (20, 1.0 g, 3.18 mmol) and H-Ala-OH (21,312 mg, 3.5 mmol) in anhydrous dimethylformamide (10.6 mL). To this was added N, N-diisopropylethylamine (1.1 mL, 6.4 mmol)The solution was stirred at 50 & lt; 0 & gt; C under N2 for 12 hours. The reaction was poured into DMSO and purified by preparative HPLC to give 22 (808 mg,88%)

Reference： [1]Current Patent Assignee: SEAGEN INC - KR2017/53648, 2017, A Location in patent: Paragraph 0634; 1230-1231

26
[ 70396-18-8 ]
tert-butyl ((S)-1-(((S)-1-((4-(bromomethyl)phenyl)amino)-1-oxopropane-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane / 12 h / 20 °C / Inert atmosphere 2: N-Bromosuccinimide; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SEAGEN INC - KR2017/53648, 2017, A

27
[ 70396-18-8 ]
(2R)-2-(((2S,3S)-1-(((1R,3R)-1-acetoxy-1-(4-(((2R,4S)-5-(tert-butoxy)-4-methyl-5-oxo-1-phenylpentane-2-yl)carbamoyl)thiazole-2-yl)-4-methylpentane-3-yl)(methyl)amino)-3-methyl-1-oxopentan-2-yl)carbamoyl)-1-(4-((S)-2-((S)-2-(((tert-butoxy)carbonyl)amino)-3-methylbutaneamido)propaneamido) benzyl )-1-methylpiperidine-1-ium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane / 12 h / 20 °C / Inert atmosphere 2: N-Bromosuccinimide; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; butanone / 12 h / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SEAGEN INC - KR2017/53648, 2017, A

28
[ 70396-18-8 ]
(2R)-2-(((2S,3S)-1-(((1R,3R)-1-acetoxy-1-(4-(((2R,4S)-4-carboxy-1-phenylpentane-2-yl)carbamoyl)thiazole-2-yl)-4-methylpentane-3-yl)(methyl)amino)-3-methyl-1-oxopentan-2-yl)carbamoyl)-1-((4-((S)-2-((S)-2-amino-3-methylbutanamido)-3-methylbutaneamido)propaneamido)benzyl)-1-methylpiperidine-1-ium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane / 12 h / 20 °C / Inert atmosphere 2: N-Bromosuccinimide; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; butanone / 12 h / 80 °C / Inert atmosphere 4: trifluoroacetic acid / dichloromethane / 4 h / 0 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SEAGEN INC - KR2017/53648, 2017, A

29
[ 623-04-1 ]
[ 70396-18-8 ]
tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropane-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 20℃; for 72h; Darkness;
68%	Stage #1: 4-aminobenzenemethanol; (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 20℃; for 1h; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran for 0.0833333h; Stage #3: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran	C tert-Butyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2- yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (7-2): A solution (terf-butoxycarbonyl)-L-valyl-L-alanine (285 mg,0.988 mmol) and 4-aminobenzyl alcohol (183 mg,1 .483 mmol) in THF (5 ml)) was treated with EEDQ (367 mg,1.483 mmol) then the solution was stirred at room temperature. After 1 h,no product was observed. DMF (5 ml) and HATU (564 mg,1.483 mmol) were added. After 5 min,N,N-diisopropylethylamine (0.689 ml,3.95 mmol) was added after which LCMS showed completion. The mixture was stirred for an additional 1 h. The volatile solvents were removed under reduced pressure. The crude was diluted with EtOAc. The organic layer was washed with water (x 3). A small amount of brine was added to break any suspension that has formed. It was washed with brine and dried over Na2S04. It was concentrated down,loaded on celite and dried. The crude was purified over Isco (12g silica column; eluent EtOAc/Hexanes: 0-70% then 70%) to afford the title compound 7-2 as an off-white solid (265 mg,68% yield). 1H NMR (DMSO-d6,500 MHz) d 9.93 (br s,1 H),8.05 (br d,1 H,J= 6.7 Hz),7.53 (br d,2H,J= 8.2 Hz),7.24 (br d,2H, J=8.1 Hz),6.74 (br d,1 H,J= 8.7 Hz),5.10 (t,1 H,J= 5.6 Hz),4.43 (br d, 2H,J= 5.3 Hz),3.84 (br t,1 H,J= 7.5 Hz); 1.9-2.0 (m,1 H),1 .39 (s,9H),1 .30 (br d,3H,J= 6.8 Hz),0.87 (br d,3H,J=6.5 Hz),0.82 (br d,3H,J=6.4 Hz); LCMS [M+H]+ 394.
68%	Stage #1: 4-aminobenzenemethanol; (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In tetrahydrofuran at 20℃; for 1h; Stage #2: With HATU In tetrahydrofuran; N,N-dimethyl-formamide for 0.0833333h; Stage #3: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide	C tert-Butyl((S)- I -(((S)- I -((4-(hydroxymethyl)phenyl)amino)-I -oxopropan-2- yI)amino)-3-methyl-I -oxobutan-2-yI)carbamate (4-2): A solution (tert-butoxycarbonyl)-L-valyl-L-alanine (285 mg, 0.988 mmol) and 4-aminobenzyl alcohol (183 mg, 1.483 mmol) in THF (5 ml) was treated with EEDQ (367 mg, 1.483 mmol). The solution was stirred at room temperature. After 1 h no product was observed. DMF (5 ml) and HATU (564 mg, 1.483 mmol) were added. After 5 mi N,N-diisopropylethylamine (0.689 ml, 3.95 mmol) was added after which LCMS showed completion. The mixture was stirred for an additional lh. The volatile solvents were removed under reduced pressure. The crude was diluted with EtOAc. The organic layer was washed with water (x 3). A small amount of brine was added to break any suspension that has formed. It was then washed with brine and dried over Na2SO4. The organic layer was concentrated down, loaded on celite and dried. It was purified over Isco (1 2g silica column, eluent EtOAc/Hexanes: 0-70% then 70%) to afford the title compound 4-2 as an off-white solid (265 mg, 68% yield).1H NMR (DMSO-d6, 500 MHz) O 9.93 (br 5, 1 H), 8.05 (br d, 1 H, J=6.7 Hz), 7.53 (brd, 2H, J=8.2 Hz), 7.24 (brd, 2H, J=8.1 Hz), 6.74 (brd, 1H, J=8.7 Hz), 5.10 (t, 1 H, J=5.6 Hz), 4.43 (br d, 2H, J=5.3 Hz), 3.84 (br t, 1 H, J=7.5 Hz); 1.9-2.0 (m, 1H), 1.39 (5, 9H), 1.30 (brd, 3H, J=6.8 Hz), 0.87 (brd, 3H,J=6.5 Hz), 0.82 (brd, 3H, J=6.4 Hz); LCMS [M+H] 394.

