Name: 1639939-40-4|4-((S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate|98%
Brand: Ambeed
SKU: A1365551
Rating: 90 (22 reviews)

1
[ 1639939-39-1 ]
[ 1639939-40-4 ]
[ 1639939-41-5 ]

Yield	Reaction Conditions	Operation in experiment
12%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 18h;	19 Example 19 Ethyl (2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((2S,3S)-2-((R)-1-(6-aminohexyl)piperidine-2-carboxamido)-N,3-dimethylpentanamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate (281, 13 mg, 15.5 μmol), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl)carbonate (282, 15 mg, 23.0 μmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (5 mg, 36.7 μmol), and diisopropylethylamine (0.05 ml, 287 μmol) in dimethylformamide (0.20 ml) was stirred for 18 h. The solution was diluted with water and directly purified by reverse phase HPLC to afford 2.6 mg (12% yield) of ethyl (2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((2S,3S)-2-((R)-1-(6-((((44(S)-24(S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)hexyl)piperidine-2-carboxamido)-N,3-dimethylpentanamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoate, 283, as a white solid. The remaining material was impure or had lost the acetate during the reaction.

Reference： [1]Current Patent Assignee: MAGENTA THERAPEUTICS INC - US2014/363454, 2014, A1 Location in patent: Paragraph 0296

2
[ 1639939-40-4 ]
[ 1639939-49-3 ]
[ 1639939-30-2 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 18h;	11 Example 11 Example 11 (2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((2S,3S)-N,3-dimethyl-2-((R)-piperidine-2-carboxamido)pentanamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoic acid hydrochloride (T4HCl, 12 mg, 16.0 μmol), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl(4-nitrophenyl) carbonate (24 mg, 36.8 μmol), diisopropylethylamine (0.10 ml, 574 μmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (2 mg, 14.6 μmol) in dimethylformamide (0.50 ml) was stirred for 18 h. The solution was purified by reverse phase prep HPLC to yield 12 mg (61% yield) of (2S,4R)-4-(2-((1R,3R)-1-acetoxy-3-((2S,3S)-2-((R)-1-(((4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)piperidine-2-carboxamido)-N,3-dimethylpentanamido)-4-methylpentyl)thiazole-4-carboxamido)-2-methyl-5-phenylpentanoic acid, 263, as a white solid.

Reference： [1]Current Patent Assignee: MAGENTA THERAPEUTICS INC - US2014/363454, 2014, A1 Location in patent: Paragraph 0281

3
[ 130878-68-1 ]
4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate [ No CAS ]

Reference： [1]Patent: US2014/363454,2014,A1

4
[ 1061614-69-4 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: trifluoroacetic acid / dichloromethane 2: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide / tetrahydrofuran 3: N,N-dimethyl acetamide 4: 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide 5: N,N-dimethyl-formamide

Reference： [1]Current Patent Assignee: MAGENTA THERAPEUTICS INC - US2014/363454, 2014, A1

5
[ CAS Unavailable ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide / tetrahydrofuran 2: N,N-dimethyl acetamide 3: 4-methyl-morpholine; N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate / N,N-dimethyl-formamide 4: N,N-dimethyl-formamide
	Multi-step reaction with 4 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 36 h / 20 °C 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N,N-dimethyl-formamide / 6 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 4 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 36 h / 20 °C / Darkness 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N,N-dimethyl-formamide / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C

Multi-step reaction with 4 steps 1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / ethyl acetate / 0.5 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: 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 / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Current Patent Assignee: MAGENTA THERAPEUTICS INC - US2014/363454, 2014, A1
[2]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[3]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]
[4]Audisio, Davide; Babin, Victor; Barbe, Peggy; Beau, Fabrice; Correia, Isabelle; Devel, Laurent; Dubois, Steven; Feuillastre, Sophie; Ge, Xin; Keck, Mathilde; Lee, Ki Baek; Lequin, Olivier; Malgorn, Carole; Palazzolo, Alberto; Pieters, Gregory; Sallustrau, Antoine; Thai, Robert; Cahuzac, Héloïse; Garcia-Argote, Sébastien; Nozach, Hervé [Journal of Medicinal Chemistry, 2022]

6
[ 1394238-91-5 ]
4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl)carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl acetamide 2: 4-methyl-morpholine; N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate / N,N-dimethyl-formamide 3: N,N-dimethyl-formamide
	Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 2: N,N-dimethyl-formamide / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C

Multi-step reaction with 3 steps 1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 2: 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 / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Current Patent Assignee: MAGENTA THERAPEUTICS INC - US2014/363454, 2014, A1
[2]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[3]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]
[4]Audisio, Davide; Babin, Victor; Barbe, Peggy; Beau, Fabrice; Correia, Isabelle; Devel, Laurent; Dubois, Steven; Feuillastre, Sophie; Ge, Xin; Keck, Mathilde; Lee, Ki Baek; Lequin, Olivier; Malgorn, Carole; Palazzolo, Alberto; Pieters, Gregory; Sallustrau, Antoine; Thai, Robert; Cahuzac, Héloïse; Garcia-Argote, Sébastien; Nozach, Hervé [Journal of Medicinal Chemistry, 2022]

7
[ 1343476-44-7 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 4-methyl-morpholine; N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate / N,N-dimethyl-formamide 2: N,N-dimethyl-formamide
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 6 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C

Multi-step reaction with 2 steps 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 / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Current Patent Assignee: MAGENTA THERAPEUTICS INC - US2014/363454, 2014, A1
[2]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[3]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]
[4]Audisio, Davide; Babin, Victor; Barbe, Peggy; Beau, Fabrice; Correia, Isabelle; Devel, Laurent; Dubois, Steven; Feuillastre, Sophie; Ge, Xin; Keck, Mathilde; Lee, Ki Baek; Lequin, Olivier; Malgorn, Carole; Palazzolo, Alberto; Pieters, Gregory; Sallustrau, Antoine; Thai, Robert; Cahuzac, Héloïse; Garcia-Argote, Sébastien; Nozach, Hervé [Journal of Medicinal Chemistry, 2022]

8
[ 1870916-87-2 ]
[ 7693-46-1 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide

Reference： [1]Current Patent Assignee: MAGENTA THERAPEUTICS INC - US2014/363454, 2014, A1 Location in patent: Paragraph 0341

9
[ 1639939-40-4 ]
[ 1942056-01-0 ]
[ 1942058-33-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 20℃; for 72h;	2.30 2.30. Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[([(3S)-1-{8-(1,3-benzothiazol-2-ylcarbamoyl)-2-[6-carboxy-5-(1-[3-(2-methoxyethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-6-yl}pyrrolidin-3-yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon NR) Example 1.17.10 (40 mg) was dissolved in dimethyl sulfoxide (0.3 mL), and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl(4-nitrophenyl)carbonate(31 mg) and triethylamine (33 μL) were added. The reaction mixture was stirred for 72 hours at roomtemperature, and purification by reverse phase chromatography (C18 column), eluting with 10-90%acetonitrile in 0.1% TFA water, provided the title compound. MS (ESI) m/e 1357.4 (M+H)+, 1355.5 (M-H)-

Reference： [1]Current Patent Assignee: ABBVIE INC - US2016/158377, 2016, A1 Location in patent: Paragraph 0942