60%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In dichloromethane at 20℃; for 12h; Inert atmosphere;	15 Example: 15 tert-butyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropane-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate The flame-dried flask was treated with dipeptide 22 (808 mg, 2.8 mmol) in anhydrous dichloromethane (14 mL)And 4-aminobenzoalcohol23 (345 mg, 2.8 mmol). It was added as a solid and was stirred at room temperature under nitrogen for 12 hours. The reaction was then condensed and purified on silica via a Biotage column (CH2Cl2 / MeOH, 0% -10%)To give 24 (660 mg, 60%).
5.45 g	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; Inert atmosphere;

Reference： [1]Gallo, Francesca; Korsak, Barbara; Müller, Christoph; Hechler, Torsten; Yanakieva, Desislava; Avrutina, Olga; Kolmar, Harald; Pahl, Andreas [Journal of Medicinal Chemistry, 2021, vol. 64, # 7, p. 4117 - 4129]
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/109188, 2019, A1 Location in patent: Paragraph 00300
[3]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/119141, 2019, A1 Location in patent: Paragraph 00221; 00268; 00269
[4]Current Patent Assignee: SEAGEN INC - KR2017/53648, 2017, A Location in patent: Paragraph 0634; 1232-1233
[5]Current Patent Assignee: IMMUNOGEN INC - WO2020/205564, 2020, A1 Location in patent: Paragraph 00241

30
C₇H₁₄N₂O₂*2C₂HF₃O₂ [ No CAS ]
[ 70396-18-8 ]
C₂₀H₃₆N₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
373.1 mg	With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In dichloromethane at 0 - 20℃; for 19h;	33 A cooled (0° C.) solution of 33b (376.0 mg, 1.049 mmol) in anhydrous dichloromethane (15 mL) was treated with trifluoroacetic acid (5 mL). After stirring at 0° C. for 30 min and RT for 2 h, trifluoroacetic acid (4 mL) was added. After 1 h, the volatiles were removed in vacuo and the residual trifluoroacetic acid azeotroped off with toluene (3×) to provide the bis-trifluoroacetic acid ammonium salt as an off-white solid. A cooled (0° C.) solution of the bis-trifluoroacetic acid ammonium salt and crude (S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionic acid as prepared in the previous step in anhydrous dichloromethane (15 mL) was subsequently treated with N-methylmorpholine (580 μL, 5.240 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (596.2 mg, 1.572 mmol). After stirring for 19 h at RT, the reaction was quenched with hydrochloric acid (1 M, 30 mL). The aqueous was extracted with dichloromethane (2×30 mL). The organics were combined, washed with saturated aqueous sodium bicarbonate and filtered through a phase separator. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:2 to afford the title compound (373.1 mg, 83% over 2 steps) as a white foam and as a mixture of diastereoisomers.

Reference： [1]Current Patent Assignee: CYPRALIS LTD - US2017/190737, 2017, A1 Location in patent: Paragraph 0394

31
(2S,6aS,6bR,7S,8aS,8bS,10S,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2’,1’:4,5]indeno[1,2-d][1,3]dioxol-4-one [ No CAS ]
[ 70396-18-8 ]
tert-butyl ((S)-1-(((S)-1-((3-(4-((2S,6aS,6bR 7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8adimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With HATU In tetrahydrofuran for 8h;	15 Example 15: Synthesis of tert-butyl ((S)-1-(((S)-1-((3-(4-((2S,6aS,6bR 7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8adimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate HaTU(106 mg,0.280 mmol)and 2,6-lutidine(0.1 mL,0.859 mmol)were added to a roomtemperature suspensiOn (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4(2H)-one(113mg,0.187 mmol)and(tert-butoxycarbonyl)-L-valyl-L-alanine(53.8 mg,0.187 mmol)in THF(1.25 mL).after 8h the reaction was diluted with EtOac(16 mL),then washed sequentia11y with a 1M aqueoussolution ofHCI(4 mL x 3),a saturated aqueous solution ofNaHC03(4 mL),and then a saturated aqueoussolution of brine(4 mL). Solvent was removed under reduced pressure and the product was purified bychromatography(12 g silica),eluting with a gradient of 0-10% MeOH/DCM to give the title compound(148.6 mg,0.170 mmol,91% yield). LCMS(Method r,Table 7)R1 = 0.94 min,m/z = 875.9 [M+H+]. 1H-nMR(DMSO-d6)8 9.85(s,1H),7.99(d,J = 7.1 Hz,1H),7.43(dd,J = 8.0,1.7 Hz,1H),7.36- 7.31(m,3H),7.27- 7.15(m,5H),6.89(d,J = 7.5 Hz,1H),6.67(d,J = 8.8 Hz,1H),6.27(dd,J = 10.2,1.9 Hz,1H),6.11(s,1H),5.73- 5.52(m,1H),5.50(dd,J = 4.5,1.7 Hz,1H),5.43(s,1H),5.07(t,J = 5.9 Hz,1H),4.93(d,J = 4.8 Hz,1H),4.49(dd,J = 19.5,6.4 Hz,1H),4.37(t,J = 7.0 Hz,1H),4.25- 4.12(m,2H),3.87(s,2H),3.80(t,J = 7.7 Hz,1H),2.73- 2.53(m,1H),2.23(ddd,J = 18.7,11.9,6.0 Hz,2H),2.08- 1.99(m,1H),1.93(q,J = 7.0 Hz,1H),1.77- 1.59(m,3H),1.48(s,3H),1.35(s,9H),1.25(d,J =7.0 Hz,3H),0.89- 0.74(m,9H).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2017/210471, 2017, A1 Location in patent: Paragraph 001056; 001057

32
(1S,2S,4R,8S,9S,11S,12S,13R)-8-[2-(4-aminophenoxy)acetyl]-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.02'9.04'8.013'18]icosa-14, 7-dien-16-one [ No CAS ]
[ 70396-18-8 ]
(2S)-2-amino-N-[(1S)-1-[(4-{2-[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[1.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)carbamoyl]ethyl]-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	Stage #1: (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 23℃; for 0.5h; Stage #2: (1S,2S,4R,8S,9S,11S,12S,13R)-8-[2-(4-aminophenoxy)acetyl]-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0<SUP>2</SUP>'<SUP>9</SUP>.0<SUP>4</SUP>'<SUP>8</SUP>.0<SUP>13</SUP>'<SUP>18</SUP>]icosa-14, 7-dien-16-one In dichloromethane at 23℃; for 16h; Stage #3: With trifluoroacetic acid In dichloromethane at 23℃; for 1h;	40 To a solution of Boc-Val-Ala-OH (0.29 g, 1.0 mmol) in methylene chloride (5 mL) were added DIPEA (0.26 g, 2.0 mmol) and HATU (0.46 g, 1.2 mmol), and the mixture was stirred at 23 °C for 30 minutes and to the reaction mixture was then added compound (11-5) (0.57 g, 1.1 mmol). After stirring at 23 °C for additional 16 hours, to the reaction mixture was added TFA (1.5 mL) and the resulting mixture was stirred at 23 °C for another hour. The volatiles were removed under reduced pressure and the residue was directly purified by prep-HPLC (method B) to yield 34a (0.17 g, 25% yield in 2 steps) as a white solid. ESI m/z: 692 (M + H)+. NMR (500 MHz, DMSCte) δ 10.00 (s, 1H), 8.47 (d, J= 6.5 Hz, 1H), 7.57-7.47 (m, 2H), 7.33 (d, J= 10 Hz, 1H), 6.87-6.82 (m, 2H), 6.18 (d, J= 10 Hz, 1H), 5.93 (s, 3H), 5.25-5.11 (m, 1H), 5.09 (d, J= 6.5 Hz, 1H), 4.92-4.65 (m, 3H), 4.55^1.40 (m, 1H), 4.40^1.30 (m, 1H), 2.32- 2.22 (m, 1H), 2.18-1.80 (m, 5H), 1.65-1.45 (m, 5H), 1.45-1.25 (m, 9H), 1.25-0.98 (m, 2H), 0.96-0.76 (m, 13H) ppm

Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2018/89373, 2018, A2 Location in patent: Paragraph 0678; 0681

33
(1S,2S,4R,6R,8S,9S,11S,12S,13R)-8-[2-(4-aminophenoxy)acetyl]-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0^2,9.0^4,8.0^13,18]icosa-14,17-dien-16-one [ No CAS ]
[ 70396-18-8 ]
(2S)-2-amino-N-[(1S)-1-[(4-{2-[(1S,2S,4R,6R,8S,95,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)carbamoyl]ethyl]-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20 - 25℃; for 0.5h; Stage #2: (1S,2S,4R,6R,8S,9S,11S,12S,13R)-8-[2-(4-aminophenoxy)acetyl]-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0^2,9.0^4,8.0^13,18]icosa-14,17-dien-16-one In dichloromethane for 16h; Stage #3: With trifluoroacetic acid at 20 - 25℃; for 1h;	92 Following the General Procedure E (65% yield) or F (53% yield) from R-6-VI, compound L4a was obtained as a white solid. ESI m/z: 692 (M + H)+. MR (500 MHz, DMSCto) δ 9.95 (d, J= 8.2 Hz, 1H), 8.19-8.09 (m, 1H), 7.54-7.47 (m, 2H), 7.33 (d, J= 10.1 Hz, 1H), 6.85 (d, J= 9.0 Hz, 2H), 6.22-6.13 (m, 1H), 5.93 (s, 1H), 5.14-5.04 (m, 1H), 4.86- 4.77 (m, 2H), 4.75 (d, J= 4.2 Hz, 1H), 4.70 (t, J= 4.3 Hz, 1H), 4.48-4.38 (m, 1H), 4.34 (s, 1H), 3.01 (t, J= 5.0 Hz, 1H), 2.58-2.52 (m, 1H), 2.33-2.25 (m, 1H), 2.13-2.06 (m, 1H), 2.03- 2.00 (m, 1H), 1.95-1.89 (m, 1H), 1.88-1.84 (m, 2H), 1.63-1.53 (m, 5H), 1.45-1.33 (m, 6H), 1.32-1.26 (m, 3H), 1.06-0.93 (m, 2H), 0.92-0.82 (m, 10H), 0.80-0.75 (m, 3H) ppm.

Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2018/89373, 2018, A2 Location in patent: Paragraph 0909-0910; 0913-0916

34
(1S,2S,4R,8S,9S,11S,12R,13S,19S)-8-[2-(4-aminophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-16-one [ No CAS ]
[ 70396-18-8 ]
(2S)-2-amino-N-[(1S)-1-[(4-{2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-12-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.02'9.04'8.013,18]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)carbamoyl]ethyl]-3-methylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h; Stage #2: (1S,2S,4R,8S,9S,11S,12R,13S,19S)-8-[2-(4-aminophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-16-one In N,N-dimethyl-formamide for 16h; Stage #3: With trifluoroacetic acid In dichloromethane	47 General procedure: (25)-2-[(25)-2-Amino-3-methylbutanamido]-5-(carbamoylamino)-N-(4-{2- [(l^,2^,4R,8^,9^, l l^,12^, 13R)-l l-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapenta cyclo[10.8.0.02'9.04'8.01 '18]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)pentanamide (34h) [0715] Compound (34h) as a white solid was prepared according to General procedure C after purification by prep-HPLC (method B). ESI m/z: 778 (M + H)+. MR (500 MHz, DMSCto) δ 9.97 (d, J= 12.0 Hz, 1H), 8.10 (m, 1H), 7.51 (d, J= 6.5 Hz, 2H), 7.32 (dd, J= 10.1, 2.5 Hz, 1H), 6.83 (dd, J= 15.9, 9.0 Hz, 2H), 6.17 (d, J= 10.0 Hz, 1H), 5.97 (t, J = 5.0 Hz , 1H), 5.93 (s, 1H), 5.40 (s, 2H), 5.22 (t, J= 4.8 Hz, 1H), 5.12 (d, J= 6.0 Hz, 1H), 5.09 (d, J= 6.5 Hz, 1H), 4.83-4.67 (m, 3H), 4.47-4.37 (m, 1H), 4.35-4.29 (m, 1H), 3.05-2.90 (m, 3H), 2.57-2.51(m, 1H), 2.30 (d, J= 12.0 Hz, 1H), 2.13-1.74 (m, 7H), 1.70- 1.46 (m, 7H), 1.45-1.29 (m, 7H), 1.17-0.93 (m, 2H), 0.91- 0.82 (m, 9H), 0.77 (dd, J= 6.7, 2.7 Hz, 3H) ppm.

Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2018/89373, 2018, A2 Location in patent: Paragraph 0666; 0713-0715

35
(1S,2S,4R,8S,9S,11S,12R,13S,19S)-8-[2-(4-aminophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-16-one [ No CAS ]
[ 70396-18-8 ]
C₄₄H₅₉F₂N₃O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 10℃; for 0.5h; Stage #2: (1S,2S,4R,8S,9S,11S,12R,13S,19S)-8-[2-(4-aminophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-16-one In N,N-dimethyl-formamide at 10℃; for 1h;	15-C (25)-2-Amino-N-[(i S)-i -[(4-{2-[(i S,25,4R,85,95, ii S,12R,135, 195)-12,i 9-difluoro-i i-hydroxy-9,13- dimethyl-i 6-oxo-6-propyl-5,7-dioxapentacyclo[ 10.8.0.02’9.04’8.0’3”8]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)carbamoyl]ethyl]-3-methylbutanamide TFA salt (3J) To a solution of Boc-Val-Ala-OH (2d, 0.31 g, 1.1 mmol) in DMF (15 mE) were added HATU (0.48 g, 1.3 mmol) and DIPEA (0.35 g, 2.7 mmol) at 100 C. After the mixture was stirred at 100 C. for 30 minutes, amine (ii, 0.50 g, 0.90 mmol) was added into the mixture. The reaction mixture was stirred at 100 C. for an hour until the amine was totally consumed. The mixture was quenched with water and extracted with ethyl acetate. The combined organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to give Boc-3J, which was dissolved in DCM (9 mE). To the solution was added TFA (3 mE) at 10° C. The reaction mixture was stirred at 10° C. for 2 hours and then concentrated in vacuo to give compound 3J (0.53 g, 84% yield) as TFA salt, which was used for the next step without thrther purification. ESI mlz: 728 (M+17.

Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - US2018/333504, 2018, A1 Location in patent: Paragraph 0385

36
[ 4070-48-8 ]
[ 70396-18-8 ]
[ 19794-08-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 48h; Cooling with ice;

Reference： [1]Podder, Debasish; Chowdhury, Srayoshi Roy; Nandi, Sujay Kumar; Haldar, Debasish [New Journal of Chemistry, 2019, vol. 43, # 9, p. 3743 - 3749]

37
[ 70396-18-8 ]
tert-butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C
	Multi-step reaction with 2 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C

Reference： [1]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/109188, 2019, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/119141, 2019, A1

38
[ 70396-18-8 ]
C₆₀H₉₆N₈O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C
	Multi-step reaction with 3 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C

Reference： [1]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/109188, 2019, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/119141, 2019, A1

39
[ 70396-18-8 ]
((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 0 °C
	Multi-step reaction with 4 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 0.5 h / 0 °C

Reference： [1]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/109188, 2019, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/119141, 2019, A1