10
[ 1639939-40-4 ]
[ 1949838-68-9 ]
[ 1949841-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.2.7 2.7. Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[([(2R)-1-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl}oxy)ethyl](methyl)amino}-1-oxo-3-sulfopropan-2-yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EH) 2.7. Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoyl]-L- valyl-N-{4- [({ [(2R)-1- { [2-({3- [(4-{6- [8-(l,3-benzothiazol-2-ylcarbamoyl)- 3,4-dihydroisoquinolin-2(lH)-yl]-2-carboxypyridin-3-yl}-5-methyl-lH- pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13'7]dec-l- yl}oxy)ethyl](methyl)amino}-l-oxo-3-sulfopropan-2- yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EH) [000892] To a solution of Example 1.13.8 (0.018 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro- lH-pyrrol- 1 -yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.015 g, 0.023 mmol) in N,N-dimethylformamide (0.75 mL) was added N,N-diisopropylethylamine (0.015 mL). After stirring overnight, the reaction was diluted with N,N-dimethylformamide (0.75 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. NMR (500 MHz, dimethyl sulfoxide-^) δ ppm 12.86 (s, IH), 9.93 (s, IH), 8.14 (d, IH), 8.04 (d, IH), 7.84-7.76 (m, 2H), 7.61 (d, IH), 7.57 (d, 2H), 7.53 (dd, IH), 7.47 (t, IH), 7.43 (d, IH), 7.39-7.30 (m, 4H), 7.26 (d, 2H), 6.99 (s, 2H), 6.97 (dd, IH), 4.96 (s, 2H), 4.90 (t, 2H), 4.75-4.65 (m, IH), 4.46-4.33 (m, 2H), 4.17 (dd, 2H), 3.66-3.47 (m, 4H), 3.36 (t, 4H), 3.12 (s, 2H), 3.01 (t, 2H), 2.85-2.60 (m, 4H), 2.25-2.05 (m, 5H), 2.05-1.90 (m, IH), 1.58-0.76 (m, 32H). MS (ESI) m/e 1423.2 (M+H)+.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.2.7 2.7 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L- valyl-N-{4-[([(2R)-1-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)- 3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H- pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1- yl}oxy)ethyl](methyl)amino}-1-oxo-3-sulfopropan-2- yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EH) To a solution of Example 1.13.8 (0.018 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.015 g, 0.023 mmol) in N,N-dimethylformamide (0.75 mL) was added N,N-diisopropylethylamine (0.015 mL). After stirring overnight, the reaction was diluted with N,N-dimethylformamide (0.75 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 12.86 (s, 1H), 9.93 (s, 1H), 8.14 (d, 1H), 8.04 (d, 1H), 7.84-7.76 (m, 2H), 7.61 (d, 1H), 7.57 (d, 2H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.39-7.30 (m, 4H), 7.26 (d, 2H), 6.99 (s, 2H), 6.97 (dd, 1H), 4.96 (s, 2H), 4.90 (t, 2H), 4.75-4.65 (m, 1H), 4.46-4.33 (m, 2H), 4.17 (dd, 2H), 3.66-3.47 (m, 4H), 3.36 (t, 4H), 3.12 (s, 2H), 3.01 (t, 2H), 2.85-2.60 (m, 4H), 2.25-2.05 (m, 5H), 2.05-1.90 (m, 1H), 1.58-0.76 (m, 32H). MS (ESI) m/e 1423.2 (M+H)+.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.7 2.7 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[([(2R)-1-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1-yl}oxy)ethyl](methyl)amino}-1-oxo-3-sulfopropan-2-yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EH) To a solution of Example 1.13.8 (0.018 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.015 g, 0.023 mmol) in N,N-dimethylformamide (0.75 mL) was added N,N-diisopropylethylamine (0.015 mL). After stirring overnight, the reaction was diluted with N,N-dimethylformamide (0.75 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 12.86 (s, 1H), 9.93 (s, 1H), 8.14 (d, 1H), 8.04 (d, 1H), 7.84-7.76 (m, 2H), 7.61 (d, 1H), 7.57 (d, 2H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.39-7.30 (m, 4H), 7.26 (d, 2H), 6.99 (s, 2H), 6.97 (dd, 1H), 4.96 (s, 2H), 4.90 (t, 2H), 4.75-4.65 (m, 1H), 4.46-4.33 (m, 2H), 4.17 (dd, 2H), 3.66-3.47 (m, 4H), 3.36 (t, 4H), 3.12 (s, 2H), 3.01 (t, 2H), 2.85-2.60 (m, 4H), 2.25-2.05 (m, 5H), 2.05-1.90 (m, 1H), 1.58-0.76 (m, 32H). MS (ESI) m/e 1423.2 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/94509, 2016, A1 Location in patent: Paragraph 000892
[2]Current Patent Assignee: ABBVIE INC - WO2017/214462, 2017, A2 Location in patent: Page/Page column 541
[3]Current Patent Assignee: ABBVIE INC - US2017/355769, 2017, A1 Location in patent: Paragraph 1871

11
[ 1639939-40-4 ]
[ 1949838-73-6 ]
[ 76-05-1 ]
[ 1949841-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate; 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 24h; Stage #2: trifluoroacetic acid In water; N,N-dimethyl-formamide; acetonitrile	2.2.16 2.16. Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[([2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl}oxy)ethyl](3-phosphonopropyl)carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EZ) [000903] A mixture of Example 1.14.4 (50 mg), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-lH- pyrrol-l-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (38 mg), and N,N-diisopropylethylamine (0.050 mL) in 2 mL N,N-dimethylformamide was stirred for 24 hours. The mixture was purified via reverse phase chromatography on a Biotage Isolera One system using a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water. The desired fractions were concentrated and the product was lyophilized from water and 1,4-dioxane to give the title compound as a trifluoroacetic acid salt. NMR (400MHz, dimethyl sulfoxide -d6) δ ppm 9.94 (bs, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.80 (d, 2H), 7.61 (m, 3H), 7.47 (m, 3H), 7.36 (m, 2H), 7.29 (m, 2H), 6.99 (s, 2H), 6.95 (d, 1H), 4.97 (m, 4H), 4.40 (m, 2H), 4.16 (dd, 2H), 3.50-4.10 (m, 6H), 3.68 (m, 2H), 3.55 (m, 2H), 3.25 (m, 4H), 3.02 (m, 2H), 2.94 (s, 2H), 2.79 (s, 2H), 2.15 (m, 1H), 2.08 (s, 2H), 1.65 (m, 2H), 1.40-1.50 (m, 6H), 1.20-1.30 (m, 6H), 1.08-1.19 (m, 4H), 0.97 (m, 1-2H), 0.76-0.89 (m, 12H). MS (ESI) m/e 1380.3 (M+H)+.
	Stage #1: [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate; 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 24h; Stage #2: trifluoroacetic acid In water; acetonitrile	2.16 2.16 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[([2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1-yl}oxy)ethyl](3-phosphonopropyl)carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EZ) A mixture of Example 1.14.4 (50 mg), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (38 mg), and N,N-diisopropylethylamine (0.050 mL) in 2 mL N,N-dimethylformamide was stirred for 24 hours. The mixture was purified via reverse phase chromatography on a Biotage Isolera One system using a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water. The desired fractions were concentrated and the product was lyophilized from water and 1,4-dioxane to give the title compound as a trifluoroacetic acid salt. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 9.94 (bs, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.80 (d, 2H), 7.61 (m, 3H), 7.47 (m, 3H), 7.36 (m, 2H), 7.29 (m, 2H), 6.99 (s, 2H), 6.95 (d, 1H), 4.97 (m, 4H), 4.40 (m, 2H), 4.16 (dd, 2H), 3.50-4.10 (m, 6H), 3.68 (m, 2H), 3.55 (m, 2H), 3.25 (m, 4H), 3.02 (m, 2H), 2.94 (s, 2H), 2.79 (s, 2H), 2.15 (m, 1H), 2.08 (s, 2H), 1.65 (m, 2H), 1.40-1.50 (m, 6H), 1.20-1.30 (m, 6H), 1.08-1.19 (m, 4H), 0.97 (m, 1-2H), 0.76-0.89 (m, 12H). MS (ESI) m/e 1380.3 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/94509, 2016, A1 Location in patent: Paragraph 000903
[2]Current Patent Assignee: ABBVIE INC - US2017/355769, 2017, A1 Location in patent: Paragraph 1882