40
[ 70396-18-8 ]
C₆₃H₉₄N₁₀O₁₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 0 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.58 h / 20 °C
	Multi-step reaction with 5 steps 1.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran / 1 h / 20 °C 1.2: 0.08 h 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 24 h / 20 °C 4.1: trifluoroacetic acid / dichloromethane / 0.5 h / 0 °C 5.1: HATU / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/109188, 2019, A1
[2]Current Patent Assignee: ONTARIO INSTITUTE FOR CANCER RESEARCH - WO2019/119141, 2019, A1

41
(2S,4R)-1-((S)-2-(tert-butyl)-14-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]
[ 70396-18-8 ]
(3R,5S)-1-((S)-2-(2-(2-(2-(2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl (tert-butoxycarbonyl)-L-valyl-L-alaninate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 17 - 25℃; for 2h;	Intermediate 100a: (3R,5S)-1-((S)-2-(2-(2-(2-(2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl (tert-butoxycarbonyl)-L-valyl-L-alaninate Intermediate 100a: (3R,5S)-1-((S)-2-(2-(2-(2-(2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethoxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-5-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-3-yl (tert-butoxycarbonyl)-L-valyl-L-alaninate To a solution of (2S,4R)-1-((S)-2-(tert-butyl)-14-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (150 mg, 0.15 mmol) and (tert-butoxycarbonyl)-L-valyl-L-alanine (87 mg, 0.30 mmol) in DCM (4 mL) was added 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (58 mg, 0.30 mmol) and N,N-dimethylpyridin-4-amine (4 mg, 0.03 mmol). The solution was stirred at RT for 2 hours. The mixture was diluted with DCM and washed with water, 1M HCl and saturated NaHCO3. The residue was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford the title compound (141 mg, 74%) as a white solid; 1H NMR (400 MHz, CDCl3, 27° C.) 0.85-0.96 (16H, m), 1.10 (3H, d), 1.17 (3H, d), 1.22 (3H, d), 1.30 (1H, d), 1.37 (2H, d), 1.43 (9H, d), 1.86-1.95 (1H, m), 2.11-2.24 (1H, m), 2.38 (1H, dd), 2.48 (3H, d), 2.61 (1H, dd), 2.85 (2H, dd), 3.02-3.13 (1H, m), 3.64-3.73 (10H, m), 3.75-3.81 (2H, m), 3.92 (1H, d), 4.02 (3H, dt), 4.17 (1H, d), 4.23 (1H, d), 4.31 (1H, d), 4.57 (2H, td), 4.72 (2H, q), 5.21 (2H, d), 5.36 (1H, s), 6.37 (2H, dd), 7.03-7.15 (2H, m), 7.18-7.24 (2H, m), 7.36 (4H, td), 7.44 (1H, s), 7.48-7.57 (1H, m), 8.14 (1H, d), 8.63 (1H, d).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2019/194190, 2019, A1 Location in patent: Paragraph 1351; 1352

42
9H-fluoren-9-ylmethyl N-([(4bS,8S,8aR)-8-([(1S,4aS,10aR)-6-amino-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}methyl)carbamate trifluoroacetic acid salt [ No CAS ]
[ 70396-18-8 ]
9H-fluoren-9-ylmethyl N-([(4bS,8S,8aR)-8-([(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-[(tert-butoxy)carbonyl]amino}-3-methylbutanamido]propanamido]-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 4h;	11-7 9H-Fluoren-9-ylmethyl N-([(4bS,8S,8aR)-8-([(1S,4aS,10aR)-6-[(2S)-2-[(2S)-2-[(tert- butoxy)carbonyl]amino}-3-methylbutanamido]propanamido]-1,4a-dimethyl- 1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl- 4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}methyl)carbamate (114) To a solution of compound 14a (66 mg, 0.082 mmol) in DMF (10 mL) were added Boc- Val-Ala-OH 101c (28mg, 0.098mmol), DIPEA (32 mg, 0.25 mmol) and HATU (47 mg, 0.12 mmol). The reaction mixture was stirred at RT for 4 h, and monitored by LCMS. The mixture was directly purified by reverse phase flash chromatography (50-90% acetonitrile in aq.ammonium bicarbonate (10 mM)) to give compound 114 (74 mg, 84% yield) as a white solid. ESI m/z: 978 (M Boc + 1)+.

Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2019/217591, 2019, A1 Location in patent: Paragraph 0566; 0567

43
C₁₀H₁₇NO₃ [ No CAS ]
[ 70396-18-8 ]
Boc-Val-Ala-R-Abh(OMe)-OMe [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 mg	With 4-methyl-morpholine; dmap; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In dichloromethane at 0 - 20℃; for 24h;

Reference： [1]Zhai, Luhan; Otani, Yuko; Hori, Yukiko; Tomita, Taisuke; Ohwada, Tomohiko [Chemical Communications, 2020, vol. 56, # 10, p. 1573 - 1576]

44
[ 3014-80-0 ]
[ 70396-18-8 ]
tert-butyl N-[(1S)-1-[[(1S)-2-[[(1S)-1-carbamoyl-2-methyl-propyl]amino]-1-methyl-2-oxoethyl]carbamoyl]-2-methyl-propyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: (2S)-2-((2S)-2-[(tert-butoxy)carbonyl]amino-3-methylbutyrylamino)propionic acid With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: (S)-2-amino-3-methylbutanamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;

Reference： [1]Bernadat, Guillaume; Correia, Isabelle; Lequin, Olivier; Lesma, Jacopo; Ongeri, Sandrine; Tonali, Nicolo [Organic and biomolecular chemistry, 2020, vol. 18, # 18, p. 3452 - 3458]

45
N-{4-[1-(4-amino-3-fluorobenzyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 70396-18-8 ]
N-(tert-butoxycarbonyl)-L-valyl-N-(4-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-ylcarbonyl)amino]phenyl}-4-methyl-6-oxo-5,6-dihydropyridazin-1(4H)-yl]methyl}-2-fluorophenyl)-L-alaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	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 14h;	5 N-(tert-butoxycarbonyl)-L-valyl-N-(4-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- ylcarbonyl)amino]phenyl}-4-methyl-6-oxo-5,6-dihydropyridazin-1(4H)-yl]methyl}-2- fluorophenyl)-L-alaninamide Example 5 N-(tert-butoxycarbonyl)-L-valyl-N-(4-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- ylcarbonyl)amino]phenyl}-4-methyl-6-oxo-5,6-dihydropyridazin-1(4H)-yl]methyl}-2- fluorophenyl)-L-alaninamide A mixture of N-{4-[1-(4-amino-3-fluorobenzyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3- yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (379 mg, 90 % purity, 723 mol), N-(tert-butoxycarbonyl)-L-valyl-L-alanine (250 mg, 867 mol), N-methyl-morpholine (240 l, 2.2 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate) (HATU, 412 mg, 1.08 mmol) in DMF (6 mL) was stirred at r.t. for 14 h. After that the mixture was concentrated under redcued pressure and the residue was purified by column chromatography (SiO2, dichloromethane/ethanol gradient) and preparative HPLC to give the title compound (150 mg, 27 % yield). HPLC: Instrument: Labomatic HD-3000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 4000, Knauer UV detector Azura UVD 2.15, Prepcon 5 software. Column: Chromatorex C1810M 122x50 mm. Eluent A: water + 0.1 Vol- % ammonia; Eluent B: acetonitrile; gradient: 0-20 min 15-55% B. rate 250 ml/min, temperature 25°C. LC-MS (method 2): Rt = 1.11 min; MS (ESIpos): m/z = 743 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.787 (1.21), 0.804 (1.42), 0.827 (4.20), 0.833 (3.06), 0.844 (4.48), 0.852 (2.56), 1.026 (1.92), 1.033 (2.28), 1.040 (1.99), 1.045 (1.99), 1.052 (1.99), 1.234 (2.42), 1.256 (7.54), 1.266 (8.11), 1.274 (4.55), 1.281 (3.20), 1.292 (3.63), 1.298 (2.56), 1.358 (9.39), 1.897 (0.43), 1.987 (0.64), 2.006 (0.57), 2.318 (1.42), 2.323 (3.13), 2.327 (4.48), 2.331 (3.27), 2.337 (1.85), 2.382 (1.07), 2.518 (16.00), 2.523 (11.09), 2.660 (1.42), 2.665 (3.20), 2.669 (4.41), 2.674 (3.06), 2.678 (1.35), 2.805 (0.50), 2.834 (0.43), 3.306 (0.78), 3.410 (0.50), 3.429 (0.71), 3.449 (0.43), 3.751 (0.43), 4.811 (3.06), 4.829 (3.20), 4.855 (0.78), 4.954 (0.64), 4.992 (0.71), 7.091 (1.00), 7.112 (1.07), 7.135 (0.57), 7.144 (0.64), 7.163 (0.57), 7.173 (0.57), 7.429 (1.56), 7.443 (1.64), 7.648 (2.28), 7.671 (4.48), 7.710 (3.77), 7.732 (2.06), 7.755 (0.57), 7.773 (0.50), 7.794 (0.50), 8.100 (0.43), 8.496 (2.42), 8.508 (2.20), 8.610 (3.27), 8.643 (2.70), 9.567 (0.57), 9.712 (0.57).

Reference： [1]Current Patent Assignee: BAYER AG - WO2021/13693, 2021, A1 Location in patent: Page/Page column 272-273

46
N-{4-[1-(4-aminobutyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 70396-18-8 ]
C₃₆H₅₀N₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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 14h;	N-(tert-butoxycarbonyl)-L-valyl-N-{4-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- ylcarbonyl)amino]phenyl}-4-methyl-6-oxo-5,6-dihydropyridazin-1(4H)-yl]butyl}-L-alaninamide A mixture of N-{4-[1-(4-aminobutyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}- 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (277 mg, 90 % purity, 593 mol), N-(tert- butoxycarbonyl)-L-valyl-L-alanine (285 mg, 90 % purity, 890 mol), (1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 338 mg, 890 mol) and N-methylmorpholine (200 l, 1.8 mmol) in DMF (5 mL) was stirred at r.t. for 14 h. After that the mixture was concentrated under reduced pressure and the residue was purified by column chromatography (amine-coated SiO2, dichloromethane/methanol gradient) to give the title compound (440 mg, 86 % purity, 92 % yield). LC-MS (method 1): Rt = 0.89 min; MS (ESIneg): m/z = 689 [M-H]- H-NMR (500 MHz, DMSO-d6) d [ppm]: 0.773 (0.62), 0.786 (0.66), 0.809 (0.77), 0.816 (1.07), 0.823 (1.04), 0.828 (1.15), 1.051 (0.87), 1.065 (0.91), 1.148 (0.75), 1.155 (0.90), 1.157 (0.72), 1.162 (1.19), 1.169 (1.19), 1.172 (0.92), 1.176 (0.47), 1.253 (0.42), 1.263 (0.43), 1.268 (0.51), 1.353 (0.53), 1.372 (6.28), 1.379 (2.79), 1.955 (2.71), 1.987 (0.94), 2.084 (1.07), 2.687 (16.00), 2.728 (10.46), 2.781 (2.51), 2.888 (13.12), 2.941 (3.71), 4.815 (0.57), 4.836 (0.58), 7.660 (0.69), 7.678 (0.98), 7.728 (0.96), 7.745 (0.55), 7.951 (1.68), 8.499 (0.52), 8.509 (0.50), 8.614 (0.75), 8.640 (0.60).