12
[ 1639939-40-4 ]
[ 1949838-81-6 ]
[ 1949841-12-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.2.13 2.13. Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[([(2R)-1-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl}oxy)ethyl]amino}-1-oxo-3-sulfopropan-2-yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EW) [000900] To a solution of Example 1.15 (0.020 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro- lH-pyrrol- 1 -yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.017 g) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.017 mL). The reaction was stirred overnight and was diluted with N,N-dimethylformamide (1 mL), water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. NMR (400 MHz, dimethyl sulfoxide -d6) δ ppm 12.85 (s, IH), 9.93 (s, IH), 8.12 (d, IH), 8.04 (d, IH), 7.86-7.76 (m, 3H), 7.63-7.41 (m, 7H), 7.39- 7.32 (m, 2H), 7.30 (s, IH), 7.30-7.21 (m, 2H), 6.99 (s, 2H), 6.97 (d, IH), 4.96 (s, 2H), 4.93 (s, 2H), 4.49-4.33 (m, 2H), 4.18 (dd, 2H), 4.15-4.08 (m, 2H), 3.90-3.86 (m, 2H), 3.36 (t, 2H), 3.34-3.27 (m, IH), 3.18-3.04 (m, 2H), 3.04-2.96 (m, 2H), 2.89-2.61 (m, 2H), 2.27-2.05 (m, 5H), 2.03-1.87 (m, IH), 1.59-1.42 (m, 4H), 1.42-0.91 (m, 18H), 0.91-0.76 (m, 11H). MS (-ESI) m/e 1407.5 (M-H)~.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.2.13 2.13 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L- valyl-N-{4-[([(2R)-1-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)- 3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H- pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1- yl}oxy)ethyl]amino}-1-oxo-3-sulfopropan-2- yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EW) To a solution of Example 1.15 (0.020 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.017 g) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.017 mL). The reaction was stirred overnight and was diluted with N,N-dimethylformamide (1 mL), water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.85 (s, 1H), 9.93 (s, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.86-7.76 (m, 3H), 7.63-7.41 (m, 7H), 7.39- 7.32 (m, 2H), 7.30 (s, 1H), 7.30-7.21 (m, 2H), 6.99 (s, 2H), 6.97 (d, 1H), 4.96 (s, 2H), 4.93 (s, 2H), 4.49-4.33 (m, 2H), 4.18 (dd, 2H), 4.15-4.08 (m, 2H), 3.90-3.86 (m, 2H), 3.36 (t, 2H), 3.34-3.27 (m, 1H), 3.18-3.04 (m, 2H), 3.04-2.96 (m, 2H), 2.89-2.61 (m, 2H), 2.27-2.05 (m, 5H), 2.03-1.87 (m, 1H), 1.59-1.42 (m, 4H), 1.42-0.91 (m, 18H), 0.91-0.76 (m, 11H). MS (-ESI) m/e 1407.5 (M-H)-.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.13 2.13 _Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[([(2R)-1-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1-yl}oxy)ethyl]amino}-1-oxo-3-sulfopropan-2-yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EW) To a solution of Example 1.15 (0.020 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.017 g) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.017 mL). The reaction was stirred overnight and was diluted with N,N-dimethylformamide (1 mL), water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.85 (s, 1H), 9.93 (s, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.86-7.76 (m, 3H), 7.63-7.41 (m, 7H), 7.39-7.32 (m, 2H), 7.30 (s, 1H), 7.30-7.21 (m, 2H), 6.99 (s, 2H), 6.97 (d, 1H), 4.96 (s, 2H), 4.93 (s, 2H), 4.49-4.33 (m, 2H), 4.18 (dd, 2H), 4.15-4.08 (m, 2H), 3.90-3.86 (m, 2H), 3.36 (t, 2H), 3.34-3.27 (m, 1H), 3.18-3.04 (m, 2H), 3.04-2.96 (m, 2H), 2.89-2.61 (m, 2H), 2.27-2.05 (m, 5H), 2.03-1.87 (m, 1H), 1.59-1.42 (m, 4H), 1.42-0.91 (m, 18H), 0.91-0.76 (m, 11H). MS (-ESI) m/e 1407.5 (M-H)-.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/94509, 2016, A1 Location in patent: Paragraph 000900
[2]Current Patent Assignee: ABBVIE INC - WO2017/214462, 2017, A2 Location in patent: Page/Page column 544
[3]Current Patent Assignee: ABBVIE INC - US2017/355769, 2017, A1 Location in patent: Paragraph 1879

13
[ 1639939-40-4 ]
[ 1949838-83-8 ]
[ 76-05-1 ]
[ 1949841-16-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate; 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-[3,5-dimethyl-7-(2-{2-[(3-phosphonopropyl)amino]ethoxy}ethoxy)tricyclo[3.3.1.1³'⁷] dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid trifluoroacetate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 24h; Stage #2: trifluoroacetic acid In water; N,N-dimethyl-formamide; acetonitrile	2.2.15 2.15. Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-[4-([{2-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl}oxy)ethoxy]ethyl}(3-phosphonopropyl)carbamoyl]oxy}methyl)phenyl]-L-alaninamide (Synthon EY) [000902] A mixture of Example 1.16.2 (59 mg), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-lH- pyrrol-l-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (42 mg), and N,N-diisopropylethylamine (0.042 mg) in 2 mL N,N-dimethylformamide was stirred for 24 hours. The mixture was purified via reverse phase chromatography on a Biotage Isolera One system using a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water. Fractions were concentrated and the product was lyophilized from water and 1,4-dioxane to give the title compound as a trifluoroacetic acid salt. MS (ESI) m/e 1422.6 (M-H)+.
	Stage #1: [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate; 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-[3,5-dimethyl-7-(2-{2-[(3-phosphonopropyl)amino]ethoxy}ethoxy)tricyclo[3.3.1.1³'⁷] dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid trifluoroacetate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 24h; Stage #2: trifluoroacetic acid In water; acetonitrile	2.15 2.15 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-[4-([{2-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H-pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1-yl}oxy)ethoxy]ethyl}(3-phosphonopropyl)carbamoyl]oxy}methyl)phenyl]-L-alaninamide (Synthon EY) A mixture of Example 1.16.2 (59 mg), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (42 mg), and N,N-diisopropylethylamine (0.042 mg) in 2 mL N,N-dimethylformamide was stirred for 24 hours. The mixture was purified via reverse phase chromatography on a Biotage Isolera One system using a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water. Fractions were concentrated and the product was lyophilized from water and 1,4-dioxane to give the title compound as a trifluoroacetic acid salt. MS (ESI) m/e 1422.6 (M-H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/94509, 2016, A1 Location in patent: Paragraph 000902
[2]Current Patent Assignee: ABBVIE INC - US2017/355769, 2017, A1 Location in patent: Paragraph 1881

14
[ 1639939-40-4 ]
[ 1949838-86-1 ]
[ 1949841-19-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.2.17 2.17. Synthesis of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-[3-(2-[(2S)-3-carboxy-2-([(4-[(2S)-2-[(2S)-2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3-methylbutanoyl]amino}propanoyl]amino}benzyl)oxy]carbonyl}amino)propanoyl](methyl)amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Synthon FD) [000904] To a solution of Example 1.17 (0.040 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro- lH-pyrrol- 1 -yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.034 g) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.035 mL). The reaction was stirred overnight and diluted with N,N-dimethylformamide (1 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. NMR (400 MHz, dimethyl sulfoxide -d6) δ ppm 12.84 (s, IH), 9.92 (s, IH), 8.13 (d, IH), 8.03 (d, IH), 7.79 (d, 2H), 7.62 (d, IH), 7.57 (d, 2H), 7.54- 7.41 (m, 3H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 4H), 6.99 (s, 2H), 6.95 (dd, IH), 5.01-4.89 (m, 4H), 4.78 (dq, IH), 4.45-4.30 (m, IH), 4.23-4.1 1 (m, IH), 3.88 (t, 2H), 3.80 (s, 2H), 3.42-3.26 (m, 6H), 3.06 (s, IH), 3.01 (t, 2H), 2.80 (s, 2H), 2.76-2.62 (m, IH), 2.46-2.36 (m, IH), 2.25-2.05 (m, 5H), 2.05- 1.92 (m, IH), 1.58- 1.42 (m, 4H), 1.42-0.91 (m, 20H), 0.91-0.78 (m, 9H). MS (ESI) m/e 1387.4 (M+H)+.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.2.17 2.17 Synthesis of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl]-3-(1-[3-(2-[(2S)-3-carboxy-2-([(4-[(2S)- 2-[(2S)-2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl)oxy]carbonyl}amino)pr opanoyl](methyl)amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1- yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Synthon FD) To a solution of Example 1.17 (0.040 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.034 g) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.035 mL). The reaction was stirred overnight and diluted with N,N-dimethylformamide (1 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.84 (s, 1H), 9.92 (s, 1H), 8.13 (d, 1H), 8.03 (d, 1H), 7.79 (d, 2H), 7.62 (d, 1H), 7.57 (d, 2H), 7.54- 7.41 (m, 3H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 4H), 6.99 (s, 2H), 6.95 (dd, 1H), 5.01-4.89 (m, 4H), 4.78 (dq, 1H), 4.45-4.30 (m, 1H), 4.23-4.11 (m, 1H), 3.88 (t, 2H), 3.80 (s, 2H), 3.42-3.26 (m, 6H), 3.06 (s, 1H), 3.01 (t, 2H), 2.80 (s, 2H), 2.76-2.62 (m, 1H), 2.46-2.36 (m, 1H), 2.25-2.05 (m, 5H), 2.05-1.92 (m, 1H), 1.58-1.42 (m, 4H), 1.42-0.91 (m, 20H), 0.91-0.78 (m, 9H). MS (ESI) m/e 1387.4 (M+H)+.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	2.17 2.17 Synthesis of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-[3-(2-[(2)-2-([(4-{(2S)-2-[(2S)-2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3-methylbutanoyl]amino}propanoyl]amino}benzyl)oxy]carbonyl}amino)pr opanoyl](methyl)amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Synthon FD) To a solution of Example 1.17 (0.040 g) and 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.034 g) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.035 mL). The reaction was stirred overnight and diluted with N,N-dimethylformamide (1 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.84 (s, 1H), 9.92 (s, 1H), 8.13 (d, 1H), 8.03 (d, 1H), 7.79 (d, 2H), 7.62 (d, 1H), 7.57 (d, 2H), 7.54-7.41 (m, 3H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 4H), 6.99 (s, 2H), 6.95 (dd, 1H), 5.01-4.89 (m, 4H), 4.78 (dq, 1H), 4.45-4.30 (m, 1H), 4.23-4.11 (m, 1H), 3.88 (t, 2H), 3.80 (s, 2H), 3.42-3.26 (m, 6H), 3.06 (s, 1H), 3.01 (t, 2H), 2.80 (s, 2H), 2.76-2.62 (m, 1H), 2.46-2.36 (m, 1H), 2.25-2.05 (m, 5H), 2.05-1.92 (m, 1H), 1.58-1.42 (m, 4H), 1.42-0.91 (m, 20H), 0.91-0.78 (m, 9H). MS (ESI) m/e 1387.4 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/94509, 2016, A1 Location in patent: Paragraph 000904
[2]Current Patent Assignee: ABBVIE INC - WO2017/214462, 2017, A2 Location in patent: Page/Page column 546
[3]Current Patent Assignee: ABBVIE INC - US2017/355769, 2017, A1 Location in patent: Paragraph 1883

15
[ 1639939-40-4 ]
[ 1949839-33-1 ]
[ 1949841-29-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	2.2.27 2.27. Synthesis of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-[3-(2-[(2R)-3-carboxy-2-([(4-[(2S)-2-[(2S)-2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3-methylbutanoyl]amino}propanoyl]amino}benzyl)oxy]carbonyl}amino)propanoyl](methyl)amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Synthon GW) [000914] A solution of Example 1.27 (0.043 g) in N,N-dimethylformamide (0.5 inL) was added 4- ((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanamido)-3- methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.042 g) followed by N,N- diisopropylethylamine (0.038 mL), and the reaction was stirred at room temperature. After stirring for 16 hours, the reaction was diluted with water (0.5 mL) and N,N-dimethylformamide (1 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and fireeze- dried to provide the title compound. lH NMR (400 MHz, dimethyl sulfoxide-^) δ ppm 13.05 (s, IH), 10.15 (s, IH), 8.36 (d, IH), 8.26 (d, IH), 8.02 (d, 2H), 7.95-7.77 (m, 4H), 7.77-7.63 (m, 3H), 7.63- 7.54 (m, 2H), 7.54-7.46 (m, 3H), 7.22 (s, 2H), 7.18 (dd, IH), 5.17 (d, 4H), 5.01 (dq, IH), 4.61 (p, IH), 4.39 (t, IH), 4.11 (t, 2H), 4.03 (s, 2H), 3.64-3.49 (m, 2H), 3.29 (s, IH), 3.24 (t, 2H), 3.03 (s, 2H), 2.92 (dt, IH), 2.73-2.61 (m, 4H), 2.35 (d, 4H), 2.18 (dt, IH), 1.71 (h, 4H), 1.65-1.13 (m, 18H), 1.13- 1.01 (m, 13H). MS (ESI) m/e 1387.3 (M+H)+.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	2.2.27 2.27 Synthesis of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl]-3-(1-[3-(2-[(2R)-3-carboxy-2-([(4-[(2S)- 2-[(2S)-2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl)oxy]carbonyl}amino)pr opanoyl](methyl)amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1- yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Synthon GW) A solution of Example 1.27 (0.043 g) in N,N-dimethylformamide (0.5 mL) was added 4- ((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3- methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.042 g) followed by N,N- diisopropylethylamine (0.038 mL), and the reaction was stirred at room temperature. After stirring for 16 hours, the reaction was diluted with water (0.5 mL) and N,N-dimethylformamide (1 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze- dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 13.05 (s, 1H), 10.15 (s, 1H), 8.36 (d, 1H), 8.26 (d, 1H), 8.02 (d, 2H), 7.95-7.77 (m, 4H), 7.77-7.63 (m, 3H), 7.63- 7.54 (m, 2H), 7.54-7.46 (m, 3H), 7.22 (s, 2H), 7.18 (dd, 1H), 5.17 (d, 4H), 5.01 (dq, 1H), 4.61 (p, 1H), 4.39 (t, 1H), 4.11 (t, 2H), 4.03 (s, 2H), 3.64-3.49 (m, 2H), 3.29 (s, 1H), 3.24 (t, 2H), 3.03 (s, 2H), 2.92 (dt, 1H), 2.73-2.61 (m, 4H), 2.35 (d, 4H), 2.18 (dt, 1H), 1.71 (h, 4H), 1.65-1.13 (m, 18H), 1.13-1.01 (m, 13H). MS (ESI) m/e 1387.3 (M+H)+.
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	2.27 2.27 Synthesis of 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-[3-(2-[(2R)-3-carboxy-2-([(4-[(2S)-2-[(2S)-2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3-methylbutanoyl]amino}propanoyl]amino}benzyl)oxy]carbonyl}amino)pr opanoyl](methyl)amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Synthon GW) A solution of Example 1.27 (0.043 g) in N,N-dimethylformamide (0.5 mL) was added 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.042 g) followed by N,N-diisopropylethylamine (0.038 mL), and the reaction was stirred at room temperature. After stirring for 16 hours, the reaction was diluted with water (0.5 mL) and N,N-dimethylformamide (1 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 13.05 (s, 1H), 10.15 (s, 1H), 8.36 (d, 1H), 8.26 (d, 1H), 8.02 (d, 2H), 7.95-7.77 (m, 4H), 7.77-7.63 (m, 3H), 7.63-7.54 (m, 2H), 7.54-7.46 (m, 3H), 7.22 (s, 2H), 7.18 (dd, 1H), 5.17 (d, 4H), 5.01 (dq, 1H), 4.61 (p, 1H), 4.39 (t, 1H), 4.11 (t, 2H), 4.03 (s, 2H), 3.64-3.49 (m, 2H), 3.29 (s, 1H), 3.24 (t, 2H), 3.03 (s, 2H), 2.92 (dt, 1H), 2.73-2.61 (m, 4H), 2.35 (d, 4H), 2.18 (dt, 1H), 1.71 (h, 4H), 1.65-1.13 (m, 18H), 1.13-1.01 (m, 13H). MS (ESI) m/e 1387.3 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2016/94509, 2016, A1 Location in patent: Paragraph 000914
[2]Current Patent Assignee: ABBVIE INC - WO2017/214462, 2017, A2 Location in patent: Page/Page column 550
[3]Current Patent Assignee: ABBVIE INC - US2017/355769, 2017, A1 Location in patent: Paragraph 1893

16
[ 55750-63-5 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 6 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C

Reference： [1]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[2]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]

17
[ 68858-20-8 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: dicyclohexyl-carbodiimide; 1-hydroxy-pyrrolidine-2,5-dione / tetrahydrofuran / 16 h / 20 °C 1.2: 16 h / 20 °C 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 36 h / 20 °C 3.1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 4.1: N,N-dimethyl-formamide / 6 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 5 steps 1.1: dicyclohexyl-carbodiimide; 1-hydroxy-pyrrolidine-2,5-dione / tetrahydrofuran / 16 h / 20 °C 1.2: 16 h / 20 °C 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 36 h / 20 °C / Darkness 3.1: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 4.1: N,N-dimethyl-formamide / 20 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 6 steps 1.1: dicyclohexyl-carbodiimide / tetrahydrofuran / 2 h / 0 - 20 °C 2.1: Sodium hydrogenocarbonate / tetrahydrofuran; 1,2-dimethoxyethane; lithium hydroxide monohydrate / 16 h / 20 °C 3.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / ethyl acetate / 0.5 h / 0 °C 3.2: 2 h / 0 - 20 °C 4.1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °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 / 2 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[2]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]
[3]Audisio, Davide; Babin, Victor; Barbe, Peggy; Beau, Fabrice; Correia, Isabelle; Devel, Laurent; Dubois, Steven; Feuillastre, Sophie; Ge, Xin; Keck, Mathilde; Lee, Ki Baek; Lequin, Olivier; Malgorn, Carole; Palazzolo, Alberto; Pieters, Gregory; Sallustrau, Antoine; Thai, Robert; Cahuzac, Héloïse; Garcia-Argote, Sébastien; Nozach, Hervé [Journal of Medicinal Chemistry, 2022]

18
[ 5070-13-3 ]
[ 1870916-87-2 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 5h;
51%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;
38%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 5h;	3.2.11 Synthesis of 4-[(s)-2-{(s)-2-[6-(2,5-dioxo-2,5-dihydro-1h-pyrrole-1-yl) hexaamino]-3-methylbutylamino} propylamino] benzyl (4-nitrophenyl) carbonate (14) Compound 12 (500mg, 1.03mmol) was completely dissolved in 30mL of anhydrous N,N-dimethylformamide, and then di(p-nitrophenyl) carbonate (626.7mg, 2.06mmol) and N,N-Diisopropyl ethylamine (199.3mg, 1.54mmol) were added to the solution in turn, reacting overnight at room temperature. At the end of the reaction, the reaction solution was concentrated under a reduced pressure and purified via column chromatography (dichloromethane:methanol=50:1 to 10:1 gradient elution, V/V). 253mg of compound 14 were obtained at a 38% yield. 1H NMR (400MHz, DMSO-d6): δ 9.99 (s, 1H), 8.34 - 8.24 (m, 2H), 8.16 (d, J=6.9Hz, 1H), 7.79 (d, J=8.6Hz, 1H), 7.63 (d, J=8.6Hz, 2H), 7.59 - 7.51 (m, 2H), 7.40 (d, J=8.6Hz, 2H), 6.98 (s, 2H), 5.23 (s, 2H), 4.41 - 4.14 (m, 1H), 4.16 (dd, J=8.6, 6.8Hz, 1H), 3.35 (t, J=7.0Hz, 2H), 2.21 - 2.05 (m, 2H), 1.99 - 1.91 (m, 1H), 1.50 - 1.43 (m, 4H), 1.30 (d, J=7.1Hz, 3H), 1.21 - 1.13 (m, 2H), 0.84 (dd, J=15.9, 6.8Hz, 6H). ESI m/z: calculated for C32H37N5O10 651.3; found 652.6 [M+H]+, 674.6 [M+Na]+.

Reference： [1]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[2]Audisio, Davide; Babin, Victor; Barbe, Peggy; Beau, Fabrice; Correia, Isabelle; Devel, Laurent; Dubois, Steven; Feuillastre, Sophie; Ge, Xin; Keck, Mathilde; Lee, Ki Baek; Lequin, Olivier; Malgorn, Carole; Palazzolo, Alberto; Pieters, Gregory; Sallustrau, Antoine; Thai, Robert; Cahuzac, Héloïse; Garcia-Argote, Sébastien; Nozach, Hervé [Journal of Medicinal Chemistry, 2022]
[3]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]

19
[ 474645-27-7 ]
4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate [ No CAS ]
4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl((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 ]

Reference： [1]International Journal of Molecular Sciences,2017,vol. 18

20
[ 60-32-2 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: acetic acid / 6 h / 120 °C 2: trifluoroacetic anhydride; 2,4,6-trimethyl-pyridine / tetrahydrofuran / 1.5 h / 0 - 20 °C 3: N,N-dimethyl-formamide / 6 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 4 steps 1: acetic acid / 6 h / 120 °C 2: 2,4,6-trimethyl-pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C / Cooling 3: N,N-dimethyl-formamide / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C

Reference： [1]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[2]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]

21
[ 55750-53-3 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trifluoroacetic anhydride; 2,4,6-trimethyl-pyridine / tetrahydrofuran / 1.5 h / 0 - 20 °C 2: N,N-dimethyl-formamide / 6 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C
	Multi-step reaction with 3 steps 1: 2,4,6-trimethyl-pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C / Cooling 2: N,N-dimethyl-formamide / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 5 h / 20 °C

Reference： [1]Wang, Yanming; Fan, Shiyong; Zhong, Wu; Zhou, Xinbo; Li, Song [International Journal of Molecular Sciences, 2017, vol. 18, # 9]
[2]Xiao, Dian; Luo, Longlong; Li, Jiaguo; Wang, Zhihong; Liu, Lianqi; Xie, Fei; Feng, Jiannan; Zhou, Xinbo [Bioorganic Chemistry, 2021, vol. 116]

22
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ 1942058-33-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 20℃; for 72h;	2.2.30 2.30 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoyl]-L- valyl-N-{4-[([(3S)-l-{8-(l,3-benzothiazol-2-ylcarbamoyl)-2-[6-carboxy- 5-(l-[3-(2-methoxyethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]dec-l- yl]methyl}-5-methyl- lH-pyrazol-4-yl)pyridin-2-yl] -1,2,3,4- tetrahydroisoquinolin-6-yl}pyrrolidin-3- yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon NR) Example 1.17.10 (40 mg) was dissolved in dimethyl sulfoxide (0.3 mL), and 4-((S)-2-((S)-2- (6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanamido)-3-memylbutanamido)propanamido)benzyl (4- nitrophenyl) carbonate (31 mg) and triethylamine (33 pL) were added. The reaction mixture was stirred for 72 hours at room temperature, and purification by reverse phase chromatography (CI 8 column), eluting with 10-90% acetonitrile in 0.1% TFA water, provided the title compound. MS (ESI) m/e 1357.4 (M+H)+, 1355.5 (M-H) .

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2017/214458, 2017, A2 Location in patent: Page/Page column 437

23
[ 1639939-40-4 ]
[ 1942075-82-2 ]
[ 1942058-33-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 20℃; for 72h;	2.30 2.30 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-Lvalyl-N-{ 4-[ ( [ (3S)-1-{8-(1,3-benzothiazol-2-ylcarbamoyl)-2-[ 6-carboxy-5-(1-[3-(2-methoxyethoxy)-5,7 -dimethyltricyclo[3.3.1.13,7]dec-1-yl]methyl }-5-methyl-1H-pyrazol-4-yl)pyridin-2-yl] -1,2,3,4-tetrahydroisoquinolin-6-yl}pyrrolidin-3-30 yl]carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon NR) Example 1.17.10 (40 mg) was dissolved in dimethyl sulfoxide (0.3 mL), and 4-((S)-2-((S)-2-( 6-(2,5-dioxo-2,5-dihydro-IH -pyrrol-1-yl)hexanamido )-3-methylbutanamido )propanamido )benzyl ( 4-nitrophenyl) carbonate (31 mg) and triethylamine (33 f1L) were added. The reaction mixture wasstirred for 72 hours at room temperature, and purification by reverse phase chromatography (CIS35 column), eluting with 10-90% acetonitrile in 0.1% TFA water, provided the title compound. MS(ESI) m/e 1357.4 (M+Ht, 1355.5 (M-H).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2017/214301, 2017, A1 Location in patent: Page/Page column 384

24
[ 1639939-40-4 ]
[ 1949838-73-6 ]
[ 76-05-1 ]
[ 1949841-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate; 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 24h; Stage #2: trifluoroacetic acid In water; N,N-dimethyl-formamide; acetonitrile	2.2.16 2.16 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L- valyl-N-{4-[([2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H- pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1-yl}oxy)ethyl](3- phosphonopropyl)carbamoyl}oxy)methyl]phenyl}-L-alaninamide (Synthon EZ) A mixture of Example 1.14.4 (50 mg), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (38 mg), and N,N-diisopropylethylamine (0.050 mL) in 2 mL N,N-dimethylformamide was stirred for 24 hours. The mixture was purified via reverse phase chromatography on a Biotage Isolera One system using a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water. The desired fractions were concentrated and the product was lyophilized from water and 1,4-dioxane to give the title compound as a trifluoroacetic acid salt. 1H NMR (400MHz, dimethyl sulfoxide-d6) δ ppm 9.94 (bs, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.80 (d, 2H), 7.61 (m, 3H), 7.47 (m, 3H), 7.36 (m, 2H), 7.29 (m, 2H), 6.99 (s, 2H), 6.95 (d, 1H), 4.97 (m, 4H), 4.40 (m, 2H), 4.16 (dd, 2H), 3.50-4.10 (m, 6H), 3.68 (m, 2H), 3.55 (m, 2H), 3.25 (m, 4H), 3.02 (m, 2H), 2.94 (s, 2H), 2.79 (s, 2H), 2.15 (m, 1H), 2.08 (s, 2H), 1.65 (m, 2H), 1.40-1.50 (m, 6H), 1.20-1.30 (m, 6H), 1.08-1.19 (m, 4H), 0.97 (m, 1-2H), 0.76-0.89 (m, 12H). MS (ESI) m/e 1380.3 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2017/214462, 2017, A2 Location in patent: Page/Page column 546

25
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ 1949841-16-0 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide for 24h;	2.2.15 2.15 Synthesis of N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L- valyl-N-[4-([{2-[2-({3-[(4-{6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4- dihydroisoquinolin-2(1H)-yl]-2-carboxypyridin-3-yl}-5-methyl-1H- pyrazol-1-yl)methyl]-5,7-dimethyltricyclo[3.3.1.1^3,7]dec-1- yl}oxy)ethoxy]ethyl}(3-phosphonopropyl)carbamoyl]oxy}methyl) phenyl]-L-alaninamide (Synthon EY) A mixture of Example 1.16.2 (59 mg), 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (42 mg), and N,N-diisopropylethylamine (0.042 mg) in 2 mL N,N-dimethylformamide was stirred for 24 hours. The mixture was purified via reverse phase chromatography on a Biotage Isolera One system using a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water. Fractions were concentrated and the product was lyophilized from water and 1,4-dioxane to give the title compound as a trifluoroacetic acid salt. MS (ESI) m/e 1422.6 (M-H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2017/214462, 2017, A2 Location in patent: Page/Page column 545

26
[ 1020412-43-4 ]
[ 1639939-40-4 ]
[ 2101204-24-2 ]

Yield	Reaction Conditions	Operation in experiment
18%	Stage #1: 1-(4-amino-2-((ethylamino)methyl)-1H-imidazo[4,5-c]quinolin-2-yl)-2-methylpropan-2-ol With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate In N,N-dimethyl-formamide for 24h;	8.A Step A: Preparation of ATAC22 A solution of compound 1(150 mg, 0.479 mmol) and N,N’-diisopropylethylamine (145.4 mg, 1.437 mmol) in dry DMF was stirred at room temperature for 5 mm., followed by addition of maleimidocaproyl-valine-alanine-p-aminobenzyl alcohol p-nitrophenyl-carbonate (MC-Val-AlaPAB-PNP, 343.6 mg, 0.527 mmol). After stirring for 24 h, volatile organics were removed under vacuum. The residue obtained was triturated with dry acetonitrile. The precipitated solid was collected by filtration, washed with acetonitrile and dried under vacuum to obtain unreacted MCVal-Ala-PAB-PNP (130 mg) as beige solid. The filtrate and washings were combined and concentrated under vacuum. The residue obtained was purified by flash column chromatography on silica gel, eluting with step gradients of MeOH in dichloromethane at a ratio of v/v 1:20, 1:15,and 1:10, to afford the target product mc-Val-Ala-PAB-GDQ (70 mg, 18% yield) as beige colored foamy solid. ‘H NMR (DMSO-d6) ö 10.1 - 9.75 (br m, 1H), 8.58 - 8.24 (br m, 1H), 8.15 (d, 1=6.6 Hz, 1H), 8.01 (br s, 1H), 7.81 (d, 1=8.4 Hz, 1H), 7.71 (d, 1=8.4 Hz, 1H), 7.65 - 7.48 (m, 2H), 7.46 -7.34 (m, 2H), 7.29 (br s, 1H), 7.18 (br s, 1H), 6.99 (s, 2H), 5.03 (br s, 2H), 4.96 (br s, 1H), 4.72 (br s, 1H), 4.48 - 4.26 (m, 1H), 4.26 - 4.04 (m, 1H), 2.22 - 2.02 (m, 2H), 2.02 - 1.80 (m, 1H), 1.58 - 1.37 (m, 4H), 1.36 -0.92 (br m, 15H), 0.92 -0.53 (br m, 7H). MS (ESI+) m/z 826 (M+1).

Reference： [1]Current Patent Assignee: SILVERBACK THERAPEUTICS INC - WO2018/140831, 2018, A2 Location in patent: Paragraph 0632; 0633

27
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
15.2%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 112.08h;	7 7. Preparation of 6-Maleimidohexenoyl-L-Val-L-Ala-PAB-S-deoxy-6-amino amanitin HDP 30.2540 6-(Maleimido)hexanoyl-L-Val-L-Ala-PABA-4-nitrophenyl-carboxylate (HDP 30.2079) was prepared in analogy to step 6.1/6.2 with 6-(maleinnido)hexanoic acid N-hydroxysuccinimide ester (EMCS) as starting material. (0297) 1H NMR (500 MHz, DMSO-d6) d 9.96 (s, 1 H), 8.35 - 8.27 (m, 2H), 8.1 1 (d, J = 7.0 Hz, 1 H), 7.77 (d, J = 8.6 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 2H), 7.60 - 7.53 (m, 2H), 7.41 (d, J = 8.6 Hz, 2H), 6.98 (s, 2H), 5.25 (s, 2H), 4.41 (p, J = 7.1 Hz, 1 H), 4.18 (dd, J = 8.6, 6.8 Hz, 1 H), 3.37 (t, J = 7.1 Hz, 2H), 2.24 - 2.08 (m, 2H), 1 .98 (h, J = 6.8 Hz, 1 H), 1 .58 - 1 .42 (m, 4H), 1 .32 (d, J = 7.0 Hz, 3H), 1 .20 (p, J = 7.6 Hz, 2H), 0.88 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H). (0298) 13C NMR (126 MHz, DMSO-d6) d 172.21 , 171 .10, 170.91 , 170.89, 155.19, 151 .82, 145.08, 139.32, 134.30, 129.28, 129.18, 125.25, 122.44, 1 18.98, 70.16, 57.50, 48.96, 36.92, 34.83, 30.23, 27.64, 25.69, 24.77, 19.09, 18.06, 17.78. MS (ESI+) found: 674.36 [M+ Na]+; calc: 674.24 (0299) [00147] HDP 30.2528 (5 mg, 5.5 μηηοΙ) was coupled with HDP 30.2079 (7.1 mg, 1 1 .0 μιτιοΙ) in 275 μΙ DMF and addition of diisopropylethylamine (9.4 μΙ, 55 μιτιοΙ). After 16 h, HDP 30.2079 (3.5 mg, 5.4 μηηοΙ) and diisopropylethylamine (9.4 μΙ, 55 μιτιοΙ) were added. The reaction was stirred for 4 days. The reaction mixture was directly purified by preparative chromatography. (0300) Yield: 1 .18 mg, 15.2% (0301) HPLC: 100% (0302) MS (ESI+) found: 1437.6 [M+ Na]+; calc: 1414.7 (CesHs/NisOigS)

Reference： [1]Current Patent Assignee: DIEVINI HOPP BIOTECH HOLDING GMBH & CO. KG - WO2019/30171, 2019, A1 Location in patent: Paragraph 00146-00147

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;	Preparation of Maleimidopropionyl-L-Val-L-Ala-PABA-4-nitrophenyl- carboxylate HDP 30.2586 General procedure: 200.0 mg (0.45 mmol) Maleimidopropionyl-L-Val-L-Ala-PABA HDP 30.2559 were dissolved in 4 ml dry dimethylformamide (DMF). 273.9 mg (0.90 mmol) bis-(4-nitrophenyl-carbonate) and 1 17.6 μΙ DIPEA (87.3mg, 0.68 mmol) were added, and the reaction mixture was stirred for three hours at ambient temperature under argon. The reaction mixture was precipitated with 40 ml cold n-hexane/MTBE 1 :1 and separated with a centrifuge. The solid was washed two times with cold MTBE and filtrated. The remaining solid is pure enough for the next step. (0280) Yield 231 .3 mg (84.3%) of a white solid (0281) MS (ESI+) found: 610.08 [M+H]+; calc: 609.21 (C29H31 N5O10) (0282) MS (ESI+) found: 632.25 [M+Na]+; calc: 632.42 (C29H3i N5NaOio) MS (ESI+) found: 1241 .00 [2M+Na]+; calc: 1241 .42 (C58H62NioNaO2o)

29
[ 1639939-40-4 ]
[ 2378776-16-8 ]
[ 2395887-32-6 ]

Yield	Reaction Conditions	Operation in experiment
13.28%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	1.1.3.1.3 Linker-Payload (ADL6-D81: 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1 H-pyrrol- (1609) 1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (5 mg, 7.673 pmol) in DMF (238 mI_,3.069 mmol) was added Hunig's base (4.02 mI_, .023 mmol). The reaction mixture was cooled to 0°C, and added (2S,3S,6S,7R,10R,E)- (1610) 6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan- (1611) 2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en- (1612) 7-yl piperazine-1 -carboxylate. The reaction mixture was stirred at RT until consumption of starting material. The reaction mixture was concentrated in vacuo. HPLC purification afforded ADL6-D8 (1.2 mg,1.019 pmol,13.28 % yield). LC/MS (ESI, m/z),1199.9 (1613) [M+Na]+. [963] 1H NMR (400 MHz, CHCls-d): d ppm 0.78 - 1.04 (m,18 H) 1.15 - 1.52 (m,58 H) 1.64 - 1.72 (m,3 H) 1.78 (d, =6.53 Hz,4 H) 2.04 - 2.19 (m,3 H) 2.21 - 2.30 (m,1 H) 2.44 - 2.67 (m,4 H) 2.76 (dd, J= 6.09, 2.95 Hz,1 H) 2.90 -3.02 (m,1 H) 3.42 -3.57 (m, 8 H) 3.61 -3.70 (m,1 H) 3.77 (br s,1 H) 4.10 - 4.27 (m,1 H) 4.58 (br d, J= 6.65 Hz,1 H) 5.01 - 5.26 (m,4 H) 5.52 - 5.70 (m, 2 H) 5.88 (s,1 H) 5.93 - 6.02 (m,1 H) 6.08 - 6.18 (m,1 H) 6.47 - 6.58 (m,1 H) 7.29 - 7.35 (m, 2 H) 7.55 (d, =8.66 Hz,1 H).

Reference： [1]Current Patent Assignee: EISAI CO LTD - WO2019/232449, 2019, A1 Location in patent: Paragraph 0920; 952; 962-963

30
[ 1639939-40-4 ]
[ 2378776-17-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃;	1.1.3.1.5 General procedure: Payload (1.0 equiv.), Hunig’s base (3.0 equiv.), DMF (0.1 M), and 4-((S)-2-((S)- 2-(6-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)hexanamido)-5-ureidopentanamido)-3- methylbutanamido)benzyl (4-nitrophenyl) carbonate (1.2 equiv.) were combined and stirred at RT overnight. The reaction mixture was then concentrated and purified via column chromatography (MeOH in DCM) or reverse-phase HPLC to afford the product.

Reference： [1]Current Patent Assignee: EISAI CO LTD - WO2019/232449, 2019, A1 Location in patent: Paragraph 920; 944-945; 982-984; 1038; 1046-1048

31
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
17%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	19.1 Step 1: 4-[(2S)-2-[(2S)-2-[6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl [4-({9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}amino)-2,2-dimethyl-4-oxobutyl]methylcarbamate, Compound 20 To a solution of [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3- methyl-butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate (47.9 mg, 0.037 mmol) and 1-hydroxy-7-azabenzotriazole (4.08 mg, 0.03 mmol) in DMF (0.60 mL) and N,N-diisopropylethylamine (26 uL, 0.15 mmol) was added a solution of N-{9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}-3,3-dimethyl-4-(methylamino)butanamide as the 2,2,2-trifluoroacetate salt (Intermediate 14, 20 mg, 0.02 mmol) in DMF (0.54 mL) at rt. The reaction mixture was allowed to stir at rt for 16 h. Celite was added and the mixture was concentrated to dryness. The crude residue absorbed onto Celite was purified by reverse phase flash column chromatography (0-100% ACN/aqueous ammonium acetate (10 mM)) to provide 4-[(2S)-2-[(2S)-2-[6-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl [4-({9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}amino)-2,2-dimethyl-4-oxobutyl]methylcarbamate as the ammonium salt (C-20, 4 mg, 17%). LCMS (AA): m/z = 1287.4 (M-H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2020/229982, 2020, A1 Location in patent: Paragraph 0659

32
[ 1639939-40-4 ]
[ 56-40-6 ]
[ 2553413-34-4 ]

Yield	Reaction Conditions	Operation in experiment
44%	With triethylamine In dimethyl sulfoxide; N,N-dimethyl-formamide at 20℃; for 4h;	25.1 Step 1: 2-[[4-[[(2S)-2-[[(2S)-2-[6-(2,5-Dioxopyrrol-1-yl)hexanoylamino]-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methoxycarbonylamino]acetic acid To a solution of glycine (24 mg, 0.32 mmol) in triethylamine (0.10 mL, 0.72 mmol), DMF (0.50 mL) and DMSO (0.50 mL) was added [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1- yl)hexanoylamino]-3-methyl-butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate (220 mg, 0.34 mmol) at rt. The reaction mixture was stirred at rt for 4 h. The reaction mixture was then cooled to 0 oC. Water (1 mL) was added and the solution was acidified to pH 4 by the addition of formic acid. The mixture was concentrated to dryness and the crude residue was purified by reverse phase flash column chromatography (0-100% ACN/aqueous formic acid (0.1%)) to provide 2-[[4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methoxycarbonylamino]acetic acid (87 mg, 44%). LCMS (AA): m/z = 586.3 (M-H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2020/229982, 2020, A1 Location in patent: Paragraph 0668

33
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	20 Step 1: 4-[(2S)-2-[(2S)-2-[6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl [4-({9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}amino)-2,2-dimethyl-4-oxobutyl]methylcarbamate, Compound 20 General procedure: To a solution of [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3- methyl-butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate (47.9 mg, 0.037 mmol) and 1-hydroxy-7-azabenzotriazole (4.08 mg, 0.03 mmol) in DMF (0.60 mL) and N,N-diisopropylethylamine (26 uL, 0.15 mmol) was added a solution of N-{9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}-3,3-dimethyl-4-(methylamino)butanamide as the 2,2,2-trifluoroacetate salt (Intermediate 14, 20 mg, 0.02 mmol) in DMF (0.54 mL) at rt. The reaction mixture was allowed to stir at rt for 16 h. Celite was added and the mixture was concentrated to dryness. The crude residue absorbed onto Celite was purified by reverse phase flash column chromatography (0-100% ACN/aqueous ammonium acetate (10 mM)) to provide 4-[(2S)-2-[(2S)-2-[6-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl [4-({9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}amino)-2,2-dimethyl-4-oxobutyl]methylcarbamate as the ammonium salt (C-20, 4 mg, 17%). LCMS (AA): m/z = 1287.4 (M-H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2020/229982, 2020, A1 Location in patent: Paragraph 0659-0660

34
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	20 Step 1: 4-[(2S)-2-[(2S)-2-[6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl [4-({9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}amino)-2,2-dimethyl-4-oxobutyl]methylcarbamate, Compound 20 General procedure: To a solution of [4-[[(2S)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1-yl)hexanoylamino]-3- methyl-butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate (47.9 mg, 0.037 mmol) and 1-hydroxy-7-azabenzotriazole (4.08 mg, 0.03 mmol) in DMF (0.60 mL) and N,N-diisopropylethylamine (26 uL, 0.15 mmol) was added a solution of N-{9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}-3,3-dimethyl-4-(methylamino)butanamide as the 2,2,2-trifluoroacetate salt (Intermediate 14, 20 mg, 0.02 mmol) in DMF (0.54 mL) at rt. The reaction mixture was allowed to stir at rt for 16 h. Celite was added and the mixture was concentrated to dryness. The crude residue absorbed onto Celite was purified by reverse phase flash column chromatography (0-100% ACN/aqueous ammonium acetate (10 mM)) to provide 4-[(2S)-2-[(2S)-2-[6-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]amino}-3- methylbutanoyl]amino}propanoyl]amino}benzyl [4-({9- [(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-16-hydroxy-2,10-dioxido-14-(pyrimidin-4-yloxy)-2,10- disulfanyldecahydro-5,8- methanocyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecin-7-yl]-6-oxo-6,9- dihydro-1H-purin-2-yl}amino)-2,2-dimethyl-4-oxobutyl]methylcarbamate as the ammonium salt (C-20, 4 mg, 17%). LCMS (AA): m/z = 1287.4 (M-H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2020/229982, 2020, A1 Location in patent: Paragraph 0659-0660

35
[ 1639939-40-4 ]
[ 2676202-53-0 ]
[ 2676202-73-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In pyridine; N,N-dimethyl-formamide at 20℃; for 23h; Inert atmosphere;
55 %	With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	(a) Synthesis of (NH2-Pro)-dideoxy-Ama MP-Val-Ala-PAB-linker (34). (NH2-Pro)-bicyclic octapeptide 6 (1.15 mg, 1.3 µmol) was dissolved in abs. pyridine/DMF 4:1 (v/v). MP-Val-Ala-PAB-PNP 33 (1.27 mg, 1.95 µmol) was dissolved in 35 µL of a 0.24 M HOBt solution in DMF and added to the amine, followed by DIPEA (0.443 µL, 1.95 µmol). The reaction mixture was stirred at room temperature for 23 h, then filtrated though a centrifugal filter with 0.2 µm nylon membrane and purified by preparative reversed-phase high- performance liquid chromatography (RP-HPLC). The peak corresponding to the target material was collected and lyophilized to afford the product (1.00 mg, 55%) as a white powder. HPLC (gradient J): tR = 13.54 min; λmax 286 nm. LRMS-ESI (m/z): [M+H]+ calcd. for C65H88N15O18S, 1399.6; found 1399.7.

Reference： [1]Braun, Alexandra; Gallo, Francesca; Hambira, Chido M.; Hechler, Torsten; Kato, Brandon; Müller, Christoph; Matinkhoo, Kaveh; Pahl, Andreas; Perrin, David M.; Wei, Charlie; Wong, Antonio A. W. L. [Chemistry - A European Journal, 2021, vol. 27, # 40, p. 10282 - 10292]
[2]Current Patent Assignee: UNIVERSITY OF BRITISH COLUMBIA; DIEVINI HOPP BIOTECH HOLDING GMBH & CO. KG - WO2022/120476, 2022, A1 Location in patent: Paragraph 00192

36
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
24%	With pyridine; benzotriazol-1-ol In dimethyl sulfoxide at 20℃; for 16h;

Reference： [1]Audisio, Davide; Babin, Victor; Barbe, Peggy; Beau, Fabrice; Correia, Isabelle; Devel, Laurent; Dubois, Steven; Feuillastre, Sophie; Ge, Xin; Keck, Mathilde; Lee, Ki Baek; Lequin, Olivier; Malgorn, Carole; Palazzolo, Alberto; Pieters, Gregory; Sallustrau, Antoine; Thai, Robert; Cahuzac, Héloïse; Garcia-Argote, Sébastien; Nozach, Hervé [Journal of Medicinal Chemistry, 2022]

37
[ 623-04-1 ]
[ 1639939-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / ethyl acetate / 0.5 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: 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 / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Audisio, Davide; Babin, Victor; Barbe, Peggy; Beau, Fabrice; Correia, Isabelle; Devel, Laurent; Dubois, Steven; Feuillastre, Sophie; Ge, Xin; Keck, Mathilde; Lee, Ki Baek; Lequin, Olivier; Malgorn, Carole; Palazzolo, Alberto; Pieters, Gregory; Sallustrau, Antoine; Thai, Robert; Cahuzac, Héloïse; Garcia-Argote, Sébastien; Nozach, Hervé [Journal of Medicinal Chemistry, 2022]

38
[ 1639939-40-4 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
55%	With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 23h;	(a) Synthesis of (NH2-Pro)-dideoxy-Ama MP-Val-Ala-PAB-linker (34). (NH2-Pro)-bicyclic octapeptide 6 (1.15 mg, 1.3 µmol) was dissolved in abs. pyridine/DMF 4:1 (v/v). MP-Val-Ala-PAB-PNP 33 (1.27 mg, 1.95 µmol) was dissolved in 35 µL of a 0.24 M HOBt solution in DMF and added to the amine, followed by DIPEA (0.443 µL, 1.95 µmol). The reaction mixture was stirred at room temperature for 23 h, then filtrated though a centrifugal filter with 0.2 µm nylon membrane and purified by preparative reversed-phase high- performance liquid chromatography (RP-HPLC). The peak corresponding to the target material was collected and lyophilized to afford the product (1.00 mg, 55%) as a white powder. HPLC (gradient J): tR = 13.54 min; λmax 286 nm. LRMS-ESI (m/z): [M+H]+ calcd. for C65H88N15O18S, 1399.6; found 1399.7.
55%	With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 23h;	(a) Synthesis of (NH2-Pro)-dideoxy-Ama MP-Val-Ala-PAB-linker (34). (NH2-Pro)-bicyclic octapeptide 6 (1.15 mg, 1.3 µmol) was dissolved in abs. pyridine/DMF 4:1 (v/v). MP-Val-Ala-PAB-PNP 33 (1.27 mg, 1.95 µmol) was dissolved in 35 µL of a 0.24 M HOBt solution in DMF and added to the amine, followed by DIPEA (0.443 µL, 1.95 µmol). The reaction mixture was stirred at room temperature for 23 h, then filtrated though a centrifugal filter with 0.2 µm nylon membrane and purified by preparative reversed-phase high- performance liquid chromatography (RP-HPLC). The peak corresponding to the target material was collected and lyophilized to afford the product (1.00 mg, 55%) as a white powder. HPLC (gradient J): tR = 13.54 min; λmax 286 nm. LRMS-ESI (m/z): [M+H]+ calcd. for C65H88N15O18S, 1399.6; found 1399.7.

Reference： [1]Current Patent Assignee: UNIVERSITY OF BRITISH COLUMBIA; DIEVINI HOPP BIOTECH HOLDING GMBH & CO. KG - WO2022/120476, 2022, A1 Location in patent: Paragraph 00192
[2]Current Patent Assignee: UNIVERSITY OF BRITISH COLUMBIA; DIEVINI HOPP BIOTECH HOLDING GMBH & CO. KG - WO2022/120476, 2022, A1 Location in patent: Paragraph 00192

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CAS No. :	1639939-40-4	MDL No. :	MFCD32220341
Formula :	C₃₂H₃₇N₅O₁₀	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QXMLUPPUFBNKRY-LGGPFLRQSA-N
M.W :	651.66	Pubchem ID :	100029269
Synonyms :		Chemical Name :	4-((S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate

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

Precautionary Statements-General
Code	Phrase
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Prevention
Code	Phrase
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P222	Do not allow contact with air.
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P244	Keep reduction valves free from grease and oil.
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P270	Do not eat, drink or smoke when using this product.
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P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
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P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
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P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
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P342	If experiencing respiratory symptoms:
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P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
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P411
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P413
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P422
P402 + P404	Store in a dry place. Store in a closed container.
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P411 + P235	Keep cool.
Disposal
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P501	Dispose of contents/container to ...
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
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H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1639939-40-4 ] {[proInfo.proName]}

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[ 1639939-40-4 ] Synthesis Path-Downstream 1~38

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