Reference： [1]Current Patent Assignee: BAYER AG - WO2021/13693, 2021, A1 Location in patent: Page/Page column 351-352

47
N-{4-[1-(4-aminobenzyl)-5,5-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 70396-18-8 ]
C₄₀H₅₀N₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
210 mg	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 14h;	N-(tert-butoxycarbonyl)-L-valyl-N-(4-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- ylcarbonyl)amino]phenyl}-5,5-dimethyl-6-oxo-5,6-dihydropyridazin-1(4H)-yl]methyl}phenyl)-L- alaninamide A mixture of N-{4-[1-(4-aminobenzyl)-5,5-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3- yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (300 mg, 640 mol), N-(tert- butoxycarbonyl)-L-valyl-L-alanine (222 mg, 768 mol), [Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 365 mg, 960 mol), N- methylmorpholine (210 l, 1.9 mmol) and DMF (5 mL) was stirred at r.t. for 14 h. After that the mixture was concentrated under reduced pressure and the residue was purified by column chromatography (dichloromethane/ethanol gradient) to give the title compound (210 mg, 94% purity, 44% yield). LC-MS (method 1): Rt = 1.02 min; MS (ESIpos): m/z = 739 [M+H]- 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.793 (0.25), 0.810 (0.29), 0.834 (0.46), 0.846 (0.62), 0.862 (0.37), 0.904 (0.04), 1.098 (2.15), 1.139 (0.05), 1.231 (0.06), 1.272 (0.50), 1.289 (0.50), 1.332 (1.52), 1.368 (1.80), 1.888 (0.04), 1.904 (0.05), 1.923 (0.09), 1.936 (0.05), 1.954 (0.04), 2.083 (16.00), 2.240 (0.05), 2.327 (0.06), 2.523 (0.23), 2.680 (0.92), 2.877 (0.55), 3.025 (0.16), 3.340 (0.20), 3.742 (0.18), 3.801 (0.06), 3.823 (0.07), 3.839 (0.05), 4.395 (0.07), 4.413 (0.11), 4.431 (0.08), 4.809 (0.42), 4.826 (0.43), 4.855 (0.49), 5.758 (0.04), 6.714 (0.08), 6.735 (0.07), 6.832 (0.06), 6.853 (0.06), 7.226 (0.35), 7.247 (0.39), 7.427 (0.23), 7.440 (0.24), 7.490 (0.16), 7.501 (0.16), 7.511 (0.19), 7.520 (0.34), 7.541 (0.26), 7.561 (0.14), 7.583 (0.12), 7.638 (0.24), 7.660 (0.76), 7.678 (0.61), 7.700 (0.19), 8.047 (0.09), 8.064 (0.09), 8.253 (0.05), 8.271 (0.05), 8.494 (0.32), 8.506 (0.31), 8.512 (0.18), 8.515 (0.17), 8.533 (0.15), 8.536 (0.14), 8.609 (0.45), 8.636 (0.40), 8.743 (0.14), 8.746 (0.14), 8.753 (0.14), 8.757 (0.13), 9.761 (0.10), 9.975 (0.12).

Reference： [1]Current Patent Assignee: BAYER AG - WO2021/13693, 2021, A1 Location in patent: Page/Page column 365-366

48
N-{4-[1-(4-aminobenzyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide [ No CAS ]
[ 70396-18-8 ]
C₃₉H₄₈N₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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 14h;	N-(tert-butoxycarbonyl)-L-valyl-N-(4-[3-{4-[(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2- ylcarbonyl)amino]phenyl}-4-methyl-6-oxo-5,6-dihydropyridazin-1(4H)-yl]methyl}phenyl)-L- alaninamide A mixture of N-{4-[1-(4-aminobenzyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl]phenyl}- 1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (300 mg, 70 % purity, 462 mol), N-(tert- butoxycarbonyl)-L-valyl-L-alanine (200 mg, 100 % purity, 693 mol), (1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 264 mg, 693 mol) and N-methylmorpholine (150 l, 1.4 mmol) in DMF (3.5 mL) was stirred at r.t. for 14 h. After that the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (90.0 mg, 89 % purity, 24 % yield). HPLC: Instrument: Labomatic HD-3000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 4000, Knauer UV detector Azura UVD 2.15, Prepcon 5 software. Column: Chromatorex C1810M 125x30 mm. Eluent A: water + 0.1 Vol- % HCOOH; Eluent B: acetonitrile; gradient: 0-8 min 15-55% B. rate 150 ml/min, temperature 25°C. LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 725 [M+H]+

Reference： [1]Current Patent Assignee: BAYER AG - WO2021/13693, 2021, A1 Location in patent: Page/Page column 355-356

49
[ 70396-18-8 ]
N(τ)-(triphenylmethyl)-L-histidine methyl ester hydrochloride [ No CAS ]
methyl N^α-(tert-butoxycarbonyl)-L-valyl-L-alanyl-N^τ-trityl-L-histidinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With O‑(6‑chlorobezotriazol‑1‑yl)‑N,N,N,N‑tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;

Reference： [1]Chan, Hwai-Chien; Bueno, Bianca; Le Roch, Adrien; Gagnon, Alexandre [Chemistry - A European Journal, 2021, vol. 27, # 53, p. 13330 - 13336]

50
(9H-fluoren-9-yl)methyl (S)-(5-amino-6-((2-(1-(4-((6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzyl)piperidin-4-yl)ethyl)amino)-6-oxohexyl)carbamate [ No CAS ]
[ 70396-18-8 ]
tert-butyl ((S)-1-(((S)-1-(((S)-6-amino-1-((2-(1-(4-((6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzyl)piperidin-4-yl)ethyl)amino)-1-oxohexan-2-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: (9H-fluoren-9-yl)methyl (S)-(5-amino-6-((2-(1-(4-((6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzyl)piperidin-4-yl)ethyl)amino)-6-oxohexyl)carbamate; (tert-butoxycarbonyl)-L-valyl-L-alanine With 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 23℃; for 0.166667h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.166667h;	3 tert-butyl ((S)-l-(((S)-l-(((S)-6-amino-l-((2-(l-(4-((6-amino-2-butoxy-8-oxo-7,8- dihydro-9H-purin-9-yl)methyl)benzyl)piperidin-4-yl)ethyl)amino)-l-oxohexan-2-yl)amino)-l- oxopropan-2-yl)amino)-3-methyI-l-oxobutan-2-yI)carbamate (232): To a solution of compound 231 (24 mg, 0.019 mmol) and Boc-Val-Ala-OH (6 mg, 0.021 mmol) in DMF (1 ml) was added DMTMMT (7 mg, 0.029 mmol) and DIEA (30 pL, 0.172 mmol) at 23 °C. After 10 min, piperidine (100 pL) was added to the mixture. After 10 min, the mixture was purified by Prep-LC to obtain compound 232 (24 mg, 0.018 mmol, 96 %) as a light brown solid.
96%	Stage #1: (9H-fluoren-9-yl)methyl (S)-(5-amino-6-((2-(1-(4-((6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl)benzyl)piperidin-4-yl)ethyl)amino)-6-oxohexyl)carbamate; (tert-butoxycarbonyl)-L-valyl-L-alanine With 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 23℃; for 0.166667h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.166667h;	3 tert-butyl ((S)-l-(((S)-l-(((S)-6-amino-l-((2-(l-(4-((6-amino-2-butoxy-8-oxo-7,8- dihydro-9H-purin-9-yl)methyl)benzyl)piperidin-4-yl)ethyl)amino)-l-oxohexan-2-yl)amino)-l- oxopropan-2-yl)amino)-3-methyI-l-oxobutan-2-yI)carbamate (232): To a solution of compound 231 (24 mg, 0.019 mmol) and Boc-Val-Ala-OH (6 mg, 0.021 mmol) in DMF (1 ml) was added DMTMMT (7 mg, 0.029 mmol) and DIEA (30 pL, 0.172 mmol) at 23 °C. After 10 min, piperidine (100 pL) was added to the mixture. After 10 min, the mixture was purified by Prep-LC to obtain compound 232 (24 mg, 0.018 mmol, 96 %) as a light brown solid.

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2022/40596, 2022, A1 Location in patent: Paragraph 00753
[2]Current Patent Assignee: AMBRX, INC. - WO2022/40596, 2022, A1 Location in patent: Paragraph 00753

51
[ 3392-12-9 ]
[ 70396-18-8 ]

Yield	Reaction Conditions	Operation in experiment
		R.102.a a) a) Production of (tert-butoxycarbonyl)-L-valyl-L-alanine (Compound F1) By the same approach as Reference Example 2-a), from 2,5-dioxopyrrolidin-1-yl (tert-butoxycarbonyl)-L-valinate (1.0 g), compound F1 (676 mg) was obtained. LC-MS: 278 (M-H)-/0.925 min, Measurement Condition G

Reference： [1]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2022/202948, 2022, A1

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	70396-18-8	MDL No. :	MFCD22381612
Formula :	C₁₃H₂₄N₂O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FHBCSPANXVQYCP-IUCAKERBSA-N
M.W :	288.34	Pubchem ID :	14657712
Synonyms :	Boc-Val-Ala-OH	Chemical Name :	(S)-2-((S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutanamido)propanoic acid

Num. heavy atoms :	20
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.77
Num. rotatable bonds :	9
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	73.89
TPSA :	104.73 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) :	-7.42 cm/s

Log Po/w (iLOGP) :	2.33
Log Po/w (XLOGP3) :	0.9
Log Po/w (WLOGP) :	1.12
Log Po/w (MLOGP) :	0.67
Log Po/w (SILICOS-IT) :	0.46
Consensus Log Po/w :	1.1

[ CAS No. 70396-18-8 ] {[proInfo.proName]}

Quality Control of [ 70396-18-8 ]

Related Doc. of [ 70396-18-8 ]

Product Details of [ 70396-18-8 ]

Calculated chemistry of [ 70396-18-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 70396-18-8 ]

Application In Synthesis of [ 70396-18-8 ]

[ 70396-18-8 ] Synthesis Path-Downstream 1~51

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-1.6
Solubility :	7.23 mg/ml ; 0.0251 mol/l
Class :	Very soluble
Log S (Ali) :	-2.68
Solubility :	0.596 mg/ml ; 0.00207 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.51
Solubility :	8.95 mg/ml ; 0.031 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.33

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338-P261-P301+P312-P302+P352-P304+P340	UN#:	N/A
Hazard Statements:	H302-H315-H335-H319	Packing Group:	N/A
GHS Pictogram:

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Response
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P342	If experiencing respiratory symptoms:
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P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
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P413
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P411 + P235	Keep cool.
Disposal
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P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling